WO2008066295A1 - Composition pharmaceutique contenant un composé à base de naphthoquinone pour système d'administration intestinale - Google Patents

Composition pharmaceutique contenant un composé à base de naphthoquinone pour système d'administration intestinale Download PDF

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Publication number
WO2008066295A1
WO2008066295A1 PCT/KR2007/006008 KR2007006008W WO2008066295A1 WO 2008066295 A1 WO2008066295 A1 WO 2008066295A1 KR 2007006008 W KR2007006008 W KR 2007006008W WO 2008066295 A1 WO2008066295 A1 WO 2008066295A1
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Prior art keywords
composition according
active ingredient
formulation
intestine
formula
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PCT/KR2007/006008
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English (en)
Inventor
In Geun Jo
Sang-Ku Yoo
Myung-Gyu Park
Taehwan Kwak
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Mazence Inc.
Kt & G Co., Ltd.
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Priority claimed from KR1020070102470A external-priority patent/KR20080047968A/ko
Application filed by Mazence Inc., Kt & G Co., Ltd. filed Critical Mazence Inc.
Priority to US12/513,577 priority Critical patent/US20100062065A1/en
Priority to EP07834303A priority patent/EP2094261A4/fr
Priority to JP2009538337A priority patent/JP2010510980A/ja
Publication of WO2008066295A1 publication Critical patent/WO2008066295A1/fr

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    • 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
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to an intestine-targeted pharmaceutical composition comprising a naphthoquinone-based compound. More specifically, the present invention relates to an oral pharmaceutical composition with formulation of an intestinal delivery system of a certain naphthoquinone-based compound or a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof, as an active ingredient.
  • the aforesaid naphthoquinone-based compound is a sparingly-soluble material which is soluble at a low degree of about 2 to 10% only in high-solubility solvents, such as CH 2 Cl 2 , CHCl 3 , CH 2 ClCH 2 Cl, CH 3 CCl 3 , Monoglyme, and Diglyme, but is poorly soluble in other ordinary polar or nonpolar solvents.
  • high-solubility solvents such as CH 2 Cl 2 , CHCl 3 , CH 2 ClCH 2 Cl, CH 3 CCl 3 , Monoglyme, and Diglyme
  • the aforementioned highly-insoluble naphthoquinone-based compound has a disadvantage of a significant limit in formulation of the compound into desired pharmaceutical preparations. Even though physiological activity of the naphthoquinone-based compound is elucidated by the present applicant, a dosage form of the naphthoquinone-based compound is limited to a formulation for in vivo administration via intravenous injection.
  • the drugs containing the naphthoquinone-based compound as an active ingredient do not exert therapeutic effects until they are absorbed into the body in an amount exceeding a certain concentration.
  • a variety of factors are implicated in bioavailability, the degree to which a drug or other substance becomes available to the target tissue after administration. Low bioavailability of the drug or substance raises serious problems in development of drug compositions.
  • the inventors of the present invention have discovered that when a sparingly-soluble naphthoquinone-based compound is formulated into an intestine-targeted pharmaceutical composition, it is possible to minimize inactivation of the active ingredient which may occur due to internal bodily environment such as stomach, it is possible to solve a problem of low bioavailability suffered by conventional oral administration, and finally it is possible to significantly improve pharmacokinetic properties of the naphthoquinone-based compound.
  • the present invention has been completed based on these findings.
  • an oral pharmaceutical composition wherein a naphthoquinone- based compound represented by Formula 1 below, or a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof, as an active ingredient, is prepared into an intestine-targeted formulation:
  • R 1 and R 2 are each independently hydrogen, halogen, hydroxy or C 1 -C 6 lower alkyl or alkoxy;
  • R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, hydroxy, C 1 -C 2O alkyl alkene or alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or two substituents of R 3 to R 8 may be taken together to form a cyclic structure which may be saturated or partially or completely unsaturated;
  • X is selected fi ⁇ m the group consisting of C(RXR'), N(R"), O and S, preferably O, with
  • R, R' and R" being each independently hydrogen or CpC 6 lower alkyl
  • n is 0 or 1, with proviso that when n is 0, carbon atoms adjacent to n form a cyclic structure via a direct bond.
  • the term "pharmaceutically acceptable salt” means a formulation of a compound (hat does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the pharmaceutical salt may include acid addition salts of the compound (T) with acids capable of forming a non-toxic acid addition salt containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid; organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and salicylic acid; or sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic
  • examples of pharmaceutically acceptable carboxylic acid salts include salts with alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium and magnesium, salts with amino acids such as arginine, lysine and guanidine, salts with organic bases such as dicyclohexylamine, N-methyl-D- glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine.
  • the compound in accordance with the present invention may be converted into salts thereof, by conventional methods well-known in the art.
  • prodrug means an agent that is converted into the parent drug in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration, whereas the parent may be not.
  • the prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example of a prodrug without limitation, would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transport across a cell membrane where water-solubility is detrimental to mobility, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial.
  • prodrug might be a short peptide (polyamino acid) bonded to an acidic group, where the peptide is metabolized to reveal the active moiety.
  • the pharmaceutical compounds in accordance with the present invention can include a prodrug represented by Formula Ia below as an active material:
  • R 1 , R 2 , R3, R 4 , R 5 , R 6 , R7, R 8 , X and n are as defined in Formula 1.
  • R 9 and R 10 are each independently -SO 3 -Na + or substituent represented by Formula 2 below or a salt thereof,
  • R 11 and Ri 2 are each independently hydrogen or substituted or unsubstituted Ci-C 20 linear alkyl or Ci-C 20 branched alkyl
  • R 13 is selected from the group consisting of substituents i) to viii) below: i) hydrogen;
  • Ci-C 20 linear alkyl or C 1 -C 20 branched alkyl substituted or unsubstituted Ci-C 20 linear alkyl or C 1 -C 20 branched alkyl
  • R, R' and R" are each independently hydrogen or substituted or unsubstituted Ci-C 20 linear alkyl or Cj-C 20 branched alkyl, R] 4 is selected from the group consisting of hydrogen, substituted or unsubstituted amine, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 1 is selected from the 1-5;
  • k is selected from the 0-20, with proviso that when k is 0, Ru and Ri 2 are not anything, and Rn is directly bond to a carbonyl group.
  • solvate means a compound of the present invention or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of a solvent bound thereto by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans. Where the solvent is water, the solvate refers to a hydrate.
  • the term "isomer” means a compound of the present invention or a salt thereof, that has the same chemical formula or molecular formula but is optically or sterically different therefrom.
  • D type optical isomer and L type optical isomer can be present in the Formula 1 , depending on the R 3 -R 8 types of substituents selected.
  • naphthoquinone-based compound is intended to encompass a compound per se, and a pharmaceutically acceptable salt, prodrug, solvate and isomer thereof.
  • alkyl refers to an aliphatic hydrocarbon group.
  • the alkyl moiety may be a "saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties.
  • the alkyl moiety may also be an "unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety.
  • alkene moiety refers to a group in which at least two carbon atoms form at least one carbon-carbon double bond
  • an "alkyne” moiety refers to a group in which at least two carbon atoms form at least one carbon-carbon triple bond.
  • the alkyl moiety regardless of whether it is substituted or unsubstituted, may be branched, linear or cyclic.
  • heterocycloalkyl means a carbocyclic group in which one or more ring carbon atoms are substituted with oxygen, nitrogen or sulfur and which includes, for example, but is not limited to furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine and triazine.
  • aryl refers to an aromatic substituent group which has at least one ring having a conjugated pi ( ⁇ ) electron system and includes both carbocyclic aryl (for example, phenyl) and heterocyclic aryl (for example, pyridine) groups. This term includes monocyclic or fused-ring polycyclic (Le., rings which share adjacent pairs of carbon atoms) groups.
  • heteroaryl refers to an aromatic group that contains at least one heterocyclic ring.
  • aryl or heteroaryl examples include, but are not limited to, phenyl, furan, pyran, pyridyl, pyrimidyl and triazyl.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 in Formula 1 in accordance with the present invention may be optionally substituted.
  • the substituent group(s) is(are) one or more group(s) individually and independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O- carbamyl, N carbamyl, 0-thiocarbamyl, N-tbiocarbamyl, C-amido, N-amido, S-sulfonamido, N- sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfony
  • Compounds of Formula 3 are compounds wherein n is 0 and adjacent carbon atoms form a cyclic structure (furan ring) via a direct bond therebetween and are often referred to as “furan compounds” or “furano-o-naphthoquinone derivatives” hereinafter.
  • Compounds of Formula 4 are compounds wherein n is 1 and are often referred to as
  • each OfR 1 and R 2 is particularly preferably hydrogen.
  • furan compounds of Formula 3 particularly preferred are compounds of Formula 3a wherein R 1 , R 2 and R 4 are hydrogen, or compounds of Formula 3b wherein R 1 , R 2 and R 6 are hydrogen.
  • pyran compounds of Formula 4 particularly preferred is a compound of Formula 4a wherein R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are hydrogen.
  • composition means a mixture of a compound of Formula 1 as an active material and other components which are required for an intestine-targeted formulation. Preparation of active materials
  • compounds of Formula 1 which are active materials, as will be illustrated hereinafter, can be prepared by conventional methods known in the art and/or various processes which are based upon the general technologies and practices in the organic chemistry synthesis field.
  • the preparation processes described below are only exemplary ones and other processes can also be employed. As such, the scope of the instant invention is not limited to the following processes.
  • Tricyclic naphthoquinone (pyrano-o-naphthoquinone and furano-o-naphthoquinone) derivatives having a relatively simple chemical structure are generally synthesized in a relatively high yield via cyclization using sulfuric acid as a catalyst, Based on this process, a variety of compounds of Formula 1 can be synthesized.
  • C-alkylated derivatives thus obtained may be subjected to cyclization using sulfuric acid as a catalyst, thereby being capable of synthesizing pyrano-o-naphthoquinone or furano-o-naphthoquinone derivatives among compounds of Formula
  • Preparation method 2 Diels-Alder reaction using 3-methylene-l ,2,4-r3H]naphthalenetrione
  • a variety of pyrano-o-naphthoquinone derivatives can be relatively easily synthesized by subjecting 3- me%lene-l,2,4-[3H]r ⁇ phthalenetrione, produced upon heating 2-hydroxy-l,4-naphthoquinone and formaldehyde together, to Diels-Alder reaction with various olefin compounds.
  • This method is advantageous in that various forms of pyrano-o-naphtho-quinone derivatives can be synthesized in a relatively simplified manner, as compared to induction of cyclization using sulfuric acid as a catalyst.
  • 2-hydroxy-l,4-naphthoquinone which is then subjected to cyclization under suitable acidic catalyst conditions to synthesize various pyrano-o-naphthoquinone or furano-o-naphthoquinone derivatives.
  • an oral pharmaceutical composition passes through the stomach upon oral administration, is largely absorbed by the small intestine and then diffused into all the tissues of the body, thereby exerting therapeutic effects on the target tissues.
  • the oral pharmaceutical composition according to the present invention enhances bioabso ⁇ tion and bioavailability of a certain naphthoquinone-based compound active ingredient via intestine-targeted formulation of the active ingredient. More specifically, when the active ingredient in the pharmaceutical composition according to the present invention is primarily absorbed in the stomach, and upper parts of the small intestine, the active ingredient absorbed into the body directly undergoes liver metabolism which is then accompanied by substantial degradation of the active ingredient, so it is impossible to exert a desired level of therapeutic effects. On the other hand, it is expected that when the active ingredient is largely absorbed around and downstream of the lower small intestine, the absorbed active ingredient migrates via lymph vessels to the target tissues to thereby exert high therapeutic effects.
  • the pharmaceutical composition according to the present invention targets up to the colon which is a final destination of the digestion process, it is possible to increase the in vivo retention time of the drug and it is also possible to minimize decomposition of the drug which may take place due to the body metabolism upon administration of the drug into the body.
  • the oral pharmaceutical composition it is possible to improve pharmacokinetic properties of the drug, to significantly lower a critical effective dose of the active ingredient necessary for the treatment of the disease, and to obtain desired therapeutic effects even with administration of a trace amount of the active ingredient Further, in the oral pharmaceutical composition, it is also possible to minimize the absorption variation of the drug by reducing the between- and within-individual variation of the bioavailability which may result from intragastric pH changes and dietary uptake patterns.
  • the intestine-targeted formulation according to the present invention is configured such that the active ingredient is largely absorbed in the small and large intestines, more preferably in the jejunum, and the ileum and colon corresponding to the lower small intestine, particularly preferably in the ileum or colon.
  • the intestine-targeted formulation may be designed by taking advantage of numerous physiological parameters of the digestive tract, through a variety of methods.
  • the intestine-targeted formulation may be prepared by (1) a formulation method based on a pH-sensitive polymer, (2) a formulation method based on a biodegradable polymer which is decomposable by an intestine-specific bacterial enzyme, (3) a formulation method based on a biodegradable matrix which is decomposable by an intestine- specific bacterial enzyme, or (4) a formulation method which allows release of a drug after a given lag time, and any combination thereof.
  • the intestine-targeted formulation (1) using the pH-sensitive polymer is a drug delivery system which is based on pH changes of the digestive tract.
  • the pH of the stomach is in a range of 1 to 3, whereas the pH of the small and large intestines has a value of 7 or higher, as compared to that of the stomach.
  • the pH-sensitive polymer may be used in order to ensure that the pharmaceutical composition reaches the lower intestinal parts without being affected by pH fluctuations of the digestive tract.
  • pH-sensitive polymer may include, but are not limited to, at least one selected from the group consisting of methacrylic acid- ethyl acrylate copolymer (Eudragit: Registered Trademark of Rohm Pharma GmbH), hydr ⁇ xypropylmethyl cellulose phthalate (HPMCP) and a mixture thereof.
  • methacrylic acid- ethyl acrylate copolymer Eudragit: Registered Trademark of Rohm Pharma GmbH
  • HPP hydr ⁇ xypropylmethyl cellulose phthalate
  • the pH-sensitive polymer may be added by a coating process.
  • addition of the polymer may be carried out by mixing the polymer in a solvent to form an aqueous coating suspension, spraying the resulting coating suspension to form a film coating, and drying the film coating.
  • the intestine-targeted formulation (2) using the biodegradable polymer which is decomposable by the intestine-specific bacterial enzyme is based on the utilization of a degradative ability of a specific enzyme that can be produced by enteric bacteria Examples of the specific enzyme may include azoreductase, bacterial hydrolase glycosidase, esterase, polysaccharidase, and the like.
  • the biodegradable polymer may be a polymer containing an azoaromatic linkage, for example, a copolymer of styrene and hydroxyethylmethacrylate (HEMA).
  • HEMA hydroxyethylmethacrylate
  • the active ingredient may be liberated into the intestine by reduction of an azo group of the polymer via the action of the azoreductase which is specifically secreted by enteric bacteria, for example, Bacteroides fragilis and Eubacterium limosum.
  • the biodegradable polymer may be a naturally-occurring polysaccharide or a substituted derivative thereof.
  • the biodegradable polymer may be at least one selected from the group consisting of dextran ester, pectin, amylase, ethyl cellulose and a pharmaceutically acceptable salt thereof.
  • the active ingredient may be liberated into the intestine by hydrolysis of the polymer via the action of each enzyme which is specifically secreted by enteric bacteria, for example, Bifidobacteria and Bacteroides spp.
  • the intestine-targeted formulation (3) using the biodegradable matrix which is decomposable by an intestine-specific bacterial enzyme may be a form in which the biodegradable polymers are cross-linked to each other and are added to the active ingredient or the active ingr ⁇ ent-containing formulation.
  • the biodegradable polymer may include naturally- occurring polymers such as chondroitin sulfate, guar gum, chitosan, pectin, and the like.
  • the degree of drug release may vary depending upon the degree of cross-linking of the matrix-constituting polymer.
  • the biodegradable matrix may be a synthetic hydrogel based on N-substituted acrylamide.
  • a hydrogel synthesized by cross-linking of N-tert-butylacryl amide with acrylic acid or copolymerization of 2- hydroxyethyl methacrylate and 4-methacryloyloxyazobenzene as the matrix.
  • the cross-linking may be, for example an azo linkage as mentioned above, and the formulation may be a form where the density of cross-linking is maintained to provide the optimal conditions for intestinal drug delivery and the linkage is degraded to interact with the intestinal mucous membrane when the drug is delivered to the intestine.
  • the intestine-targeted formulation (4) with time-course release of the drug after a lag time is a drug delivery system utilizing a mechanism that is allowed to release the active ingredient after a pi ⁇ etermined time irrespective of pH changes.
  • the formulation should be resistant to the gastric pH environment, and should be in a silent phase for 5 to 6 hours corresponding to a time period taken for delivery of the drug from the body to the intestine, prior to release of the active ingredient into the intestine.
  • the time-specific delayed-release formulation may be prepared by addition of the hydrogel prepared from ⁇ polymerization of polyethylene oxide with polyurethane.
  • the delayed-release formulation may have a configuration in which the formulation absorbs water and then swells while it stays within the stomach and the upper digestive tract of the small intestine, upon addition of a hydrogel having the above-mentioned composition after applying the drug to an insoluble polymer, and then migrates to the lower part of the small intestine which is the lower digestive tract and liberates the drug, and the lag time of drug is determined depending upon a length of the hydrogel.
  • ethyl cellulose may be used in the delayed- release dosage formulation.
  • EC is an insoluble polymer, and may serve as a factor to delay a drug release time, in response to swelling of a swelling medium due to water penetration or changes in the internal pressure of the intestines due to a peristaltic motion.
  • the lag time may be controlled by the thickness of EC.
  • hydroxypropylmethyl cellulose (HPMC) may also be used as a retarding agent that allows drug release after a given period of time by thickness control of Ihe polymer, and may have a lag time of 5 to 10 hours.
  • the active ingredient may have a crystalline structure with a high degree of crystallinity, or a crystalline structure with a low degree of crystallinity.
  • the term "degree of crystallinity" is defined as the weight fraction of the crystalline portion of the total compound and may be determined by a conventional method known in the art. For example, measurement of the degree of crystallinity may be carried out by a density method or precipitation method which calculates the crystallinity degree by previous assumption of a preset value obtained by addition and/or reduction of appropriate values to/from each density of the crystalline portion and the amorphous portion, a method involving measurement of the heat of fusion, an X-ray method in which the ciystallinity degree is calculated by separation of the crystalline diffraction fraction and the noncrystalline diffraction fraction from X-ray diffraction intensity distribution upon X-ray diffraction analysis, or an infrared method which calculates the crystallinity degree from a peak of the width between crystalline bands of the infrared absorption spectrum.
  • the crystallinity degree of the active ingredient is preferably 50% or less. More preferably, the active ingredient may have an amorphous structure from which the intrinsic crystallinity of the material was completely lost
  • the amorphous naphthoquinone compound exhibits a relatively high solubility, as compared to the crystalline naphthoquinone compound, and can significantly improve a dissolution rate and in vivo absorption rate of the drug.
  • the amorphous structure may be formed during preparation of the active ingredient into microparticles or fine particles (micronization of the active ingredient).
  • the microparticles may be prepared, for example by spray drying of active ingredients, melting methods involving formation of melts of active ingredients with polymers, co- precipitation involving formation of co-precipitates of active ingredients with polymers after dissolution of active ingredients in solvents, inclusion body formation, solvent volatilization, and the like. Preferred is spray drying.
  • the spray drying is a method of making fine particles by dissolving the active ingredient in a certain solvent and the spray-drying the resulting solution. During the spray-drying process, a high percent of the crystallinity of the naphthoquinone compound is lost to thereby result in an amorphous state, and therefore the spray-dried product in the form of a fine powder is obtained.
  • the mechanical milling is a method of grinding the active ingredient into fine particles by applying strong physical force to active ingredient particles.
  • the mechanical milling may be carried out by using a variety of milling processes such as jet milling, ball milling, vibration milling, hammer milling, and the like. Particularly preferred is jet milling which can be carried out using an air pressure, at a temperature of less than 40 °C .
  • the particle diameter of the active ingredient may be in a range of 5 ran to 500 ⁇ m. In this range, the particle agglomeration or aggregation can be maximally inhibited, and the dissolution rate and solubility can be maximized due to a high specific surface area of the particles.
  • a surfactant may be additionally added to prevent the particle agglomeration or aggregation which may occur during formation of the fine particles, and/or an antistatic agent may be additionally added to prevent the occurrence of static electricity.
  • a moisture-absorbent material may be further added during the milling process.
  • the naphthoquinone-based compound of Formula 1 has a tendency to be crystallized by water, so incorporation of the moisture-absorbent material inhibits recrystallization of the naphthoquinone-based compound over time and enables maintenance of increased solubility of compound particles due to micronization. Further, the moisture-absorbent material serves to suppress coagulation and aggregation of the pharmaceutical composition while not adversely affecting therapeutic effects of the active ingredient.
  • the surfactant may include, but are not limited to, anionc surfactants such as docusate sodium and sodium lauryl sulfate; cationic surfactants such as benzalkonium chloride, benzethonium chloride and cetrimide; nonionic surfactants such as glyceryl monooleate, polyoxyethylene sorbitan fatty acid ester, and sorbitan ester; amph philic polymers such as polyethylene-polypropylene polymer and polyoxye ⁇ iylene-polyoxypropylene polymer (Poloxamer), and GelucireTM series (Gattefosse Corporation, USA); propylene glycol monocaprylate, oleoyl macrogol-6-glyceride, linoleoyl macrogol-6-glyceride, caprylocaproyl macrogol-8-glyceride, propylene glycol monolaurate, and polyglyceryl-6-dioleate. These materials may be used alone or in
  • moisture-absorbent material may include, but are not limited to, colloidal silica, light anhydrous silicic acid, heavy anhydrous silicic acid, sodium chloride, calcium silicate, potassium aluminosilicate, calcium aluminosilicate, and the like. These materials may be used alone or in any combination thereof.
  • moisture absorbents may also be used as the antistatic agent
  • the surfactant, antistatic agent, and moisture absorbent are added in a certain amount that is capable of achieving the above-mentioned effects, and such an amount may be appropriately adjusted depending upon micronization conditions.
  • the additives may be used in a range of 0.05 to 20% by weight, based on the total weight of the active ingredient.
  • water-soluble polymers, solubilizers and disintegration-promoting agents may be further added.
  • formulation of the composition into a desired dosage form may be made by mixing the additives and the particulate active ingredient in a solvent and spray-drying the mixture.
  • the water-soluble polymer is of help to prevent aggregation of the particulate active ingredients, by rendering surroundings of naphthoquinone-based compound molecules or particles hydrophilic to consequently enhance water solubility, and preferably to maintain the amorphous state of the active ingredient naphthoquinone-based compound.
  • the water-soluble polymer is a pH-independent polymer, and can bring about crystallinity loss and enhanced hydrophilicity of the active ingredient, even under the between- and within-individual variation of the gastrointestinal pH.
  • Preferred examples of the water-soluble polymers may include at least one selected from the group consisting of cellulose derivatives such as methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, ethyl cellulose, hydroxyethylmethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, sodium carboxymethyl cellulose, and carboxymethylethyl cellulose; polyvinyl alcohols; polyvinyl acetate, polyvinyl acetate phthalate, polyvinylpyrrolidone (PVP), and polymers containing the same; polyalkene oxide or polyalkene glycol, and polymers containing the same. Preferred is hydroxypropylmethyl cellulose.
  • an excessive content of the water-soluble polymer which is higher than a given level provides no further increased solubility, but disadvantageously brings about various problems such as overall increases in the hardness of the formulation, and non-penetration of an eluent into the formulation, by formation of films around the formulation due to excessive swelling of water-soluble polymers upon exposure to the eluent.
  • the solubilizer is preferably added to maximize the solubility of the formulation by modifying physical properties of the naphthoquinone-based compound.
  • the solubilizer serves to enhance solubilization and wettability of the sparingly-soluble naphthoquinone-based compound, and can significantly reduce the bioavailability variation of the naphthoquinone-based compound originating from diets and the time difference of drug administration after dietary uptake.
  • the solubilizer may be selected from conventionally widely used surfactants or amphiphiles, and specific examples of the solubilizer may refer to the surfactants as defined above.
  • the disintegration-promoting agent serves to improve the drug release rate, and enables rapid release of the drug at the target site to thereby increase bioavailability of the drug.
  • Preferred examples of the disintegration-promoting agent may include, but are not limited to, at least one selected from the group consisting of Croscarmellose sodium, Crospovidone, calcium carboxymethylcellulose, starch glycolate sodium and lower substituted hydroxypropyl cellulose. Preferred is Croscarmellose sodium. Upon taking into consideration various factors as described above, it is preferred to add 10 to 1000 parts by weight of the water-soluble polymer, 1 to 30 parts by weight of the disintegration- promoting agent and 0.1 to 20 parts by weight of the solubilizer, based on 100 parts by weight of the active ingredient.
  • the solvent for spray drying is a material exhibiting a high solubility without modification of physical properties thereof and easy volatility during the spray drying process.
  • Preferred examples of such a solvent may include, but are not limited to, dichloromethane, chloroform, methanol, and ethanol. These materials may be used alone or in any combination thereof.
  • a content of solids in the spray solution is in a range of 5 to 50% by weight, based on the total weight of the spray solution.
  • the above-mentioned intestine-targeted formulation process may be preferably carried out for formulation particles prepared as above.
  • the oral pharmaceutical composition according to the present invention may be formulated by a process comprising the following steps:
  • the surfactant, moisture-absorbent material, water-soluble polymer, solubilizer and disintegration-promoting agent are as defined above.
  • the plasticizer is an additive added to prevent hardening of the coating, and may include, for example polymers such as polyethylene glycol.
  • formulation of the active ingredient may be carried out by sequential or concurrent spraying of vehicles of Step (b) and intestine-targeted coating materials of Step (c) onto jet-milled active ingredient particles of Step (a) as a seed.
  • the oral pharmaceutical composition suitable for use in the present invention contains the active ingredient in an amount effective to achieve its intended purpose, that is therapeutic purpose. More specifically, a therapeutically effective amount refers to an amount of the compound effective to prevent, alleviate or ameliorate symptoms of disease. Determination of the therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the oral pharmaceutical composition according to the present invention is particularly effective for the treatment and/or prevention of metabolic diseases, degenerative diseases, and mitochondrial dysfunction-related diseases.
  • the metabolic diseases may include, but are not limited to, obesity, obesity complications, liver diseases, arteriosclerosis, cerebral apoplexy, myocardial infarction, cardiovascular diseases, ischemic diseases, diabetes, diabetes- related complications and inflammatory diseases.
  • Complications caused from obesity include, for example hypertension, myocardiac infarction, varicosis, pulmonary embolism, coronary artery diseases, cerebral hemorrhage, senile dementia, Parkinson's disease, type 2 diabetes, hyperlipidemia, cerebral apoplexy, various cancers
  • heart diseases such as uterine cancer, breast cancer, prostate cancer, colon cancer and the like
  • heart diseases gall bladder diseases, sleep apnea syndrome, arthritis, infertility, venous ulcer, sudden death, fatty liver, hypertrophic cardiomyopathy (HCM), thromboembolism, esophagitis, abdominal wall hernia (Ventral Hernia), urinary incontinence, cardiovascular diseases, endocrine diseases and the like.
  • HCM hypertrophic cardiomyopathy
  • thromboembolism esophagitis
  • abdominal wall hernia Vastral Hernia
  • urinary incontinence such as uterine cancer, breast cancer, prostate cancer, colon cancer and the like.
  • Diabetic complications include, for example hyperlipidemia, hypertension, retinopathy, renal insufficiency, and the like.
  • Examples of the degenerative diseases may include Alzheimer's disease, Parkinson's disease and Huntington's disease.
  • Diseases arising from mitochondrial dysfunction may include for example, multiple sclerosis, encephalomyelitis, cerebral radiculitis, peripheral neuropathy, Reye's syndrome, Friedrich's ataxia, Alpers syndrome, MELAS, migraine, psychosis, depression, seizure and dementia, paralytic episode, optic atrophy, optic neuropathy, retinitis pigmentosa, cataract, hyperaldosteronemia, hyrwparathyroidism, myopathy, amyotrophy, myoglobinuria, muscular hypotonia, myalgia, reduced exercise tolerance, renal tubulopathy, renal failure, hepatic failure, hepatic dysfunction, hepatomegaly, sideroblastic anemia (iron-deficiency anemia), neutropenia, thrombocytopenia, diarrhea, villous atrophy, multiple vomiting, dysphagia, constipation, sensorineural hearing loss (SNHL), mental retardation, epilepsy, and the like.
  • multiple sclerosis encephalomyelitis,
  • treatment 5 refers to stopping or delaying of the disease progress, when the drug is used in the subject exhibiting symptoms of disease onset.
  • prevention refers to stopping or delaying of symptoms of disease onset, when the drug is used in the subject exhibiting no symptoms of disease onset but having high risk of disease onset.
  • FIG. 1 is a graph showing a residual amount of a naphthoquinone-based compound in the jejunum, ileum and large intestine, respectively, when single-pass intestinal perfusion was carried out according to Experimental Example 4;
  • FIG. 2 is a graph showing outlet steady-state concentrations of a naphthoquinone-based compound under perfusion in Experimental Example 4.
  • Octanol and phosphate buffer (pH 7.4) were saturated with a counter-solvent for 24 hours or more.
  • a given amount of a naphthoquinone-based compound (Compound 1 of Table 1 below) was dissolved in the thus-saturated octanol, mixed with triple-distilled water and stirred using a magnetic stirrer at 200 rpm for 13 hours or more.
  • Samples were taken, filtered through a 0.45 ⁇ m RC Membrane filter and diluted with methanol. The diluted sample materials were analyzed by HPLC. A partition coefficient versus an amount of Compound 1 was determined. The results thus obtained are given in Table 2.
  • the partition coefficient was a value of 2.299, thus representing that Compound 1 is relatively fat-soluble. This result means that Compound 1 has octanol-solubility 100-fold higher than water-solubility, and sufficiently passes through a hydrophobic layer inside the cell membrane, followed by intracellular absorption.
  • Example 1 Micronization of active ingredient using Jet mill
  • Micronizing of an active ingredient was carried out using a Jet mill (SJ-IOO, Nisshin, Japan). Operation was run at a supply pressure of 0.65 Mpa, and a feed rate of 50 to 100 g/hr.
  • the synthesized naphthoquinone-based compound (Compound 1 of Table 1) or the naphthoquinone-based compound of Example 1 (including micronized and non-micronized particles) was added to methylene chloride, and a salt such as sodium chloride, a saccharide such as white sugar or lactose, or a vehicle such as microcrystalline cellulose, monobasic calcium phosphate, starch or mannitoL, a lubricant such as magnesium stearate, talc or glyceryl behenate, and a solubilizer such as Poloxamer were added to a given amount of ethanol, followed by homogeneous dispersion to prepare a spray-drying solution which will be used for subsequent spray-drying.
  • a salt such as sodium chloride
  • a saccharide such as white sugar or lactose
  • a vehicle such as microcrystalline cellulose, monobasic calcium phosphate, starch or mannitoL
  • a lubricant such
  • Example 2 To the spray-dried product of Example 2 were added approximately an equal amount of a water-soluble polymer (hydroxypropylmethyl cellulose) relative to an active ingredient, and vehicles such as Croscarmellose sodium and light anhydrous silicic acid, and the mixture was formulated without causing interference of disintegration. A drug dissolution test was carried out in a buffer (pH 6.8). All the compositions exhibited drug dissolution of 90% or higher after 6 hours.
  • a water-soluble polymer hydroxypropylmethyl cellulose
  • vehicles such as Croscarmellose sodium and light anhydrous silicic acid
  • the steady-state intestinal effective permeability (P eff ) can be expressed according to the following equation.
  • the radius (r) and length (L) of the jejunum, ileum and large intestine used in experiments are as follows: (r: jejunum, 0.21 cm; ileum, 0.22 cm; large intestine, 0.23 cm, and L: 10 cm)
  • the steady-state was confirmed by the ratio of the outlet to inlet concentrations (Cout/Qn) versus time.
  • the outlet steady-state concentration of the compound under perfusion was calculated.
  • the results thus obtained are given in Table 4 and FIG. 2, respectively.
  • the effective permeability was measured at 4 points of each intestinal tissue. As shown in Table 4 and FIG. 2, it can be seen that the highest permeability was observed in the large intestine.
  • the spray-dried formulation prepared in Experimental Example 2 was added to an ethanol solution containing about 20% by weight of Eudragit S-IOO as a pH-sensitive polymer and about 2% by weight of PEG #6,000 as a plasticizer, and the mixture was then spray-dried to prepare an intestine-targeted formulation.
  • the intestine-targeted formulation prepared in Example 3 was exposed to pH 1.2 and pH 6.8, respectively. After 6 hours, the intestine-targeted formulation was removed and washed, and a content of an active ingredient was analyzed by HPLC. An effective amount of the active ingredient was assessed as a measure of the acid resistance. The acid resistance exhibited a very excellent result of 90 to 100%, thus suggesting that the intestine-targeted formulation is chemically stable in the stomach or small intestine.
  • mice 10-week-old ob/ob male mice (Jackson Lab) as an obese mouse model of type 2 diabetes were purchased from Orient Co. (Kyungki-do, Korea) and were allowed to acclimate to a new environment of the breeding room for 10 days prior to experiments. Animals were fed a solid feed
  • mice (P5053, Labdiet) as a laboratory animal feed.
  • the ob/ob male mice were housed and allowed to acclimate to a new environment for 10 days, in a breeding room maintained at a temperature of 22 ⁇ 2 ° C, humidity of 55 ⁇ 5%, and a 12-h light/dark (UD) cycle (light fiOin 8:00 am. to 8:00 p.m.).
  • UD 12-h light/dark
  • the thus-acclimated animals were randomly divided into four groups, each consisting of 7 animals: a control group with administration of sodium lauryl sulfate (10 mg/kg), a group with administration of simply finely-divided powder of a naphthoquinone-based compound (200 mg/kg), a group with administration of a jet-milled naphthoquinone-based compound, and a group with administration of an intestine-targeted formulation of a ground naphthoquinone-based compound.
  • Each group of animals was given perorally (PO) 200 mg/kg of samples. Animals were fed solid feed pellets and water ad libitum.
  • an oral pharmaceutical composition according to the present invention increases a bioabsorption rate and an in vivo retention time of an active ingredient to thereby improve pharmacokinetic properties of the drug.

Abstract

Composition pharmaceutique orale possédant une biodisponibilité améliorée et des propriétés pharmacocinétiques d'un médicament. Celle-ci est obtenue par augmentation du taux de bioabsorption et d'un temps de rétention in vivo d'un ingrédient actif au moyen d'une préparation ciblant les intestins et contenant un composé spécifique à base de naphthoquinone ou un sel pharmacocompatible, un promédicament, un solvate ou un isomère de ce composé, en tant qu'ingrédient actif.
PCT/KR2007/006008 2006-11-27 2007-11-26 Composition pharmaceutique contenant un composé à base de naphthoquinone pour système d'administration intestinale WO2008066295A1 (fr)

Priority Applications (3)

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US12/513,577 US20100062065A1 (en) 2006-11-27 2007-11-26 Pharmaceutical composition containing naphthoquinone-based compound for intestine delivery system
EP07834303A EP2094261A4 (fr) 2006-11-27 2007-11-26 Composition pharmaceutique contenant un composé à base de naphthoquinone pour système d'administration intestinale
JP2009538337A JP2010510980A (ja) 2006-11-27 2007-11-26 腸送達系のためのナフトキノンベース化合物を含有する医薬組成物

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KR20060117685 2006-11-27
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KR1020070102470A KR20080047968A (ko) 2006-11-27 2007-10-11 나프토퀴논계 화합물 함유 장 표적용 약제 조성물

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
JP2010510980A (ja) * 2006-11-27 2010-04-08 マゼンス インコーポレイテッド 腸送達系のためのナフトキノンベース化合物を含有する医薬組成物
EP2217225A2 (fr) * 2007-10-11 2010-08-18 Mazence Inc. Composition pharmaceutique contenant des particules micronisées d'un composé à base de naphtoquinone
EP2231148A2 (fr) * 2007-12-31 2010-09-29 Mazence Inc. Composition pharmaceutique utilisée dans le traitement et la prévention d'une maladie cardiaque
EP2520294A2 (fr) * 2009-12-28 2012-11-07 Mazence Inc. Composition comprenant un composé de naphtoquinone pour traiter et prévenir la perte d'audition

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US6541046B2 (en) * 2001-02-12 2003-04-01 Kaiyuan Wei Herbal composition and method for controlling body weight and composition
WO2005063232A1 (fr) * 2003-12-30 2005-07-14 Md Bioalpha Co., Ltd. Traitement de l'obesite et du syndrome metabolique avec des derives de tanshinone augmentant l'activite metabolique
WO2006088315A1 (fr) * 2005-02-16 2006-08-24 Md Bioalpha Co., Ltd. Composition pharmaceutique pour le traitement ou la prevention de pathologies comprenant l'obesite, le diabete, les syndromes metaboliques, les maladies neurodegeneratives, et les maladies liees a une dysfonction mitochondriale

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US6541046B2 (en) * 2001-02-12 2003-04-01 Kaiyuan Wei Herbal composition and method for controlling body weight and composition
WO2005063232A1 (fr) * 2003-12-30 2005-07-14 Md Bioalpha Co., Ltd. Traitement de l'obesite et du syndrome metabolique avec des derives de tanshinone augmentant l'activite metabolique
WO2006088315A1 (fr) * 2005-02-16 2006-08-24 Md Bioalpha Co., Ltd. Composition pharmaceutique pour le traitement ou la prevention de pathologies comprenant l'obesite, le diabete, les syndromes metaboliques, les maladies neurodegeneratives, et les maladies liees a une dysfonction mitochondriale

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010510980A (ja) * 2006-11-27 2010-04-08 マゼンス インコーポレイテッド 腸送達系のためのナフトキノンベース化合物を含有する医薬組成物
EP2217225A2 (fr) * 2007-10-11 2010-08-18 Mazence Inc. Composition pharmaceutique contenant des particules micronisées d'un composé à base de naphtoquinone
EP2217225A4 (fr) * 2007-10-11 2012-12-19 Mazence Inc Composition pharmaceutique contenant des particules micronisées d'un composé à base de naphtoquinone
EP2231148A2 (fr) * 2007-12-31 2010-09-29 Mazence Inc. Composition pharmaceutique utilisée dans le traitement et la prévention d'une maladie cardiaque
EP2231148A4 (fr) * 2007-12-31 2011-04-27 Mazence Inc Composition pharmaceutique utilisée dans le traitement et la prévention d'une maladie cardiaque
EP2520294A2 (fr) * 2009-12-28 2012-11-07 Mazence Inc. Composition comprenant un composé de naphtoquinone pour traiter et prévenir la perte d'audition
JP2013515765A (ja) * 2009-12-28 2013-05-09 ケイティー アンド ジー ライフ サイエンシズ コーポレイション ナフトキノン系化合物を含む難聴の治療又は予防のための組成物
EP2520294A4 (fr) * 2009-12-28 2013-09-11 Mazence Inc Composition comprenant un composé de naphtoquinone pour traiter et prévenir la perte d'audition
KR101495223B1 (ko) * 2009-12-28 2015-02-26 주식회사 케이티앤지생명과학 나프토퀴논계 화합물을 포함하는 난청의 치료 또는 예방을 위한 조성물

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