WO2011132826A1 - Transdermal drug delivery system and pharmaceutical composition for preventing or treating bone diseases - Google Patents

Transdermal drug delivery system and pharmaceutical composition for preventing or treating bone diseases Download PDF

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WO2011132826A1
WO2011132826A1 PCT/KR2010/005890 KR2010005890W WO2011132826A1 WO 2011132826 A1 WO2011132826 A1 WO 2011132826A1 KR 2010005890 W KR2010005890 W KR 2010005890W WO 2011132826 A1 WO2011132826 A1 WO 2011132826A1
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bisphosphonate
daim
amino
delivery system
hydroxy
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Jong Sang Park
So Hee Nam
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SNU R&DB Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders

Definitions

  • the present invention relates to a transdermal drug delivery system comprising (i) a bisphosphonate-based drug and (ii) a cationic amine compound linked to the bisphosphonate- based drug via an ionic bond, and a pharmaceutical composition comprising the drug delivery system for preventing or treating a bone disease.
  • Osteoporosis is a common disease characterized by low bone mass and structural deterioration of bone tissue, resulting in decreased bone strength and increased susceptibility to fractures.
  • the risk of fragility fractures increases in the hips and spines of postmenopausal women suffering from osteoporosis.
  • Hyperkyphosis which refers to an accentuated concave curvature and loss of vertebrata height, commonly affects patients with osteoporosis due to a weakened vertebrate.
  • the cause of osteoporosis is still undear, but low body weighty low calcium intake, sedentary life style and declining estrogen levels at menopause can result in increased bone turnover and a loss of bone mass.
  • Alendronate marketed under the brand name FOSAMAX, is one of the nitrogen- containing bisphosphonate agents that specifically inhibit bone resoption mediated by osteoclasis.
  • FOSAMAX is known to be poorly absorbed and cause adverse effects on the gastrointestinal tract.
  • Pamidronate disodium (AREDIA) is a commercially available drug for inhibiting bone resorption, usually administered as an intravenous infusion. Common side effects include pain, stiffening and irritation at the catheter insertion site, loss of appetite, vomiting, diantiea, dyspepsia, esophagitis and stomatitis.
  • Risedronate sodium (trade name ACTONEL) is water soluble but insoluble in organic solvents and has adverse effect on the upper gastrointestinal tract.
  • Ibandronate sodium (trade name BONIVA) is a white/grey colored powder soluble in water but insoluble in organic solvents. This drug has adverse side effects in the upper GI tract. It is recommended that no food be taken for 2 hours after taking etidronate sodium (trade name DIDRONEL) due to its adverse gastrointestinal side-effects.
  • Zbledronate (trade name ZOMETA) is the only bisphosphonate developed solely for use as an IV administration. However, fever, nausea, vomiting and higher incidents of upper GI disorders were reported in some patient groups.
  • transdermal delivery may be a desirable alternative to oral treatment.
  • a transdermal delivery system is beneficial when dealing with drugs that can cause adverse GI events or undergo liver metabolism, or for drugs that are poorly absorbed or easily disintegrated in GI. Transporting drugs across the skin layer is known to be an effective way to improve the bioavailability of the drug, and to reduce the potential GI adverse effects
  • bisphosphonates have low bioavailability and high upper GI adverse effects.
  • Currently developed bisphosphonate-based drugs are highly charged, and have trouble penetrating the lipid bilayer. These drugs also have high affinity to polycationic metal ions, such as calcium ions, that form a water insoluble complex that is difficult to be absorbed by the cell membrane of the GI tract [Int J Pharm 21:143-154(1984)].
  • the acidic pH of the small intestine pH 6-8) reduce the absorption of bisphosphonate drugs to less than
  • transdermal delivery system of bisphosphonate-based drugs Successful development of a transdermal delivery system of bisphosphonate-based drugs is expected to increase bioavailability and decreased the adverse side effects of the drug, therefore likely leading to increased patient compliance to the drug. Little information is available regarding transdermal delivery system of bisphosphonate throughout the world. This could be due to the low absorption rate of this drug in the patient body. Even oral administration of bisphosphonate shows less than 1% of bioavailability, therefore developing an appropriate penetration activator could successfully enhance the efficacy of this low level of bisphosphonate delivery.
  • Vertebral fracture is a common consequence of osteoporosis if left untreated. This can lead to chronic pain and decreased quality of life, which in turn could be a great burden on government health care. A therapeutic intervention that decreases fracture risk is essential for reducing the consequences of this debilitating condition.
  • the object of this invention is to develop a transdermal delivery system of risedronate and compare its efficacy with oral administration using animal models or healthy human subjects.
  • the ultimate goal of this invention is to apply our accumulated pharmacokinetic and clinical trial data into commercializing of a novel transdermal delivery system for bisphosphonate.
  • the present inventors have made intensive researches to enhance skin penetration and in vivo absorption rate of bisphosphonate-based drugs for prevention or treatment of bone diseases.
  • cationic amine compounds linked to bisphosphonate-based drugs via an ionic bond makes the bisphosphonate-based drug less hydrophilic and more hydrophobic, thereby dramatically increasing its skin penetration rate.
  • Figs, la and lb are graphs showing increased solubility of risedronate linked to diethylenetriamine (DETA) or L-arginine via ionic bonds in xylene or propylene carbonate.
  • DETA diethylenetriamine
  • Rg. 2a is a graph showing in vitro ⁇ penetration of risedronate linked to L-arginine via ionic bonds.
  • Rg. 2b is a graph showing in vitro skin penetration of risedronate linked to L-lysine via ionic bonds.
  • Rg. 3 is a graph showing in vitro skin penetration of risedronate linked to diethylenetriamine (DETA) via ionic bonds.
  • Rg.4 is an image showing results of the skin irritation test performed using risedronate with viscosity by Xanthan gum aqueous solution.
  • Rg.5 is an image showing representative results of the skin irritation test performed using risedronate and L-arginine (molar ratio 1:2) ionic compound with viscosity by Xanthan gum aqueous solution.
  • Rg.6 is an image showing representative results of the skin irritation test performed using risedronate and diethylenetriamine (DETA, molar ratio 1:1) ionic compound with viscosity by Xanthan gum aqueous solution.
  • DETA diethylenetriamine
  • Fig. 7a represents micro CT images of femur from ovariectomized mouse model treated with (a) Sham, (b) OVX-cti, (c) OVX-0.2% or (d) OVX-2%.
  • OVX-cti, OVX-0.2% and OVX-2% represent the drug delivery system of this invention containing 0 wt% risedronate, 0.2 wt% risedronate and 2 wt% risedronate linked to L-arginine, respectively.
  • Rg. 7b represents two-dimensional micro CT images of femur from ovariectomized mouse model treated with (a) Sham, (b) OVX-cti, (c) OVX-0.2% or (d) OVX-2%.
  • Rgs. 8a-8e represent BMC (Bone mineral contents), BMD (mg/cc; Bone Mineral Density), TMC (mg; Total Mineral Contents), TMD (mg/cc; Total Mineral Density) and BVF (Bone volume fraction) of ovariectomized mouse model treated with (A) OVX-cti, (B) OVX- 0.2% or (C) OVX-2%.
  • a transdermal drug delivery system comprising (i) a bisphosphonate-based drug and (ii) a cationic amine compound linked to the bisphosphonate-based drug via an ionic bond.
  • a method for delivering a drug via transdermal route which comprises administering to a subject a composition comprising (i) a bisphosphonate-based drug; and (ii) a cationic amine compound linked to the bisphosphonate-based drug via an ionic bond.
  • the present inventors have made intensive research to enhance skin penetration and in vivo absorption rate of bisphosphonate-based drugs for prevention or treatment of bone diseases.
  • cationic amine compounds linked to bisphosphonate-based drugs via an ionic bond makes the bisphosphonate-based drug less hydrophilic and more hydrophobic, thereby dramatically increasing its skin penetration rate.
  • bisphosphonate refers to a pyrophosphate analogue where the center oxygen atom in a P-O-P moiety is substituted with a carbon atom to from a P-C-P moiety. It should be noted that the term “bisphosphonate” as used herein in referring to the therapeutic agents of the present invention are meant to also encompass diphosphonates, biphosphonic acids, and diphosphonic acids, as well as salts and derivatives of these materials.
  • Ri is hydrogen, hydroxy or halo
  • R 2 is halo, CMO alkyl, CM 0 cydoalkyl, CMO heterocydoalkyl, C O heteroaryl, CMO aryi or CMO arylalkyl; the alkyl, cydoalkyl, aryl, arylalkyl, heterocydoalkyl and heteroaryl are substituted with halo, sulfur, amino, Ci -5 alkylamino or -s dialkylamino and contains 1-3 nitrogen atoms.
  • halo means halogen atoms, for instance induding fluoro, chloro, bromo, and iodo, preferably fluoro, chloro or bromo.
  • -Qo alkyl is defined herein to be a straight chain or branched chain saturated hydrocarbon groups containing 1-10 carbon atoms, induding methyl, ethyl, /7-propyl, isopropyl, isobutyl, /7-butyl, f-butyl, /7-hexyl, /Hxtyl and foctyl.
  • Cydoalkyl refers to cyclic hydrocarbon radicals containing 1- 10 carbon atoms, preferably “C 3 -Q cydoalkyl", induding cydopropyl, cydobutyl and cyclopentyl and cydooctyl. Cydoalkyl may be substituted with alkyl groups having 1-3 carbon atoms, preferably 1-methylcyclopropyl, 2-methylcydopentyl and 2-methylcydooctyl.
  • heterocydoalkyl refers to cydoalkyl in which one or more of the atoms forming the ring is a heteroatom selected, independently from N, 0, or S.
  • Non- exdus ' rve examples of heterocydoalkyl indude piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, peitiydropyrrolizinyl, 1,4-diazaper ydroepinyl, 1,3-dioxanyl, 1,4-dioxanyl and the like.
  • aryl means totally or partially unsaturated, substituted or unsubstituted monocylic or polycydic carbon rings, preferably phenyl, naphthyl, anthracene or pyrene. Meet preferably, the aryl group is substituted or unsubstituted phenyl, naphthyl or pyrene.
  • the monoaryl group e.g., phenyl may be substituted with various substituents, preferably halo, hydroxy, nitro, cyano, Q-Q alkyl and Q-Q alkoxy group. More preferably, nitro and Q-Q alkoxy groups.
  • alkoxy means -O alkyl groups, preferably methoxy. Where substituted with Q-Q substituted alkyl groups, halo, preferably chloro or fluoro substituted alkyl substituents may be used.
  • R 2 is biary, e.g. naphthyl, it may be substituted in various positions with various substituents, preferably halo, hydroxy, nitro, cyano, straight or branched, substituted or unsubstituted Q-Q alkyl, straight or branched Q-Q alkoxy, or substituted or unsubstituted amino groups, more preferably nitro or Q-Q alkoxy.
  • arylalkyl means aryl groups linked to a structure comprised of one or more alkyl groups, e.g. benzyl. More preferably, arylalkyl is alkylphenyl, alkylnaphthalene, alkyl anthracene, or alkylpyrene, most preferably, benzyl, methylnaphthalene or methylpyrene.
  • heteroaryl means heterocyclic aromatic groups containing heteroatoms such as N, O and S.
  • heteroaryl is heterobiaryl containing N atom as heteroatom.
  • alkylamino means alkyl groups having amino substituents.
  • dialkylamino refers to two alkyl groups having amino substituents.
  • the bisphosphonate-based drug is (4-amino-l- hydroxybutylidene)-bisphosphonate or 4-amine-l-hydroxybutane-l,l-bisphosphonic acid(alendronate); (dichloromethylene)-bisphosphonate (dodronate); (1-hydroxyethylidene)- bisphosphonate(etidronate); [l-hydroxy-3-(methylpentylamino) propylidene] bisphosphonate(evandronate); [(cydoheptylamino)-methylene] bisphosphonate (dmadronate, incadronate); [l-hydroxy-2-imidazo-(l,2-a) pyridine-3-ylethyledne] bisphosphonate (minodronate); (6-amino-l-hydroxyhexyleden) bisphosphonate (neridronate); [3- (dimethylamino)-hydroxy-propylidene] bisphosphonate (o
  • salts means salts of the bisphosphonate-based drug which are pharmaceutically acceptable, and which possess the desired pharmacological activity.
  • Such salts indude add addition salts formed with inorganic adds such as hydrochloric add, hydrobromic add, sulfuric add, nitric add, phosphoric add, and the like; or with organic adds such as acetic add, propionic add, hexanoic add, heptanoic add, cydopentanepropionic add, glycolic add, pyruvic add, lactic add, malonic add, sucdnic add, malic add, maleic add, flimaric add, tartatic add, citric add, benzoic add, o-( -hydroxybenzoyl)benzoic add, dnnamic add, mandelic add, methanesulfonic add, ethanesulfonic add, 1,2-ethanedisulfonic add, 2- hydroxyethanesul
  • Pharmaceutically acceptable salts also indude base addition salts which may be formed when addic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases indude sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and caldum hydroxide.
  • Acceptable organic bases indude ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
  • the cationic amine compound used in the drug delivery system of this invention is selected from the group consisting of an amino add, diethylenetriamine (DETA), spermine, ethylene diamine, triethylene tetramine and tris(2- aminoethyl amine). More preferably, the cationic amine compound is the amino add.
  • amino add means compounds having both an amino group and carboxyl group.
  • the amino add indudes alanine, arginine, asparagine, aspartic add, citrulline, cysteine, cystine, selenocysteine, glutamine, glydne, histidine, isoleudne, leudne, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, hydroxy proline, y-carboxyglutamate, or Ophosphoserine.
  • Each amino acid has its typical isoelectric point (pi) where its mean charge becomes zero. For instance, certain amino adds have higher pi values than the physiological pH value (pH 7.4) and are positively charged under physiological pH conditions.
  • the cationic amine compound is used to form ionic bonds with oxygen anions from phophonate groups of bisphosphonate drugs, decreasing hydrophilic properties of bisphosphonate drugs.
  • the amino adds are used as cationic amine compounds, a suitable amino add can be selected depending on pH values of solutions for preparation of materials having ion bonds ⁇ i.e., drug delivery system of this invention).
  • the solution for preparing the drug delivery system has a pH value of 2
  • all amino adds described above with pi values of above 2 are positively charged.
  • the solution for preparing the drug delivery system has a pH 4-9.
  • the amino add as cationic amine compound is preferably Arg or Lys.
  • Non-limiting examples of solvents for forming ion bonds between the bisphosphonate- based drug and the cationic amine compound indude water, ethanol, 1,3-butylene glycol, glycerin, propylene glycol and combinations thereof.
  • the drug delivery system has the molar ratio of the bisphosphonate-based drug and the cationic amine compound of 1:0.01-50, more preferably 1:1-40, most preferably 1:2-30.
  • the molar ratio of 1:0.01-50 is advantageous for decreasing hydrophilic properties of bisphosphonate-based drugs by formation of ion bonds.
  • the molar ratio of the bisphosphonate-based drug to the cationic amine compound is preferably 1:0.01-10, more preferably 1:1-6, most preferably 1:1-4.
  • the molar ratio of the bisphosphonate-based drug to the cationic amine compound is preferably 1:0.01-10, more preferably 1:0.1-6, most preferably 1:0.5-5.
  • the bisphosphonate-based drug is contained in the amount of 0.01-20 wt% (more preferably 0.1-10 wt%, most preferably 1-5 wt%) based on the total weight of the drug delivery system.
  • the amount of 0.01-20 wt% for bisphosphonate-based drugs is desirable for the decrease in hydrophilic properties of bisphosphonate-based drugs by formation of ion bonds.
  • the drug delivery system of the present invention is developed for overcoming shortcomings associated with oral and intravenous administration of bisphosphonate-based drugs and suggests transdermal administration as alternatives.
  • the drug delivery system may be prepared in various forms such as solution, lotion, W/O emulsion, O/W emulsion, suspension, liposome, gel, hydrogel, cream, paste, patch or ointment
  • the drug delivery system may be prepared in the form of liposomes using phospholipids.
  • liposome encompasses any compartment enclosed by a lipid bilayer. Liposomes are also referred to as lipid vesides. In order to form a liposome the lipid molecules comprise elongated non-polar (hydrophobic) portions and polar (hydrophilic) portions. The hydrophobic and hydrophilic portions of the molecule are preferably positioned at two ends of an elongated molecular structure.
  • phospholipids used herein means any phospholipid capable of forming liposomes unless otherwise indicated, including lecithin (phosphatidyl choline), phosphatidyl serine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol and sphingomyelin, but not limited to.
  • lecithin phosphatidyl choline
  • phosphatidyl serine phosphatidyl serine
  • phosphatidylethanolamine phosphatidylglycerol
  • phosphatidylinositol phosphatidylinositol
  • phospholipids useful in this invention are lecithin, most preferably, hydrogenated lecithin.
  • Lecithin can be made from egg, soybean and other plants, most preferably, soybean.
  • Lecithin useful in this invention which is synthetic, semisynthetic or natural, includes, but not limited to, soybean lecithin, distearoylphosphatidyldholine, hydrogenated soybean lecithin, egg lecithin, dioleoylphosphatidylcholine, hydrogenated egg lecithin, dielaidoylphosphatidylcholine, dipalmitoylphosphatidylcholine and dimyristoylphosphatidylcholine.
  • phospholipid used in this invention is hydrogenated soybean lecithin.
  • Trie liposomes may be prepared using high pressure homogenizer, sonicator, microfluidizer, extrusion apparatus or French press.
  • the drug delivery system may be fabricated in the form of hydrogel by using conventional materials for preparing hydrogel such as natural/synthetic hydrophilic polymers, cross-linking agents, skin softner, transdermal enhancer, preservatives, surfactant and pH modifier.
  • gelation agents may be used, including carbopol and/or xanthan gum, preferably carbopol 60 and/or xanthan gum.
  • polyethyleneglycol, xanthan gum, carbopol, carbomer and hydroxypropylcellulose are added in the amount of 0.01-20 wt% based the total weight to water to prepare hydrogel and then a bisphosphonate-based drug and a cationic amine compound are introduced in the amount of 0.01-20.00 wt%.
  • a pharmaceutical composition for preventing or treating a bone disease via transdermal route which comprises (a) a pharmaceutically effective amount of a drug delivery system containing (i) a bisphosphonate- based drug and (ii) a cationic amine compound linked to the bisphosphonate-based drug via an ionic bond; and (b) a pharmaceutically acceptable earner.
  • a method for preventing or treating a bone disease via transdermal route which comprises administering to a subject a pharmaceutical comprising (a) a pharmaceutically effective amount of a drug delivery system containing (i) a bisphosphonate-based drug and (ii) a cationic amine compound linked to the bisphosphonate-based drug via an ionic bond; and (b) a pharmaceutically acceptable earner.
  • the present pharmaceutical composition comprises the drug delivery system described above, the common descriptions between them are omitted in order to avoid undue redundancy leading to the complexity of this specification.
  • the drug delivery system is contained in the amount of 0.001-50 wt% (more preferably 0.1-40 wt%, most preferably 10-30 wt ) based on the total weight of the composition.
  • the pharmaceutical composition of this invention is provided in various forms such as solution, lotion, W/O emulsion, O/W emulsion, suspension, liposome, gel, hydrogel, cream, paste, patch or ointment
  • the bone disease prevented or treated by the present pharmaceutical composition includes osteoporosis, Pagers disease, rickets, osteopenia, rheumatoid arthritis, osteomalacia, renal osteodystrophy, osteogenesis imperfecta, hyperthyroidism, bone loss due to rheumatoid arthritis, inflammatory arthritis, subchondral osteosclerosis, subchondral osteocystoma, osteophytosis, athralgia, hyperparathyroidism, sarcoidosis and hypercalcemia, more preferably osteoporosis, Pagers disease, rickets, osteomalacia, renal osteodystrophy, hyperthyroidism and hyperparathyroidism, most preferably osteoporosis.
  • the pharmaceutically acceptable earner may be conventional one for formulation, including carbohydrates (e.g., lactose, amylose, dextrose, sucrose, sorbitol, mannitol, starch, cellulose), gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpynOlidone, water, salt solutions, alcohols, gum arabic, syrup, vegetable oils (e.g., com oil, cotton-seed oil, peanut oil, olive oil, coconut oil), polyethylene glycols, methyl cellulose, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil, but not limited to.
  • carbohydrates e.g., lactose, amylose, dextrose, sucrose, sorbitol, mannitol, starch, cellulose
  • gum acacia calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl
  • compositions of this invention further may contain wetting agent, sweetening agent, emulsifier, buffer, suspending agent, preservatives, flavors, perfumes, lubricant, stabilizer, or mixtures of these substances.
  • wetting agent sweetening agent, emulsifier, buffer, suspending agent, preservatives, flavors, perfumes, lubricant, stabilizer, or mixtures of these substances.
  • the pharmaceutical composition of this invention may be administered via transdermal route.
  • the correct dosage of the pharmaceutical compositions of this invention will be varied according to the particular formulation, the mode of application, age, body weight and sex of the patient, diet, time of administration, condition of the patient, drug combinations, reaction sensitivities and severity of the disease. It is understood that the ordinary skilled physician will readily be able to determine and prescribe a correct dosage of this pharmaceutical compositions.
  • suitable dosage unit for human host is to administer once a day with the composition of 0.001-100 mg/kg(body weight) per day.
  • compositions of this invention can be formulatedwith pharmaceutical acceptable carrier and/or vehicle as described above, finally providing several forms including a unit dosage form.
  • the present invention provides drug delivery systems and pharmaceutical compositions ensuring trandermal administration of conventional bisphosphonate-based drugs by forming ionic bonds between bisphosphonate-based drugs and cationic amine compounds.
  • novel approaches of the present invention is to decrease hydrophilicity and increase hydrophobicity of bisphosphonate-based drugs by forming ionic bonds with cationic amine compounds, contributing to dramatic increase in skin penetration into cell membrane.
  • the present invention completely overcomes shortcomings associated with conventional bisphosphonate drugs for oral administration such as poor bioavailability (as much as 1%) and irritation of gastrointestinal tract
  • the drug delivery systems and pharmaceutical compositions of this invention may be prepared in a relatively convenient fashion with no decrease in therapeutic effects of bisphosphonate drugs.
  • the drug delivery systems and pharmaceutical compositions of this invention may be transdermally applied with much higher patient compliance suffering from bone diseases, particularly osteoporosis.
  • mice Male hairless mice (6-8 weeks old) purchased from Orientalbio, Inc. (Korea) were used in our In vitro experiment within one week of delivery.
  • risedronate and diethylenetriamine (DETA) each dissolved in distilled water were homogeneously mixed at molar ratio of 1:1, 1:2 or 1:4 and kept to stand at room temperature for 1 hr. This facilitates the ionic bonding between anionic risedronate and cationic diethylenetriamine (DETA).
  • L-Arginine, L-Lysine were used also to form an ionic bond with risedronate.
  • the concentration of the risedronate ionic complex was 2 wt% and the solution was adjusted to pH 6.
  • hydrogel containing risedronate ionic compound were prepared in accordance witii formulations presented in Table 1.
  • hydrogel was prepared by dissolving polyethylene glycol (PEG), Xanthan gum, carbopol, carbomer and hydroxypropyl cellulose (HPC) in the water solution according to the formula presented below.
  • PEG polyethylene glycol
  • HPC hydroxypropyl cellulose
  • risedronate was added according to the weight ratio shown below.
  • Risedronate ionic compound in Table 1 had a molar ratio of risedronate: DETA of 1:1.
  • the dorsal skin of 6 week old hairless mouse was excised and used for this experiment Hairless mouse was anesthetized with ether and fixed on the surgical table. Subcutaneous fat layer, tissue and blood vessel was carefully removed from epidermal layer.
  • a C-18 column (5 pm diameter particles size, 150 x 4.6 mm dimensions, Waters) was used for separation.
  • a 93/7 of buffer A/bufferB were used as mobile phase, where buffer A consisted of 0.005M pyrophosphate sodium, 0.005M tetrabutyl ammonium hydroxide at the ratio of 1:1, adjusted to pH 7 using phosphoric acid, and buffer B was HPLC grade acetonitrile.
  • the column was operated at a flow rate of 1 ml/min and eluted samples were detected at the UV absorbance at 262 nm with a UV spectrophotometer. Samples were quantified by calibrating the relative area of the sample peaks from the chromatogram. This result is presented in Rg. 2 and Rg. 3.
  • mice Three 6-week old mice were used for each formulation group. Control group used solely risedronate. In two experiment groups (i) the first group used risedronate and L-arginine ionic compound (molar ratio 1:2) and (ii) the second group used risedronate and DEETA ionic compound (molar ratio 1:1). Reagents were mixed homogenously with 1% xanthan gum solution. This solution was applied onto the same size of mouse skin for 30 min, rinsed and monitored for 72 hrs before measuring the skin irritation by taking pictures. The concentration of risedronate was 2 wt %; Xanthan gum was used to increase the viscosity of the solution. Ovariectomized mouse model
  • mice Following a 1 week of adaptation, 14 week old mice underwent ovariectomy. Four days after surgery, drug treatment was initiated once every 2 days, for four weeks. Sham- operated surgical controls underwent laparotomy to give the same stress level as the ovariectomy performed experimental group. The back hair on mice was removed using animal electrical dipper and a shave. After 4 weeks of treatment mouse femurs were sampled and scanned with micro-CT. The range of drug concentration used for the treatment based on risedronate was 0.2 wt% (lowest) to 2 wt% (highest) that were linked with L-arginine via ionic bond. The molar ratio of risedronate to L-arginine is 1:2.
  • anionic risedronate and cationic DETA or amino acids like L-arginine and L-lysine form an ionic compound that makes risedronate less hydrophilic and becomes more hydrophobic, thereby increasing its solubility in organic solvents.
  • a solvent such as xylene (Rg. la) and propylene carbonate (Rg. lb).
  • Rg. 2a shows in vitro skin penetration experiment of risedronate ionic compound, which were previously separated by HPLC.
  • risedronate ionic compound which were previously separated by HPLC.
  • Example group containing risedronate: L- arginine at molar ratio of 1:1, 1:2 and 1:4 showed a time dependent increase in skin penetration.
  • Control group containing risedronate alone alone showed negligent increase of skin penetration during the observation period.
  • Risedronate: L-arginine at the molar ratio of 1:2 showed greater penetration than those at a ratio of 1:4.
  • Rg. 2b shows in nfrpskin penetration of risedronate linked to L-lysine via ionic bonds.
  • Ovariectomized mouse experiment showed an increase in both cortical and cancellous bone area in risedronate treated experimental groups.
  • Experimental group treated with 0.2 wt% risedronate-Arg ionic complex showed a significant increase in bone density, especially in cancellous bone density as shown in micro CT images of Rgs. 7a and 7b.
  • Total bone mineral content, total mineral density and bone volume fraction showed highest increase in 0.2 wt% risedronate-Arg ionic complex treatment group (Rgs. 8a-8e). This increase was higher man that of the sham-operated surgical group, suggesting that bisphosphonate drugs (e.g. risedronate) linked to cationic amine compounds (e.g. Arg) via ion bonds have significant therapeutic effects on osteoporosis by transdermal administration.
  • bisphosphonate drugs e.g. risedronate
  • cationic amine compounds e.g. Arg

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Abstract

The present invention relates to a transdermal drug delivery system comprising (i) a bisphosphonate-based drug and (ii) a cationic amine compound linked to the bisphosphonate-based drug via an ionic bond, and a pharmaceutical composition comprising the drug delivery system for preventing or treating a bone disease. The novel approaches of the present invention is to decrease and increase hydrophilicity and hydrophobicity of bisphosphonate-based drugs, respectively, by forming ionic bonds with cationic amine compounds, contributing to dramatic increase in skin penetration into cell membrane. The present invention completely overcomes shortcomings associated with conventional bisphosphonate drugs for oral administration such as poor bioavailability (as much as 1%) and irritation of gastrointestinal tract.

Description

TRANSDERMAL DRUG DELIVERY SYSTEM AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING BONE DISEASES
BACKGROUND OF THE INVENTION FIELD OF THE INVENTION
The present invention relates to a transdermal drug delivery system comprising (i) a bisphosphonate-based drug and (ii) a cationic amine compound linked to the bisphosphonate- based drug via an ionic bond, and a pharmaceutical composition comprising the drug delivery system for preventing or treating a bone disease.
DESCRIPTION OF THE RELATED ART
Osteoporosis is a common disease characterized by low bone mass and structural deterioration of bone tissue, resulting in decreased bone strength and increased susceptibility to fractures. The risk of fragility fractures increases in the hips and spines of postmenopausal women suffering from osteoporosis. Hyperkyphosis, which refers to an accentuated concave curvature and loss of vertebrata height, commonly affects patients with osteoporosis due to a weakened vertebrate. The cause of osteoporosis is still undear, but low body weighty low calcium intake, sedentary life style and declining estrogen levels at menopause can result in increased bone turnover and a loss of bone mass.
Several therapies and pharmaceutical compounds have demonstrated antifracture efficacy in the treatment of osteoporosis. Most of the compounds are bisphosphonate or other bone strengthening phosphonates [J.Y. Reginster et al., "Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis," Osteoporosis Internationa/, 11:83-91(2000); and Steven T. Ham's, MD et al., "Effects of Risedronate Treatment of Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis, A Randomized controlled Trial," JAMA, 282(14): 1344-52(1999)]. Risedronate (chemical name, [l-hydroxy-2-(3-pyridinyl) ethylidene] bis [phosphonic acid] monosodium salt) is a member of the bisphosphonate family, which is the leading compound for the treatment of osteoporosis (U.S. Pat. No. 5,583,122).
Alendronate, marketed under the brand name FOSAMAX, is one of the nitrogen- containing bisphosphonate agents that specifically inhibit bone resoption mediated by osteoclasis. FOSAMAX is known to be poorly absorbed and cause adverse effects on the gastrointestinal tract. Pamidronate disodium (AREDIA) is a commercially available drug for inhibiting bone resorption, usually administered as an intravenous infusion. Common side effects include pain, stiffening and irritation at the catheter insertion site, loss of appetite, vomiting, diantiea, dyspepsia, esophagitis and stomatitis. Risedronate sodium (trade name ACTONEL) is water soluble but insoluble in organic solvents and has adverse effect on the upper gastrointestinal tract. Ibandronate sodium (trade name BONIVA) is a white/grey colored powder soluble in water but insoluble in organic solvents. This drug has adverse side effects in the upper GI tract. It is recommended that no food be taken for 2 hours after taking etidronate sodium (trade name DIDRONEL) due to its adverse gastrointestinal side-effects. Zbledronate (trade name ZOMETA) is the only bisphosphonate developed solely for use as an IV administration. However, fever, nausea, vomiting and higher incidents of upper GI disorders were reported in some patient groups. Ginical studies suggested continuous and regular dosage of bisphosphonate alone or supplemented with parathyroid hormone, calcium and vitamin D, were an effective treatment method for osteoporosis [American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis, "Recommendations for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis," Arthritis & Rheumatism, 44(7): 1496-1503 (2001); J.Y. Reginster, et al., "Randomized Trial of the Effects of Risedronate on Vertebral Fractures in
Women with Established Postmenopausal Osteoporosis," Osteoporosis International, 11: 83-
91 (2000); Steven T. Harris, MD, et al., "Effects of Risedronate Treatment of Vertebral and
Nonvertebral Fractures in Women With Postmenopausal Osteoporosis, A Randomized controlled Trial," JAMA, 282 (14): 1344-52 (1999)].
Even though calcium supplementation is recommended to high risk or established osteoporosis patients, food containing calcium or calcium supplements can decrease the absorption and efficacy of bisphosphonate. These adverse side effects can be minimized by asking patients to take oral bisphosphonate on an empty stomach with sufficient plain water, and remaining in an upright position for at least 30 minutes. Patients are recommended to take calcium supplement at a different time or day from bisphosphonate dosing [Hardman J.G. and Limbird LE., Goodman & Gilmans' The Pharmacological Baas of Therapeutics, 10th ed„ ppl733-1735 (1997)]. Strict adherence to treatment regimens could be difficult for patients undergoing long-term bisphosphonate treatment "Therefore, developing a simplified drug administration method would benefit the patient and help them adhere to their regimen of drug therapy.
Despite continued improvements in patient dosing regimens, patients experienced adverse GI tract events and noncompliance to daily dosing, strongly suggesting that an alternative delivery method to oral administration of bisphosphonate drug is needed.
Due to problems mentioned above, transdermal delivery may be a desirable alternative to oral treatment. A transdermal delivery system is beneficial when dealing with drugs that can cause adverse GI events or undergo liver metabolism, or for drugs that are poorly absorbed or easily disintegrated in GI. Transporting drugs across the skin layer is known to be an effective way to improve the bioavailability of the drug, and to reduce the potential GI adverse effects
[ 7. Pharmacol. Therapeutics 58, 288-209 (1995)].
As mentioned above, bisphosphonates have low bioavailability and high upper GI adverse effects. Currently developed bisphosphonate-based drugs are highly charged, and have trouble penetrating the lipid bilayer. These drugs also have high affinity to polycationic metal ions, such as calcium ions, that form a water insoluble complex that is difficult to be absorbed by the cell membrane of the GI tract [Int J Pharm 21:143-154(1984)]. The acidic pH of the small intestine (pH 6-8) reduce the absorption of bisphosphonate drugs to less than
10% due to anionic character of bisphosphonate [Barry J. Gertz et al., "Studies of the oral bioavailability of alendronate," din. Pharmacol. Therapeutics^: 288-209 (1995)].
Successful development of a transdermal delivery system of bisphosphonate-based drugs is expected to increase bioavailability and decreased the adverse side effects of the drug, therefore likely leading to increased patient compliance to the drug. Little information is available regarding transdermal delivery system of bisphosphonate throughout the world. This could be due to the low absorption rate of this drug in the patient body. Even oral administration of bisphosphonate shows less than 1% of bioavailability, therefore developing an appropriate penetration activator could successfully enhance the efficacy of this low level of bisphosphonate delivery.
Vertebral fracture is a common consequence of osteoporosis if left untreated. This can lead to chronic pain and decreased quality of life, which in turn could be a great burden on government health care. A therapeutic intervention that decreases fracture risk is essential for reducing the consequences of this debilitating condition.
Successful commercialization of a transdermal delivery system for bisphosphonate using our accumulated knowledge could provide a novel therapeutic intervention of osteoporosis, which would reduce substantial economic burden on patients and government health care systems. The object of this invention is to develop a transdermal delivery system of risedronate and compare its efficacy with oral administration using animal models or healthy human subjects. The ultimate goal of this invention is to apply our accumulated pharmacokinetic and clinical trial data into commercializing of a novel transdermal delivery system for bisphosphonate. However, there is no description of or development of a transdermal delivery system for bisphosphonate in references presented in this invention. Based on our quantification and transdermal penetration experiments with bisphosphonate, we confirmed that a transdermal delivery system compromising bisphosphonate is a safe therapeutic method with a prolonged drug delivery capacity for osteoporosis, thus our invention satisfies the requirements as an alternative to oral drug administration for the treatment of osteoporosis.
Throughout this application, various patents and publications are referenced and citations are provided in parentheses. The disclosure of these patents and publications in their entities are hereby incorporated by references into this application in order to more fully describe this invention and the state of the art to which this invention pertains.
SUMMARY OF THE INVENTION
The present inventors have made intensive researches to enhance skin penetration and in vivo absorption rate of bisphosphonate-based drugs for prevention or treatment of bone diseases. As results, we have discovered that cationic amine compounds linked to bisphosphonate-based drugs via an ionic bond makes the bisphosphonate-based drug less hydrophilic and more hydrophobic, thereby dramatically increasing its skin penetration rate.
Accordingly, it is an object of this invention to provide a transdermal drug delivery system.
It is another object of this invention to provide a pharmaceutical composition for preventing or treating bone disease via transdermal route.
It is still another object of this invention to provide a method for delivering a drug via transdermal route.
It is further object of this invention to a method for preventing or treating a bone disease via transdermal route.
Other objects and advantages of the present invention will become apparent from the detailed description to follow and together with the appended daims and drawings. BRIEF DESCRIPTION OF THE DRAWINGS
Figs, la and lb are graphs showing increased solubility of risedronate linked to diethylenetriamine (DETA) or L-arginine via ionic bonds in xylene or propylene carbonate.
Rg. 2a is a graph showing in vitro αη penetration of risedronate linked to L-arginine via ionic bonds.
Rg. 2b is a graph showing in vitro skin penetration of risedronate linked to L-lysine via ionic bonds.
Rg. 3 is a graph showing in vitro skin penetration of risedronate linked to diethylenetriamine (DETA) via ionic bonds.
Rg.4 is an image showing results of the skin irritation test performed using risedronate with viscosity by Xanthan gum aqueous solution.
Rg.5 is an image showing representative results of the skin irritation test performed using risedronate and L-arginine (molar ratio 1:2) ionic compound with viscosity by Xanthan gum aqueous solution.
Rg.6 is an image showing representative results of the skin irritation test performed using risedronate and diethylenetriamine (DETA, molar ratio 1:1) ionic compound with viscosity by Xanthan gum aqueous solution.
Fig. 7a represents micro CT images of femur from ovariectomized mouse model treated with (a) Sham, (b) OVX-cti, (c) OVX-0.2% or (d) OVX-2%. OVX-cti, OVX-0.2% and OVX-2% represent the drug delivery system of this invention containing 0 wt% risedronate, 0.2 wt% risedronate and 2 wt% risedronate linked to L-arginine, respectively.
Rg. 7b represents two-dimensional micro CT images of femur from ovariectomized mouse model treated with (a) Sham, (b) OVX-cti, (c) OVX-0.2% or (d) OVX-2%.
Rgs. 8a-8e represent BMC (Bone mineral contents), BMD (mg/cc; Bone Mineral Density), TMC (mg; Total Mineral Contents), TMD (mg/cc; Total Mineral Density) and BVF (Bone volume fraction) of ovariectomized mouse model treated with (A) OVX-cti, (B) OVX- 0.2% or (C) OVX-2%.
DETAILED DESCRIPTION OF THIS INVETNION
In one aspect of this invention, there is provided a transdermal drug delivery system comprising (i) a bisphosphonate-based drug and (ii) a cationic amine compound linked to the bisphosphonate-based drug via an ionic bond.
In another aspect of this invention, there is provided a method for delivering a drug via transdermal route, which comprises administering to a subject a composition comprising (i) a bisphosphonate-based drug; and (ii) a cationic amine compound linked to the bisphosphonate-based drug via an ionic bond.
The present inventors have made intensive research to enhance skin penetration and in vivo absorption rate of bisphosphonate-based drugs for prevention or treatment of bone diseases. As results, we have discovered that cationic amine compounds linked to bisphosphonate-based drugs via an ionic bond makes the bisphosphonate-based drug less hydrophilic and more hydrophobic, thereby dramatically increasing its skin penetration rate.
The term used herein "bisphosphonate" refers to a pyrophosphate analogue where the center oxygen atom in a P-O-P moiety is substituted with a carbon atom to from a P-C-P moiety. It should be noted that the term "bisphosphonate" as used herein in referring to the therapeutic agents of the present invention are meant to also encompass diphosphonates, biphosphonic acids, and diphosphonic acids, as well as salts and derivatives of these materials.
According to a preferred embodiment the bisphosphonate-based drug contained in the transdermal drug delivery system of the present invention is represented by the following
Formula 1:
Figure imgf000008_0001
(1)
where Ri is hydrogen, hydroxy or halo; R2 is halo, CMO alkyl, CM0 cydoalkyl, CMO heterocydoalkyl, C O heteroaryl, CMO aryi or CMO arylalkyl; the alkyl, cydoalkyl, aryl, arylalkyl, heterocydoalkyl and heteroaryl are substituted with halo, sulfur, amino, Ci-5 alkylamino or -s dialkylamino and contains 1-3 nitrogen atoms.
The bisphosphonate-based compound earned by the drug delivery system of the present invention is represented by Formula 1. The term used herein "halo" means halogen atoms, for instance induding fluoro, chloro, bromo, and iodo, preferably fluoro, chloro or bromo. The term " -Qo alkyl" is defined herein to be a straight chain or branched chain saturated hydrocarbon groups containing 1-10 carbon atoms, induding methyl, ethyl, /7-propyl, isopropyl, isobutyl, /7-butyl, f-butyl, /7-hexyl, /Hxtyl and foctyl.
The term "cydoalkyl" used herein refers to cyclic hydrocarbon radicals containing 1- 10 carbon atoms, preferably "C3-Q cydoalkyl", induding cydopropyl, cydobutyl and cyclopentyl and cydooctyl. Cydoalkyl may be substituted with alkyl groups having 1-3 carbon atoms, preferably 1-methylcyclopropyl, 2-methylcydopentyl and 2-methylcydooctyl.
The term "heterocydoalkyl" used herein refers to cydoalkyl in which one or more of the atoms forming the ring is a heteroatom selected, independently from N, 0, or S. Non- exdus'rve examples of heterocydoalkyl indude piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, peitiydropyrrolizinyl, 1,4-diazaper ydroepinyl, 1,3-dioxanyl, 1,4-dioxanyl and the like.
The term used herein "aryl" means totally or partially unsaturated, substituted or unsubstituted monocylic or polycydic carbon rings, preferably phenyl, naphthyl, anthracene or pyrene. Meet preferably, the aryl group is substituted or unsubstituted phenyl, naphthyl or pyrene. The monoaryl group, e.g., phenyl may be substituted with various substituents, preferably halo, hydroxy, nitro, cyano, Q-Q alkyl and Q-Q alkoxy group. More preferably, nitro and Q-Q alkoxy groups. The term "alkoxy" means -O alkyl groups, preferably methoxy. Where substituted with Q-Q substituted alkyl groups, halo, preferably chloro or fluoro substituted alkyl substituents may be used.
Where R2 is biary, e.g. naphthyl, it may be substituted in various positions with various substituents, preferably halo, hydroxy, nitro, cyano, straight or branched, substituted or unsubstituted Q-Q alkyl, straight or branched Q-Q alkoxy, or substituted or unsubstituted amino groups, more preferably nitro or Q-Q alkoxy.
The term "arylalkyl (aralkyl)" means aryl groups linked to a structure comprised of one or more alkyl groups, e.g. benzyl. More preferably, arylalkyl is alkylphenyl, alkylnaphthalene, alkyl anthracene, or alkylpyrene, most preferably, benzyl, methylnaphthalene or methylpyrene.
The term "heteroaryl" means heterocyclic aromatic groups containing heteroatoms such as N, O and S. Preferably, heteroaryl is heterobiaryl containing N atom as heteroatom.
The term "alkylamino" means alkyl groups having amino substituents. The term "dialkylamino" refers to two alkyl groups having amino substituents.
According to a preferred embodiment the bisphosphonate-based drug is (4-amino-l- hydroxybutylidene)-bisphosphonate or 4-amine-l-hydroxybutane-l,l-bisphosphonic acid(alendronate); (dichloromethylene)-bisphosphonate (dodronate); (1-hydroxyethylidene)- bisphosphonate(etidronate); [l-hydroxy-3-(methylpentylamino) propylidene] bisphosphonate(evandronate); [(cydoheptylamino)-methylene] bisphosphonate (dmadronate, incadronate); [l-hydroxy-2-imidazo-(l,2-a) pyridine-3-ylethyledne] bisphosphonate (minodronate); (6-amino-l-hydroxyhexyleden) bisphosphonate (neridronate); [3- (dimethylamino)-hydroxy-propylidene] bisphosphonate (olpadronate); (3-amino-l- hydroxypropylidene) bisphosphonate (pamidronate); [l-hydroxy-2-(3-pyridinyl ethylidene] bisphosphonate [[(4-chlorophenyl)thio]-methylene] bisphosphonate (tiludronate); [1- hydroxy-2-(lH-imidazole-l-yl) ethylidene] bisphosphonate (zolendronate); dichloromethylene bisphosphonate (dodronate); paridronate; 5-amino-l-hydroxy pentane-l,l-bisphosphonic add; or difluoro-methane bisphosphonic add; or a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salts" means salts of the bisphosphonate-based drug which are pharmaceutically acceptable, and which possess the desired pharmacological activity. Such salts indude add addition salts formed with inorganic adds such as hydrochloric add, hydrobromic add, sulfuric add, nitric add, phosphoric add, and the like; or with organic adds such as acetic add, propionic add, hexanoic add, heptanoic add, cydopentanepropionic add, glycolic add, pyruvic add, lactic add, malonic add, sucdnic add, malic add, maleic add, flimaric add, tartatic add, citric add, benzoic add, o-( -hydroxybenzoyl)benzoic add, dnnamic add, mandelic add, methanesulfonic add, ethanesulfonic add, 1,2-ethanedisulfonic add, 2- hydroxyethanesulfonic add, benzenesulfonic add, p-chlorobenzenesulfonic add, 2- naphthalenesulfonic add, p-toluenesulfbnic add, camphorsulfonic add, 4- methylbicydo[2.2 ]c)rt-2-ene-l-carboxylic add, glucoheptonic add, 4,4'-methylenebis(3- hydroxy-2-ene-l-carboxylic add), 3-phenylpropionic add, trimethylacetic add, tertiary butylacetic add, lauryl sulfuric add, gluconic add, glutamic add, hydroxynaphthoic add, salicylic add, stearic add, muconic add and the like. Pharmaceutically acceptable salts also indude base addition salts which may be formed when addic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases indude sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and caldum hydroxide. Acceptable organic bases indude ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
In accordance with a preferred embodiment, the cationic amine compound used in the drug delivery system of this invention is selected from the group consisting of an amino add, diethylenetriamine (DETA), spermine, ethylene diamine, triethylene tetramine and tris(2- aminoethyl amine). More preferably, the cationic amine compound is the amino add.
The term used herein "amino add" means compounds having both an amino group and carboxyl group. For example, the amino add indudes alanine, arginine, asparagine, aspartic add, citrulline, cysteine, cystine, selenocysteine, glutamine, glydne, histidine, isoleudne, leudne, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, hydroxy proline, y-carboxyglutamate, or Ophosphoserine. Each amino acid has its typical isoelectric point (pi) where its mean charge becomes zero. For instance, certain amino adds have higher pi values than the physiological pH value (pH 7.4) and are positively charged under physiological pH conditions.
In the present invention, the cationic amine compound is used to form ionic bonds with oxygen anions from phophonate groups of bisphosphonate drugs, decreasing hydrophilic properties of bisphosphonate drugs. Where the amino adds are used as cationic amine compounds, a suitable amino add can be selected depending on pH values of solutions for preparation of materials having ion bonds {i.e., drug delivery system of this invention).
The isoelectric point (pi) values of amino adds are: arginine (pl= 10.76), lysine (pl=9.60), histidine (pl=7.60), proline (pl=6.30), glydne (pl=6.06), isoleudne (pl=6.05), alanine (pl=6.01), leudne (pl=6.01), valine (pl=6.00), tryptophan (pl=5.89), methionine (pl=5.74), serine (pl=5.68), glutamine (pl=5.65), tyrosine (pl=5.64), threonine (pl=5.60), selenocysteine (pl=5.50), phenylalanine (pl=5.49), asparagine (pl=5.41), cysteine (pl=5.05), glutamic add (pl=3.15) and aspartic add (pl=2.85).
For instance, where the solution for preparing the drug delivery system has a pH value of 2, all amino adds described above with pi values of above 2 are positively charged. F*referably, the solution for preparing the drug delivery system has a pH 4-9.
Given a physiological pH of about 7.4, the amino add as cationic amine compound is preferably Arg or Lys.
Non-limiting examples of solvents for forming ion bonds between the bisphosphonate- based drug and the cationic amine compound indude water, ethanol, 1,3-butylene glycol, glycerin, propylene glycol and combinations thereof.
According to a preferred embodiment the drug delivery system has the molar ratio of the bisphosphonate-based drug and the cationic amine compound of 1:0.01-50, more preferably 1:1-40, most preferably 1:2-30. The molar ratio of 1:0.01-50 is advantageous for decreasing hydrophilic properties of bisphosphonate-based drugs by formation of ion bonds.
Where Arg is used as cationic amine compounds, the molar ratio of the bisphosphonate-based drug to the cationic amine compound is preferably 1:0.01-10, more preferably 1:1-6, most preferably 1:1-4. In the case of using diethylenetriamine (DETA) as cationic amine compounds, the molar ratio of the bisphosphonate-based drug to the cationic amine compound is preferably 1:0.01-10, more preferably 1:0.1-6, most preferably 1:0.5-5.
According to a preferred embodiment, the bisphosphonate-based drug is contained in the amount of 0.01-20 wt% (more preferably 0.1-10 wt%, most preferably 1-5 wt%) based on the total weight of the drug delivery system. The amount of 0.01-20 wt% for bisphosphonate-based drugs is desirable for the decrease in hydrophilic properties of bisphosphonate-based drugs by formation of ion bonds.
The drug delivery system of the present invention is developed for overcoming shortcomings associated with oral and intravenous administration of bisphosphonate-based drugs and suggests transdermal administration as alternatives. The drug delivery system may be prepared in various forms such as solution, lotion, W/O emulsion, O/W emulsion, suspension, liposome, gel, hydrogel, cream, paste, patch or ointment
The drug delivery system may be prepared in the form of liposomes using phospholipids.
The term "liposome" encompasses any compartment enclosed by a lipid bilayer. Liposomes are also referred to as lipid vesides. In order to form a liposome the lipid molecules comprise elongated non-polar (hydrophobic) portions and polar (hydrophilic) portions. The hydrophobic and hydrophilic portions of the molecule are preferably positioned at two ends of an elongated molecular structure.
The term "phospholipids" used herein means any phospholipid capable of forming liposomes unless otherwise indicated, including lecithin (phosphatidyl choline), phosphatidyl serine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol and sphingomyelin, but not limited to. Preferably, phospholipids useful in this invention are lecithin, most preferably, hydrogenated lecithin. Lecithin can be made from egg, soybean and other plants, most preferably, soybean. Lecithin useful in this invention, which is synthetic, semisynthetic or natural, includes, but not limited to, soybean lecithin, distearoylphosphatidyldholine, hydrogenated soybean lecithin, egg lecithin, dioleoylphosphatidylcholine, hydrogenated egg lecithin, dielaidoylphosphatidylcholine, dipalmitoylphosphatidylcholine and dimyristoylphosphatidylcholine. Most preferably, phospholipid used in this invention is hydrogenated soybean lecithin. Trie liposomes may be prepared using high pressure homogenizer, sonicator, microfluidizer, extrusion apparatus or French press.
In addition, the drug delivery system may be fabricated in the form of hydrogel by using conventional materials for preparing hydrogel such as natural/synthetic hydrophilic polymers, cross-linking agents, skin softner, transdermal enhancer, preservatives, surfactant and pH modifier. Furthermore, for generating hydrogel, gelation agents may be used, including carbopol and/or xanthan gum, preferably carbopol 60 and/or xanthan gum.
In a specific example for preparing the drug delivery system in the form of hydrogel, polyethyleneglycol, xanthan gum, carbopol, carbomer and hydroxypropylcellulose are added in the amount of 0.01-20 wt% based the total weight to water to prepare hydrogel and then a bisphosphonate-based drug and a cationic amine compound are introduced in the amount of 0.01-20.00 wt%.
In still another aspect of this invention, there is provided a pharmaceutical composition for preventing or treating a bone disease via transdermal route, which comprises (a) a pharmaceutically effective amount of a drug delivery system containing (i) a bisphosphonate- based drug and (ii) a cationic amine compound linked to the bisphosphonate-based drug via an ionic bond; and (b) a pharmaceutically acceptable earner.
In further aspect of this invention, there is provided a method for preventing or treating a bone disease via transdermal route, which comprises administering to a subject a pharmaceutical comprising (a) a pharmaceutically effective amount of a drug delivery system containing (i) a bisphosphonate-based drug and (ii) a cationic amine compound linked to the bisphosphonate-based drug via an ionic bond; and (b) a pharmaceutically acceptable earner.
Since the present pharmaceutical composition comprises the drug delivery system described above, the common descriptions between them are omitted in order to avoid undue redundancy leading to the complexity of this specification.
According to a preferred embodiment the drug delivery system is contained in the amount of 0.001-50 wt% (more preferably 0.1-40 wt%, most preferably 10-30 wt ) based on the total weight of the composition. The pharmaceutical composition of this invention is provided in various forms such as solution, lotion, W/O emulsion, O/W emulsion, suspension, liposome, gel, hydrogel, cream, paste, patch or ointment
According to a preferred embodiment, the bone disease prevented or treated by the present pharmaceutical composition includes osteoporosis, Pagers disease, rickets, osteopenia, rheumatoid arthritis, osteomalacia, renal osteodystrophy, osteogenesis imperfecta, hyperthyroidism, bone loss due to rheumatoid arthritis, inflammatory arthritis, subchondral osteosclerosis, subchondral osteocystoma, osteophytosis, athralgia, hyperparathyroidism, sarcoidosis and hypercalcemia, more preferably osteoporosis, Pagers disease, rickets, osteomalacia, renal osteodystrophy, hyperthyroidism and hyperparathyroidism, most preferably osteoporosis.
In the pharmaceutical compositions of this invention, the pharmaceutically acceptable earner may be conventional one for formulation, including carbohydrates (e.g., lactose, amylose, dextrose, sucrose, sorbitol, mannitol, starch, cellulose), gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpynOlidone, water, salt solutions, alcohols, gum arabic, syrup, vegetable oils (e.g., com oil, cotton-seed oil, peanut oil, olive oil, coconut oil), polyethylene glycols, methyl cellulose, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil, but not limited to. The pharmaceutical compositions of this invention, further may contain wetting agent, sweetening agent, emulsifier, buffer, suspending agent, preservatives, flavors, perfumes, lubricant, stabilizer, or mixtures of these substances. Details of suitable pharmaceutically acceptable cam'ersand formulations can be found in Remington's Pharmaceutical Sciences (19th ed., 1995), which is incorporated herein by reference.
The pharmaceutical composition of this invention may be administered via transdermal route. The correct dosage of the pharmaceutical compositions of this invention will be varied according to the particular formulation, the mode of application, age, body weight and sex of the patient, diet, time of administration, condition of the patient, drug combinations, reaction sensitivities and severity of the disease. It is understood that the ordinary skilled physician will readily be able to determine and prescribe a correct dosage of this pharmaceutical compositions. Where the pharmaceutical compositions is administered via transdermal route, suitable dosage unit for human host is to administer once a day with the composition of 0.001-100 mg/kg(body weight) per day.
According to the conventional techniques known to thoseskilled in the art; the pharmaceutical compositions of this invention can be formulatedwith pharmaceutical acceptable carrier and/or vehicle as described above, finally providing several forms including a unit dosage form.
The features and advantages of the present invention will be summarized as follows:
(a) The present invention provides drug delivery systems and pharmaceutical compositions ensuring trandermal administration of conventional bisphosphonate-based drugs by forming ionic bonds between bisphosphonate-based drugs and cationic amine compounds.
(b) The novel approaches of the present invention is to decrease hydrophilicity and increase hydrophobicity of bisphosphonate-based drugs by forming ionic bonds with cationic amine compounds, contributing to dramatic increase in skin penetration into cell membrane.
(c) The present invention completely overcomes shortcomings associated with conventional bisphosphonate drugs for oral administration such as poor bioavailability (as much as 1%) and irritation of gastrointestinal tract
(d) The drug delivery systems and pharmaceutical compositions of this invention may be prepared in a relatively convenient fashion with no decrease in therapeutic effects of bisphosphonate drugs.
(e) The drug delivery systems and pharmaceutical compositions of this invention may be transdermally applied with much higher patient compliance suffering from bone diseases, particularly osteoporosis.
The present invention will now be described in further detail by examples. It would be obvious to those skilled in the art that these examples are intended to be more concretely illustrative and the scope of the present invention as set forth in the appended daims is not limited to or by the examples.
EXAMPLES MATERIALS AND METHODS Materials
.Experimental animals
Male hairless mice (6-8 weeks old) purchased from Orientalbio, Inc. (Korea) were used in our In vitro experiment within one week of delivery.
Reagents
Risedronic acid, a potent bisphosphonate was provided by Lanfang Shinya Chemical. L- Arginine, L-Lysine and diethylenetriamine (DETA) serving as cationic binding partners were purchased from Sigma Chemical (St Louis, MO, USA). Sodium chloride as receptor media was purchased from Daejung (Korea). Pyrophosphate sodium (Samchun, Korea), tetrabutyl ammonium hydroxide (TBAH; Sigma Chemical Co., St Louis, MO, USA) and phosphoric acid (Sigma Chemical Co., St Louis, MO, USA) were used as HPLC buffer. HPLC grade aceton'rtril (Rscher, USA) was used. Water used in these experiments was distilled and purified through ultra water purification system.
Equipment and apparatus
High performance liquid chromatography (HPLC; Agilent 1100 series, USA) and Franz Cell Permeation system (Labotech, Korea) were used in these experiments. Preparation of risedronate ionic compound
Risedronate and diethylenetriamine (DETA) each dissolved in distilled water were homogeneously mixed at molar ratio of 1:1, 1:2 or 1:4 and kept to stand at room temperature for 1 hr. This facilitates the ionic bonding between anionic risedronate and cationic diethylenetriamine (DETA). L-Arginine, L-Lysine were used also to form an ionic bond with risedronate. The concentration of the risedronate ionic complex was 2 wt% and the solution was adjusted to pH 6.
Preparation of transdermal delivery system (hydroqel) comprising risedronate ionic complex As formulation examples for this invention, hydrogel containing risedronate ionic compound were prepared in accordance witii formulations presented in Table 1. First, hydrogel was prepared by dissolving polyethylene glycol (PEG), Xanthan gum, carbopol, carbomer and hydroxypropyl cellulose (HPC) in the water solution according to the formula presented below. Then, the active compound, risedronate was added according to the weight ratio shown below. Risedronate ionic compound in Table 1 had a molar ratio of risedronate: DETA of 1:1.
TABLE 1
Figure imgf000017_0001
Skin penetration test of risedronate ionic compound
(1) Skin extraction
The dorsal skin of 6 week old hairless mouse was excised and used for this experiment Hairless mouse was anesthetized with ether and fixed on the surgical table. Subcutaneous fat layer, tissue and blood vessel was carefully removed from epidermal layer.
(2) Skin penetration test
The skin excised from hairless mouse, as mentioned above, were loaded with 200 μΙ of risedronate ionic compound, attached and mounted on Franz Cell Permeation System. Ten ml of 0.9% sodium chloride were added to the receptor cell. 0.5 ml of permeated solution was collected from receptor cell at 2, 4, 8, 12 and 24 hrs. The receptor cell was supplemented with the same volume of 0.9% sodium chloride. Thirty μΙ of sample was injected and the accumulated penetration amount was calculated by integrating the peak area from the HPLC chromatogram.
(3) Quantification of risedronate by HPLC
A C-18 column (5 pm diameter partide size, 150 x 4.6 mm dimensions, Waters) was used for separation. A 93/7 of buffer A/bufferB were used as mobile phase, where buffer A consisted of 0.005M pyrophosphate sodium, 0.005M tetrabutyl ammonium hydroxide at the ratio of 1:1, adjusted to pH 7 using phosphoric acid, and buffer B was HPLC grade acetonitrile. The column was operated at a flow rate of 1 ml/min and eluted samples were detected at the UV absorbance at 262 nm with a UV spectrophotometer. Samples were quantified by calibrating the relative area of the sample peaks from the chromatogram. This result is presented in Rg. 2 and Rg. 3.
(4) Skin irritation test
Three 6-week old mice were used for each formulation group. Control group used solely risedronate. In two experiment groups (i) the first group used risedronate and L-arginine ionic compound (molar ratio 1:2) and (ii) the second group used risedronate and DEETA ionic compound (molar ratio 1:1). Reagents were mixed homogenously with 1% xanthan gum solution. This solution was applied onto the same size of mouse skin for 30 min, rinsed and monitored for 72 hrs before measuring the skin irritation by taking pictures. The concentration of risedronate was 2 wt %; Xanthan gum was used to increase the viscosity of the solution. Ovariectomized mouse model
Following a 1 week of adaptation, 14 week old mice underwent ovariectomy. Four days after surgery, drug treatment was initiated once every 2 days, for four weeks. Sham- operated surgical controls underwent laparotomy to give the same stress level as the ovariectomy performed experimental group. The back hair on mice was removed using animal electrical dipper and a shave. After 4 weeks of treatment mouse femurs were sampled and scanned with micro-CT. The range of drug concentration used for the treatment based on risedronate was 0.2 wt% (lowest) to 2 wt% (highest) that were linked with L-arginine via ionic bond. The molar ratio of risedronate to L-arginine is 1:2. RESULTS
At optimal pH, anionic risedronate and cationic DETA or amino acids like L-arginine and L-lysine form an ionic compound that makes risedronate less hydrophilic and becomes more hydrophobic, thereby increasing its solubility in organic solvents. In Rgs. la and lb, as the ratio of added DETA or L-arginine is increased, there was an increase in the amount of risedronate dissolved in a solvent such as xylene (Rg. la) and propylene carbonate (Rg. lb).
Rg. 2a shows in vitro skin penetration experiment of risedronate ionic compound, which were previously separated by HPLC. [Experimental group containing risedronate: L- arginine at molar ratio of 1:1, 1:2 and 1:4 showed a time dependent increase in skin penetration. Control group containing risedronate alone alone showed negligent increase of skin penetration during the observation period. Risedronate: L-arginine at the molar ratio of 1:2 showed greater penetration than those at a ratio of 1:4.
Rg. 2b shows in nfrpskin penetration of risedronate linked to L-lysine via ionic bonds. Experimental groups containing risedronate: L-lysine at molar ratios of 1:2 and 1:4 showed a time dependent increase in skin penetration. Control group containing risedronate alone showed negligent increase of skin penetration during the observation period. Risedronate: L- lysine at the molar ratio of 1:4 showed greater penetration than those of at a ratio of 1:2.
In addition, as shown in Rg. 3, the experimental group containing risedronate: DETA at molar ratio of 1:1 and 1:4 showed a time dependent increase in penetration. Control groups containing risedronate alone did not show any increase of transdermal penetration during the time observed.
As shown in Rgs. 4-6, no skin irritation was observed in either control or experiment groups.
Ovariectomized mouse experiment showed an increase in both cortical and cancellous bone area in risedronate treated experimental groups. Experimental group treated with 0.2 wt% risedronate-Arg ionic complex showed a significant increase in bone density, especially in cancellous bone density as shown in micro CT images of Rgs. 7a and 7b. Total bone mineral content, total mineral density and bone volume fraction showed highest increase in 0.2 wt% risedronate-Arg ionic complex treatment group (Rgs. 8a-8e). This increase was higher man that of the sham-operated surgical group, suggesting that bisphosphonate drugs (e.g. risedronate) linked to cationic amine compounds (e.g. Arg) via ion bonds have significant therapeutic effects on osteoporosis by transdermal administration.
Having described a preferred embodiment of the present invention, it is to be understood that variants and modifications thereof falling within the spirit of the invention may become apparent to those skilled in this art, and the scope of this invention is to be determined by appended daims and their equivalents.

Claims

Whatisdaimed is:
1. A transdermal drug delivery system, comprising (i) a bisphosphonate-based drug; and (ii) a cationic amine compound linked to the bisphosphonate-based drug via an ionic bond.
2. The transdermal drug delivery system according to daim 1, wherein the bisphosphonate- based drug is a compound represented by the following Formula 1:
Figure imgf000021_0001
where Ri is hydrogen, hydroxy or halo; R2 is halo, CM0 alkyl, CM0 cydoalkyl, Q-io heterocydoalkyl, CMO heteroaryl, Cuo aryl or Cuo arylalkyl; the alkyl, cydoalkyl, aryl, arylalkyl, heterocydoalkyl and heteroaryl are substituted with halo, sulfur, amino, Ci-5 alkylamino or Q-s dialkylamino and contains 1-3 nitrogen atoms.
3. The transdermal drug delivery system according to daim 1 or 2, wherein the bisphosphonate-based drug is (4-amino-l-hydroxybutylidene)-bisphosphonate or 4-amine-l- hydroxybutane-l,l-bisphosphonic add(alendronate); (dichloromethylene)-bisphosphonate (dodronate); (l-hydroxyethylidene)-bisphosphonate(etidronate); [l-hydroxy-3- (methylpentylamino) propylidene] bisphosphonateCevandronate); [(cydoheptylamino)- methylene] bisphosphonate (dmadronate, incadronate); [l-hydroxy-2-imidazo-(l,2-a) pyridine-3-ylethyledne] bisphosphonate (minodronate); (6-amino-l-hydroxyhexyleden) bisphosphonate (neridronate); [3-(dimethylamino)-hydroxy-propylidene] bisphosphonate (olpadronate); (3-amino-l-hydroxypropylidene) bisphosphonate (pamidronate); [l-hydroxy-2- (3-pyridinyl)-ethylidene] bisphosphonate [[(4-chlorophenyl)thio]-methylene] bisphosphonate (tiludronate); [l-hydroxy-2-(lH-imidazole-l-yl) ethylidene] bisphosphonate (zolendronate); dichloromethylene bisphosphonate (dodronate); paridronate; 5-amino-l-hydroxy pentane- 1,1-bisphosphonic add; or difluoro-methane bisphosphonic add; or a pharmaceutically acceptable salt thereof.
4. The transdermal drug delivery system according to daim 1, wherein trie cationic amine compound is selected from trie group consisting of an amino add, diethylenetriamine (DEETA), spermine, ethylene diamine, triethylene tetramine and tris(2-aminoethyl amine).
5. The transdermal drug delivery system according to daim 4, wherein the cationic amine compound is the amino add.
6. The transdermal drug delivery system according to daim 5, wherein the amino add is arginine or lysine.
7. The transdermal drug delivery system according to daim 1, wherein the drug delivery system has the molar ratio of the bisphosphonate-based drug and the cationic amine compound of 1:0.01-50.
8. The transdermal drug delivery system according to daim 1, wherein the bisphosphonate- based drug is contained in the amount of 0.01-20 wt% based on trie total weight of the drug delivery system.
9. The transdermal drug delivery system according to daim 1, wherein the drug delivery system is in the form of solution, lotion, W/O emulsion, O/W emulsion, suspension, liposome, gel, hydrogel, cream, paste, patch or ointment.
10. A pharmaceutical composition for preventing or treating a bone disease via transdermal route, which comprises (a) a pharmaceutically effective amount of a drug delivery system containing (i) a bisphosphonate-based drug and (ii) a cationic amine compound linked to the bisphosphonate-based drug via an ionic bond; and (b) a pharmaceutically acceptable earner.
11. The pharmaceutical composition according to daim 10, wherein the bisphosphonate- based drug is a compound represented by the following Formula 1:
Figure imgf000023_0001
(i) where Ri is hydrogen, hydroxy or halo; l¾ is halo, CM0 alkyl, CMO cydoalkyl, CM0 heterocydoalkyl, CMO heteroaryl, CMO ar l or CMO arylalkyl; the alkyl, cydoalkyl, aryl, arylalkyl, heterocydoalkyl and heteroaryl are substituted with halo, sulfur, amino, Q-s alkylamino or dialkylamino and contains 1-3 nitrogen atoms.
12. The pharmaceutical composition according to daim 10 or 11, wherein the bisphosphonate-based drug is (4-amino-l-hydroxybutylidene)-bisphosphonate or 4-amine-l- hydrOxybutane-l,l-bisphosphonic add(alendronate); (dichloromethylene)-bisphosphonate (dodronate); (l-hydroxyethylidene)-bisphosphonate(etidronate); [l-hydroxy-3- (methylpentylamino) propylidene] bisphosphonate(evandronate); [(cydoheptylamino)- methylene] bisphosphonate (dmadronate, incadronate); [l-hydroxy-2-imidazo-(l,2-a) pyridine-3-ylethyledne] bisphosphonate (minodronate); (6-amino-l-hydroxyhexyleden) bisphosphonate (neridronate); [3-(dimethylamino)-hydrOxy-propylidene] bisphosphonate (olpadronate); (3-amino-l-hydroxypropylidene) bisphosphonate (pamidronate); [l-hydroxy-2- (3-pyridinyl)-ethylidene] bisphosphonate [[(4-chlorophenyl)thio]-methylene] bisphosphonate (tiludronate); [l-hydroxy-2-(lH-imidazole-l-yl) ethylidene] bisphosphonate (zolendronate); dichloromethylene bisphosphonate (dodronate); paridronate; 5-amino-l-hydroxy pentane- 1,1-bisphosphonic add; or difluoro-methane bisphosphonic add; or a pharmaceutically acceptable salt thereof.
13. The pharmaceutical composition according to daim 10, wherein the cationic amine compound is selected from the group consisting of an amino add, diethylenetriamine (DETA), spermine, ethylene diamine, methylene tetramine and tris(2-aminoethyl amine).
14. The pharmaceutical composition according to daim 13, wherein the cationic amine compound is the amino acid.
15. The pharmaceutical composition according to daim 14, wherein the amino add is arginine or lysine.
16. The pharmaceutical composition according to daim 10, wherein the drug delivery system has the molar ratio of the bisphosphonate-based drug and the cationic amine compound of 1:0.01-50.
17. The pharmaceutical composition according to daim 10, wherein the bisphosphonate- based drug is contained in the amount of 0.01-20 wt% based on the total weight of the drug delivery system.
18. The pharmaceutical composition according to daim 10, wherein the drug delivery system is contained in the amount of 0.001-50 wt% based on the total weight of the composition.
19. The pharmaceutical composition according to claim 10, wherein the composition is solution, lotion, W/O emulsion, O/W emulsion, suspension, liposome, gel, hydrogel, cream, paste, patch or ointment
20. The pharmaceutical composition according to daim 10, wherein the bone disease is osteoporosis, Pagefs disease, rickets, osteopenia, rheumatoid arthritis, osteomalada, renal osteodystrophy, osteogenesis imperfecta, hyperthyroidism, bone loss due to rheumatoid arthritis, inflammatory arthritis, subchondral osteosderosis, subchondral osteocystoma, osteophytosis, athralgia hyperparathyroidism, sarcoidosis or hypercalcemia.
21. A method for delivering a drug via transdermal route, which comprises administering to a subject a composition comprising (i) a bisphosphonate-based drug; and (ii) a cationic amine compound linked to the bisphosphonate-based drug via an ionic bond.
22. The method according to daim 21, wherein the bisphosphonate-based drug is a compound represented by the following Formula 1:
Figure imgf000025_0001
where Ri is hydrogen, hydroxy or halo; R2 is halo, CM0 alkyl, CM0 cydoalkyl, CM0 heterocydoalkyl, Cuo heteroaryl, CMO aryl or Q-io arylalkyl; the alkyl, cydoalkyl, aryl, arylalkyl, heterocydoalkyl and heteroaryl are substituted with halo, sulfur, amino, Ci-5 alkylamino or C1-5 dialkylamino and contains 1-3 nitrogen atoms.
23. The method according to daim 21 or 22, wherein the bisphosphonate-based drug is (4- amino-l-hydroxybutylidene)-bisphosphonate or 4-amin l-hydroxybutane-l, 1-bisphosphonic add(alendronate); (dichloromethylene)-bisphosphonate (dodronate); (1-hydroxyethylidene)- bisphosphonate(etidronate); [l-hydroxy-3-(methylpentylamino) propylidene] bisphosphonate(evandronate); [(cydoheptylamino)-methylene] bisphosphonate (dmadronate, incadronate); [l-hydroxy-2-imidazo-(l,2-a) pyridine-3-ylethyledne] bisphosphonate (minodronate); (6-amino-l-hydroxyhexyleden) bisphosphonate (neridronate); [3- (dimethylamino)-hydroxy-propylidene] bisphosphonate (olpadronate); (3-amino-l- hydroxypropylidene) bisphosphonate (pamidronate); [l-hydroxy-2-(3-pyridinyl)-ethylidene] bisphosphonate [[(4-chlorophenyl)thio]-methylene] bisphosphonate (tiludronate); [1- hydroxy-2-(lH-imidazole-l-yl) ethylidene] bisphosphonate (zolendronate); dichloromethylene bisphosphonate (dodronate); paridronate; 5-amino-l-hydroxy pentane-l,l-bisphosphonic add; or difluoro-methane bisphosphonic add; or a pharmaceutically acceptable salt thereof.
24. The method according to daim 21, wherein the cationic amine compound is selected from the group consisting of an amino add, diethylenetriamine (DETA), spennine, ethylene diamine, triethylene tetramine and tris(2-aminoethyl amine).
25. The method according to daim 24, wherein the cationic amine compound is the amino acid.
26. The method according to daim 25, wherein the amino add is arginine or lysine.
27. The method according to daim 21, wherein the drug delivery system has the molar ratio of the bisphosphonate-based drug and the cationic amine compound of 1:0.01-50.
28. The method according to daim 21, wherein the bisphosphonate-based drug is contained in the amount of 0.01-20 wt% based on the total weight of the drug delivery system.
29. The method according to daim 21, wherein the drug delivery system is in the form of solution, lotion, W/O emulsion, O/W emulsion, suspension, liposome, gel, hydrogel, cream, paste, patch or ointment
30. A method for preventing or treating a bone disease via transdermal route, which comprises administering to a subject a pharmaceutical comprising (a) a pharmaceutically effective amount of a drug delivery system containing (i) a bisphosphonate-based drug and (ii) a cationic amine compound linked to the bisphosphonate-based drug via an ionic bond; and (b) a pharmaceutically acceptable earner.
31. The method according to daim 30, wherein the bisphosphonate-based drug is a compound represented by the following Formula 1:
Figure imgf000026_0001
(1) where Ri is hydrogen, hydroxy or halo; R2 is halo, Cuo alkyl, CM0 cydoalkyl, Cuo heterocydoalkyl, Cuo heteroaryl, Q-io aryl or C 0 arylalkyl; the alkyl, cydoalkyl, aryl, arylalkyl, heterocydoalkyl and heteroaryl are substituted with halo, sulfur, amino, Ci-5 aikylamino or Q-s dialkylamino and contains 1-3 nitrogen atoms.
32. The method according to daim 30 or 31, wherein the bisphosphonate-based drug is (4- amino-l-hydroxybutylidene)-bisphosphonate or 4-amine-l-hydroxybutane-l,l-bisphosphonic add(alendronate); (dichloromethylene)-bisphosphonate (dodronate); (1-hydroxyethylidene)- bisphosphonate(etidronats); [l-hydroxy-3-(methylpentylamino) propylidene] bisphosphonate(evandiOnate); [(cydoheptylamino)-methylene] bisphosphonate (dmadronate, incadronate); [l-hydroxy-2-imidazo-(l,2-a) pyridine-3-ylethyledne] bisphosphonate (minodronate); (6-amino-l-hydroxyhexyleden) bisphosphonate (neridronate); [3- (dimethylamino)-hydroxy-propylidene] bisphosphonate (olpadronate); (3-amino-l- hydroxypropylidene) bisphosphonate (pamidronate); [l-hydroxy-2-(3-pyridinyl)-ethylidene] bisphosphonate [[(4-chlorophenyl)thio]-methylene] bisphosphonate (tiludronate); [1- hydroxy-2-(lH-imidazole-l-yl) ethylidene] bisphosphonate (zolendronate); dichloromethylene bisphosphonate (dodronate); paridronate; 5-amino-l-hydroxy pentane-l,l-bisphosphonic add; or difluoro-methane bisphosphonic add; or a pharmaceutically acceptable salt thereof.
33. The method according to daim 30, wherein the cationic amine compound is selected from the group consisting of an amino add, diethylenetriamine (DETA), spermine, ethylene diamine, Methylene tetramine and tris(2-aminoethyl amine).
34. The method according to daim 33, wherein the cationic amine compound is the amino add.
35. The method according to daim 34, wherein the amino add is arginine or lysine.
36. The method according to daim 30, wherein the drug delivery system has the molar ratio of the bisphosphonate-based drug and the cationic amine compound of 1:0.01-50.
37. The method according to daim 30, wherein the bisphosphonate-based drug is contained in the amount of 0.01-20 wt based on the total weight of the drug delivery system.
38. The method according to daim 30, wherein the drug delivery system is contained in the amount of 0.001-50 wt% based on the total weight of the composition.
39. The method according to daim 30, wherein the composition is solution, lotion, W/O emulsion, O/W emulsion, suspension, liposome, gel, hydrogel, cream, paste, patch or ointment.
40. The method according to daim 30, wherein the bone disease is osteoporosis, Pagefs disease, rickets, osteopenia, rheumatoid arthritis, osteomalada, renal osteodystrophy, osteogenesis imperfecta, hyperthyroidism, bone loss due to rheumatoid arthritis, inflammatory arthritis, subchondral osteosderosis, subchondral osteocystoma, osteophytosis, athralgia ,hyperparathyroidism, sarcoidosis or hypercalcemia.
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