WO2001005376A1 - New pharmaceutical formulation - Google Patents

New pharmaceutical formulation Download PDF

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Publication number
WO2001005376A1
WO2001005376A1 PCT/SE1999/002474 SE9902474W WO0105376A1 WO 2001005376 A1 WO2001005376 A1 WO 2001005376A1 SE 9902474 W SE9902474 W SE 9902474W WO 0105376 A1 WO0105376 A1 WO 0105376A1
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WO
WIPO (PCT)
Prior art keywords
formulation according
solubihzer
felodipine
formulation
weight
Prior art date
Application number
PCT/SE1999/002474
Other languages
French (fr)
Inventor
Marianne Eklund
Jan-Erik Löfroth
Mats Sundgren
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to EP99964928A priority Critical patent/EP1113786A1/en
Priority to AU30956/00A priority patent/AU3095600A/en
Priority to KR1020007011312A priority patent/KR20010078703A/en
Priority to CA002328102A priority patent/CA2328102A1/en
Priority to JP2001510433A priority patent/JP2003504392A/en
Priority to NO20004816A priority patent/NO20004816L/en
Publication of WO2001005376A1 publication Critical patent/WO2001005376A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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

Abstract

An extended relase preparation of felodipine containing the active compound dissolved or dispersed in a solubilizer as well as a process for the preparation thereof.

Description

NEW PHARMACEUTICAL FORMULATION
Field of the invention
The present invention relates to a pharmaceutical extended release formulation of felodipine, and to methods of prepaπng such a formulation
The object of this invention is to obtain a solid formulation with good bioavailabihty and extended release of the active substance
10
Background of the invention
Pharmaceuticals with very poor water solubility present formulation problems due to their slow rate of dissolution Their efficacy can be severely limited and large inteπndividual ID vaπations of absorption can occur 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 arteπal hypertension Felodipine has a solubility of only 0 5 mg/1 in water at 25 °C
0 Several ways to increase drug absorption have been descπbed in the pπor literature One way is descπbed in DE-A-3024858, where a spaπngly soluble substituted dihydropyπdine, mcardipme, is used in its amorphous form in order to obtain increased absorption of the active compound from the intestine Another way is descπbed in EP-A-47899, where very small crystals of a practically insoluble dihydropyπdine, mfedipine, have been used in ^ order to increase the extent of the biovailabihty These methods and others are also descπbed in "Techniques of solubilization of drugs", Ed S H Yalkowsky in Drugs and the pharmaceutical sciences, Vol 12 Of particular relevance to the present invention is that surfactant solubihzmg agents may be employed in order to increase the bioavailabihty of the drugs with very low solubility It is stated that the improvement of absorption o properties can be ascπbed to three processes (1) increased wetting, (2) increased permeability of membranes and (3) solubilization The cited publication descπbes several examples and serves as a good review of the state of the art concerning the solubi zmg of drugs, especially in order to increase the bioavailabihty of drugs with very low solubility
From DE-A-3400106 controlled release preparations are known containing one or more natural, partially synthetic or synthetic polymers, one or more lipophilic and/or hydrophilic solvent(s) or thιckener(s) together with one or more pharmaceutically active compound(s) In the examples it is descπbed to use a solubi zer in an amount by weight to the active compound which is much less than 1 1
In the medical treatment of vaπous diseases, e g in the cardiovascular, gastrointestinal and chemotherapeutic field, it is an advantage to have a constant concentration of the administered drug in the blood Thus an extended release of the drug from the pharmaceutical preparation is wanted
It is important that the extended release preparation delivers the amount of drug needed to maintain an adequate and even effect duπng 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 lrπtating drugs having potential πsk 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 contπbute to a reproducible absorption, have no toxic or lrπtating constituents and be suitable also for high dosage drugs Conventionally, extended release is achieved by controlling dissolution and/or diffusion of medicament from the dosage form Several mateπals are employed for this purpose e g waxes, fatty mateπals, polymers, natural, synthetic and semisynthetic gums Among the gums, hydroxypropyl methylcellulose (HPMC) constitutes an important class because of its pH-independent properties as well as its semisynthetic oπgm A review of cellulose ethers in hydrophilic matπces for oral controlled release dosage forms is given by Alderman D A Int J Pharm Tech &Prod Mir (1984), 5(3) 1-9 The chemical treatment of HPMC to generate a desired constitution and the use of these qualities are disclosed in US 3 087 790, US 4 226 849, US 4 357 469 and US 4 369 172 SE-A-8008646-5 descπbes a combination of HPMC and hvdroxypropyl cellulose which is used to control the release rate of a pharmaceutically active compound
When a hydrophilic matπx is used 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 loweπng 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 Descπption of the invention
It is an object of the present invention to provide a formulation of felodipine that shows prolonged and nearly constant rate of drug absorption for a peπod of at least 24 hours and concuπently maintains a high extent of bioavailabihty 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
In a first embodiment the present invention relates to a solid formulation with extended release of felodipine compπsmg 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 deπvative, a polyoxyethylene stearate or another fatty acid ester with PEG, a glyceπde, a sorbitan ester, and a sucroglyceπde
In a further embodiment 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 characteπzed in that it compπses 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 deπvative, a polyoxyethylene stearate or another fatty acid ester with PEG, a glyceπde, a sorbitan ester, and a sucroglyceπde, whereafter the mixture is incorporated into a suitable release controlling system in a known way and formed to a pharmaceutical dosage unit The solubihzers suitable for the formulations according to the invention are semi-solid or liquid non-ionic surface active agents at ambient temperature, such as non-ionic esters and/or ethers of polylethylene glycols:
a) Polvsorbates - complex mixtures of partial esters of sorbitol and it mono- and di- anhydπdes condensed with an approximate number of moles of ethylene oxide. Examples - Tweens, Cπllets; Capmul deπvatives; Liposorbs; etc. See page 375 ( the reference here and later is to Handbook of Pharmaceutical Excipients, 2n ed; Eds: A Wade and PJ Woller, Pharmaceutical Press 1994)
b) Poll oxvethvlated glycol monoethers (polvoxvethvlene alkvl ethers), l e alkyl chains with ethylene oxide chains. Examples are C16E7 (heptaoxyethylene glycol monohexadecylether), Cetomacrogol 1000 BPC, Bπj or Atlas seπes. See page 367 + 556
c) Poly oxvethvlated alkyl phenols, e g Tritons;
d) Poloxamers, I e block copolymers of the type PEO-PPO-PEO where PEO = polyethylene oxide and PPO = polypropylene oxide with different chamlengths (also known as e g Pluronics). See page 352.
e) Polvoxvethvlene castor oil derivatives - ethylene oxide reacted with (hydrogenated) castor oil (tπglyceπdes of (hydrogenated) steaπc acid). Example Chremophors See page
371.
j) Polvoxvethvlene stearates and other fatty acid esters with PEG. Examples Solutol and Labrasol. See page 379.
g) Special substances, e g TPGS (tocopheryl polyethylene glycol succinate); glycofurol (See page 213). Further solubihzers, not belonging to the class of non-ionic esters and/or ethers of polyethylene glycols, suitable for the preparation according to the invention are
h) Glycerides (mono-glycerides), e g, Monoolein (Glyceryl monooleate), Capmul, Captex, Imwitor, Gelucire, Myverol etc. See page 207.
i) Sorbitan esters - partial esters of sorbitol and its mono- and di-anhydrides with oleic acid, eg Spans etc. See page 473.
i'i j) Sucroglycerides - sucrose esters of fatty acids.
k) Special substances - cyclodextrins solid; See page 147.
Particularly prefeπed solubihzers are within categories a)-g):
15
- Different types of Chremophor: Chremophor EL, RH 40, RH 60
- Pluromcs F127 or F68 (Poloxamer 407 and 188)
- Solutol HS 15
- Labrasol 0 - Cetomacrogol 1000 or Brij 97
and within categories h)-k):
- Gelucire 44/14 or Gelucire 50/13 5 - Imwitor 742
- Monoolein (glyceryl monooleate) in combination with a medium chain monoglyceride, i e Myverol 18-99 + Capmul
- Span 20 or Span 80. r^ i i&Hi yi u.t ; •*
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 matπx Accordmg to the invention the solubihzed drug is preferably combined with a hydrophilic gel system, namely a hydrophilic swelling matπx e g HPMC This form of controlled release mechanism is a suitable ay to control the release of the micelles of drug and solubihzer The technical properties are good and also the performance in vivo is good Among different hydrophilic materials tested, HPMC, hvdroxypropyl methylcellulose, is the best gel-forming mateπal Other examples of suitable compounds effecting the release of the active compound from the hydrophilic gel system are guar gum, xanthan gum, carboxypolymethylene, different cellulosic mateπals e g hydroxyethyl cellulose, sodium carboxymethvlcellulose and hydroxyprop\ 1 cellulose, lactose, aluminium silicate and polyethylene oxide
The preparation according to the invention contains 20-80% by weight, preferably 30-50% by weight of the hydrophilic gel system
It is especially preferable to use 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 By a careful choice of fillers and binders as well as gel forming material 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 In the formulation accordmg to the invention 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 When any of the solubihzers a) - g) is selected the proportions is preferably in the range from 1 0 01 to 1 1
Also other types of controlled release formulations may be used according to the invention e g tablets with an inert porous matπx, capsules compπsmg granules with a diffusion retarding coating or a disintegrating coating
The tablets with an inert porous matπx 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 deπvative, 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 polyvinylpyπohdone Also
11 a lubπcatmg 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 compπsing granules with extended release characteπstics 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 mateπal could e g be prepared by mixing the drug and the solubihzer with carefully selected fillers such as lactose, sorbitol, starch, cellulose deπvatives 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 ι 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 chloπde and/or isopropyl alcohol and water insoluble polymers e g ethylcellulose The granules are filled in hard gelatine capsules Working Examples
The following examples illustrate the invention In all expeπments 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 tπmethylammomum bromide), Gelucirevgj, and sulfobetaine Filler and lubπcants were AMS (aluminium magnesium silicate) and SSF (sodium stearyl fumarate) The tablets were typically made by dissolving felodipine in ethanol A mixture of AMS and surfactant were then granulated with the felodipine solution The granulate was dried at 50 °C for about 16 hrs, and then mixed with the polymer and SSF The tablets (diameter = 9 mm) were then made with a Kihan hydraulic press with a round punch
In-vitro Dissolution (drug release)
Tablets were tested in 500 ml of phosphate buffer pH 6 5 containing 0 4 % cetyl tnmethvlammonium- bromide (CTAB) using USP dissolution apparatus II A specially made quadrangular basket of gauze wire was used m order to keep the tablets in well defined position in the dissolution vessel The stirπng rate was 100 rpm and the temperature 37°C The surfactant CTAB was added to the dissolution media to obtain sink conditions Samples were withdrawn for analysis (absorbance of felodipine at 362 run in a 1 cm cell) Amounts released of felodipine were determined from a calibration curve obtained from measurements of the absorbance of standard felodipine solutions based on the same medium as used in the release expeπments Example 1. Formulations of felodipine in PEO 4' with felodipine/surfactant = 1/1 w/w.
Figure imgf000011_0001
Result: % released felodipine from the different formulations of example 1.
Figure imgf000011_0002
Example 2. Formulations of felodipine in PEO 4' with felodipine/surfactant = 1/0.1 w/w.
Figure imgf000012_0001
Result: % released felodipine from the different formulations of example 2.
Figure imgf000012_0002
Example 3. Formulations of felodipine in PEO 2' with felodipine/surfactant = 1/1 w/w.
Figure imgf000013_0001
Result: % released felodipine from the formulation of example 3. Results from duplicate experiments reported.
Figure imgf000013_0002
Example 4. Formulations of felodipine in PEO 0.9' with felodipine/surfactant = 1/1 w/w.
Figure imgf000014_0001
Result: % released felodipine from the formulation of example 4. Results from duplicate experiments reported. The tablets were completely dissolved before 6 hrs.
Figure imgf000014_0002
Example 5. Formulations of felodipine in PEO 4' with felodipine/surfactant = 1/7 w/w.
Figure imgf000015_0001
Result: % released felodipine from the formulation of example 5.
Figure imgf000015_0002
Example 6. Formulations of felodipine in HPMC 60SH50/10 000 with felodipine/surfactant = 1/1 w/w.
Figure imgf000016_0001
Result: % released felodipine from the different formulations of example 6.
Figure imgf000016_0002
Example 7. Formulations of felodipine in HPMC 60SH50/10 000 with felodipine/surfactant = 1/0.1 w/w.
Figure imgf000017_0001
Result: % released felodipine from the different formulations of example 7.
Figure imgf000017_0002
Example 8. Formulations of felodipine in HEC HHX with felodipine/surfactant = 1/1 w/w.
Figure imgf000018_0001
Result: % released felodipine from the different formulations of example 8.
Figure imgf000018_0002
Example 9. Formulations of felodipine in HEC HHX with felodipine/surfactant
1/0.1 w/w.
Figure imgf000019_0001
Result: % released felodipine from the different formulations of example 9.
Figure imgf000019_0002
Example 10. Formulations of felodipine in HEC M with felodipine/surfactant = 1/1 w/w.
Figure imgf000020_0001
Result: % released felodipine from the formulation of example 10. The results from duplicate experiments are reported.
Figure imgf000020_0002
Example 11. Formulations of felodipine in HEC HX with felodipine/surfactant = 1/1 w/w.
Figure imgf000021_0001
Result: % released felodipine from the formulation of example 11. Results from duplicate experiments are reported.
Figure imgf000021_0002

Claims

Claims
1 A solid formulation with extended release of felodipine comprising 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 deπvative, a polyoxyethylene stearate or another fatty acid ester with PEG, a glyceπde, a sorbitan ester, and a sucroglyceπde
2 A formulation according to claim 1, wherein the solubihzer is a poloxyethylated glycol monoether
3 A formulation according to claim 2, wherein the solubihzer is Cetomacrogol 1000 or Bπj 97
4 A formulation according to claim 1, wherein the solubihzer is a poloxamer
5 A formulation according to claim 4, wherein the solubihzer is Pluromcs F 127 or F 68
6 A formulation according to claim 1 , wherein the solubihzer is a polyoxyethylene castor oil deπvative and the proportion of the amount of weight of felodipine amount of weight of the solubihzer is in the range from 1 0 01 to 1 1
7 A formulation according to claim 6, wherein the solubihzer is a Chremophor
8 A formulation according to claim 1, wherein the solubihzer is a polyoxyethylene stearate or another fatty acid ester with PEG
9 A formulation according to claim 8, wherein the solubihzer is Solutol HS 15 or Labrasol
10 A formulation according to claim 1, wherein the solubihzer is a glyceπde
1 1 A formulation according to claim 10, wherein the solubihzer is Gelucire 44/14, Gelucire 50/13, Imwitor 742, monoolein in combination with a medium chain monoglyceπde
12 A formulation according to claim 1, wherein the solubihzer is a sorbitan ester
13 A formulation according to claim 12, wherein the solubihzer is Span 20 or Span 80
14 A formulation according to any of the preceding claims, wherein proportion of the amount of weight of felodipine amount of weight of the solubihzer is in the range from 1 0 01 to 1 10, preferably from 1 0 1 to 1 8, and most preferably 1 0 5 to 1 6
15 A formulation according to any of the preceding claims wherein the release is controlled by an inert porous matπx, a diffusion retarding coating or a disintegrating coating
16 A formulation according to any of the preceding claims wherein the release is controlled by a hydrophilic gel system
17 A formulation according to claim 16 wherein the hydrophilic gelformmg component constitutes between 20-80% by weight of the formulation
18 A formulation according to claims 16 and 17 wherein the hydrophilic gel system compπses hydroxypropyl methylcellulose
19 A formulation according to claim 18 wherein the hydroxypropyl methylcellulose has a hydroxypropyl content of 4-12%o by weight
20. A formulation according to one or more of the claims 16-19 wherein the hydrophilic gel system contains carboxypolymethylene.
21. A formulation according to one or more of the claims 16-19, wherein the hydrophilic gel system contains guar gum or xanthan gum.
22. A formulation according to one or more of the claims 16-19, wherein the hydrophilic gel system contains a cellulosic material, such as hydroxyethyl cellulose, sodium carboxymethyl cellulose or hydroxypropyl cellulose.
23. A formulation according to one or more of the claims 16-19, wherein the hydrophilic gel system contains lactose, aluminium silicate or polyethylene oxide.
24. A process for the preparation of a solid formulation with extended release of felodipine characterized in that the active compound is dissolved or dispersed in a solubihzer selected from the group consisting of a solid formulation with extended release of felodipine characterized in that it comprises 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 derivative, a polyoxyethylene stearate or another fatty acid ester with PEG, a glyceride, a sorbitan ester, and a sucroglyceride, whereafter the mixture is incorporated into a suitable release controlling system in a known way and formed to a pharmaceutical dosage unit.
PCT/SE1999/002474 1999-07-20 1999-12-22 New pharmaceutical formulation WO2001005376A1 (en)

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WO2003094895A1 (en) * 2002-05-07 2003-11-20 Bernard Charles Sherman Extended release tablets comprising felodipine
WO2004028503A1 (en) * 2002-09-30 2004-04-08 Universiteit Gent Controlled delivery system for bioactive substances

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CN101103964B (en) * 2006-07-14 2010-09-29 海南盛科生命科学研究院 Sustained-release preparation containing felodipine and preparation method thereof
KR100841877B1 (en) * 2006-08-31 2008-06-27 조선대학교산학협력단 Locally solubilized controlled release matrix tablet of poorly soluble drugs
CN102784128B (en) * 2012-07-31 2015-01-07 北京协和药厂 Felodipine sustained release preparation and preparation method of felodipine sustained release preparation

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WO2003094895A1 (en) * 2002-05-07 2003-11-20 Bernard Charles Sherman Extended release tablets comprising felodipine
WO2004028503A1 (en) * 2002-09-30 2004-04-08 Universiteit Gent Controlled delivery system for bioactive substances

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