KR20130003099A - An anti-eumycetes composition and a method of the same - Google Patents
An anti-eumycetes composition and a method of the same Download PDFInfo
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- KR20130003099A KR20130003099A KR1020110064152A KR20110064152A KR20130003099A KR 20130003099 A KR20130003099 A KR 20130003099A KR 1020110064152 A KR1020110064152 A KR 1020110064152A KR 20110064152 A KR20110064152 A KR 20110064152A KR 20130003099 A KR20130003099 A KR 20130003099A
- Authority
- KR
- South Korea
- Prior art keywords
- itraconazole
- ammonium
- antifungal
- composition
- levan
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 49
- 238000000034 method Methods 0.000 title claims abstract description 19
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims abstract description 60
- 229960004130 itraconazole Drugs 0.000 claims abstract description 60
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000002114 nanocomposite Substances 0.000 claims abstract description 26
- AIHDCSAXVMAMJH-GFBKWZILSA-N levan Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@@H]1[C@@H](O)[C@H](O)[C@](CO)(CO[C@@H]2[C@H]([C@H](O)[C@@](O)(CO)O2)O)O1 AIHDCSAXVMAMJH-GFBKWZILSA-N 0.000 claims abstract description 24
- 230000000843 anti-fungal effect Effects 0.000 claims abstract description 16
- 229940121375 antifungal agent Drugs 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 150000004676 glycans Chemical class 0.000 claims abstract 2
- 229920001282 polysaccharide Polymers 0.000 claims abstract 2
- 239000005017 polysaccharide Substances 0.000 claims abstract 2
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- 238000012986 modification Methods 0.000 claims description 4
- 229910000273 nontronite Inorganic materials 0.000 claims description 4
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- FJLUATLTXUNBOT-UHFFFAOYSA-N 1-Hexadecylamine Chemical compound CCCCCCCCCCCCCCCCN FJLUATLTXUNBOT-UHFFFAOYSA-N 0.000 claims description 3
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 claims description 3
- PLZVEHJLHYMBBY-UHFFFAOYSA-N Tetradecylamine Chemical compound CCCCCCCCCCCCCCN PLZVEHJLHYMBBY-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- -1 beidelite Inorganic materials 0.000 claims description 3
- 229910000278 bentonite Inorganic materials 0.000 claims description 3
- 239000000440 bentonite Substances 0.000 claims description 3
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 claims description 3
- YOUGRGFIHBUKRS-UHFFFAOYSA-N benzyl(trimethyl)azanium Chemical compound C[N+](C)(C)CC1=CC=CC=C1 YOUGRGFIHBUKRS-UHFFFAOYSA-N 0.000 claims description 3
- 229920006317 cationic polymer Polymers 0.000 claims description 3
- 239000003093 cationic surfactant Substances 0.000 claims description 3
- RLGQACBPNDBWTB-UHFFFAOYSA-N cetyltrimethylammonium ion Chemical compound CCCCCCCCCCCCCCCC[N+](C)(C)C RLGQACBPNDBWTB-UHFFFAOYSA-N 0.000 claims description 3
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical group O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 claims description 3
- OGQYPPBGSLZBEG-UHFFFAOYSA-N dimethyl(dioctadecyl)azanium Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC OGQYPPBGSLZBEG-UHFFFAOYSA-N 0.000 claims description 3
- KWLMIXQRALPRBC-UHFFFAOYSA-L hectorite Chemical compound [Li+].[OH-].[OH-].[Na+].[Mg+2].O1[Si]2([O-])O[Si]1([O-])O[Si]([O-])(O1)O[Si]1([O-])O2 KWLMIXQRALPRBC-UHFFFAOYSA-L 0.000 claims description 3
- 229910000271 hectorite Inorganic materials 0.000 claims description 3
- 239000010445 mica Substances 0.000 claims description 3
- 229910052618 mica group Inorganic materials 0.000 claims description 3
- 229910052901 montmorillonite Inorganic materials 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- PDSVZUAJOIQXRK-UHFFFAOYSA-N trimethyl(octadecyl)azanium Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)C PDSVZUAJOIQXRK-UHFFFAOYSA-N 0.000 claims description 3
- GLFDLEXFOHUASB-UHFFFAOYSA-N trimethyl(tetradecyl)azanium Chemical compound CCCCCCCCCCCCCC[N+](C)(C)C GLFDLEXFOHUASB-UHFFFAOYSA-N 0.000 claims description 3
- ZNEOHLHCKGUAEB-UHFFFAOYSA-N trimethylphenylammonium Chemical compound C[N+](C)(C)C1=CC=CC=C1 ZNEOHLHCKGUAEB-UHFFFAOYSA-N 0.000 claims description 3
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical compound CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 0.000 claims description 2
- 150000002894 organic compounds Chemical class 0.000 claims description 2
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical compound [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 claims description 2
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- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 7
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- 239000000843 powder Substances 0.000 description 6
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
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- 229920003149 Eudragit® E 100 Polymers 0.000 description 3
- 239000011149 active material Substances 0.000 description 3
- 229920000249 biocompatible polymer Polymers 0.000 description 3
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 3
- 238000005341 cation exchange Methods 0.000 description 3
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- DXCOFNFGKMHPFL-UHFFFAOYSA-N C(C1=CC=CC=C1)[N+](CC)(CC)CC.C(C1=CC=CC=C1)[N+](CC)(CC)CC Chemical compound C(C1=CC=CC=C1)[N+](CC)(CC)CC.C(C1=CC=CC=C1)[N+](CC)(CC)CC DXCOFNFGKMHPFL-UHFFFAOYSA-N 0.000 description 1
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- IHTAVMHKEISGKU-UHFFFAOYSA-N N[SiH3].N[SiH3] Chemical compound N[SiH3].N[SiH3] IHTAVMHKEISGKU-UHFFFAOYSA-N 0.000 description 1
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- 238000010521 absorption reaction Methods 0.000 description 1
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- 239000003429 antifungal agent Substances 0.000 description 1
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- 150000003851 azoles Chemical class 0.000 description 1
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- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
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- 239000000138 intercalating agent Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- VHVPQPYKVGDNFY-ZPGVKDDISA-N itraconazole Chemical compound O=C1N(C(C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-ZPGVKDDISA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
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- 239000002547 new drug Substances 0.000 description 1
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- 150000003904 phospholipids Chemical class 0.000 description 1
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- 230000002265 prevention Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 235000015136 pumpkin Nutrition 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
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- 238000002407 reforming Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/50—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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an antifungal nanocomposite composition and a method for preparing the same for improving solubility, preventing recrystallization, and ultimately improving bioavailability of itraconazole, a poorly soluble drug. The present invention provides a nanocomposite drug delivery composition comprising a system using leban, a polysaccharide-based material having excellent biocompatibility, as a solubilizer and a recrystallization inhibitor, and a layered silicate, an inorganic additive, as a molecular agent of a drug, and its It relates to a manufacturing method.
Index
Drug Delivery Technology, Itraconazole, Levan, Solubility Improvement
(Drug delivery system, Itraconazole, Levan, Solubility improvement)
Description
The present invention is a nanocomposite antifungal nanocomposite composition composed of levan and layer silicate for improving solubility, preventing recrystallization, controlling dissolution rate and improving bioavailability of itraconazole, a poorly soluble drug, and It is about the manufacturing method.
Itraconazole is a drug known to exhibit excellent efficacy in treating mycosis among tricyclic azole compounds. Itraconazole has the chemical name (±) -cis-4- [4- [4- [4-[[2- (2,4-dichlorophenyl) -2- (1H-1,2, 4-triazol-1-yl Methyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H-1, It is represented by 2,4-triazol-3one, has a molecular formula of C35H30C12N8O4 and a molecular weight of 705.64, and the powder is white to pale yellow. It is difficult to dissolve in water (1 μg / ml or less), slightly soluble in alcohol (300 μg / ml), well soluble in methylene chloride (239 mg / ml), and weakly basic (pKa = 3.7). Almost ionized in the situation. Pharmacologically, it is known to exhibit antifungal activity in a wide range of areas upon oral, injection and topical application.
In terms of pharmaceuticals, itraconazole is difficult to develop into an effective dosage form as a poorly soluble drug which is pH dependent and insoluble in water. In the case of poorly soluble drugs, since the dissolution from the solid preparation is slow and the dissolution acts as a rate-determining step in the absorption process, the dissolution rate directly affects the expression time, strength and duration of the drug. Therefore, preparations of poorly soluble drugs require attempts to increase the dissolution rate of the drug. Pharmaceutical methods for increasing the dissolution rate of poorly soluble drugs include particle size, polymorphism, amorphous form, mixed grinding, and high-solid complex of the drug. , Clathrate compounds, solvates, protein bonds, and interactions with additives. Prior arts related to the development of effective formulations of itraconazole include the following.
WO 1985/02767 and US Pat. No. 4,764,604 attempt to increase the solubility and bioavailability of drugs by forming complexes using cyclodextrins or derivatives thereof, and in WO 1990/11754 reducing the particle size of drugs. It was developed as an aerosol formulation that can be easily administered by inhalation. In WO 1993/15719, a liposome containing itraconazole was prepared using phospholipid and a solvent system, and WO 1995/31178. Discloses a method of preparing an emulsion or an aqueous solution using a cyclodextrin or a derivative thereof and then formulating the drug into an external preparation capable of adhering the drug to the nasal or vaginal mucosa.
However, for oral administration, there was a need to further improve the bioavailability of itraconazole, and such attempts include the following prior arts.
In WO 1994/05263, a pharmaceutical coating layer containing a hydrophilic polymer, hydroxypropylmethylcellulose and a drug is coated on a very small sugar sphere of about 25 to 30 mesh to increase the solubility and bioavailability of the drug. Forbidden bead formulation drugs are disclosed, and SPORANOX ™ is now commercially available in formulations using this technique. In WO 1997/44014, a drug and a water-soluble polymer are prepared as a solid dispersion using a melt injection method to increase the dissolution rate of the drug to increase the bioavailability of the drug and to reduce the change in the bioavailability of the drug according to food intake or not. I wanted to. In addition, Korean Patent Laid-Open Publication No. 1999-1564 describes a method of increasing the solubility and dissolution rate by using spray drying to reduce the particle size of the poorly soluble drug itraconazole and to lower the crystallinity. In this patent document, the particle size of itraconazole is in the range of about 0.5 μm to 10 μm and the average particle size is about 3.7 μm, indicating that the particle size is reduced by 7 times compared to the itraconazole raw material and the solubility is increased by 62 times. In addition, Korean Patent Laid-Open Publication No. 1999-51527 discloses a technique for melting water-soluble sugars together with itraconazole and cooling the melt mixture to reduce particle size of itraconazole and to change crystallinity to increase solubility and dissolution rate. . In addition, the Republic of Korea Patent Publication No. 10-2006-0044200 discloses the improvement of the dissolution properties of the drug by stabilizing and molecularization between the silicate layer of the drug using the intercalation reaction of the layered silicate.
As described above, in the case of drug delivery nanocomposites using layered silicates, nano-organization that can increase the solubility and stability of drugs by intercalating drug molecules between layers has been effectively achieved, but the problem of limitation of dissolution rate due to lack of water swelling is pointed out. It became. In addition, to further improve the bioavailability of itraconazole, it is required to improve the bioavailability of itraconazole in a simpler process and in an easy and repeatable manner.
The present invention is to solve the above problems by providing an antifungal nanocomposite composition in which nano-composites of extremely poorly soluble itraconazole and layered silicates having hydrophilic properties using the high-density biocompatible polymer Levan provides effective swelling of layered silicates. It is intended to achieve dissolution control and material stabilization of itraconazole.
Another object of the present invention is to develop a new drug delivery material as a composition composed of levane / lamellar silicate for the prevention of recrystallization of extremely poorly soluble drugs, fast dissolution rate and improved bioavailability.
The antifungal nanocomposite composition of the present invention comprises poorly soluble itraconazole, polysaccharide-type levane and swellable layered silicate, and the polysaccharide-type levane has a low molecular weight having an average molecular weight of 300,000 or less and an average molecular weight of 300,000 or more and 3 million. It is characterized by the following polymeric levan.
The swellable layered silicate is montmorillonite, bentonite, hectorite, saponite, beidelite, nondellite, nontronite, and the like as clay having excellent water swellability. It is preferred that one is selected from one or two or more mixtures from swellable mica and vermicullite.
The antifungal nanocomposite composition is characterized in that it comprises 50 to 200 parts by weight of itraconazole, 50 to 150 parts by weight, 20 to 60 parts by weight of the modifier compared to 100 parts by weight of the layered silicate.
The antifungal nanocomposite composition comprises the steps of intercalating the interlayer of layered silicate clay having hydrophilic properties into an organic modifier having lipophilic properties; Intercalating the itraconazole following intercalation of the modifier; The layered silicate is prepared by intercalating an organic modifier and itraconazole after intercalation and mixing the levane between layers.
As the organic material for the interlayer modification, amines such as tetradecylamine, hexadecylamine, octadecylamine, and salts thereof, dimethyldistearyl ammonium, trimethyltetradecyl ammonium (trimethyltetradecyl) alkyl and aromatics of ammonium, trimethylhexadecyl ammonium, trimethyloctadecyl ammonium, benzyltrimethyl ammonium, benzyltriethyl ammonium, phenyltrimethyl ammonium One may be selected from one or a mixture of two or more from the group consisting of quaternary ammonium, cationic surfactants and cationic polymers.
In addition, the swellable layered silicate may be modified by an organosilicon compound, and the organic compound may be tetramethoxy silicate, tetraethoxysilcate, propyltrimethoxysilicate, octyltriethoxysilicate. (octyltriethoxy silicate) and aminosilane (aminosilane) is characterized in that one selected from the group consisting of one or two or more.
The effect of the present invention is a very ideal nanocomposite drug carrier that combines the effective swelling phenomena of the target active material and hydrophilicity of the Levan's high-density biocompatible polymer, the molecular stabilization of the layered silicate, and the control of dissolution rate. To prepare a greatly improved solubility of the poorly soluble drug itraconazole and to be eluted quickly regardless of food intake to provide an itraconazole-containing drug delivery composition to improve the bioavailability of itraconazole.
1 is itraconazole dissolution test results
The present invention provides a novel drug delivery system for an antifungal agent composed of Levan / Layer silicate / itraconazole as a novel composition for drug delivery system for effective delivery of poorly soluble drug itraconazole.
Levan is a natural substance found in very few quantities in some plants and microorganisms. It is a biopolymer consisting of tens of thousands to tens of thousands of fructose, and our representative traditional food, Cheonggukjang and pumpkin, onion, garlic and other healthy barley It is contained in plants such as cactus, grasses, and functions like prebiotics and soluble fiber in the human body. Frectan, which exists in nature, generally has a structure in which one molecule of glucose is connected to tens of thousands of fructose. If the plant levan is a relatively low molecule with less than 10 to 200 fructose linked by beta-2,6 single bond, the microorganism-derived levan is linked to several thousand to tens of thousands of fructose by beta-2,6 bond. It is a high molecular weight fructan with different ratios of beta-2,1 branched bonds. Levans are representative biopolymers found in plants and in particular in microbial products. The average molecular weight of Levan has a wide range of molecular weights ranging from tens of thousands to millions, and the hydrophilicity is very excellent, which makes it easy to disperse in millions of polymer Levando water. In addition, the pH of 1% levane is stable, not decomposed in the range of pH 3 to pH 12 from 4.0 to 5.0, and has a property of decomposing at pH 2.
Therefore, in the novel composition for drug delivery of the present invention, the levan has a high hydrophilicity and high packing density of the polymer to keep the active ingredient stable, and when introduced into the body, effectively releases the substance contained by the expression of the swelling characteristic due to hydrophilicity. It is characterized by giving a function to enable.
The use of the levane can be classified into high molecular weight levane (average molecular weight 200 ~ 300 million) and low molecular weight levane (average molecular weight 300,000 or less) according to the molecular weight and in the present invention can be used for drug delivery without particular limitation. . The content of levane in the composition may be changed in conjunction with the content of the drug and the content of the inorganic excipient, and preferably includes 50 to 150 parts by weight relative to the layered silicate. If it is less than 50 parts by weight, the water swelling characteristics of the levane are difficult to be realized. If it is more than 150% by weight, the content of the active substance, i.e. extremely poorly soluble itraconazole, is limited. Can be.
In addition, the layered silicate (aka clay) material in the new composition for delivery is also a biocompatible material, which is already registered with the FDA and KFDA, and due to its inherent surface properties, the target active material is dispersed at the molecular level. It acts to stabilize, and to control the elution characteristics of active ingredients by diffusion and ion exchange.
The layer silicates (layer silicates) that can be utilized in the present invention are swellable clays, smectite-type clays, montmorillonite, bentonite, hectorite, saponite, and saponite. ), Beidelite, nontronite, swellable mica, or vermicullite. The clay may be used without particular limitation synthetic or naturally derived materials.
In addition, the cation exchange capacity (CEC) of the layered silicate in the present invention preferably has a cation exchange capacity of 60 ~ 200 meq / 100g. When the cation exchange capacity is 60 or less or 200 or more due to the properties of the layered silicate, the swelling property of the silicate layer is markedly lowered, so that the intercalation of drug molecules does not proceed effectively.
Considering that the antifungal properties of itraconazole powder of the present invention have very low solubility in water, a nanocomposite composition may be prepared by treating a layered silicate and a layered silicate having a hydrophilic property with a modifier when necessary for effective nanocompositing. It is also preferable. In this case, the nanocomposite composition which can prevent crystallization of itraconazole by uniformly compounding itraconazole on the layered silicate layer or surface by reforming the layered silicate layer with cationic organic material having lipophilic properties for effective intercalation. It can be.
In addition, if necessary, the interlayers of the layered silicates may be modified with the desired organic or inorganic materials. Typical organic modifiers include amines such as tetradecylamine, hexadecylamine, octadecylamine, and salts thereof, Dimethyldistearyl ammonium, trimethyltetradecyl ammonium, trimethylhexadecyl ammonium, trimethyloctadecyl ammonium, benzyltrimethyl ammonium, benzyltriethyl ammonium benzyltriethyl ammonium, alkyl and aromatic quaternary ammonium of phenyltrimethyl ammonium, cationic surfactants and cationic polymers.
In addition, if necessary, it can be applied to the supporting of drugs after the interlayer modification using the following organosilicon compounds. Exemplary organosilicon compounds are groups consisting of tetramethoxy silicate, tetraethoxysilcate, propyltrimethoxysilicate, octyltriethoxysilicate, and aminosilane Can be selected from.
Accordingly, the present invention provides a drug carrier in an ideal nanocomposite form that combines the swelling effect of the target active material and the hydrophilicity of the high-density biocompatible polymer of Levan, the molecular stabilization of the layered silicate, and the dissolution rate control properties. Composition manufacturing technology.
The antifungal nanocomposite composition composition content of the present invention is preferably in consideration of the CEC contained in the layered silicate, the content of the modifier and itraconazole, which are the intercalation targets. Therefore, when the amount of the modifier and itraconazole complexed than the CEC of the layered inorganic compound is increased, the modifier and the itraconazole material present on the particle surface without intercalation between the layers of the layered silicate are not nanocomposite and are not effective.
In particular, the modifier for modifying the layered silicate is preferably a medium in which the itraconazole and the layered silicate are nanocomposites, and it is preferable to add an amount such that the itraconazole can form an effective nanocomposite with the layered silicate. In other words, when a large amount of modifier is added, it is difficult to insert itraconazole between layers of layered silicate due to the modifier, and when a small amount of modifier is used, nanocomplexing becomes difficult because it cannot help uniform mixing with the hydrophilic inorganic carrier. Is generated.
Accordingly, the antifungal nanocomposite composition is composed of 50-200 parts by weight of itraconazole and 20-60 parts by weight of modifier in consideration of physical properties such as CEC of the layered silicate. Nanocomposites in which this itraconazole and modifiers are uniformly complexed can be constructed. Herein, in order to increase the effective swelling phenomenon caused by the supporting property of the active substance and hydrophilicity described above, 50 to 150 parts by weight of a bio-compatible polymer, Levan, is used. It is characterized by including the configuration.
Hereinafter, the present invention will be described in detail with reference to preferred examples. However, these embodiments are intended to describe the present invention in more detail, and various modifications are possible within the scope of the present invention is not limited thereto without departing from the technical spirit of the present invention.
Example 1
Itraconazole complex composition according to the present invention was prepared according to the composition of [Table 1].
To 30 mg of Magnabrite F (trade name: Amcol international), 10 mg of Cetyltrimethyl ammonium bromide is added together with 30 mg of ethanol solvent, and ground and mixed in an agate mortar. As the mixing proceeds, ethanol is volatilized to obtain intercalated clay-organic intermediate powder of Magnabrite F-cetyltrimethyl ammonium bromide. At this time, in order to obtain a powder from which all volatiles have been removed, it may be dried at 100 ° C. for 1 hour. 30 mg of itraconazole is added to the clay-organic intermediate thus obtained, and 30 mg of methylene chloride solvent, which is a solvent capable of dissolving itraconazole, is added and ground in an agate mortar in the same manner as the synthesis of the intermediate. To promote intercalation of itraconazole, the mixture was reacted at 120 ° C. for 1 hour to synthesize a powdery itraconazole-Magnabrite F-cetyltrimethyl ammonium bromide complex.
Example 2
The itraconazole composite composition according to the present invention was prepared according to the composition of Table 2 using Levan Fiber (III) (Real Biotech Co., Ltd.).
10 mg of Cetyltrimethyl ammonium bromide is added to 30 mg of Magnabrite F with 30 mg of ethanol solvent, and then ground and mixed in an agate mortar. As the mixing proceeds, ethanol is volatilized to obtain intercalated clay-organic intermediate powder of Magnabrite F-cetyltrimethyl ammonium bromide. At this time, in order to obtain a powder from which all volatiles have been removed, it may be dried at 100 ° C. for 1 hour. 30 mg of itraconazole is added to the clay-organic intermediate thus obtained, and 30 mg of methylene chloride solvent, which is a solvent capable of dissolving itraconazole, is added and ground in an agate mortar in the same manner as the synthesis of the intermediate. To promote intercalation of itraconazole, the mixture was reacted at 120 ° C. for 1 hour to synthesize a powdery itraconazole-Magnabrite F-cetyltrimethyl ammonium bromide complex. 30 mg of Levanfiba (III) is added thereto, and ground and mixed in an agate mortar for 1 hour. At this time, a small amount (30 mg) of distilled water may be added to promote the mixing of the levanization (III).
Example 3
Lebanese low molecular weight (Real Biotech Co., Ltd.) of the type of Leban was prepared according to the composition of the present invention according to the composition of [Table 3]. At this time, the average molecular weight of the low molecular weight levan is about 320,000. The synthesis method is the same as in Example 2. However, it was made into the low molecular weight Leban instead of the levanfiber (III) of Example 2.
Example 4
Using the Levan polymer (Real Biotech Co., Ltd.) among the kinds of Levan was prepared the itraconazole composite composition according to the present invention according to the composition of [Table 4]. At this time, the average molecular weight of the levane polymer is 2 to 3 million. The synthesis method is the same as in Example 2. However, it was set as a levan polymer instead of levanfiber (III) of Example 2.
Example 5
As a comparative example, the itraconazole composite composition according to the present invention was prepared according to the composition of [Table 5] using Eudragit E-100, which is a water swellable synthetic polymer, instead of Levan.
Test Example (Dissolution Test of Examples 1 to 5)
The dissolution rate of the compositions of Examples 1 to 5 was measured and compared under the KFDA notification dissolution test conditions. The test method was the dissolution test method and the 2 method (paddle method) of the general test method of the pharmacopoeia, pH 1.2 buffer solution was used as the eluent, 10, 20, 30, 40, 60, for 3 hours while maintaining at 36.5 ℃ 5 ml of the sample was taken at 120 and 180 minutes, filtered using a 0.2 μm filter, and the filtrate was analyzed using an ultraviolet-visible absorption spectrometry. The dissolution test results are shown in FIG. 1. As a result of the experiment, when the Levan was used as an additive, it was found that the flight was improved in Eudragit E-100 of Example 5. In addition, it was confirmed that the low molecular Leban was most effective in improving the dissolution rate of itraconazole.
Claims (7)
Intercalating the itraconazole following intercalation of the modifier;
Method of producing an antifungal nanocomposite composition by intercalating the layered silicate and intercalating an organic modifier and itraconazole between layers.
The layered silicate clay is a method for producing an anti-depressant composition, characterized in that the interlaminar or particle surface is partially or partially modified by the organosilicon compound.
The organic compound may be selected from the group consisting of tetramethoxy silicate, tetraethoxysilcate, propyltrimethoxysilicate, octyltriethoxysilicate and aminosilane. A method for producing an antifungal nanocomposite composition, characterized in that one is selected from one kind or a mixture of two or more kinds.
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