KR101730399B1 - Drug delivery system comprising axitinib and preparing method thereof - Google Patents
Drug delivery system comprising axitinib and preparing method thereof Download PDFInfo
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- KR101730399B1 KR101730399B1 KR1020150051735A KR20150051735A KR101730399B1 KR 101730399 B1 KR101730399 B1 KR 101730399B1 KR 1020150051735 A KR1020150051735 A KR 1020150051735A KR 20150051735 A KR20150051735 A KR 20150051735A KR 101730399 B1 KR101730399 B1 KR 101730399B1
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- 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
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- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
Abstract
The present invention relates to polypeptide-coated hybrid liposomal nanoparticles (Axitinib, P-LNP / AXT) coated with axitinib-filled polypeptides, which have a pH- And has a higher inhibitory effect on neovascularization than the existing acctinib drug and exhibits a higher inhibitory effect on the expression of HIF-1a, an important gene in the tumor. Therefore, it is useful as a medicament for chemotherapy .
Description
The present invention relates to a drug delivery system which encapsulates axitinib to enhance anticancer effect in a hypoxic state.
Cancer is one of the most deadly diseases worldwide, and despite the remarkable development of modern medicine, deaths from cancer continue to increase, resulting in huge losses both nationally and socially, including individuals, due to their diagnosis and treatment .
Cancer therapies currently in use include surgical therapy to remove cancerous tissue with surgery, radiation therapy, and chemotherapy using cytotoxic anticancer drugs. Chemotherapy using an anticancer drug is widely used in cancer treatment, but it shows cytotoxicity not only in cancer cells but also in normal cells, resulting in a risk of side effects. Therefore, in the field of chemotherapy using an anticancer agent, studies for maximizing the effect of the cancer treatment have been continuously carried out while reducing side effects of the anticancer agent.
Nanoparticles are one of drug delivery materials for selective target site delivery of drugs including anticancer drugs, and refer to heterogeneously dispersed particles on a colloidal phase having a large surface area with a particle size of several nm to several hundred nm in diameter. Nanoparticles encapsulated with anticancer agents can be targeted as cancer tissues for cancer treatment without adverse effects on normal tissues without any cancer cell target residues. This targeting effect of nanoparticles is obtained by the specific pathophysiological characteristics of cancer cells, called enhanced permeability and retention (EPR) effects. The neoplasm in the body grows faster than the normal tissue, essentially requiring the supply of a lot of nutrients and oxygen, which leads to the rapid production of new blood vessels around the cancer cells. That is, blood vessels are rapidly formed around the cancer cells, and these neoplastic blood vessels have large drainage holes large enough to allow the nanoparticles to escape from the blood vessels. Thus, nanoparticles will accumulate in cancer tissues.
Therefore, various attempts have been made to develop nanoparticles encapsulating an anticancer agent and the like, but conventional nanoparticles have problems such as short residence time and circulation in the living body or poor.
Cancer, especially solid cancer cells, have proliferative properties and become hypoxic with deeper parts of the tumor. Tumor cells show stronger proliferation and resistance to anticancer drugs in hypoxic conditions than in normal oxygen conditions. Hypoxia is a common phenomenon in solid cancer cells. Solid cancer cells have various genetic changes and are adapted to these hypoxic conditions. Cancer cells become more malignant and become resistant to anticancer drugs. It is known as a major inducer of malignant cancer.
Hypoxia-inducible factor 1 (HIF-1a) is the most important molecule that regulates the adaptation of cancer cells to such hypoxic conditions. It is known that the amount of HIF-1α protein has a close correlation with the prognosis of cancer patients . HIF-1 a is produced by the inactivation of cancer suppressor genes such as hypoxic conditions, stimulation of growth factors, activation of oncogene or von Hippel-Lindau tumor suppressor protein (pVHL) in cancer cells When activated, hexokinase 2,
Therefore, the object of the present invention is to provide nanoparticles encapsulating axitinib as an anticancer agent.
Another object of the present invention is to provide a method for producing nanoparticles encapsulating axitinib, which is an anticancer agent.
In order to accomplish the above object, the present invention provides a pharmaceutical composition containing axitinib and containing dipalmitoyl phosphatidyl choline (DPPC), cholesterol and didodecyldimethyl-ammonium bromide (DDAB) Provided is an acacinthium-encapsulated drug carrier coated with a polyethylene glycol-PolyAspartic Acid.
According to another aspect of the present invention, there is provided a method for producing a liposome comprising the steps of: preparing a liposome comprising phosphatidylcholine (DPPC), cholesterol and didodecyldimethyl-ammonium bromide (DDAB); Filling the liposome with acacinib; And coating the liposome packed with acacithin with polyethylene glycol-polyaspartic acid. The present invention also provides a method for preparing an acacinit encapsulated drug carrier, comprising the steps of:
Hybrid liposomal nanoparticles (Axitinib, P-LNP / AXT) coated with acacinib-packed polypeptides according to the present invention have pH-dependent release characteristics and sustained-release characteristics, It is more effective in inhibiting angiogenesis than acctinib drugs and has a higher inhibitory effect on the expression of HIF-1a, an important gene in tumors, and thus can be used as a medicament for chemotherapy.
FIG. 1 is a schematic view of a polypeptide-coated hybrid liposomal nanoparticles / Axitinib (P-LNP / AXT) packed with a polypeptide according to the present invention and confirmed by transmission electron microscopy (TEM) Image,
2 is a graph showing drug release of P-LNP / AXT according to the present invention in a pH 5.0 (acetic acid buffer) and pH 7.4 (phosphate buffer) environment,
FIG. 3 shows the results of confirming the effect of P-LNP / AXT according to the present invention on the expression of hypoxia-inducible factor 1 (HIF-1a) in various cancer cell lines,
4 is a result of confirming the anticancer effect after administering P-LNP / AXT according to the present invention to a cancer-induced mouse model,
FIG. 5 shows the results of confirming the expression of apoptotic proteins and neovascularization-related proteins after administration of P-LNP / AXT according to the present invention to a cancer-induced mouse model.
The inventors of the present invention conducted studies to improve the retention and circulation of axitinib in vivo, and found that axitinib is filled with dipalmitoyl phosphatidylcholine (DPPC) The inventors of the present invention completed the present invention by developing a drug delivery vehicle containing an acacinthium-containing liposome composed of cholesterol and didodecyldimethyl-ammonium bromide (DDAB) coated with polyethylene glycol-PolyAspartic Acid Respectively.
The axitinib is represented by the following formula (1) and is approved by the FDA in January 2013 as a drug for advanced kidney cancer.
It is known that axitinib inhibits vascular endothelial growth factor receptor (VEGFR), a protein that affects cancer growth.
Accordingly, the present invention relates to a liposome comprising axitinib and consisting of dipalmitoyl phosphatidyl choline (DPPC), cholesterol and didodecyldimethyl-ammonium bromide (DDAB), a polyethylene glycol -Acid Citinib encapsulated drug carrier coated with polyethylene glycol-PolyAspartic Acid can be provided.
Wherein the drug delivery system comprises 5 to 20% by weight acantinib and also comprises 20 to 40% by weight of phosphatidylcholine (DPPC), 5 to 15% by weight of cholesterol, didodecyldimethyl-ammonium bromide bromide, DDAB) and 30 to 70% by weight of polyethylene glycol-PolyAspartic Acid (PEG-PAsp).
In the pharmaceutical composition according to the present invention, if acctitinib is contained in an amount exceeding the above content range, serious side effects such as elevated blood pressure, heart failure, and cardiac arrest may occur. If it is contained in a small amount, Tribal problems can be caused.
If DPPC, cholesterol, DDAB, and PEG-PAsp are contained in an excess amount beyond the above range, problems may occur that the drug is not released in a proper environment. If the DPPC, cholesterol, DDAB and PEG-PAsp are contained in a small amount, Can be reduced.
The pharmaceutical compositions according to the present invention may further comprise suitable carriers, excipients or diluents conventionally used in the production of pharmaceutical compositions.
Examples of the carrier, excipient or diluent which can be used in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.
The pharmaceutical composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method .
In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose sucrose), lactose, gelatin, and the like.
In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included .
The dose of the pharmaceutical composition according to the present invention may vary depending on the age, sex and body weight of the patient, but it is administered in an amount of 5 mg / m² / day to 7 mg / m² / day twice a week for 1 to 4 cycles can do.
Such dosage may be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, and the like. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.
In addition, acacinib, which constitutes the pharmaceutical composition according to the present invention, has already been prescribed as an anticancer agent, and thus has safety.
The composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, or intraperitoneally) depending on the intended method, and the dose may be appropriately determined depending on the body weight, age, sex, Diet. The range varies depending on the administration time, method of administration, excretion rate and severity of disease.
The present invention also provides a method for preparing a liposome comprising the steps of: preparing a liposome consisting of phosphatidylcholine (DPPC), cholesterol and didodecyldimethyl-ammonium bromide (DDAB); Filling the liposome with acacinib; And coating the liposome packed with acacithin with polyethylene glycol-polyaspartic acid. The present invention also provides a method for preparing an acacinit encapsulated drug delivery device, comprising the steps of:
BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
< Reference example 1> Preparation of reagent
Axitinib (AXT) was purchased from LC Labs (LC Labs, MO, USA). Polyethylene glycol-PolyAspartic Acid (PEG-b-PAsp, MW: 6400) was purchased from Alamanda Polymers, Huntsville, AL, USA. Polyethylene glycol (PEG) and polyaspartic acid (PAs) contained 113,10 repeats blocks, respectively. 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was purchased from NOF America Corporation, White Plains, NY, USA). Cholesterol, dimethyldioctadecylammonium bromide (DDAB) and 1-palmitoyl-2- {6- [7-nitro-2-l, 3-benzoxadiazol-4- yl) amino] hexanoyl} amino-hexanoyl} -s n-glycero-3-phosphocholine (1-palmitoyl-2- { (Sigma-Aldrich, St. Louis, Mo.) was added to a solution of 6 - [(7-nitro-2-1,3-benzoxadiazol-4-yl) amino] hexanoyl} -sn- glycero- MO, USA). All chemicals were used without further purification.
< Example 1> Akh City Nip Filled Polypeptide coated hybrid Liposome Nanoparticles (polypeptide-coated hybrid liposomal nanoparticles / Axitinib , P- LNP / AXT )
Liposomal nanoparticles (LNP) were prepared using thin film hydration techniques.
Briefly, the organic phase was prepared by dissolving DPPC, cholesterol and DDAB in a weight ratio of 7: 2: 0.37 in CHCl 3 / methanol (4: 1) with acctinib.
The thin lipid membrane was formed by evaporating the organic solvent in a rotary evaporator (EYELA, Tokyo, Japan) while maintaining the temperature at 60 ° C.
The resulting membrane was hydrated using phosphate-buffered saline (PBS), and then subjected to a mini-extruder (Avanti Polar Lipids®) for 11 cycles to obtain monodispersed nanoscale LNPs. Inc., Alabaster, AL, USA) through a 100 nm pore filter.
LNP (AXT-loaded LNPs, LNP / AXT) filled with axitinib was prepared by adding 10% (w / w) acacitinium to the lipid mixture before thin-film hydration.
Then, PEG-b-PAsp solution was added to the cationic LNP dispersions and vortexed for 30 minutes.
The exact amount of polymer for coating the LNP surface was determined through various mixing ratios of the two solutions to produce nanoparticles with a uniform size distribution.
Then, the prepared hybrid liposomal nanoparticles (Axitinib, P-LNP / AXT) coated with a polypeptide packed with acacinib were confirmed using a transmission electron microscope (TEM) .
As a result, as shown in Fig. 1, the structure of the pegylated liposome was confirmed.
< Example 2> pH5 .0( Acetic acid buffer solution )and pH7 .4( Phosphate buffer Lt; RTI ID = 0.0 > Akh City Nip Filled Polypeptide coated hybrid Liposome Nano-mouth Polypeptide-coated hybrid liposomal nanoparticles / Axitinib , P- LNP / AXT ) Of drug release characteristics
coated hybrid liposomal nanoparticles / Axitinib (P) coated with the axitinib-loaded polypeptide prepared in Example 1 under the conditions of pH 5.0 (acetic acid buffer) and pH 7.4 (phosphate buffer) -LNP / AXT) was measured using a dialysis membrane.
The release of AXT from LNP / AXT and P-LNP / AXT was measured using a Spectra / Pore 3500 Da-cut-off membrane tubing in PBS (pH 7.4, 0.14 M NaCl) and acetate-buffered saline (pH 5.0, 0.14 M NaCl) (Spectra / Por 3500 Da-cutoff membrane tubing).
Samples of the medium (0.5 mL) were collected at intervals and replaced with an equal volume of fresh buffer. The concentration of AXT was measured by high performance liquid chromatography (HPLC), expressed as a percentage of the total drug possible, and plotted as a function of time.
As a result, it was confirmed that, as shown in Fig. 2, it exhibited the release characteristics in addition to the pH-dependent release characteristics. Such a mechanism induces drug release due to pH change in cancer cells, thereby maximizing the efficacy of anticancer drugs and reducing the side effects thereof, especially when treating cancer resistant cancer cells.
<
Example
3> Hypoxia in various cancer cell lines
Induction factor
(
Hypoxia
-
The expression of Hypoxia-inducible factor 1 (HIF-1a), in which hydroxyproline of three kinds of cancer cells was activated under two conditions of normoxia and hypoxia, LNP / AXT prepared in Example 1 was confirmed. Squamous cell carcinoma (SCC-7) and breast cancer cell line (BT-474) or human neuroblastoma cell line (SH-SY5Y) were used as the cancer cells.
Cells were seeded in 12 well plates and allowed to attach in an incubator for 24 hours.
Hypoxic conditions were formed through mixing gases (1% O 2 , 5% CO 2 , 94% N 2 ) for 18 hours.
Cells were cultured and harvested for 24 h after exposure to AXT and P-LNP / AXT.
The harvested cells were lysed, treated with proteinase inhibitors and incubated on ice for 40 min.
The mixture was centrifuged at 4000 rpm for 20 minutes at a rate of 13000 rpm and the protein obtained was determined using a Bicinchoninic Acid (BCA) protein assay kit (BCA Protein Assay Kit, Thermo scientific, USA) .
The protein of the extract was isolated using a 12% bis-tris-polyacrylamide gel (12% bis-Tris-polyacrylamide gel) and transferred to a poly vinylidenedifluoride (PVDF) membrane at 150 mA for 120 minutes Respectively.
The cells were then incubated with PBS
As a result, as shown in FIG. 3, it was confirmed that P-LNP / AXT increases the expression of hydroxy HIF-1a in a hypoxic state. Thus, it was confirmed that P-LNP / AXT effectively inhibited the expression of HIF-1a.
< Example 4 > cancer-induced mouse model of the P- LNP / AXT Identification of anti-cancer effect after administration
In order to confirm the anticancer effect of the nanoparticles according to the present invention in a cancer-induced mouse model, a SCC-7 cancer cell-induced mouse model was first prepared.
All animal care and experimental protocols were performed according to the guidelines of the Animal Ethics Committee of Yeungnam University, Korea (Institutional Animal Ethical Committee, Yeungnam University, South Korea).
The tumor xenograft model was prepared by subcutaneously injecting 1 × 10 6 SCC7 cells (100 μL) into the thigh (lateral) of female BALB / c nude mice. When the tumor volume reached almost 100 mm 3 , Respectively.
1 mg kg -1 of AXT, LNP / AXT or P-LNP / AXT was injected through the tail vein of mice.
The tumor volume of each group was measured using a vernier caliper and calculated as follows:
Body weights were measured to evaluate the toxicity of each formulation and all animals were euthanized using the CO 2 inhalation method.
As a result, as shown in Fig. 4, the development of the tumor was remarkably suppressed in the group administered with P-LNP / AXT, and it was confirmed that mice in each group had little change in body weight.
In other words, it was judged that the growth of tumor was inhibited because no new blood vessels were produced and the expression of various cytokines and growth factors was not observed.
< Example 5 > cancer-induced mouse model of the P- LNP / AXT Expression of apoptotic proteins and neovascularization-related proteins after administration
The SCC-7 tumor cell-induced mouse model of Example 4 was euthanized, and tumor tissue was extracted and hematoxylin and eosin staining (H & E staining) and immunohistochemistry staining were performed.
1. Hematoxylin & Oxine dyeing( Hematoxylin & eosin staining, H & E staining)
Hematoxylin & Eosin staining was performed to determine histomorphological changes in the tumors of the experimental group.
Tumor tissue sections of cancer-induced mice were fixed with 10% neutral-buffered formalin. Fragments were trimmed to two separate sections in each tumor (up to 6 tumor samples per group) and streaked successively on paraffin (3-4 mm).
Then, the cells were stained with hematoxylin and auxin and observed with an optical microscope (Nikon, Tokyo, Japan).
The central area of each tumor was evaluated and the area occupied by tumor volume and total tumor cells (% of tumor mass in mm 2 ) was measured using an automated image analyzer (iSolution FL ver. 9.1, IMTi-solution Inc., Quebec, Canada).
As a result, it was confirmed that the growth of the cells in the tumor tissue was remarkably inhibited in the P-LNP / AXT-administered group as in A of FIG.
2. Immunochemical staining ( immunohistochemistry staining)
Anti-caspase-3 and anti-cleaved poly (ADP-ribose) polymerase antibodies (anti-cleaved PARP antibodies) in each tumor fragment ), And proliferation (anti-Ki-67 antibody) were analyzed using the avidin-biotin-peroxidase complex (ABC) method.
First, the activity of endogenous peroxidase was blocked by incubating the sections in methanol and 0.3% H 2 O 2 for 30 minutes, and the non-specific binding of the immunoglobulin was measured by incubating normal horse serum for 1 hour in a humidified chamber Lt; / RTI >
The sections were then incubated with primary antisera overnight at 4 ° C and reacted with detection reagents for 1 hour at room temperature.
The tumor sections were washed three times with 0.01M PBS between each step and then reacted with a peroxidase substrate kit for 3 minutes and the intensity of caspase-3, PARP, CD31 and Ki-67 And 20% of positive cells were positive.
The percentage of the areas occupied by caspase-3, PARP, CD31 and Ki-67 expressing cells was measured using an automated image analyzer (per mm 2 of tumor mass).
As a result, the expression of caspase-3 and poly (ADP-ribose) polymerase (PARP) was remarkably increased as shown in B and C of FIG. 5 there was. In addition, the cluster of differentiation 31 (CD31) and Ki-67 were markedly decreased, indicating anti-angiogenesis.
In summary, the present invention relates to polypeptide-coated hybrid liposomal nanoparticles (Axitinib, P-LNP / AXT) coated with axitinib-filled polypeptides, which have pH- And it has a higher release inhibitory effect on HIF-1a expression, which is an important gene in tumor, compared with the existing acctinib drug itself.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that such detail is solved by the person skilled in the art without departing from the scope of the invention. will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (4)
Wherein the drug delivery vehicle comprises 5 to 20% by weight of acuminositin.
Wherein the drug delivery system comprises 20 to 40% by weight of phosphatidylcholine (DPPC), 5 to 15% by weight of cholesterol, 1 to 3% by weight of didodecyldimethyl-ammonium bromide (DDAB) Characterized in that it contains 30 to 70% by weight of polyethylene glycol-PolyAspartic Acid (PEG-PAsp).
Filling the liposome with acacinib; And
And coating the liposome packed with acacithin with polyethylene glycol-polyaspartic acid. The method of claim 1,
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008214324A (en) | 2007-02-28 | 2008-09-18 | Hokkaido Univ | Micelle-encapsulated liposome |
| WO2013188273A1 (en) | 2012-06-12 | 2013-12-19 | Bayer Healthcare Llc | Topical ophthalmological pharmaceutical composition containing axitinib |
| WO2014065245A1 (en) | 2012-10-22 | 2014-05-01 | 大鵬薬品工業株式会社 | WEAKLY ACIDIC pH-RESPONSIVE PEPTIDE AND LIPOSOME CONTAINING SAME |
| US20140220110A1 (en) * | 2013-02-01 | 2014-08-07 | Zoneone Pharma, Inc. | Remote loading of sparingly water-soluble drugs into liposomes |
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| CN104661647A (en) | 2012-05-03 | 2015-05-27 | 卡拉制药公司 | Pharmaceutical nanoparticles showing improved mucosal transport |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008214324A (en) | 2007-02-28 | 2008-09-18 | Hokkaido Univ | Micelle-encapsulated liposome |
| WO2013188273A1 (en) | 2012-06-12 | 2013-12-19 | Bayer Healthcare Llc | Topical ophthalmological pharmaceutical composition containing axitinib |
| WO2014065245A1 (en) | 2012-10-22 | 2014-05-01 | 大鵬薬品工業株式会社 | WEAKLY ACIDIC pH-RESPONSIVE PEPTIDE AND LIPOSOME CONTAINING SAME |
| US20140220110A1 (en) * | 2013-02-01 | 2014-08-07 | Zoneone Pharma, Inc. | Remote loading of sparingly water-soluble drugs into liposomes |
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