WO2008037809A1 - Transmucosal administration of fibrate compounds and delivery system therefor - Google Patents

Abstract

The invention provides a method and a delivery system for the administration of a fibrate compound to a subject in need thereof by bringing the delivery system into contact with a mucous membrane of the subject for a time sufficient to deliver a therapeutically effective amount of the fibrate compound. The delivery system is preferably film-shaped and comprises a solid dispersion product wherein the fibrate compound is distributed homogenously in a polymer matrix.

Description

Transmucosal administration of fibrate compounds and delivery system therefor

The present invention relates to a method for the transmucosal administration of fibrate compounds, in particular fenofibrinic acid, to a drug delivery system suitable for such a route of administration and to a process for manufacturing the drug delivery system.

Dyslipidaemia, i. e. disruption in the amount of lipids in the blood, is considered an important factor in the development of numerous disorders, in particular disorders of the cardiovascular system, which are globally the leading cause of mortality and morbidity. In the Western world, most cases of dyslipidaemia are hyperlipidaemia, i. e. excessive blood levels of cholesterol and/or triglycerides. The link between hyperlipidaemia and atherosclerosis, which accounts for a significant percentage of deaths and disability in the developed countries, has been established convincingly by now. Thus, in subjects with hyperlipidemia lipid-lowering treatment is mandatory. Such treatment may com- prise changes in lifestyle, diet and/or pharmaceutical intervention using lipid-lowering drugs.

Fibrates are a class of efficient lipid-lowering agents, among which clofibrate (now largely obsolete due to its side-effect profile), gemfibrozil, fenofibrate, bezafibrate and ciprofibrate are widely used in the treatment of hyperlipidaemia.

In particular, fenofibrate is a well-known lipid regulating agent which has been on the market for a long time. For reviews of its effects and applications, see e. g. Maki et al., Curr. Atheroscleros. Rep. 6(1 ), 2004: 1463 - 1467; Robillard et al., Handb. Exp. Phar- macol. 2005: 389 - 406; and the UK HDL-C Consensus Group, Curr. Med. Res. Opin. 20(2), 2004: 241 - 247.

Usually fenofibrate is administered orally. After its absorption which is known to take place in the duodenum and other parts of the gastrointestinal tract, fenofibrate is me- tabolized in the body to fenofibric acid. In fact, fenofibric acid represents the active principle of fenofibrate or, in other words, fenofibrate is a so-called prodrug which is converted in vivo to the active molecule, i.e. fenofibric acid. After oral administration of fenofibrate merely fenofibric acid is found in plasma.

Fenofibrate is known to be nearly insoluble in water (< 0.1 mg/l), thereby necessitating special pharmaceutical formulations to ensure good bioavailability, especially after oral administration. Accordingly, fenofibrate has been prepared in several different formulations, cf. WO 00/72825 and citations given therein, such as US-A 4,800,079, US-A 4,895,726, US-A 4,961 , 890, EP-A O 793 958 and WO 82/01649. Further formulations of fenofibrate are described in WO 02/067901 and citations given therein, such as US- A 6,074,670 and US-A 6,042,847. WO 2005/034908 discloses solid dosage forms comprising a fibrate and a statin. WO 2006/084475 describes a tablet comprising a solid dispersion or solid solution of a fibrate in a vehicle, wherein the therapeutic effect of the tablet in a patient is essentially independent of whether the tablet is administered to the patent in fed or fasted state.

The products currently on the market are based on a formulation comprising mi- cronized drug substance (TRICOR) in capsules and/or tablets. However, due to the insolubility of fenofibrate in water there is a tendency of said substance to recrystallize upon release from the formulation. This may reduce the bioavailability of the drug. In addition, even these micronized formulations do not address the problem of unreliable bioavailability unless ingested during a meal (for discussion see, e. g., Guivarc'h et al., Clinic. Therap. 26(9), 2004: 1456 - 1469). Thus, oral administration of fibrate compounds, and in particular of fenofibrate, can be recommended only for patients with a very regular lifestyle who will have their meals at fixed time points. In the majority of cases, however, blood levels of the drug and, concomitantly, the effects of treatment will be unreliable. As constant levels of blood lipids are considered desirable, this severely curtails the usefulness of oral fibrate compound formulations.

Conventional non-oral formulation approaches, e. g. parenteral formulations, do not address the issue of convenient administration. It should be kept in mind that treatment with fibrate compounds is intended to be a long-term risk-minimizing approach, and that therefore even minor inconveniences will adversely affect many patients' compliance and thus seriously jeopardize the success of the treatment. Additionally, parenteral administration of fibrate compounds generally suffers from the intrinsic prob- lems of poor solubility of the drug.

It is therefore an object of the present invention to provide formulations which make fibrate compounds sufficiently and reliably bioavailable even when not administrated in connection with a meal, and which allow for easy, convenient and unobtrusive admini- stration.

This object is achieved by a transmucosal delivery system, in particular a delivery system based on a film-shaped solid dispersion product, wherein the comparatively slow release of the fibrate compound (in comparison to burst of drug released from conven- tional buccal capsules) into the oral cavity ensures that the resorptive capacity of the mucosa is not saturated or exceeded, thereby maximizing the portion of the fibrate compound that is actually resorbed.

The present invention therefore relates to a method for the administration of a fibrate compound to a subject in need thereof, comprising bringing a fibrate compound delivery system into contact with a mucous membrane of the subject for a time that is suffi- cient to deliver a therapeutically effective amount of the fibrate compound. The present invention also relates to a delivery system for such a method of administration.

The mucous membrane is preferably a part of the oral cavity of the subject, in particular the sublingual mucosa.

As used herein, the term "fibrate compound" refers to clofibric acid, benzafibric acid, ciprofibric acid, gemfibrozil and fenofibric acid, as well as to the physiologically acceptable salts and derivatives thereof. Preferably, the fibrate compound is selected from the group consisting of fenofibric acid of formula I below, the physiologically acceptable salts and derivatives thereof.

Physiologically acceptable salts are preferably base addition salts.

The base addition salts include salts with inorganic bases, for example metal hydroxides or carbonates of alkali metals, alkaline earth metals or transition metals, or with organic bases, for example ammonia, basic amino acids such as arginine and lysine, amines, e.g. methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, 1-amino-2-propanol, 3- amino-1-propanol or hexamethylenetetraamine, saturated cyclic amines having 4 to 6 ring carbon atoms, such as piperidine, piperazine, pyrrolidine and morpholine, and other organic bases, for example N-methylglucamine, kreatine and tromethamine, and quaternary ammonium compounds such as tetramethylammonium and the like.

Preferred salts with organic bases are formed with amino acids. Preferred salts with inorganic bases are formed with Na, K, Mg and Ca cations.

Preferred physiologically acceptable derivatives are the prodrugs of the active free car- boxylic acid form of the fibrate compound. These prodrugs are preferably carboxylic acid derivatives that in vivo can be reconverted into the free carboxylic acid. The conversion of said prodrugs in vivo may occur under the physiological conditions which the prodrug experiences during its passage, or it may involve cleavage by enzymes, especially esterases, accepting said prodrug as substrate.

The term "fenofibric acid" refers to 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, of the formula I:

(I)

Preferred physiologically acceptable derivatives of fenofibric acid are compounds of the formula II:

wherein R represents OR-i, -NR₁R₂, -NH-alkylene-NR₁R₂ or -O-alkylene-NR₁R₂, with R₁ and R₂ being identical or different from each other and representing a hydrogen atom, alkyl, alkoxyalkyl, alkoyloxyalkyl, alkoxycarbonyl, aminoalkyl, alkylaminoalkyl, dialkyl- aminoalkyl, trialkylammoniumalkyl, cycloalkyl, aryl or arylalkyl substituted on the aromatic residue by one or more halogen, methyl or CF₃ groups, or R₁ and R₂ forming - together with the nitrogen atom to which they are connected - a 5- to 7-membered aliphatic heterocyclic group which may enclose a second heteroatom selected from N, O, and S, and which may be substituted by one ore more halogen, methyl and/or CF₃ groups. Particularly preferred physiologically acceptable derivatives are fenofibric acid esters, i.e. derivatives of formula Il wherein R represents OR₁ and R₁ is other than hydrogen.

These esters in particular include derivatives of formula Il wherein R₁ in -OR₁ repre- sents an alkyl group having from 1 to 6 carbon atoms, an alkoxymethyl group having from 2 to 7 carbon atoms, a phenylalkyl group composed of an alkylene group having from 1 to 6 carbon atoms and a phenyl group, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group and a dimethylaminoethyl group.

The term "alkyl, alkoxy etc." includes straight-chain or branched alkyl groups, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl or n- hexyl, preferably having - if not stated otherwise - 1 to 18, in particular 1 to 12 and particularly preferably 1 to 6, carbon atoms.

The term "cycloalkyl" includes mono- or bicyclic alkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., preferably having - if not stated otherwise - 3 to

9, in particular 3 to 7 and particularly preferably 5 or 6, carbon atoms.

"Aryl" is preferably naphthyl and in particular phenyl.

The "heterocyclic group" is in particular a 5- or 6-membered heterocyclic radical which can be aromatic or non-aromatic (aliphatic), mono- or bicyclic, and/or benzo-fused. The non-aromatic radicals include nitrogen-containing heterocyclic radicals, such as piperidinyl and piperazinyl. These also include heterocyclic radicals which contain two or more different heteroatoms, such as morpholinyl. Alkyl esters of fenofibric acid are preferred, with the 1-methylethyl ester (isopropyl ester) of fenofibric acid, i.e. fenofibrate (INN), being the most preferred. Of course, mixtures of fenofibric acid, a physiologically acceptable salt and/or deriva- tive thereof are possible.

Besides the fibrate compound, the delivery systems of the invention may comprise other active substances, in particular those with an effect like and/or complementing that of fibrate compounds, e.g. other lipid regulating agents, such as statins, e.g. lova- statin, mevinolin, pravastatin, fluvastatin, atorvastatin, itavastatin, mevastatin, rosuvas- tatin, velostatin, synvinolin, simvastatin and cerivastatin.

One embodiment of the present invention comprises single-drug delivery systems which comprise an active substance component that essentially consists of fenofibric acid.

In a preferred embodiment of the invention, the delivery system comprises a solid dispersion product wherein the fibrate compound is distributed homogenously in a polymer matrix. The solid dispersion product is essentially free of crystals or microcrystals of the fibrate compound.

Preferably, the fibrate compound is present in the solid dispersion product in an essentially amorphous form. The term "amorphous" is known to the skilled artisan and denotes a solid structure or material in which there is no long-range molecular orientation. A possibility for identifying an amorphous state (as opposed to a crystalline or micro- crystalline state) is the reduction in intensity and/or absence of typical X-ray diffraction signals in WAXS analysis (wide-angle X-ray scattering).

More preferably, the fibrate compound is present in the solid dispersion product in a state of molecular dispersion. The term "molecular dispersion" (or "solid solution") is likewise known to the skilled artisan and essentially describes systems in which a substance is homogeneously dispersed in the matrix component, so that the system is chemically and physically uniform or homogenous throughout, or consists of a single phase (as defined in thermodynamics). The state of such molecular dispersions can be investigated by known analytical methods, e.g. by differential scanning calorimetry (DSC). Measurement of a molecular dispersion in DSC analysis lacks the, usually en- dothermic, melting peak occurring with the crystalline pure substance.

Typically, the solid dispersion product comprises: from about 5 to 60 % by weight (preferably 10 to 30 % by weight) of the fibrate compound or a combination of fibrate compounds, from about 30 to 90 % by weight (preferably 50 to 80 % by weight, most preferably 60 to 75 % by weight) of a pharmaceutically acceptable polymer (or any combina- tion of such pharmaceutically acceptable polymers), from 5 to 30 % by weight (preferably 7 to 20 % by weight) of at least one pharmaceutically acceptable plasticizer, and from 0 to 20 % by weight (preferably 0 to 10 % by weight) of optional ingredients.

Generally, the pharmaceutically acceptable polymer employed in the invention has a glass transition temperature Tg of at least about +10 ⁰C, preferably at least about +25°C, most preferably from about 40 ° to 180 ⁰C. Methods for determining the Tg values of organic polymers are described in "Introduction to Physical Polymer Science", 2nd Edition by L. H. Sperling, published by John Wiley & Sons, Inc., 1992. The Tg value can be calculated as the weighted sum of the Tg values for homopolymers derived from each of the individual monomers i that make up the polymer, i.e. Tg = Σ W, X, where W is the weight percent of monomer i in the organic polymer and X is the Tg value for the homopolymer derived from monomer i. Tg values for the homopolymers are indicated in "Polymer Handbook", 2nd Edition by J. Brandrup and E. H. Immergut, Editors, published by John Wiley & Sons, Inc., 1975.

Suitable pharmaceutically acceptable polymers are the following:

homopolymers and copolymers of N-vinyllactams, in particular homopolymers and co- polymers of N-vinylpyrrolidone, e.g. polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone and vinyl acetate or vinyl propionate,

cellulose esters and cellulose ethers, in particular methylcellulose and ethylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkyl- celluloses, in particular hydroxypropylmethylcellulose, cellulose phthalates or succinates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthala- te, hydroxypropylmethylcellulose succinate or hydroxypropylmethylcellulose acetate succinate;

high molecular weight polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide,

polyacrylates and polymethacrylates such as methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl methacrylate copolymers, butyl methacrylate/ 2-dimethylaminoethyl methacrylate copolymers, poly(hydroxyalkyl acrylates), po- ly(hydroxyalkyl methacrylates), polyacrylamides,

vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially hydrolyzed polyvinyl alcohol),

polyvinyl alcohol,

oligo- and polysaccharides such as carrageenans, galactomannans and xanthans, or mixtures of one or more thereof.

Of these, homo- or copolymers of vinylpyrrolidone are particularly preferred, e.g. polyvinylpyrrolidone with Fikentscher K values of from 12 to 100, preferably 17 to 30, or copolymers of from 30 to 70% by weight N-vinylpyrrolidone (VP) and 70 to 30% by weight vinyl acetate (VA), such as, for example, a copolymer of 60% by weight VP and 40% by weight VA.

It is, of course, possible to employ mixtures of said polymers.

Plasticizers useful in the present invention comprise organic, preferably involatile compounds, such as, for example, C₇-C₃₀-alkanols, ethylene glycol, propylene glycol, glycerol, trimethylolpropane, triethylene glycol, butandiols, pentanols such as pentaerythri- tol and hexanols, polyalkylene glycols, preferably having a molecular weight of from 200 to 1 000, such as, for example, polyethylene glycols (e.g. PEG 300, PEG 400), polypropylene glycols and polyethylene/propylene glycols, silicones, aromatic carbox- ylic esters (e.g. dialkyl phthalates, trimellitic esters, benzoic esters, terephthalic esters) or aliphatic dicarboxylic esters (e.g. dialkyl adipates, sebacic esters, azelaic esters, citric and tartaric esters, in particular triethylcitrate), fatty acid esters such as glycerol mono-, di- or triacetate or sodium diethyl sulfosuccinate. Particularly preferred plasti- cizers are selected from the group consisting of glyceryl triacetate, triethyl citrate, polyethylene glycol and mixtures thereof.

It is preferred that the amount of plasticizer is selected such that the glass transition temperature of the final solid dispersion product is not lower than 40 ⁰C, preferably not lower than 70 ⁰C.

The solid dispersion product may comprise optional ingredients. These optional ingredients include pharmaceutically acceptable solubilizers, fillers, disintegrants, lubricants, flow regulators, adhesion enhancers, colorants, flavours and preservatives. These terms of the art are generally known to the skilled person. These optional ingredients are selected such that they are compatible with the active ingredient(s) and the other ingredients used.

The term "pharmaceutically acceptable surfactant" as used herein refers to a pharma- ceutically acceptable ionic or non-ionic surfactant. Incorporation of surfactants is especially preferred for matrices containing poorly water-soluble active ingredients. The surfactant may effectuate an instantaneous emulsification of the active ingredient released from the dosage form and/or prevent precipitation of the active ingredient in the aqueous fluids of the gastrointestinal tract.

Preferred surfactants are selected from sorbitan fatty acid esters, polyalkoxylated fatty acid esters such as, for example, polyalkoxylated glycerides, polyalkoxylated sorbitan fatty acid esters or fatty acid esters of polyalkylene glycols, or polyalkoxylated ethers of fatty alcohols. A fatty acid chain in these compounds ordinarily comprises from 8 to 22 carbon atoms. The polyalkylene oxide blocks comprise on average from 4 to 50 alkylene oxide units, preferably ethylene oxide units, per molecule.

Suitable sorbitan fatty acid esters are sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan tristearate, sorbitan trioleate, sorbitan monostearate, sorbitan monolaurate or sorbitan monooleate.

Examples of suitable polyalkoxylated sorbitan fatty acid esters are polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, poly- oxyethylene (20) sorbitan tristearate, polyoxyethylene (20) sorbitan trioleate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene (4) sorbitan monolaurate or polyoxyethylene (4) sorbitan monooleate.

Suitable polyalkoxylated glycerides are obtained for example by alkoxylation of natural or hydrogenated glycerides or by transesterification of natural or hydrogenated glycerides with polyalkylene glycols. Commercially available examples are polyoxyethylene glycerol ricinoleate 35, polyoxyethylene glycerol trihydroxystearate 40 (Cremophor® RH40, BASF AG) and polyalkoxylated glycerides like those obtainable under the proprietary names Gelucire® and Labrafil® from Gattefosse, e.g. Gelucire® 44/14 (lauroyl macrogol 32 glycerides prepared by transesterification of hydrogenated palm kernel oil with PEG 1500), Gelucire® 50/13 (stearoyl macrogol 32 glycerides, prepared by transesterification of hydrogenated palm oil with PEG 1500) or Labrafil M 1944 CS (oleoyl macrogol 6 glycerides prepared by transesterification of apricot kernel oil with PEG 300). A suitable fatty acid ester of polyalkylene glycols is, for example, PEG 660 hydroxy- stearic acid (polyglycol ester of 12-hydroxystearic acid (70 mol%) with 30 mol% ethylene glycol).

Suitable polyalkoxylated ethers of fatty alcohols are, for example, macrogol 6 cetylstea- ryl ether or macrogol 25 cetylstearyl ether

Solubilizers are typically included in the powder mixture in an amount of from 0.1 to 15% by weight, preferably 0.5 to 10% by weight.

Fillers useful in the present invention comprise conventional fillers such as sugar alcohols, e.g. lactose, microcrystalline cellulose, mannitol, sorbitol and xylitol, isomalt, starch saccharification products, talc, sucrose, cereal corn or potato starch.

Disintegrants useful in the present invention comprise crosslinked polyvinylpyrrolidone and crosslinked sodium carboxymethylcellulose.

Lubricants useful in the present invention comprise conventional lubricants, glidants and mould release agents such as magnesium, aluminum and calcium stearates, talc and silicones, and animal or vegetable fats, especially in hydrogenated form and those which are solid at room temperature. These fats preferably have a melting point of 30 ⁰C or above. Triglycerides of Ci₂, Ci₄, Ci₆ and Ci₈ fatty acids, sodium stearylfumarate, and lecithin may be suitably be employed. It is also possible to use waxes such as car- nauba wax. These fats and waxes may advantageously be admixed alone or together with mono- and/or diglycerides or phosphatides, in particular lecithin. The mono- and diglycerides are preferably derived from the abovementioned fatty acid types. Where present, the total amount of lubricants (including glidants and mould release agents) is preferably 0.1 to 10% by weight and, in particular, 0.1 to 2 % by weight, based on the total weight of the solid dispersion product.

Flow regulators useful in the present invention comprise conventional flow regulators, e.g. colloidal silica (highly dispersed silicon dioxide), especially the high-purity silicon dioxides having the proprietary name Aerosil®, where present in particular in an amount of 0.1 to 5% by weight based on the total weight of the mixture.

Colorants useful in the present invention comprise dyes such as azo dyes, organic or inorganic pigments such as iron oxides or titanium dioxide, or dyes of natural origin; where present in a concentration of, e. g., 0.1 to 3% by weight, based on the total weight of the solid dispersion product. Various other additives may be used, for example stabilizers such as antioxidants, light stabilizers, radical scavengers and stabilizers against microbial attack.

Suitable adhesion enhancers are selcted from, e. g., polyacrylic acid based polmers, such as polyacrylic acid, crosslinked polyacrylic acid (available as CARBOPOL®, PoIy- carbophil), polyacrylates, poly(methylvinylether-co-methacrylic)acid, poly(2-hydroxy- ethyl methacrylate), poly(methacrylate), poly(alkylcyanoacrylate), poly(isohexylcyano- acrylate), poly(isobutylcyanoacrylate); Cellulosics, such as carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, me- thyl cellulose, methylhydroxyethyl cellulose; chitosan, Guar gum, Xanthan gum, Gellan gum, Carrageenan, Pectin, Arginate, Polyvinylpyrrolidone, Poly(vinylalcohol), poly(2- hydroxypropyl methacrylamide) (pHPMAm) or mixtures of these adhesion enhancers.

Flavours impart a pleasant taste to the inventive dosage form. Sweeteners are suitable flavours. Other flavours that may be used are selected from natural or artificial flavours.

Conveniently, the solid dispersion product has a shape that facilitates the contact with a mucosa of the patient, in particular an oral mucosa. To this end, film-shaped solid dispersion products are particularly preferred.

As used herein, the term "film" refers to a predominantly two-dimensional structure, i. e. a structure whose spatial expansion in one dimension (the "thickness") is considerably lower than in either of the other two. An arrangement wherein the polymer molecules constituting the polymer matrix are oriented predominantly orthogonal to the thickness dimension is preferred. More preferred is an arrangement wherein most of the molecules are essentially parallel to a preferential direction. In preferred embodiments of the invention, the film is characterized by transparency and flexibility, in particular by its low resistance to elastic deformation when subjected to bending or rolling of the film. Furthermore, it is particularly preferred if the structure of the film is homogenous and co- herent, without any interspaces, inclusions, bubbles, lattice, sponge, net or meshwork structures.

In a preferred embodiment of the invention, the tensile strength of the film in any direction is at least 3.3 N/mm², more preferably at least 4.3 N/mm² and most preferably at least 5.5 N/mm².

Depending on the method of production of the film-shaped solid dispersion product, the film may exhibit mechanical anisotropy, i. e., its mechanical properties are different with respect to forces in a preferential direction (e. g. the machine direction in a extruded solid dispersion product) and a direction perpendicular thereto. Preferably, the anisotropy quotient, as defined by Q = L / N wherein L is the tensile strength in the machine direction, and N is the tensile strength in a direction perpendicular thereto, is from 0.6 to 1.4 preferably from 0.8 to 1.2 and more preferably from 0.9 to 1.1. A suitable method for the determination of the tensile strength of a polymer film is described in the working examples that follow.

Furthermore, it is preferred if the thickness of the polymer film is from 200 μm to 1000 μm, more preferably 400 to 600 μm.

In a preferred embodiment of the invention, the disintegration time of the film in aqueous solution is 30 minutes or less, more preferably 20 min or less and most preferably 10 min to 20 min.

The term "disintegration time in aqueous solution" is used herein to denote the time that elapses before the film is essentially dissolved when brought into contact with a large volume of aqueous medium. Preferably, the aqueous medium is phosphate buffer, more preferably phosphate buffer at pH 4.0 - 5.0, e. g. 0.1 M phosphate buffer of pH 4.5 comprising 0.5% of benzalconium chloride, at physiological temperature, e. g.

37 ⁰C.

In this aspect, it is preferred if an individual dosage form comprises a piece, patch, slice, strip or shred of said polymer film.

It is particularly preferred that the individual dosage form comprises an amount of the fibrate compound that corresponds to from 20 mg to 150 mg active fibrate compound (e. g. fenofibrinic acid).

The delivery form may comprise a multilayer formulation. In a multilayer formulation, several layers of film may be combined to form a structure which may be symmetrical or asymmetrical, preferably symmetrical, in cross-section. If more than two layers are present, the formulations will necessarily comprises layers that are exposed to the surface of the formulation and layers which are not. This may be used for improved biological, chemical or mechanical protection of the layer or layers comprising the active ingredient(s), e. g. by including anti-bacterial and/or anti-fungal, air-tight, anti-oxidative, anti-hygroscopic and/or light-protective substances into the layers with surface contact, or designing these layers so to be more resistant mechanically, in particular to puncture and abrasive stress, e. g. by using higher molecular weight polymers and/or polymers of stronger mutual cohesion. It may further be used for controlled sequential release of a number of different compounds, e. g. with the outer and/or more outward layers com- prising a substance, e. g. menthol, which increases blood flow through the mucous membrane and thus increases the membrane's uptake capacity. It may also be used for combining essentially incompatible components into a single formulation, e. g. by separating two layers comprising mutually incompatible substances by interspersion of an impermeable third layer.

Delivery systems of the invention, usually in single unit dosage form, are administered to the individual to be treated, preferably a mammal, in particular a human, agricultural or domestic animal. Whether such a treatment is indicated and what form it is to take depends on the individual case and may be subject to medical assessment (diagnosis) which includes the signs, symptoms and/or dysfunctions which are present, the risks of developing certain signs, symptoms and/or dysfunctions, and other factors.

The formulations and dosage forms of the invention are mainly used in pharmacy, for example in the pharmaceutical sector as lipid regulating agents.

In yet another aspect, the present invention relates to an individual dosage form comprising a piece, patch, slice, strip or shred of a film-shaped solid dispersion product as described above, comprising from 20 mg to 150 mg of active fibrate compound.

The dosage forms of the invention are usually packed in a suitable form. The term "packaging" is used herein to denote any structure applied or measure taken to ensure the stability and maintain the characteristics of the dosage form during transport and/or storage, as well as to facilitate transport and/or storage, but which are removed from the dosage form prior to administration. Such structures may be physically attached to or detached from the dosage form proper.

Packaging structures which are physically attached to the dosage form during transport and storage generally take the form of protective foils or lamination sheets which are pulled off before administration. Appropriate structures and materials are generally known to those skilled in the art. Essentially, any conventional protective foil may be used that is chemically compatible with the dosage form. The protective foil may be attached to the dosage form by a number of methods, e. g. by sticking or gluing in on the dosage form after forming, or by coextrusion. The only requirement is that the protective foil may be detached from the dosage form easily and without damaging the latter.

Packaging structures which are physically detached from the dosage form during transport and storage comprise all forms of packaging known to those skilled in the art, in particular blisters and film dispensers. The fibrate compound delivery system as described above may be produced by any known technology for embedding an active substance in a carriers in dispersed, preferably molecularly dispersed form.

The most common technique uses organic solvents where both the active substance(s) and the carrier(s) are soluble. Then the solvent is removed completely from the combined solution of active substance(s) and carrier(s).

For example, the delivery system is prepared by a process comprising the steps of

(a) dissolving and/or dispersing a fibrate compound, at least one pharmaceutically acceptable polymer, at least one pharmaceutically acceptable plasticizer, and optionally further ingredients in an organic solvent;

(b) casting the solution/dispersion obtained in step (b) onto a solid support; and (c) evaporating the organic solvent.

Suitable organic solvents include N-methyl pyrrolidone, acetone, dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, polethyleneglycol, tetrahydrofuran, glycofurol, glycerolformal, methylene chloride or chloroform. This process has a number of disad- vantages. The use of organic solvents may be subject to regulatory restrictions and the recovery of the solvent is laborious. Although being possible, this is not the preferred process according to the present invention.

The delivery system of the invention is preferably prepared by melt-extrusion. The melt- extrusion process comprises the steps:

(a) mixing and heating a fibrate compound, at least one pharmaceutically acceptable polymer, at least one pharmaceutically acceptable plasticizer, and optionally further ingredients to obtain a homogeneous melt; (b) forcing the melt through a die, preferably a slit die, to obtain a shaped extrudate; and

(c) solidifying the extrudate by cooling.

"Melting" means a transition into a liquid or rubbery state in which it is possible for one component to become homogeneously embedded in the other. Typically, one component will melt and the other components will dissolve in the melt, thus forming a solution. Melting usually involves heating above the softening point of the pharmaceutically acceptable polymer. The preparation of the melt can take place in a variety of ways. The mixing of the components can take place before, during or after the formation of the melt. For example, the components can be mixed first and then melted or simultaneously mixed and melted. Usually, the melt is homogenized in order to disperse the active ingredients efficiently. Also, it may be convenient first to melt the pharmaceutically acceptable polymer and then to admix and homogenize the active ingredients.

In principle, there are two possible ways by which solubilization of the active substance can be achieved during melt extrusion. On the one hand, the extrusion process is carried out at a temperature which is the higher than the melting point of the active substance and high enough for plastification of the carrier. In this case the molten active substance can be solubilized in the plastified carrier by means of mixing and kneading which takes place during extrusion (method A). On the other hand, if the solubility of the active substance in the carrier is good, a solubilization in the plastified carrier can take place without the need to melt the active substance, i. e. at a temperature below the melting point of the active ingredient (method B).

Fenofibrate is an active substance with a relatively low melting point (approximately 80 ⁰C) and therefore a melting of the active substance can be expected during extrusion which is carried out normally at temperatures higher than 80 ⁰C according to method A.

Fenofibric acid has a melting point of 184 ⁰C (Arzneimittel-Forschung 26, 885-909

(1976), see page 887), which is much higher than the melting point of fenofibrate.

Therefore solubilization of fenofibric acid in the carrier(s) may take place according to method B. Moreover, method B could be advantageous even for processing fenofibrate in order to prevent any chemical degradation of fenofibrate at temperatures exceeding the melting point of fenofibrate.

Usually, the melt temperature is in the range of 70 to 250 ⁰C, preferably 80 to 180 ⁰C, most preferably 100 to 140 ⁰C.

The melting and/or mixing takes place in an apparatus customary for this purpose. Particularly suitable are extruders or kneaders. Suitable extruders include single screw extruders, intermeshing screw extruders or else multiscrew extruders, preferably twin screw extruders, which can be corotating or counterrotating and, optionally, equipped with kneading disks or other screw elements for mixing or dispersing the melt. It will be appreciated that the working temperatures will also be determined by the kind of extruder or the kind of configuration within the extruder used. Part of the energy needed to melt, mix and dissolve the components in the extruder can be provided by heating elements. However, the friction and shearing of the material in the extruder may also provide a substantial amount of energy to the mixture and aid in the formation of a homogeneous melt of the components.

The extrudate exiting from the extruder ranges from pasty to viscous. Before allowing the extrudate to solidify, the extrudate may be directly shaped into virtually any desired shape. For example, shaping of the extrudate may be carried out by a calender with two counter-rotating smooth rollers. If the rollers do not have depressions on their surface, films can be obtained. Alternatively, the extrudate is subjected to profile extrusion and cut into pieces, either before (hot-cut) or after solidification (cold-cut). Preferably, the melt is forced through a slit die. The flat extrudate emerging from the die may be expanded to yield a film-shaped structure.

Additionally, foams can be formed if the extrudate contains a propellant such as a gas, e.g. carbon dioxide, or a volatile compound, e.g. a low molecular-weight hydrocarbon, or a compound that is thermally decomposable to a gas. The propellant is dissolved in the extrudate under the relatively high pressure conditions within the extruder and, when the extrudate emerges from the extruder die, the pressure is suddenly released. Thus the solvability of the propellant is decreased and/or the propellant vaporises so that a foam is formed.

FIGURES

Figure 1 - Plasma concentrations of fenofibric acid (open symbols) and fenofibrate (full symbols) vs. time after transmucosal administration in dogs.

Figure 2 - Tensile strengths of polymer films comprising fenofibric acid and fenofibrate. Fig. 2a shows the elongation of films of composition A when subjected to increasing parallel and to perpendicular stress, respectively, and fig. 2b shows the elongation of films of composition B when subjected to increasing parallel and to perpendicular stress, respectively,

Protocol of Bioavailability Evaluation

For each delivery system under evaluation, three Beagle dogs (mixed sexes, weighing approximately 10 kg) were anaesthetized and placed in an upright position, with the head level to the floor. A patch comprising approximately 50 mg of the fibrate compound was placed on the floor of each dog's mouth, under the tongue. Circa 15 minutes after the application of the patch, about 500 μl of water were dispensed on the film. About 30 minutes after the application of the patch, the remaining film was re- moved, and the oral cavity was wiped with gauze to remove residual drug; then the anaesthesia was stopped and the dogs were left to recover during the next 10 - 15 minutes. 12 hours after dosing, serial blood samples were obtained from a limb vein of each dog, and plasma concentrations of fenofibric acid were determined by HPLC- MS/MS. Bioavailability was calculated from comparison of the values with the results obtained after intravenous injection of the respective drug (5 mg/mg body weight) in a separate control group of dogs.

EXAMPLES

Example 1 - Melt Extrusion

Table 1

* triethyl citrate

Blends of fibrate compounds, polymer(s) and excipient(s) were produced by dry mixing of the ingredients given in table 1 above. The ingredients were then molten and processed by using a laboratory twin screw extruder. The extrusion temperature was 125 to 135 ⁰C at a torque of 14 to 18 Nm.

The extruder was equipped with a foil die (gap width 50 mm, gap height 1 mm) and a haul-off unit, resulting in films of 400 - 1000 μm thickness, and approximately 10 mm width.

After solidification of the extruded films, single round film patches having a diameter of 18 mm were excised and subjected to bioavailability analysis as described above.

Results are shown in Fig. 1. The values (mean ± standard deviation) of peak values (C_ma_x)_> area under the curve (AUC) and bioavailability are given in Table 2.

Table 2

^max [μg/ml] T max [h] AUC [h - μg/ml] Bioavailability [%]

Fenofibrate 0.26 ± 0.05 2 .3 ± 0 3 0.95 ± 0 15 2.4 ± 0.4

Fenofibric acid 1.70 ± 0.59 1 .5 ± 0 5 5.86 ± 1 80 14.4 ± 4.4

These plasma concentration profiles are consistent with a slow absorption through the mucosa of the oral cavity, with peak concentrations for fenofibric acid being reached approximately 1.5 to 2 hours after administration. This shows considerable prolongation of the effective phase in contrast to fenofibric acid administered orally, where maximum concentrations were found immediately after administration, i. e., plasma levels began to decrease as early as 15 minutes after administration.

Both peak plasma concentrations (C_max) and areas under the curve (AUC) of fenofibric acid derived from the application of free fenofibric acid were markedly higher than those obtained by administration of fenofibrate.

Example 2 - Mechanical Properties of Fibrate-Loaded Polymer Films of the Invention

In order to characterize the mechanical properties and stress-resistance of the polymer films of the invention, the films of Example 1 (compositions A and B) were subjected to determination of force-elongation relation using a TA.XTplus Texture Analyzer (Stable Micro Systems, Godalming, UK) equipped with a 50 kg load cell, TA-96 grips and Texture Exponent 32 Software.

Film samples of 10 mm width and 400 to 600 μm thickness which were free from physical imperfections, as determined by visual inspection, and whose thickness had been determined by means of a micrometer screw, were held between two grips whose separation was set at 10 mm. Thus, the square film sample had the dimensions of 10 mm x 10 mm x measured thickness. Film samples were tested for stress resilience both in the parallel and the perpendicular direction of the melt flow during extrusion. Crosshead speed was set to 500 μm/sec. Tensile strength was calculated as described in Peh, K. K. et al., J. Pharm. Pharmaceut. Sci. 3(3): 303-311 , 2000.

Results are shown in Fig. 2.

As can be seen, the films of Example 1 are generally characterized by both softness and flexibility (elasticity). It will be seen that the mechanical properties of the films show marked anisotropy, with resilience parallel to the direction of the melt flow being higher than perpendicular to the melt flow. Without wishing to be bound by theory, it is assumed that this reflects the dominant orientation of the polymer chains within the film, so that distortion forces parallel to the direction of the melt flow are encountered by inter- and intramolecular effects, whereas perpendicular forces are encountered essentially by intramolecular cohesion alone. These findings will be appreciated for industrial application.

These results demonstrate that it is possible to obtain fibrate-containing films with satisfactory mechanical stability for use as drug delivery systems.

Example 3 - Disintegration testing It is important for a transmucosal delivery system to dissolve over a time period which is neither so short that the ensuing burst of released drug saturates the mucosal uptake capacity, nor so long that it causes discomfort to the recipient.

Therefore the films from Example 1 (compositions A and B; round patches of 18 mm diameter) were subjected to dissolution testing by placing them in 800 ml 0.1 M phosphate buffer, pH 4.5, comprising 0.5% benzalconium chloride at +37 ⁰C and visual inspection of the dissolution process. Dissolution was considered to be complete when the film had essentially disappeared. All measurements were performed in duplicate.

Results are given in Table 3.

Table 3

These results demonstrate that fibrate-containing polymer films can be manufactured to show disintegration behaviour that renders them useful for transmucosal drug delivery.

Claims

Claims

1. A method for the administration of a fibrate compound to a subject in need thereof, comprising bringing a fibrate compound delivery system into contact with a mucous membrane of the subject for a time sufficient to deliver a therapeutically effective amount of the fibrate compound.

2. The method according to claim 1 , wherein the mucous membrane is a membrane of the oral cavity.

3. The method according to claim 1 or 2, wherein the fibrate compound is selected from the group consisting of fenofibric acid, the physiologically acceptable salts and derivatives thereof.

4. The method of claim 3, wherein the fibrate compound is fenofibric acid.

5. The method according to any of claims 1 to 4, wherein the delivery system comprises a solid dispersion product wherein the fibrate compound is distributed ho- mogenously in a polymer matrix.

6. The method according to claim 5, wherein the fibrate compound is present in essentially amorphous form.

7. The method according to claim 5 or 6, wherein the fibrate compound is present in a state of molecular dispersion.

8. The method according to any of claims 5 to 7, wherein the solid dispersion product contains from about 5 to 60 % by weight of the fibrate compound.

9. The method according to any of claims 5 to 8, wherein the delivery system comprises a film-shaped solid dispersion product.

10. The method according to claim 9, wherein the thickness of the film is from 200 μm to 1000 μm.

1 1. The method according to any of claims 5 to 10, wherein the polymer is selected from the group consisting of cellulose derivatives and homo- or copolymers of vi- nylpyrrolidone, and mixtures thereof.

12. The method according to claim 11 , wherein the polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hy- droxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate; copolymers of vinylpyrrolidone and vinyl acetate; and mixtures thereof.

13. The method according to any of claims 5 to 12, wherein the solid dispersion product additionally comprises at least one pharmaceutically acceptable plasticizer.

14. The method according to any of claims 5 to 13, wherein the solid dispersion product additionally comprises at least one pharmaceutically acceptable excipient selected from the group consisting of solubilizers, adhesion enhancers, colorants, disintegrants, flavours and preservatives.

15. The method according to any of claims 9 to 14, wherein the tensile strength of the film in any direction is at least 3.3 N/mm².

16. The method according to claim 14, wherein the tensile strength of the film in any direction is at least 4.3 N/mm².

17. Fibrate compound delivery system for transmucosal delivery of a fibrate compound.

18. The delivery system according to claim 17, wherein the fibrate compound is selected from the group consisting of fenofibric acid, the physiologically acceptable salts and derivatives thereof.

19. The delivery system of claim 18, wherein the fibrate compound is fenofibric acid.

20. The delivery system according to any of claims 17 to 20, wherein the delivery system comprises a solid dispersion product wherein the fibrate compound is distributed homogenously in a polymer matrix.

21. The delivery system according to claim 20, wherein the fibrate compound is present in essentially amorphous form.

22. The delivery system according to claim 20 or 21 , wherein the fibrate compound is present in a state of molecular dispersion.

23. The delivery system according to any of claims 20 to 22, wherein the solid dispersion product contains from 5 to 60 % by weight of the fibrate compound.

24. The delivery system according to any of claims 20 to 23, wherein the delivery system comprises a film-shaped solid dispersion product.

25. The delivery system according to claim 24, wherein the thickness of the film is from 200 μm to 1000 μm.

26. The delivery system according to any of claims 20 to 25, wherein the polymer is selected from the group consisting of cellulose derivatives and homo- or copolymers of vinylpyrrolidone.

27. The delivery system according to claim 26, wherein the polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate; copolymers of vinylpyrrolidone and vinyl acetate; and mixtures thereof.

28. The delivery system according to any of claims 20 to 27, wherein the solid dis- persion product additionally comprises at least one pharmaceutically acceptable plasticizer.

29. The delivery system according to any of claims 20 to 28, wherein the solid dispersion product additionally comprises at least one pharmaceutically acceptable excipient selected from the group consisting of solubilizers, adhesion enhancers, colorants, disintegrants, flavours and preservatives.

30. The delivery system according to any of claims 24 to 29, wherein the tensile strength of the film in any direction is at least 3.3 N/mm².

31. The delivery system according to claim 30, wherein the tensile strength of the polymer film in any direction is at least 4.3 N/mm².

32. The delivery system according to any of claims 24 to 31 , wherein the disintegra- tion time of the film in aqueous solution is 30 minutes or less.

33. The delivery system according to any of claims 24 to 32, wherein the delivery system is present in unit dosage forms and an individual dosage form comprises a piece, patch, slice, strip or shred of the film-shaped solid dispersion product.

34. The delivery system according to claim 33, wherein the individual dosage form comprises from 20 mg to 150 mg of active fibrate.

35. The delivery system according to any of claims 20 to 34, wherein the solid dis- persion product contains

from about 5 to 60 % by weight of at least one fibrate compound, from about 30 to 90 % by weight of at least one pharmaceutically acceptable polymer, from 7 to 30 % by weight of at least one pharmaceutically acceptable plasticizer, and, from 0 to 20 % by weight of optional ingredients.

36. Process for manufacturing a fibrate delivery system according to claim 20, com- prising the steps of

(a) dissolving and/or dispersing a fibrate compound, at least one pharmaceutically acceptable polymer, at least one pharmaceutically acceptable plasticizer, and optionally further ingredients in an organic solvent; (b) casting the solution/dispersion obtained in step (b) onto a solid support; and

(c) evaporating the organic solvent.

37. Process for manufacturing a fibrate delivery system according to claim 20, comprising the steps of

(a) mixing and heating a fibrate compound, at least one pharmaceutically acceptable polymer, at least one pharmaceutically acceptable plasticizer, and optionally further ingredients to obtain a homogeneous melt; (b) forcing the melt through a die, preferably a slit die, to obtain a shaped ex- trudate; and (c) solidifying the extrudate by cooling.