WO2008066301A1

WO2008066301A1 - Anticancer composition containing naphthoquinone-based compound for intestine delivery system

Info

Publication number: WO2008066301A1
Application number: PCT/KR2007/006015
Authority: WO
Inventors: Taehwan Kwak; In Geun Jo; Joo Seog Yoon; Sang-Ku Yoo; Myung-Gyu Park
Original assignee: Mazence Inc.; Kt & G Co., Ltd.
Priority date: 2006-11-27
Filing date: 2007-11-26
Publication date: 2008-06-05

Abstract

Provided is an oral pharmaceutical composition with improved bioavailability and pharmacokinetic properties of a drug, by increasing a bioabsorption rate and an in vivo retention time of an active ingredient via intestine-targeted formulation of a certain naphthoquinone-based compound or a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof, as an active ingredient having therapeutic effects on prevention or treatment of i) cancer, or treatment of ii) bacterial, fungal or parasitic infectious diseases and/or iii) dermatological diseases.

Description

ANTICANCER COMPOSITION CONTAINING NAPHTHOQUINONE- BASED COMPOUND FOR INTESTINE DELIVERY SYSTEM

FIELD OF THE INVENTION

The present invention relates to an oral pharmaceutical composition with formulation of an intestinal delivery system of a naphthoquinone-based compound represented by Formula 1 or a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof, as an active ingredient having therapeutic effects on prevention or treatment of i) cancer, or treatment of ii) bacterial, fungal or parasitic infectious diseases and/or ϋi) dermatological diseases.

BACKGROUND OF THE INVENTION

Naphthoquinone-based compounds are known to have therapeutic effects on prevention or treatment of cancer, and treatment of bacterial or parasitic infectious diseases and dermatological diseases. For example, US Patent Application No. 2005/0222246 Al and PCT WO 05/082357 disclose a method for treatment of a mammal having a variety of solid tumors (or cancers), comprising administering an effective amount of a naphthoquinone-based compound or a derivative thereof to a mammal in need thereof, based on the fact that a certain naphthoquinone-based compound has significant anticancer effects. Further, US Patent No. 7070797 and EP1387677 disclose a method of treating a hematologic tumor or malignancies in a subject, the method comprising administering to the subject a therapeutically effective amount of a Gl and/or S5 phase drug, or a derivative thereof, which is a naphthoquinone-based compound.

However, the aforesaid naphthoquinone-based compound is a sparingly-soluble material which is soluble at a low degree of about 2 to 4% only in high-solubility solvents, such as CH₂Cl₂, CHCl₃, CHICICH₂CI, CH₃CCl₃, Monoglyme, and Diglyme, but is poorly soluble in other ordinary polar or non-polar solvents. For this reason, the aforesaid naphthoquinone-based compound suffers from various difficulties associated with formulation of preparations for in vivo administration, in spite of its excellent pharmacological effects. Further, a poorly water-soluble drug usually exhibits significant difference in the between- and within-individual variability of absorption degree and absorption profiles even though it is designed to exhibit easy bioabsorption, so such variability of drug absorption properties makes it more difficult to achieve the desired pharmaceutical formulations.

For these reasons, highly-insoluble naphthoquinone-based compounds have a disadvantage of a significant limit in formulation of the compound into desired pharmaceutical preparations. Further, even though physiological activity of the naphthoquinone-based compound is elucidated, a dosage form of the naphthoquinone-based compound is limited to a formulation for in vivo adrninistration via intraperitoneal or intravenous injection.

However, drug administration via an injection route imposes a heavy burden of pain on cancer patients who are in need of chronic or long-term administration of the drug, in conjunction with the potential problems associated with the risk of secondary infections and pain and hypersensitivity which may occur upon administration of the drug.

Further, when the naphthoquinone-based compound that is a sparingly-soluble drug is administered by itself or in the form of a conventional simple formulation via an injection route, there is substantially no absorption of the compound into the body due to the nature of the drug, that is the bioavailability of the drug is very low, so it is impossible to exert the intrinsic efficacy of the drug.

These facts are supported by the recent study conducted by Jing et al, reporting that an absorption rate of cryptotanshinone which is a quinone compound is very low (2.05%) when it is orally administered. It is known that this is because absorption of cryptotanshinone is greatly affected by poor solubility of the drug and the problems of first-pass metabolism due to being used as a substrate for P-glycoprotein (PgP) (Journal of Pharmacology & Experimental Therapeutics 23, 2006).

Meanwhile, 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 significant problems in development of drug compositions. Therefore, in order to sufficiently and satisfactorily exploit inherent pharmacological properties of the naphthoquinone-based compounds, there is an urgent need for development and introduction of a method capable of maximizing the bioavailability of these drug compounds.

SUMMARY OF THE INVENTION

Therefore, the present invention has been made to solve the above problems and other technical problems that have yet to be resolved.

As a result of a variety of extensive and intensive studies and experiments to solve the problems as described above, the inventors of the present invention have discovered that when a sparingly-soluble naphthoquinone-based compound is formulated into an intestine-targeted pharmaceutical preparation, it is possible to minimize inactivation of the active compound which may occur due to internal bodily environment such as stomach, and it is possible to solve a problem of low bioavailability suffered upon injection administration of the drug or absorption thereof in the small intestine. Further, the present inventors have discovered that pharmacokinetic properties of the naphthoquinone-based compound are significantly improved via the present invention and therefore such a naphthoquinone-based compound exhibits excellent therapeutic effects on treatment of cancers or bacterial skin diseases. The present invention has been completed based on these findings.

hi accordance with an aspect of the present invention, the above and other objects can be accomplished by the provision of an oral pharmaceutical composition wherein a naphthoquinone- based compound represented by Formula 1, or a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof, as an active ingredient having therapeutic effects on prevention or treatment of i) cancer, or treatment of ϋ) bacterial, fungal or parasitic infectious diseases and/or iϋ) dermatologjcal diseases, is formulated for intestine-targeting:

wherein

R₁ and R₂ are each independently hydrogen, halogen, hydroxy or C₁-C₆ lower alkyl or alkoxy, or R₁ and R₂ may be taken together to form a substituted or unsubstituted cyclic structure which may be saturated or partially or completely unsaturated;

R₃, R₄, R₅, R₆, R₇ and R₈ are each independently hydrogen, hydroxy, Ci-C₂₀ alkyl, alkene or alkoxy, C₄-C₁₀ cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or two substituents of R₃ to R₈ may be taken together to form a cyclic structure which may be saturated or partially or completely unsaturated;

X is selected from the group consisting of C(R)(R'), N(R"), O and S, preferably O, with R, R' and R" being independently hydrogen or Ci-C₆ lower alkyl;

Y is C, S or N, preferably C, with proviso that when Y is S, R₇ and R₈ are not any substituent, and when Y is N, R₇ is hydrogen or C₁-C₆ lower alkyl and R₈ is not any substituent; and 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.

As used the present disclosure, the term "pharmaceutically acceptable salt" means a formulation of a compound that 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. Examples of the pharmaceutical salt may include acid addition salts of the compound of Formula 1 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 acid. Specifically, 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.

As used herein, the term "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. A further example of the prodrug might be a short peptide (polyamino acid) bonded to an acidic group, where the peptide is metabolized to reveal the active moiety.

As an example of such prodrug, the pharmaceutical compounds in accordance with the present invention can include a prodrug represented by Formula 1 a below as an active material:

wherein,

R₁, R₂, R₃, R₄, R₅, R₆, R₇, Rs, X and n are as defined in Formula 1 ,

R₉ and R₁₀ are each independently -SO₃-Na⁺ or substituent represented by Formula 2 below or a salt thereof,

*12 (2) wherein,

R₁₁ and R₁₂ are each independently hydrogen or substituted or unsubstituted C₁- C20 linear alkyl or C₁-C₂O branched alkyl

Ri₃ is selected from the group consisting of substituents i) to vϋi) below:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₂₀ linear alkyl or CJ-C₂₀ branched alkyl;

iii) substituted or unsubstituted amine;

iv) substituted or unsubstituted C₃-Q₀ cycloalkyl or C₃-Q₀ heterocycloalkyl;

v) substituted or unsubstituted C₄-C₁₀ aryl or C₄-C₁₀ heteroaryl;

vi) -(CRR'-NR"CO>-R₁₄, wherein R, R' and R" are each independently hydrogen or substituted or unsubstituted C₁-C₂₀ linear alkyl or C₁-C₂₀ branched alkyl, Ri₄ is selected from the group consisting of hydrogen, substituted or unsubstituted amine, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, 1 is selected from the 1-5;

vϋ) substituted or unsubstituted carboxyl;

viii) -OSO₃TCa⁺; k is selected from the 0-20, with proviso that when k is 0, R₁₁ and R₁₂ are not anything, and R₁₃ is directly bond to a carbonyl group.

As used herein, the term "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.

As used herein, 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 R₃-Rs types of substituents selected.

Unless otherwise specified, the term "naphthoquinone-based compound" is intended to encompass a compound per se, and a pharmaceutically acceptable salt, prodrug, solvate and isomer thereof.

As used herein, the term "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. Alternatively, the alkyl moiety may also be an "unsaturated alkyl" moiety, which means that it contains at least one alkene or alkyne moiety. The term "alkene" moiety refers to a group in which at least two carbon atoms form at least one carbon-carbon double bond, and 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. As used herein, the term "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.

As used herein, the term "aryl" refers to an aromatic substituent group which has at least one ring having a conjugated pi (π) 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 (i.e., rings which share adjacent pairs of carbon atoms) groups.

As used herein, the term "heteroaryl" refers to an aromatic group that contains at least one heterocyclic ring.

Examples of aryl or heteroaryl include, but are not limited to, phenyl, furan, pyran, pyridyl, pyrimidyl and triazyl.

Ri, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ in Formula 1 in accordance with the present invention may be optionally substituted. When 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-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N- sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino including mono- and di- substituted amino, and protected derivatives thereof. Further, in Formula Ia, where Rn, Ri₂ and Rj₃ are substituted, they may be substituted by the above substituents.

Among compounds of Formula 1 , preferred are compounds of Formula 3 and 4 below.

Compounds of Formula 3 are compounds wherein n is 0 and adjacent carbon atoms form a cyclic structure (fiiran ring) via a direct bond therebetween and are often referred to as "fiiran compounds" or "furano-o-naphthoquinone derivatives" hereinafter.

Compounds of Formula 4 are compounds wherein n is 1 and are often referred to as "pyran compounds" or "pyrano-o-naphthoquinone" hereinafter.

Among the fiiran compounds of Formula 3, preferred are compounds of Formula 3a wherein R₁, R₂ and R₄ are hydrogen, or compounds of Formula 3b wherein R₁, R₂ and R₆ are hydrogea

Further, the furan compounds of Formula 3, particularly preferred are compounds below.

Further, among the pyran compounds of Formula 4, particularly preferred are compounds of Formula 4a in which R₁, R₂, R₅, R₆, R₇ and R₈ are independently hydrogen, or compounds of Formula 4b or 4c in which Ri and R₂ are taken together to form a substituted or unsubstituted cyclic structure.

In accordance with another aspect of the present invention, there is provided an oral pharmaceutical composition wherein a compound represented by Formula 5, or a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof, as a substance having therapeutic eflfects on prevention or treatment of i) cancer, or treatment of ii) bacterial, fungal or parasitic infectious diseases and/or in) dermatological diseases, is formulated for intestine-targeting:

wherein R₁, R₂, R₃, R₄, R₅, R_& R₇, R₈, X, Y and n are as defined in Formula 1.

Among compounds of Formula 5, preferred without limitation are compounds of Formula

5a and 5b below.

Among the compounds of Formula 5, compounds of Formula 5a below are compounds in which n is 0 and adjacent carbon atoms form a cyclic structure via a direct bond therebetween.

Compounds of Formula 5b below are compounds wherein n is 1 and Y is C in Formula 1.

The term "pharmaceutical composition" as used herein means a mixture of a compound of Formula 1 or Formula 5 as an active material and other components which are required for an intestine-targeted formulation.

In the present invention, effective substance which have to exert therapeutic effects on prevention or treatment of i) cancer, or treatment of ii) bacterial, fungal or parasitic infectious diseases and/or ϋi) dermatological diseases in the present invention comprising a compound represented by the above-mentioned Formula and is often referred to as "active ingredient" hereinafter.

Preparation of active ingredient

In the pharmaceutical composition in accordance with the present invention, the compounds which are active ingredient, as will be illustrated hereinafter, can be prepared. 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.

In general, tricyclic naphthoquinone (pyrano-o-naphthoquinone and fUrano-o- naphthoquinone) derivatives can be synthesized mainly by two methods. One is to derive cyclization reaction using 3-allyl-2-hydroxy-l,4-naphthoquinone in acid catalyst condition, as the following β- lapachone synthesis scheme.

That is, 3-allyloxy-l,4-phenanthrenequinone can be obtained by deriving Diels-Alder reaction between 2-allyloxy-l,4-benzoquinone and styrene or 1-vinylcyclohexane derivatives and dehydrating the resulting intermediates using oxygen present in the air or oxidants such as NaIO₄ and DDQ. By further re-heating the above compound, 2-allyl-3-hydroxy-l,4-phenanthrenequinone of Lapachole form can be synthesized via Claisen rearrangement.

When the thus obtained 2-allyl-3-hydroxy-l,4-phenanthrenequinone is ultimately subjected to cyclization in an acid catalyst condition, various 3,4-phenanthrenequinone-based or

5,6J,8-tet^ydro-3,4-phenanthrenequinone-based compounds can be synthesized. In this case, 5 or 6-cyclic cyclization occurs depending on the types of substituents (R_2I, R_Ώ, R_B in the above formula) represented in the above formula, and also they are converted to the corresponding, adequate substituents (R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆ in the below formula).

Further, 3-allyloxy-l,4-phenanthrenequinone is hydrolyzed to 3-oxy-l,4- phenanthrenequinone, in the condition of acid (H⁺) or alkali (OH) catalyst, which is then reacted with various allyl halides to synthesize 2-allyl-3-hydroxy-l,4-phenanώrenequinone by C-alkylation. The thus obtained 2-allyl-3-hydroxy-l,4-phenanthrenequinone derivatives are subject to cyclization in the condition of acid catalyst to synthesize various 3,4-phenanthrenequinone-based or 5,6,7,8- tetrahydro-3,4-naphthoquinone-based compounds. In this case, 5 or 6-cyclic cyclization occurs depending on the lypes of substituents (R₂₁, R₂₂, R₂₃, R₂₄ in the above formula) represented in the above formula, and also they are converted to the corresponding, adequate substituents (R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆ in the below formula).

However, compounds in which substituents Rn and R₁₂ are simultaneously hydrogen cannot be obtained by acid-catalyzed cyclization. These derivatives are obtained on the basis of a method reported by J. K. Snyder et al (Tetrahedron Letters 28 (1987), 3427-3430), more specifically, by first obtaining furanobenzoquinone introduced furan ring by cyclization, and then obtaining tricyclic phenanthroquinone by cyclization with 1-vinylcyclohexene derivatives, followed by reduction via hydrogen-addition. The above synthesis process can be summarized as follows.

Besides the above synthetic method, compounds according to present invention in which substituents R₁₁ and R₁₂ are simultaneously hydrogen can be synthesized by the following method.

Preparation method 1 is a synthesis of active ingredient by acid-catalyzed cyclization which may be summarized in the general chemical reaction scheme as follows.

That is, when 2-hydroxy-l,4-naphihoquinone is reacted with various allylic bromides or equivalents thereof in the presence of a base, a C-alkylation product and an O-alkylation product are concurrently obtained. It is also possible to synthesize either of two derivatives only depending upon reaction conditions. Since O-alkylated derivative is converted into another type of C-alkylated derivative through Claisen Rearrangement by refluxing the O-alkylated derivative using a solvent such as toluene or xylene, it is possible to obtain various types of 3-substituted-2-hydroxy-l,4- naphthoquinone derivatives. The various types of 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 1.

Preparation method 2 is Diels-Alder reaction using 3-methylene- 1,2,4- [3H]naphthalenetrione. As taught by V. Nair et al, Tetrahedron Lett.42 (2001), 4549-4551, it is reported that a variety of pyrano-o-naphthoquinone derivatives can be relatively easily synthesized by subjecting

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.

Preparation method 3 is Haloakylation and cyclization by radical reaction. The same method used in synthesis of Cryptotanshinone and 15,16-dihydiO-tanshinone can also be conveniently employed for synthesis of furano-o-naphthoquinone derivatives. That is, as taught by A. C. Baillie et al (J. Chem. Soc. (C) 1968, 48-52), 2-haloethyl or 3-haloethyl radical chemical species, derived from 3-halopropanoic acid or 4-halobutanoic acid derivative, can be reacted with 2- hydroxy-l,4-naphthoquinone to thereby synthesize 3-(2-haloethyl or 3-halopropyl)-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.

Preparation method 4 is Cyclization of 4,5-benzofurandione by Diels-Alder reaction.

Another method used in synthesis of Cryptotanshinone and 15,16-dihydro- tanshinone may be a method taught by J. K. Snyder et al (Tetrahedron Letters 28 (1987), 3427-3430). According to this method, furano-o-naphthoquinone derivatives can be synthesized by cycloaddition via Diels-Alder reaction between 4,5-benzofurandione derivatives and various diene derivatives.

¹T 1) Heating y 2) Dehydrogenation

In addition, based on the above-mentioned preparation methods, various derivatives may be synthesized using relevant synthesis methods, depending upon kinds of substituents. Specific examples of compounds according to present invention are exemplified in Table 1 below. [Table 1]

C17H18O3 270.32 method 1

C20H16O3 304.34 method 1

C18H18O3 282.33 method 1

C17H16O3 268.31 method 1

C13H8O3 212.20 method 1

C13H8O3 212.20 method 4

Generally, 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 die target tissues.

In this connection, the oral pharmaceutical composition according to the present invention enhances bioabsorption 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.

Further, as it is constructed in such a way that 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. As a result, 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. Therefore, 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. In one preferred embodiment of the present invention, 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.

Specifically, 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 more, which is higher compared to that of the stomach. Based on this fact, 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 Examples of the 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), hydroxypropylmethyl cellulose phthalate (HPMCP) and a mixture thereof. Preferably, the pH-sensitive polymer may be added by a coating process. For example, 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.

When it is desired to design the intestine-targeted formulation using azoreductase as a target, the biodegradable polymer may be a polymer containing an azoaromatic linkage, for example, a copolymer of styrene and hydroxyethylmethacrylate (HEMA). When the polymer is added to the formulation containing the active ingredient, 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.

When it is desired to design the intestine-targeted formulation using glycosidase, esterase, or polysaccharidase as a target, the biodegradable polymer may be a naturally-occurring polysaccharide or a substituted derivative thereof. For example, 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. When the polymer is added to the active ingredient, 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 Bacteroiaes spp. These polymers are natural materials, and have an advantage of low risk of in vivo toxicity.

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 ingredient-containing formulation. Examples of 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.

In addition to the naturally-occurring polymers, the biodegradable matrix may be a synthetic hydrogel based on N-substituted acrylamide. For example, there may be used 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.

Further, 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 predetermined time irrespective of pH changes. In order to achieve enteric release of the active drug, 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 die 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 copolymerization of polyethylene oxide with polyurethane.

Specifically, 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.

As another example of the polymer, ethyl cellulose (EC) 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. As an additional example, 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 the polymer, and may have a lag time of 5 to 10 hours.

In the oral pharmaceutical composition according to the present invention, the active ingredient may have a crystalline structure with a high degree of crystallinity, or a crystalline structure with a low degree of crystallinity. As used herein, 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 crystallinity 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.

In the oral pharmaceutical composition according to the present invention, 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.

In one preferred embodiment of the present invention, 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. Even when the active ingredient is not of an amorphous structure, that is, has a crystalline structure or semi-crystalline structure, micronization of the active ingredient into fine particles via mechanical milling contributes to improvement of solubility, due to a large specific surface area of the particles, consequently resulting in improved dissolution rate and bioabsorption rate of the active drug.

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 .

Meanwhile, irrespective of the crystalline structure, a decreasing particle diameter of the particulate active ingredient leads to an increasing specific surface area, thereby increasing the dissolution rate and solubility. However, an excessively small particle diameter makes it difficult to prepare fine particles having such a size and also brings about agglomeration or aggregation of particles which may result in deterioration of the solubility. Therefore, in one preferred embodiment, the particle diameter of the active ingredient may be in a range of 5 nni to 500 μm. 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. Preferably, 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.

If necessary, a moisture-absorbent material may be further added during the milling process. The compound of Formula 1 or 5 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 tiie active ingredient.

Examples of the surfactant may include, but are not limited to, anionc surfactants such as docusate sodium and sodium lauryl sulfate; canonic surfactants such as benzalkonium chloride, benzethonium chloride and cetrimide; nonionic surfactants such as glyceryl monooleate, polyoxyethylene sorbitan fatty acid ester, and sorbitan ester; amphophilic polymers such as polyethylene-polypropylene polymer and polyoxyethylene-polyoxypropylene polymer (Poloxamer), and Gelucire™ 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 any combination thereof.

Examples of the 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.

Some of the above-mentioned 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. Preferably, the additives may be used in a range of 0.05 to 20% by weight, based on the total weight of the active ingredient.

In one preferred embodiment, during formulation of the pharmaceutical composition according to the present invention into preparations for oral administration, water-soluble polymers, solubilizers and disintegration-promoting agents may be further added. Preferably, 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 the compound molecules or particles according to Formula 1 or 5 hydrophilic to consequently enhance water solubility, and preferably to maintain the amorphous state of the active ingredient naphthoquinone-based compound.

Preferably, 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, hydrøxyethyl 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.

In the pharmaceutical composition of the present invention, 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. Accordingly, the solubilizer is preferably added to maximize the solubility of the formulation by modifying physical properties of the compound of Formula 1 or 5.

In this respect, the solubilizer serves to enhance solubilization and wettability of the sparingly-soluble compound according to Formula 1 or 5, 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.

In addition to the above-mentioned ingredients, other materials known in the art in connection with formulation may be optionally added, if necessary.

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. Preferably, 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.

In one preferred embodiment, the oral pharmaceutical composition according to the present invention may be formulated by a process comprising the following steps: (a) adding the compound of Formula 1 or 5 alone or in combination with a surfactant and a moisture-absorbent material, and grinding the compound of Formula 1 or 5 with a jet mill to prepare active ingredient microparticles;

(b) dissolving the active ingredient microparticles in conjunction with a water-soluble polymer, a solubilizer and a disintegration-promoting agent in a solvent and spray-drying the resulting solution to prepare formulation particles; and

(c) dissolving the formulation particles in conjunction with a pH-sensitive polymer and a plasticizer in a solvent and spray-drying the resulting solution to carry out intestine-targeted coating on the formulation particles.

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.

Alternatively, 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. Further, the oral pharmaceutical composition in accordance with the present invention, as defined above, is effective particularly for prevention or treatment of i) cancer, or prevention and treatment of ii) bacterial or parasitic infectious diseases and ϋi) dermatological diseases.

As used herein, the term "cancer" encompasses a precancerous condition referring to a condition of cells or cell populations immediately prior to changes of cells into a cancer state, and cell proliferative diseases. Examples of the cancer includes solid tumors, such as lung, breast, colon, ovarian, prostate, malignant melanoma and non-melanoma skin cancers, as well as hematologic tumors and/or malignancies, such as childhood leukemia and lymphomas, multiple myeloma,

Hodgkin's disease, lymphomas of lymphocytic and cutaneous origin, acute and chronic leukemia such as acute lymphoblastic, acute myelocytic or chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm and the like.

Further, examples of the precancerous conditions may include, but are not limited to, epidermic and dermoid cysts, lipomas, adenomas, capillary and cutaneous hemangiomas, lymphangiomas, nevi lesions, teratomas, nephromas, myofibromatosis, osteoplastic tumors, and other dysplastic masses and the like.

The dermatological condition may be any one selected from the group consisting of contact dermatitis, bacterial infections, superficial fungal infections, parasitic infections of the skin, disorders of hair follicles and sebaceous glands, and scaling papular diseases. Examples of the contact dermatitis may include, but are not limited to, atopic dermatitis; seborrheic dermatitis; nummular dermatitis; chronic dermatitis of hands and feet; generalized exfoliative dermatitis; stasis dermatitis; and localized scratch dermatitis. Examples of the bacterial infections of the skin may include, but are not limited to, Staphylococcal diseases of the skin, Staphylococcal scalded skin syndrome; erysipelas; folliculitis; furuncles; carbuncles; hidradenitis suppurativa; paronychial infections and erythrasma.

Examples of the superficial fungal infections may include dermatophyte infections; yeast infections; candidiasis; and tinea versicolor. Examples of the parasitic infections of the skin may include scabies; pediculosis; and creeping eruption. Further, examples of the disorders of hair follicles and sebaceous glands may include acne; rosacea; perioral dermatitis; hypertrichosis; alopecia; Pseudofolliculitis barbae; and keratinous cyst, and examples of the scaling papular diseases may include psoriasis; pityriasis rosea; lichen planus; pressure sores; benign tumors and malignant tumors. Particularly preferred is psoriasis. As used herein, the term "psoriasis" refers to disorders involving keratinocyte hyperproliferation, inflammatory cell infiltration, and cytokine alteration.

As used herein, the term "treatment" refers to stopping or delaying of the disease progress, when the drug is used in the subject exhibiting symptoms of disease onset. The term "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.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

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; and FIG. 2 is a graph showing outlet steady-state concentrations of a naphthoquinone-based compound under perfusion in Experimental Example 4.

FIG. 3 is a graph showing changes in a volume of prostate cancer cells with respect to anticancer activity of drugs in Experimental Example 7;

FIG.4 is a photograph showing proliferation results of prostate cancer cells with respect to anticancer activity of drugs in Experimental Example 8;

FIG. 5 is a graph showing volume measurement results of prostate cancer cells with respect to anticancer activity of drugs in Experimental Example 10;

FIG. 6 is a photograph showing proliferation results of prostate cancer cells with respect to anticancer activity of drugs in Experimental Example 10; and

FIG. 7 is a graph showing measurement results of a tumor cell size after administration of a spray-dried product into 6-week-old male BALB/c mice with dorsal/ventral subcutaneous injection of colon cancer cell line (Colon-26) in Experimental Example 11.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Now, the present invention will be described in more detail with reference to the following

Examples. These examples are provided only for illustrating the present invention and should not be construed as limiting the scope and spirit of the present invention.

Preparation Example 1 : Synthesis of a naphthoquinone compound (Compound 1) 17.4 g (0.10M) of 2-hydroxy-l,4-naphthoquinone was dissolved in 120 ml of DMSO, and 0.88 g (0.1 IM) of LiH was gradually added thereto. Here, this should be done with care because hydrogen evolves. The reaction solution was stirred, and after confirming no further production of hydrogen, was additionally stirred for another 30 min. Then, 15.9 g (O.IOM) of prenyl bromide (1- bromo-3-methyl-2-butene) and 3.35 g (0.025M) of LiI were gradually added thereto. The reaction solution was heated to 45 °C and then stirred vigorously for 12 hours at that temperature. The reaction solution was cooled below 10°C, and 76 g of ice was first added and 250 ml of water was then added. Thereafter, 25 ml of concentrated HCl was gradually added to maintain the resulting solution at an acidic pH>l. 200 ml of EtOAc was added to the reaction mixture which was then stirred vigorously, thereby producing white solids that were not dissolved in EtOAc. These solids were filtered and an EtOAc layer was separated. The aqueous layer was extracted once again with 100 ml of EtOAc and was combined with the previously extracted organic layer. The organic layer was washed with 150 ml of 5% NaHCθ₃, and was concentrated. The resulting concentrates were dissolved in 200 ml OfCH₂Cl₂, and were vigorously shaken to separate two layers with addition of 70 ml of an aqueous 2N NaOH solution. A CH₂Cl₂ layer was further separated twice with treatment of an aqueous 2N NaOH solution (70 ml x 2). The thus-separated aqueous solutions were combined together and adjusted to an acidic pH > 2, thereby forming solids. The resulting solids were filtered and separated to give Lapachol. The thus-obtained Lapachol was recrystallized from 75% EtOH. The resulting Lapachol was mixed with 80 ml of sulfuric acid, and the mixture was vigorously stirred at room temperature for 10 min and 200 g of ice was added thereto to complete the reaction. 60 ml OfCH₂Cl₂ was added to the reaction materials which were then shaken vigorously. Thereafter, a CH₂Cl₂ layer was separated and washed with 5% NaHCO₃. An aqueous layer was extracted once again using 30 ml of CH₂Cl₂, washed with 5% NaHCO₃ and combined with the previously extracted organic layer. The organic layer was dried over MgSO₄ and concentrated to give impure naphthoquinone compound. The thus-obtained the naphthoquinone compound was recrystallized from isopropanol, thereby obtaining 8.37 g of pure β-Lapachone.

IH-NMR (CDCD, δ): 8.05 (IH, dd, J=I, 8Hz), 7.82 (IH, dd, J=I, 8 Hz), 7.64 (IH, dt, J-I, 8 Hz), 7.50 (IH, dt, J=I, 8 Hz), 2.57 (2H, t, J=6.5 Hz), 1.86 (2H, t, J=6.5 Hz) 1.47 (6H, s)

Experimental Example 1 : Determination of partition coefficients

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) 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 μm 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.

[Table 2]

* average partition coefficient: 2.299 (σ =0.255)

As can be seen from 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

Mcronizing 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.0.2 g of sodium lauryl sulfate (SLS) and 1O g of a naphthoquinone-based compound (Compound 1 of Table 1) were mixed and ground. Micronized particles were recovered and a particle size was determined by zeta potential measurement. An average particle diameter was 1500 nm.

Example 2: Preparation of spray-dried product

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. Experimental Example 2: Dissolution of spray-dried formulation

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.

Experimental Example 3: Evaluation of relative bioavailability of formulations

10 male Sprague-Dawley rats were fasted, and the relative bioavailability in animals was evaluated for various formulations. Specifically, evaluation of the relative bioavailability was made for a preparation where a naphthoquinone-based compound was roughly ground and was added in conjunction with 2% by weight of sodium lauryl sulfate (SLS) to an aqueous solution (preparation prior to grinding of an active ingredient), a preparation where a naphthoquinone-based compound was ground into microparticles with a Jet mill, and was added in conjunction with 2% by weight of SLS to an aqueous solution (preparation after grinding of an active ingredient), a preparation where a formulation composed of the spray-dried product of Example 2 and the vehicle of Experimental Example 2 was added to an aqueous solution (spray-dried preparation), and a preparation where a naphthoquinone-based compound was ground into microparticles with a Jet mill, formulated using the vehicle of Experimental Example 2 and added to an aqueous solution (solid-dispersed preparation). Randomized crossover evaluation of the bioavailability was carried out by administering 50 mg/kg of the active ingredient to each animal group. The blood concentration profiles of the active ingredient thus obtained are given in Table 3 below.

[Table 3]

As can be seen from the results of Table 3, the spray-dried formulation and the solid- dispersed formulation, which were added to an aqueous solution, exhibited an about 3-fold increase of the bioavailability in a fasted state, as compared to the comparative formulation containing the same amount of the active ingredient, particularly the formulation prior to grinding of the active ingredient.

Experimental Example 4: Intestinal absorption of compounds

In order to determine intestinal absorption (%) of a naphthoquinone-based compound, a single-pass intestinal perfusion technique was carried out in internal organs of rats, including jejunum, ileum and large intestine.

The steady-state intestinal effective permeability (P_eff) can be expressed according to Hie following equation.

/A

- Pe_ff : Steady-state intestinal effective permeability (cm/s)

- Qj_n : Perfusion flow rate (0.4 mL/min)

- Cj_n, C_0Ut : Inlet and fluid-transport-corrected outlet solution concentrations

- A : Mass transfer surface area within intestinal segment (2πrL),

- r, L : Radius and length of intestinal segment 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 (Com/Qn) versus time. The steady-state is established when the C_ou/Q_n ratio of the naphthoquinone-based compound is maintained at a constant value (n = 3, error bars with respect to S.D.).

Residual amounts of the naphthoquinone-based compound in the above three intestinal organs were measured at different time points. The results thus obtained are shown in FIG. 1.

As shown in FIG. 1, a relatively large amount of the naphthoquinone-based compound permeated through the intestinal tissues for the first 20 min and thereafter remained with substantially no permeation. Further, the intestinal permeability was high in the order of the large intestine, ileum and jejunum.

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.

[Table 4]

Example 3: Preparation of intestine-targeted formulation

The spray-dried formulation prepared in 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.

Experimental Example 5: Acid resistance of 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.

Experimental Example 6: Measurement of drug-dissolution profiles

After the intestine-targeted formulation was exposed to acidic environment of pH 1.2, as in Experimental Example 5, the acidity was changed to a value of pH 6.8 under artificial environment. A residual amount of the dissolved active ingredient was measured by HPLC. The results thus obtained are given in Table 5 below.

[Table 5]

Experimental Example 7: Therapeutic efficacy of intestine-targeted formulation under high-fat diet conditions (!) Each composition of Table 6 in terms of active ingredient content was administered to COP rats, and anti-tumor effects of drugs on animals were examined under HFD (high-fat diet) conditions.

9-week-old male COP rats were purchased from Japan SLC, Inc., (Hamamatsu, Japan) and were allowed to acclimate to a new environment for 7 days prior to experiments, 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 from 8:00 am. to 8:00 pin.).

2^χlO⁴ cells/head of prostate cancer cell line (R3327 AT-3.1) were injected into the dorsal and ventral hypodermis of the animals and the cell growth was measured.

The thus-acclimated COP rats were randomly divided into three groups: a HFD control group, a group with administration of HFTH-intestine-targeted formulation, and a group with administration of HFD+Taxel, according to animal groups which were treated with Taxel as a commercially available anticancer drug and the intestine-targeted formulation of the present invention. The tumor volume was measured by determination of the tumor diameter once every two days.

[Table 6]

The growth profiles and volume of tumor cells with respect to anti-tumor activity of the intestine-targeted pharmaceutical composition in accordance with the present invention were examined and measured. The results thus obtained are shown in FIG.3.

Referring to FIG. 3, it can be seen that the HFD-fed group with administration of the intestine-targeted formulation in accordance with the present invention exhibited the smallest final tumor volume, and also showed a very low proliferation degree of tumor cells, as compared to tumor cells of the Taxel-treated group or the HFD control group. Therefore, it can be confirmed through these results that the intestine-targeted formulation of the present invention can maintain significantly high bioavailability of the drug to thereby more effectively inhibit proliferation of cancer cells, as compared to any known anticancer drug. Further, the inhibition of cancer cell proliferation can also prevent metastasis of cancer cells into other tissues or regions in the body. Accordingly, it is expected that the intestine-targeted pharmaceutical composition in accordance with the present invention can be used for preparation of oral dosage formulations which are capable of exerting excellent anticancer effects.

Experimental Example 8 : Therapeutic efficacy of intestine-targeted formulation (2)

Each composition of Table 7 in terms of active ingredient content was administered to COP rats, and anticancer effects of drugs on animals were examined. 9-week-old male COP rats were purchased from Japan SLC, Inc., (Hamamatsu, Japan) and were allowed to acclimate to a new environment for 7 days prior to experiments, in a breeding room maintained at a temperature of 22±2°C, humidity of 55±5%, and a 12-h light/dark (L/D) cycle (light from 8:00 am. to 8:00 p.m.).

5xlO⁴ cells/head of prostate cancer cell line (R3327 AT-3.1) were injected into the prostate gland of the animals and the cell growth was measured.

The thus-acclimated COP rats were randomly divided into four groups: a Taxel- administered group, a normal control group, a control group with no administration of any drug, and a group with administration of an intestine-targeted formulation. The tumor mass was then weighed.

[Table 7]

The growth profiles of prostate cancer cells with respect to anticancer activity of the intestine-targeted pharmaceutical composition in accordance with the present invention were examined and measured. The results thus obtained are shown in FIG.4.

Referring to FIG.4, it can be confirmed that the group with administration of the intestine- targeted formulation in accordance with the present invention exhibited a remarkable reduction of the prostate cancer mass, as compared to the Taxel-administered group. Therefore, it can be seen that the intestine-targeted formulation in accordance with the present invention exhibits excellent anticancer effects, in conjunction with significantly improved pharmacokinetic properties of the drug.

Experimental Example 9: Therapeutic efficacy of intestine-targeted formulation (3)

9-week-old male COP rats were purchased from Japan SLC, Inc., (Hamamatsu, Japan) and were allowed to acclimate to a new environment for 7 days prior to experiments, in a breeding room maintained at a temperature of 22±2^°C, humidity of 55±5%, and a 12-h light/dark (L/D) cycle (light from 8:00 am. to 8:00 p.m.).

According to a randomized blocks design, the thus-acclimated rats 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 of preparation example 1(250 mg/kg), a group with administration of a jet-milled naphthoquinone-based compound, and a group with administration of the intestine-targeted formulation of a naphthoquinone-based compound subjected to a milling process. Each group of animals was given perorally (PO) 250 mg/kg of drug samples. Animals were fed solid feed pellets and water ad libitum. The results detailing antiproliferative effects of the drug on tumor cells are given in Table 8 below.

[Table 8]

As can be seen from Table 8, it was confirmed that the group with administration of the intestine-targeted formulation of a naphthoquinone-based compound subjected to a milling process exhibits significant anti-tumor effects, as compared to the group with administration of the simply finely-divided powder. Further, it can be seen that the group with administration of the intestine- targeted formulation exhibits the smallest tumor size, thus representing the highest anti-tumor activity.

Experimental Example 10: Therapeutic efficacy of combined administration of intestine-targeted formulation with Taxel Each composition of Table 9 in terms of active ingredient content was administered to COP rats, and anticancer effects on animals were examined.

8-week-old male COP rats were purchased from Charles River Laboratories (CRL), USA and were allowed to acclimate to a new environment for 7 days prior to experiments, 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 from 8:00 am. to 8:00 ρ.m.).

IxIO⁴ cells/head of prostate cancer cell line (R3327 AT-3.1) were injected into the prostate gland of the animals, and the cell growth was measured after 22 days.

The thus-acclimated COP rats were randomly divided into four groups: a control group with no administration of any drug, a group with administration of an intestine-targeted formulation in accordance with the present invention (Example 3), a Taxel-administered group, and a group with combined administration of intestine-targeted formulation with Taxel. The prostate tumor weight and volume of each COP rat group were measured. The results thus obtained are given in FIGS. 5 and 6.

[Table 9]

As shown in FIG. 6, it can be seen that the group with combined administration of intestine-targeted drug and oral Taxel formulation exhibited a tumor volume of about 10000 mm , which is a significant decrease of prostate tumor corresponding to an about 1/6-fold of the control group (about 56000 mm³). Further, the combined administration group exhibited a very significant decrease of the tumor volume as compared to the group with administration of Taxel alone.

Such reduction of the tumor volume can also be confirmed from the results for growth of prostate tumor as shown in FIG.7, and it can be seen that the group with combined administration of intestine-targeted drug and oral Taxel formulation exhibits the most remarkable reduction of the tumor volume, thus resulting in the smallest volume of prostate tumor.

From these experimental results, it can be seen that combined administration of Ihe intestine-targeted formulation of the present invention with Taxel leads to more significant anticancer effects, as compared to anticancer effects exhibited by administration of a conventionally known anticancer drug, Taxel alone.

Experimental Example 11 : Therapeutic efficacy of spray-dried formulation 6-week-old male BALB/c mice were purchased from Japan SLC, Inc., (Hamamatsu, Japan) and were allowed to acclimate to a new environment for 7 days prior to experiments, 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 fiom 8:00 am. to 8:00 p.m.).

l*10⁵ cells/head of colon cancer cell line (Colon-26) were injected into the dorsal and ventral hypodermis of animals, followed by administration of the spray-dried product under the conditions as set forth in Table 10 below. The tumor cell size was measured for each animal group including the control group. The results thus obtained are shown in FIG.7.

[Table 10]

As shown in FIG. 7, the control group exhibited a significant increase of the tumor cell size over time, whereas the group with administration of the naphthoquinone formulation of the present invention showed a very low proliferation degree of tumor cells. Therefore, it can be confirmed through these results that the naphthoquinone formulation in accordance with the present invention can maintain significantly high bioavailability of the drug to thereby more effectively inhibit proliferation of cancer cells. INDUSTRIAL APPLICABILITY

As apparent from the above description, an oral pharmaceutical composition according to the present invention increases a bioabsorption rate and an in vivo retention time of an active ingredient having desired therapeutic effects of the present invention to thereby improve pharmacokinetic properties of the drug. As a result, it is possible to achieve excellent therapeutic effects on cancer or various dermatological diseases including bacterial skin diseases, by increasing the bioavailability of a certain naphthoquinone-based compound as the active ingredient

Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.

Claims

WHAT IS CLAIMED IS

1. An oral pharmaceutical composition wherein a naphthoquinone-based compound represented by Formula 1, or a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof, as an active ingredient having therapeutic effects on prevention or treatment of i) cancer, or treatment of ii) bacterial, fungal or parasitic infectious diseases and/or ϋi) dermatological diseases, is formulated for intestine-targeting:

wherein

R₁ and R₂ are each independently hydrogen, halogen, hydroxy or C₁-C₆IoWeT alkyl or alkoxy, or R₁ and R₂ may be taken together to form a substituted or unsubstituted cyclic structure which may be saturated or partially or completely unsaturated;

R₃, R₄, R₅, R₆, R₇ and R₈ are each independently hydrogen, hydroxy, C₁-C₂O alkyl, alkene or alkoxy, C₄-C₁₀ cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or two substituents of R₃ to R₈ may be taken together to form a cyclic structure which may be saturated or partially or completely unsaturated; X is selected from the group consisting of C(R)(R.'), N(R"), O and S, with R, R' and R" being each independently hydrogen or C₁-C₆ lower alkyl;

Y is C, S or N, with proviso that when Y is S, R₇ and Rg are not any substituent, and when Y is N, R₇ is hydrogen or C₁-C₆ lower alkyl and R₈ is not any substituent; and

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.

2. The oral pharmaceutical composition according to claim 1 , wherein X is O.

3. The oral pharmaceutical composition according to claim 1, wherein the prodrug is a compound represented by Formula Ia below:

wherein,

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, X and n are as defined in Formula 1 ;

RQ and R₁₀ are each independently -SOs-Na⁺ or substituent represented by Formula 2 below or a salt thereof,

wherein,

R₁₁ and R₁₂ are each independently hydrogen, or substituted or unsubstituted C₁-C₂₀ linear alkyl or C₁-C₂₀ branched alkyl

R₁₃ is selected from the group consisting of substituents i) to viii) below:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₂₀ linear alkyl or C₁-C₂₀ branched alkyl;

iii) substituted or unsubstituted amine;

iv) substituted or unsubstituted C₃-C₁₀ cycloalkyl or C₃-C₁₀heterocycloalkyl;

v) substituted or unsubstituted C₄-Ci₀ aiyl or C₄-Ci₀ heteroaryl;

vi) -(CRR'-NR"CO>-Ri₄, wherein, R, R' and R" are each independently hydrogen, or substituted or unsubstituted Q-C₂₀ linear alkyl or C₁-C₂₀ branched alkyl, R^ is selected from the group consisting of hydrogen, substituted or unsubstituted amine, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and 1 is selected from the 1-5;

vϋ) substituted or unsubstituted carboxyl; viii) -OSO₃ ^"Na⁺;

k is selected from the O-20, with proviso that when k is O, R₁₁ and R₁₂ are not anything, and R₁₃ is directly bond to a carbonyl group.

4. The oral pharmaceutical composition according to claim 1, wherein the compound of Formula 1 is selected from compounds of Formulas 3 and 4 below:

wherein, R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined in Formula 1.

5. The oral pharmaceutical composition according to claim 4, wherein the compound of Formula 3 is selected from compounds below:

6. The oral pharmaceutical composition according to claim 4, wherein the compound of

Formula 4 is a compound of Formula 4a below in which Ri, R₂, R₅, R₆, R₇ and R₈ are respectively hydrogen, or a compound of Formula 4b or Formula 4c below in which Ri and R₂ are taken together to form a substituted or unsubstituted cyclic structure.

7. An oral pharmaceutical composition wherein a naphthoquinone-based compound represented by Formula 5, or a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof, as a substance having therapeutic effects on i) prevention or treatment of cancer, or ii) bacterial, fungal or parasitic infectious diseases and/or ϋi) dermatological diseases, is formulated for intestine- targeting:

wherein R_1, R₂, R₃, R₄, R₅, R₆, R₇, Rg, X, Y and n are as defined in Formula 1.

8. The oral pharmaceutical composition according to claim 7, wherein the compound of

Formula 5 is a compound of Formula 5a below in which n is 0 and adjacent carbon atoms form a cyclic structure via a direct bond therebetween and Y is C, or a compound of Formula 5b below in whichnis l andYisC.

9. The oral pharmaceutical composition according to claim 1 or claim 7, wherein the intestine-targeted formulation is carried out by addition of a pH sensitive polymer.

10. The oral pharmaceutical composition according to claim 9, wherein the pH sensitive polymer is one or more selected from the group consisting of methacrylic acid-ethyl acrylate based copolymer (Eudragit: Registered Trademark of Rohm Pharma GmbH), hydroxypropylmeihyl cellulose phthalate (HPMCP), and a mixture thereof.

11. The oral pharmaceutical composition according to claim 9, wherein the pH sensitive polymer is added by a coating process.

12. The oral pharmaceutical composition according to claim 1 or claim 7, wherein the intestine-targeted formulation is carried out by addition of a biodegradable polymer which is decomposable by an intestine-specific bacterial enzyme.

13. The oral pharmaceutical composition according to claim 12, wherein the polymer contains an azoaromatic linkage.

14. The oral pharmaceutical composition according to claim 13, wherein the polymer containing the azoaromatic linkage is a copolymer of styrene and hydroxyethylmethacrylate (HEMA).

15. The oral pharmaceutical composition according to claim 12, wherein the polymer is a naturally-occurring polysaccharide or a substituted derivative thereof.

16. The oral pharmaceutical composition according to claim 15, wherein the polysaccharide or substituted derivative thereof is one or more selected fora the group consisting of dextran ester, pectin, amylose and ethylcellulose or pharmaceutically acceptable salt thereof.

17. The oral pharmaceutical composition according to claim 1 or claim 7, wherein the intestine-targeted formulation is carried out by addition of a biodegradable matrix which is decomposable by an intestine-specific bacterial enzyme.

18. The oral pharmaceutical composition according to claim 17, wherein the matrix is a synthetic hydrogel based on N-substituted acrylamide.

19. The oral pharmaceutical composition according to claim 1 or claim 7, wherein the intestine-targeted formulation is carried out by a configuration with time-course release of the drug after a lag time ('time-specific delayed-release formulation').

20. The oral pharmaceutical composition according to claim 19, wherein the time-specific delayed-release formulation is carried out by addition of a hydrogel.

21. The oral pharmaceutical composition according to claim 1 or claim 7, wherein the active ingredient have a crystalline structure.

22. The oral pharmaceutical composition according to claim 1 or claim 7, wherein the active ingredient have a crystalline structure in which the crystallinity degree is 50% or less.

23. The oral pharmaceutical composition according to claim 22, wherein the active ingredient have an amorphous structure.

24. The oral pharmaceutical composition according to claim 1 or claim 7, wherein the active ingredient is contained in the form of a fine particle.

25. The oral pharmaceutical composition according to claim 24, wherein the fine particles have particle diameters within a range of 5 ran to 500 μm.

26. The oral pharmaceutical composition according to claim 24, wherein the fine particles are prepared by spray drying of active material or mechanical milling.

27. The oral pharmaceutical composition according to claim 26, wherein the mechanical milling is carried out by jet milling.

28. The oral pharmaceutical composition according to claim 24, wherein one or more selected from the group consisting of surfactant, antistatic agent and moisture-absorbent is added during formation of the fine particles.

29. The oral pharmaceutical composition according to claim 28, wherein the surfactant is one or more selected from the group consisting of anionc surfactants of docusate sodium and sodium lauryl sulfate; cationic surfactants of benzalkonium chloride, benzethonium chloride and cetrimide; nonionic surfactants of glyceryl monooleate, polyoxyethylene sorbitan fatty acid ester and sorbitan ester; amphiphilic polymers of polyethylene-polypropylene polymer and polyoxyethylene- polyoxypropylene polymer (Poloxamer), and Gelucire™ 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.

30. The oral pharmaceutical composition according to claim 28, wherein the moisture- absorbent is one or more selected from the group consisting of colloidal silica, light anhydrous silicic acid, heavy anhydrous silicic acid, sodium chloride, calcium silicate, potassium aluminosilicate, and calcium aluminosilicate.

31. The oral pharmaceutical composition according to claim 1 or claim 7, wherein during preparation of the formulation for oral administration, a water-soluble polymer, solubilizer and disintegration-promoting agent are added.

32. The oral pharmaceutical composition according to claim 31, wherein the formulation is made by mixing additives and the active ingredient in the form of a fine particle in a solvent and then spray-drying the resulting mixture.

33. The oral pharmaceutical composition according to claim 31, wherein the water-soluble polymer is one or more selected from the group consisting of methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, ethyl cellulose, hydroxyethylmethyl cellulose, carboxyrneihyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmetiiyl cellulose phthalate, sodium carboxymethyl cellulose, and carboxymethylethyl cellulose.

34. The oral pharmaceutical composition according to claim 33, wherein the water-soluble polymer is hydroxypropylmethyl cellulose.

35. The oral pharmaceutical composition according to claim 31, wherein the disintegration- promoting agent is one or more selected from the group consisting of Croscarmellose sodium, Crospovidone, calcium carboxymethylcellulose, starch glycolate sodium and lower substituted hydroxypropyl cellulose.

36. The oral pharmaceutical composition according to claim 35, wherein the disintegration- promoting agent is Croscarmellose sodium.

37. The oral pharmaceutical composition according to claim 31, wherein the solubilizer is a surfactant or amphiphile.

38. The oral pharmaceutical composition according to claim 31 , wherein 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 are added based on 100 parts by weight of the active ingredient

39. The oral pharmaceutical composition according to claim 1 or claim 7, wherein the intestine-targeted formulation is prepared by a process comprising the following steps:

(a) adding the compound of Formula 1 or 5 alone or in combination with a surfactant and a moisture-absorbent material, and grinding the compound of Formula 1 or 5 with a jet mill to prepare active ingredient microparticles;

40. The oral pharmaceutical composition according to claim 1 or claim 7, wherein the cancer is selected from the group consisting of prostate cancer, multiple myeloma, malignant melanoma, non-melanoma skin cancers, hematologic malignancies, colon cancer, ovarian cancer, and breast cancer.

41. The oral pharmaceutical composition according to claim 1 or claim 7, wherein the dermatological diseases is selected from the group consisting of bacterial infections, superficial fungal infections, parasitic infections of the skin, disorders of hair follicles and sebaceous glands, and scaling papular diseases

42. Use of the oral pharmaceutical composition of claim 1 or claim 7 for prevention or treatment of i) cancer, or treatment of ϋ) bacterial, fungal or parasitic infectious diseases and/or iii) dermatological diseases.

43. The use according to claim 42, wherein the oral pharmaceutical composition of claim 1 or claim 7 is administrated in combination with Taxel.