Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• • 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
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic 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
  • A61K9/2004—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
  • 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
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

• the present invention relates to a pharmaceutical extended release formulation of felodipine, and to methods of prepa ⁇ ng such a formulation
• the object of this invention is to obtain a solid formulation with good bioavailabihty and extended release of the active substance
• Felodipine is a drug having very low solubility
• Felodipine is commonly classified as a calcium antagonist, which are widely used for the treatment of cardiovascular disorders such as lschaemic heart disease and arte ⁇ al hypertension Felodipine has a solubility of only 0 5 mg/1 in water at 25 °C
• the extended release preparation delivers the amount of drug needed to maintain an adequate and even effect du ⁇ ng the entire therapeutic dosage interval This usually means that the drug should be delivered at a constant rate to give an even concentration of administered drug in the blood This is of specific importance for drugs having a small therapeutic index, that is a small difference between effective and toxic concentration
• a delayed and constant release of the drug will also be of importance for locally lr ⁇ tating drugs having potential ⁇ sk of causing gastrointestinal disturbances when present m large local concentrations or for drugs having a short elimination half-life In the latter case a less frequent administration and thus better patient compliance (cf Hayes R B et al Clm Pharm Ther (1977), 22, p 125-130) may be obtained with extended release preparations compared with conventional dosage forms
• a drug in extended release form is generally given via the oral route
• the preparations should preferably give an extended and reproducible release of drug and cont ⁇ bute to a reproducible absorption, have no toxic or lr ⁇ tating constituents and be suitable also for high dosage drugs
• extended release is achieved by controlling dissolution and/or diffusion of medicament from the dosage form
• mate ⁇ als e g waxes, fatty mate ⁇ als, polymers, natural, synthetic and semisynthetic gums
• HPMC hydroxypropyl methylcellulose
• HPMC hydroxypropyl methylcellulose
• the soluble polymer forms a gelatinous layer around the tablet after the exposure of the tablet to gastro-intestmal fluids or saliva
• the relase of the drug is limited by the rate of water penetration into, and diffusion of drug through, the gel formed (Bamba et al Int J Pharm (1979), 2, 307) Erosion of the gel structure is also an important release mechanism of a drug from the system
• the polymers used have to hydrate rapidly in order to protect the tablet from fast dissolution (Alderman 1984)
• the rate of absorption of a drug with very low solubility into the circulation from the intestinal tract is closely related to the rate of dissolution Since a low dissolution rate generally results m a low extent of bioavailabihty it is difficult to decrease the rate of absorption, l e increase the duration, without at the same time lowe ⁇ ng the extent of bioavailabihty
• US 4 803 081 discloses an extended release preparation of an active compound with very low solubility containing the active compound dissolved or dispersed in a serm-sohd or liquid non-ionic solubihzer and whereby the amount by weight of the solubihzer is at least equal to the amount by weight of the active compound Desc ⁇ ption of the invention
• a further object is to provide a formulation that is easy to manufacture
• a still further object of the invention is to provide a formulation that contains a low amount of solubihzer
• the solubihzers suitable according to the invention are defined below
• the active compound is preferably dissolved or dispersed in the solubihzer In the solution the drug is included in a micell-structure formed by the solubihzer
• the mixture of the drug and the solubihzer is incorporated into a pharmaceutical formulation, which gives prolonged release
• the present invention relates to a solid formulation with extended release of felodipine comp ⁇ smg felodipine dissolved or dispersed in a solubihzer selected from the group consisting of a polysorbate, a poloxyethylated glycol monoether, a polyoxyethylated alkyl phenol, a poloxamer, a polyoxyethylene castor oil de ⁇ vative, a polyoxyethylene stearate or another fatty acid ester with PEG, a glyce ⁇ de, a sorbitan ester, and a sucroglyce ⁇ de
• a solubihzer selected from the group consisting of a polysorbate, a poloxyethylated glycol monoether, a polyoxyethylated alkyl phenol, a poloxamer, a polyoxyethylene castor oil de ⁇ vative, a polyoxyethylene stearate or another fatty acid ester with PEG, a glyce ⁇ de, a sorb
• the present invention relates to a process for the preparation of a solid formulation with extended release of felodipine whereby the active compound is dissolved or dispersed in a solubihzer selected from the group consisting of a solid formulation with extended release of felodipine characte ⁇ zed in that it comp ⁇ ses felodipine dissolved or dispersed in a solubihzer selected from the group consisting of a polysorbate, a poloxyethylated glycol monoether, a polyoxyethylated alkyl phenol, a poloxamer, a polyxyethylene castor oil de ⁇ vative, a polyoxyethylene stearate or another fatty acid ester with PEG, a glyce ⁇ de, a sorbitan ester, and a sucroglyce ⁇ de, whereafter the mixture is incorporated into a suitable release controlling system in a known way and formed to a pharmaceutical dosage unit
• a solubihzers suitable for the formulations according to the invention are semi-
• Glycerides (mono-glycerides), e g, Monoolein (Glyceryl monooleate), Capmul, Captex, Imwitor, Gelucire, Myverol etc. See page 207.
• Sorbitan esters - partial esters of sorbitol and its mono- and di-anhydrides with oleic acid, eg Spans etc. See page 473.
• solubihzers are within categories a)-g):
• Chremophor EL Chremophor EL
• RH 40 Chremophor EL
• RH 60 Chremophor EL
• the active compound mixed with the solubihzer is incorporated into different kinds of known controlled release systems, e g a hydrophilic gel system, beads coated with a rate controlling membrane, which can be a diffusion retarding coating or a disintegrating coating or tablets with an inert porous mat ⁇ x
• the solubihzed drug is preferably combined with a hydrophilic gel system, namely a hydrophilic swelling mat ⁇ x e g HPMC
• a hydrophilic swelling mat ⁇ x e g HPMC This form of controlled release mechanism is a suitable ay to control the release of the micelles of drug and solubihzer
• HPMC hvdroxypropyl methylcellulose
• suitable compounds effecting the release of the active compound from the hydrophilic gel system are guar gum, xanthan gum, carboxypolymethylene, different cellulosic mate ⁇ als e g hydroxyethyl cellulose, sodium
• the preparation according to the invention contains 20-80% by weight, preferably 30-50% by weight of the hydrophilic gel system
• HPMC having a hvdroxypropyl content of 4-12% by weight, especially about 8 5% by weight and a viscosity lower than 100 cps.
• e g 6 15 and/or 50 cps The viscosity is measured by a standardized method described e g in United States Pharmacopeia XXI, 1985, p 672
• the final formulation is e g in the form of a gel tablet
• the preparation can be manufactured into a commercially acceptable form, e g a tablet or a hard gelatin capsule comprising the gel forming granulate, that shows unexpectedly good absorption of the actn e compound as well as a prolonged duration of action
• the proportions between the active compound and the solubihzer varies in the range from 1 0 01 to 1 10, preferably in the range from 1 0 1 to 1 8, and most preferably in the range from 1 0 5 to 1 6
• the proportions is preferably in the range from 1 0 01 to 1 1
• controlled release formulations e g tablets with an inert porous mat ⁇ x, capsules comp ⁇ smg granules with a diffusion retarding coating or a disintegrating coating
• the tablets with an inert porous mat ⁇ x are obtained by mixing the drug and solubihzer with water-insoluble polymers or waxes and with fillers and binders Polyvmylacetate, i ) polw mylchlonde, ethylcellulose, paraffin and cellulose acetate phthalate could be used as suitable diffusion-retarding polymers
• the files and binders are solid, powdered earners such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose de ⁇ vative, gelatine or other suitable carrier
• the mixture is moistened with a solvent, e g water or ethanol or a solution consisting of e g water and a polymer e g polyvinylpy ⁇ ohdone
• a solvent e g water or ethanol or a solution consisting of e g water and a polymer e g polyvinylpy ⁇ ohdone
• a lub ⁇ catmg agent e g magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethyleneglycol wax may be added The mixture is then formed to tablets
• the capsules comp ⁇ sing granules with extended release characte ⁇ stics are obtained by making a core material containing the drug and the solubihzer together with fillers The 0 surface of the core is then coated with diffusion-retarding water insoluble polymers or waxes The granules are then filled into hard gelatine capsules
• the core mate ⁇ al could e g be prepared by mixing the drug and the solubihzer with carefully selected fillers such as lactose, sorbitol, starch, cellulose de ⁇ vatives or other suitable fillers
• the mixture is moistened with a solvent, e g water or ethanol or a solution consisting of e g water and a ⁇ polymer e g polyvmylpyrrohdone
• the mass is formed to granules e g by extrusion and spheromzation
• the surfaces of the cores formed are coated with a solution consisting of a solvent e g methylene
• the following examples illustrate the invention In all expe ⁇ ments the formulations were made with different types of polymers and solubihzers
• the polymers used were PEO (polyethylene oxide) with molecular weights of 4,000,000 g/mol (PEO 4 ), 2,000,000 g/mol (PEO 2 ), and 900,000 (PEO 0 9 ), HPMC (hydroxypropyl methyl cellulose) with two different viscosities (60SH50 and 10,000), and HEC (hydroxy ethyl cellulose) of high (HEC HHX), medium (HEC HX), and low (HEC M) molecular weights
• the surfactants used were SDS (sodium dodecylsulfate), CTAB (cetyl t ⁇ methylammomum bromide), Gelucirevgj, and sulfobetaine Filler and lub ⁇ cants were AMS (aluminium magnesium silicate) and SSF (sodium stearyl fumarate)
• the tablets were typically
• Example 9 Formulations of felodipine in HEC HHX with felodipine/surfactant

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• 1999
  • 1999-07-20 SE SE9902742A patent/SE9902742D0/sv unknown
  • 1999-12-22 EP EP99964928A patent/EP1113786A1/en not_active Withdrawn
  • 1999-12-22 WO PCT/SE1999/002474 patent/WO2001005376A1/en not_active Application Discontinuation
  • 1999-12-22 CA CA002328102A patent/CA2328102A1/en not_active Abandoned
  • 1999-12-22 KR KR1020007011312A patent/KR20010078703A/ko not_active Application Discontinuation
  • 1999-12-22 AU AU30956/00A patent/AU3095600A/en not_active Abandoned
  • 1999-12-22 JP JP2001510433A patent/JP2003504392A/ja active Pending
  • 1999-12-22 CN CN99811100A patent/CN1319004A/zh active Pending
• 2000
  • 2000-09-26 NO NO20004816A patent/NO20004816L/no not_active Application Discontinuation

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