Liposomes with ginsenoside as membrane material and preparations and use thereof

• US 10,639,276 B2
• Filed: 08/19/2016
• Issued: 05/05/2020
• Est. Priority Date: 08/19/2015
• Status: Active Grant

• Current Assignee: Xiamen Ginposome Pharmaceutical Co., Ltd.
• Original Assignee: Shanghai Ginposome PharmaTech Co., Ltd.
• Inventors: Li, Chong, Wang, Yahua, Zhan, Huaxing
• Primary Examiner(s): Packard, Benjamin J
• Application Number:
  US15/300,688
• Publication Number:
  US 20170172920A1
• Time in Patent Office: 1,355 Days
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Among others, the present invention provides a blank liposome, preparation methods thereof, and a loaded liposome including the blank liposome and an active substance. The liposomes have a membrane comprising lipids and a ginsenoside of Formula I, and may further comprise a surfactant, a heat-sensitive excipient, a pH sensitive material, or an ion additive.

Claims

1. A blank liposome having a membrane, wherein the membrane comprises lipid and a ginsenoside of Formula I:

2. The blank liposome of claim 1, wherein the ginsenoside comprises ginsenoside Rg5, ginsenoside Rg6, ginsenoside Rk1, ginsenoside Rk2, ginsenoside Rk3, ginsenoside Rk4, ginsenoside Rh3, ginsenoside Rh4, ginsenoside F4, ginsenoside Rs4, ginsenoside Rs5, ginsenoside Rs6, ginsenoside Rs7, notoginsenoside T5, damulin A, or damulin B.

3. The blank liposome of claim 1, wherein the lipid in the membrane comprises phospholipid;

and the mass ratio of the phospholipid to the ginsenoside is in the range of 0.5;

1 to 100;

1, 0.5;

1 to 20;

1, or 0.5;

1 to 2;

1.

4. The blank liposome of claim 1, wherein the lipid in the membrane comprises phospholipid;

the membrane further comprises cholesterol;

the mass ratio of the phospholipid to the ginsenoside of Formula I in the membrane is in the range of 1;

0.01 to 1;

3, 1;

0.05 to 1;

0.9, or 1;

0.1 to 1;

0.9; and

the mass ratio of the ginsenoside of Formula I to the cholesterol is in the range of 0.1;

1 to 100;

1, 0.5;

1 to 10;

1, or 1.5;

1 to 6;

1.

5. The blank liposome of claim 4, wherein the mass percentage of the ginsenoside of Formula I in the membrane is in the range of 0.01% to 80%, 10% to 80%, 10% to 40%, or 20% to 40%;

the mass percentage of the phospholipid in the membrane is in the range of 5% to 99.9%, 10% to 70%, 30% to 70%, or 30% to 60%; and

the mass percentage of the cholesterol in the membrane is lower than 50% or is in the range of 0.5% to 50%, 5% to 40%, or 5% to 30%.

6. The blank liposome of claim 3, further comprising and encapsulating within the membrane an antioxidant, a cryoprotectant, or soybean oil and/or sodium oleate, wherein the antioxidant'"'"'s mass percentage in the blank liposome is no more than 25%, in the range of 0.001% to 15%, 0.01% to 10%, or 0.01% to 5%;

the mass percentage of the cryoprotectant in the blank liposome is no more than 80% or is in the range of 0.5% to 60%, 5% to 60%, or 30% to 60%; and

the mass percentage of soybean oil and/or sodium oleate in the blank liposome is in the range of 1% to 90%, 15% to 80%, 20% to 70%, 20% to 30%, or 60% to 70%.

7. The blank liposome of claim 3, wherein the phospholipid comprises a natural phospholipid, semisynthetic phospholipid, or fully synthetic phospholipid;

the natural phospholipid comprises natural lecithin, soyabean lecithin, egg lecithin, or cephalin;

the semisynthetic phospholipid or the fully synthetic phospholipid comprises a phospholipid of phosphatidylcholline, phosphatidylserine, phosphatidylinositol, a phospholipid of phosphatidylethanolamine, phosphatidylglycerol, dicetyl phosphate, a PEG-modified phospholipid, cholesterol succinate, or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine;

the phospholipid of phosphatidylcholline comprises hydrogenated soybean lecithin, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, dilauroyl phosphatidylcholine, dioleoyl phosphatidylcholine, phosphatidylcholine, single palmitoyl phosphatidylcholine, or glycerol phosphatidylcholine;

the phospholipid of phosphatidylethanolamine comprises 1-palmitoyl-2-oleoyl phosphatidylethanolamine, dilauroyl phosphatidylethanolamine, dierucoyl phosphatidylethanolamine, dioleoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, or dimyristoyl phosphatidylethanolamine;

the PEG-modified phospholipid comprises phosphatidylethanolamine-PEG, dipalmitoyl phosphatidylethanolamine-PEG, distearoyl phosphatidylethanolamine-PEG, dioleoyl phosphatidylethanolamine-PEG, C8 ceramide-PEG, C16 ceramide-PEG, distearoyl phosphatidylethanolamine-PEG-succinyl, distearoyl phosphatidylethanolamine-PEG-carboxyl, distearoyl phosphatidylethanolamine-PEG-maleimide, distearoyl phosphatidylethanolamine-PEG-propionamide bis-mercaptopyridine, distearoyl phosphatidylethanolamine-PEG-cyanuric chloride, distearoyl phosphatidylethanolamine-PEG-amino, distearoyl phosphatidylethanolamine-PEG-biotin, distearoyl phosphatidylethanolamine-PEG-folate, distearoyl phosphatidylethanolamine-PEG-folate, dilauroyl phosphatidylethanolamine-PEG, distearoyl phosphatidylethanolamine-PEG-active ester, phosphatidylethanolamine-PEG-active ester, dipalmitoyl phosphatidylethanolamine-PEG-active ester, dilauroyl phosphatidylethanolamine-PEG-active ester, distearoyl phosphatidylethanolamine-PEG-maleimide, phosphatidylethanolamine-PEG-maleimide, dipalmitoyl phosphatidylethanolamine-PEG-maleimide, dilauroyl phosphatidylethanolamine-PEG-maleimide, distearoyl phosphatidylethanolamine-PEG-biotin, distearoyl phosphatidylethanolamine-PEG-fluorescein, distearoyl phosphatidylethanolamine-PEG-hydroxyl, distearoyl phosphatidylethanolamine-PEG-amino, phosphatidylethanolamine-PEG-amino, dipalmitoyl phosphatidylethanolamine-PEG-amino, dilauroyl phosphatidylethanolamine-PEG-amino, distearoyl phosphatidylethanolamine-PEG-carboxyl, phosphatidylethanolamine-PEG-carboxyl, dipalmitoyl phosphatidylethanolamine-PEG-carboxyl, dilauroyl phosphatidylethanolamine-PEG-carboxyl, distearoyl phosphatidylethanolamine-PEG-thiol, distearoyl phosphatidylethanolamine-PEG-silane, distearoyl phosphatidylethanolamine-PEG-azide, cholesterol-PEG, methoxyl-PEG-cholesterol, cholesterol-PEG-active ester, cholesterol-PEG-maleimide, cholesterol-PEG-biotin, cholesterol-PEG-fluorescein, cholesterol-PEG-carboxyl, cholesterol-PEG-amino, or cholesterol-PEG-thiol;

the antioxidant comprises sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid, α

-tocopherol, α

-hydroxy acid, flavonoid, a phenylpropanoid phenolic compound, vitamin E, vitamin C, fumaric acid, cysteine, methionine, butyl hydroxy anisole, butyl hydroxytoluene, thiodipropionic acid, sulfites, hydrosulphite, dithioaminobenzoic acid compounds, citric acid, malic acid, sorbitol, glycerol, propylene glycol, hydroquinone, hydroxycoumarin, ethanolamine, phosphoric acid, or phosphorous acid;

the cryoprotectant comprises a glucide, a polyol, an amino acid, or a buffer reagent;

the glucide comprises a monosaccharide, a disaccharide, or a polysaccharide;

the monosaccharide comprises glucose, mannitol, xylitol, or sorbitol, the disaccharide comprises sucrose, lactose, maltose, or galactose, the polysaccharide comprises trehalose;

the polyol comprises propanediol or glycerol;

the amino acid comprises an α

-amino acid selected from the group consisting of threonine, glycine, glutamic acid, arginine and histidine;

the buffer reagent comprises a buffer solution of pH in the range of 3 to 10, or 5 to 7, the buffer solution comprises an ethanol-acetic acid buffer solution, a tris(hydroxymethyl)aminomethane buffer solution, a barbital buffer solution, a sodium formate buffer solution, a phthalate buffer solution, a citrate buffer solution, a citric acid-disodium hydrogen phosphate buffer solution, an ammonia-ammonium chloride buffer solution, a borax-calcium chloride buffer solution, an acetate buffer solution, an acetic acid-lithium salt buffer solution, an acetic acid-sodium acetate buffer solution, an acetic acid-ammonium acetate buffer solution, a phosphoric acid-triethylamine buffer solution, or a phosphate buffer solution.

8. The blank liposome of claim 1, further comprising and encapsulating within the membrane a surfactant, a heat-sensitive excipient, a pH sensitive material, or an ion additive;

the surfactant comprises polyethylene glycol and/or polysorbate;

the polyethylene glycol has a number-average molecular weight of 200 to 8000; and

the polysorbate comprises polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan trioleate, PEG-phosphatidylethanolamine, PEG-polylactic acid, polylysine-polyl(actic-co-glycolic acid), polyetherimide-polylactic acid, PEG-polycaprolactone, PEG-poly-(lactic-co-glycolic) acid, poloxamer 188, polyoxyethylene fatty acid ester, polyoxyethylene fatty acid ether, or polyoxyethylene methyl castor oil ether;

the heat-sensitive excipient comprises a polymer, a drug, or a surfactant and brings heat-sensitivity to the liposome;

the polymer comprises polyisoprene acrylamide, polyisoprene acrylic acid, polyphosphate, or poly phospholipid-amide copolymer;

the drug comprises zedoary turmeric oil, elemene, or brucea javanica oil;

the ion additive comprise a cationic additive or an anion additive;

the cationic additive comprises octadecylamine; and

the anion additive comprises phosphatidic acid or phosphatidylserine.

9. A process for preparing the blank liposome of at least one of claims 1 to 8, comprising a first method or a second method, wherein the first method or the blank liposome prepared thereby does not include a cryoprotectant, and the second method or the blank liposome prepared thereby includes a cryoprotectant;

the first method includes the steps of;

(1) mixing a lipid and a ginsenoside of Formula I, optionally, a cholesterol, a hydrophobic antioxidant, soybean oil and/or sodium oleate, a hydrophobic surfactant, a hydrophobic heat-sensitive excipient, a hydrophobic pH sensitive material, and/or a hydrophobic ion additive in an organic solvent to obtain a clear solution; and

(2) removing the organic solvent of the clear solution obtained in step (1), filming, mixing the film with water optionally containing a hydrophilic antioxidant, a hydrophilic surfactant, a hydrophilic heat-sensitive excipient, a hydrophilic pH sensitive material, and/or a hydrophilic ion additive to obtain an aqueous mixture, filtering the mixture after an operation of ultrasound, high pressure homogenization or pushing through a membrane to obtain an aqueous solution containing a blank liposome, drying to get the blank liposome;

the second method includes the steps of;

(1) mixing a lipid and a ginsenoside of Formula I, optionally, a cholesterol, a hydrophobic antioxidant, soybean oil and/or sodium oleate, a hydrophobic surfactant, a hydrophobic heat-sensitive excipient, a hydrophobic pH sensitive material, and/or a hydrophobic ion additive in an organic solvent to obtain a clear solution, and

(2) removing the organic solvent of the clear solution obtained in step (1), filming, mixing the film with an aqueous solution containing a cryoprotectant and optionally a hydrophilic antioxidant, a hydrophilic surfactant, a hydrophilic heat-sensitive excipient, a hydrophilic pH sensitive material, and/or a hydrophilic ion additive to give a mixture, filtering the mixture after an operation of ultrasound, high pressure homogenization or pushing through a membrane to obtain an aqueous solution containing a blank liposome, drying to get the blank liposome;

wherein the lipid, the ginsenoside of Formula I, the cholesterol, the antioxidant, the soybean oil and/or sodium oleate, the cryoprotectant, the surfactant, the heat-sensitive excipient, the pH sensitive material, and the ion additive are as defined in claims 1 to 8; and

the organic solvent comprises a nitrile solvent, a C_1-4 alcohol solvent, a ketone solvent, an alkane solvent, an ether solvent, a halogenated hydrocarbon solvent, a sulfoxide solvent, or an aldehyde solvent.

10. The process of claim 9, wherein the organic solvent comprises a C_1-4 alcohol solvent, a nitrile solvent, an ether solvent, or a halogenated hydrocarbon solvent;

the nitrile solvent comprises acetonitrile;

the C_1-4 alcohol solvent comprises methanol, ethanol, isopropanol, or n-butanol;

the ether solvent comprises tetrahydrofuran or diethyl ether;

the halogenated hydrocarbon solvent comprises chloroform or dichloromethane;

the ketone solvent comprises acetone or butanone;

the alkane solvent comprises petroleum ether;

the ratio of the organic solvent'"'"'s volumn to the total mass of the components dissolved in the organic solvent in step (1) of the first or second method is 5 to 20 mL/g;

step (1) of the first or second method is carried out at the temperature of 0 to 80°

C., 10 to 80°

C., or 10 to 65°

C.;

in step (2) of the first or second method, removal of the organic solvent of the clear solution obtained in step (1) is conducted with a rotary evaporator or a membrane evaporator at the temperature of 25 to 80°

C.,

in step (2) of the first or second method, the filtration is microporous membrane filtration, and the pore size of the microporous membrane preferably is 0.22 micron; and

in step (2) of the second method, the aqueous cryoprotectant solution has a 5% to 10% mass percentage of the cryoprotectant;

in step (2) of the first or second method, a freeze dryer is used for drying.

11. A loaded liposome comprising a blank liposome of at least one of claims 1 to 8 and an active substance loaded to and encapsulating within the liposome'"'"'s membrane, wherein the active substance comprises a drug, a cosmetically active substance, or a substance with healthcare function;

and the liposome is a blank liposome of at least one of claims 1 to 8.

12. The loaded liposome of claim 11, wherein the drug comprises an antitumor drug, an antifungal drug, an antiviral drug, an antibiotic, a non-steroidal anti-inflammatory drug, a calcium ion antagonist, an immunosuppressive agent, an anesthetic, a cardiovascular or vasodilation drug, a gastrointestinal drug, an antidepressant drug, a biological agent, a polynucleotide, or an oligonucleotide (including ribonucleotides and deoxyrbonucleotides);

the antitumor drug comprises paclitaxel, docetaxel, cabazitaxel, irinotecan hydrochloride, hydroxycamptothecin, aminocamptothecin, 7-ethyl-10-hydroxy camptothecin, topotecan hydrochloride, lurtotecan, topotecan, belotecan, cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, satraplatin, miriplatin, amyl platinum, aroplatin, carmustine, chlorambucil, melphalan, harringtonine, homoharringtonine, triptolide, tacrolimus, daunorubicin, pingyangmycin, doxorubicin hydrochloride, idarubicin, fluorouracil, cytarabine, methotrexate, etoposide phosphate, desoxy-podophyllotoxin, huperzine-A, vinorelbine tartrate, vincristine sulfate, vinblastine sulfate, vinorelbine, vindesine sulfate, temozolomide, tegafur, cyclophosphamide, ifosfamide, dacarbazine, epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, epothilone F, bortezomib, gemcitabine hydrochloride, fludarabine phosphate, capecitabine, decitabine, pemetrexed disodium, sorafenib, recombinant human interferon a2b, cytosine arabinoside, all trans retinoic acid, interleukin-2, etoposide, thymidylate synthase inhibitor, mitoxantrone, minoxidil, azithromycin, epirubicin hydrochloride, doxorubicin hydrochloride (adriamycin), amrubicin hydrochloride, 5-aminolevulinic acid, gefitinib, imatinib, erlotinib, sunitinib, dasatinib, lapatinib, axitinib, apatinib, nilotinib, bosutinib, vandetanib, telatinib, neratinib, canertinib, saracatinib, octenidine, sorafenib, icotinib, mubritinib, lestaurtinib, tandutinib, dovitinib, 3′

,5′

-dipalmitotyl cyclocytidine, or curcumenol;

the antifungal drug comprises amphotericin B, gentamicin, indomethacin, penicillin G, econazole nitrate, flucytosine, fluconazole, itraconazole, voriconazole, posaconazole, ravuconazole, caspofungin, micafungin, anidulafungin, cefpiramide sodium, cefotaxime sodium, ceftriaxone, cefoperazone, cefditoren pivoxil, cefoxitin sodium, cefalexin, cefuroxime sodium, cefixime, cefpodoxime, cefmenoxime, cefodizime, cefsulodin, cefazonam, ceftizoxime, cefetamet pivoxil, cefterampivoxil, ceftibuten, cefdinir, cefamandole, cefotiam, ceforanide, cefonicid, ceftazidime, cefradine, cefprozil, cefazolin sodium, cefadroxil, cephalothin, cefathiamidine, cefaloridine, cephacetrile, ceftezole, cefapirin, cefpirome, cefclidin, cefepime, fusidate sodium, florfenicol, or tigecycline;

the antiviral drug comprises ribavirin, acyclovir, cytarabine, idoxuridine, acyclovir laurate, acyclovir palmitate, iododeoxyuridine, cyclocytidine, dipalmitoyl cyclocytidine, phosphoric acid formate, phosphoric acid acetate, cimetidine, dipyridamole, rifampin, isoniazid, praziquantel, doxycycline, saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, tipranavir, BMS232632, lamivudine, zidovudine, didanosine, zalcitabine stavudine, abacavir, adefovirdipivoail, tenofovi, fluoro lamivudine, nevirapine, delavirdin, efavirens, interleukin-2, tilmicosin, or diclazuril;

the antibiotic comprises penicillin, penicillin V, amoxicillin, ampicillin, oxacillin, cloxacillin, procaine penicillin, benzathine penicillin, piperacillin, mezlocillin, ticarcillin, azlocillin, mezlocillin, carbenicillin, sulbenicillin, furbucillin, nafcillin, dicloxacillin, pivampicillin, apalcillin, amoxicillin, pivmecillinam, methicillin, lenampicillin, fomidacillin, flucloxacillin, kanamycin, natamycin, mitomycin, amikacin, tylosin, verteporfin, cefpiramide sodium, netilmicin sulfate, azithromycin, ofloxacin, ciprofloxacin, enoxacin, lomefloxacin, pefloxacin, rufloxacin, sparfloxacin, fleroxacin, moxifloxacin, grepafloxacin, trovafloxacin, norfloxacin, gemifloxacin, gatifloxacin, tosufloxacin, pazufloxacin, sparfloxacin, clarithromycin, clindamycin, polymyxin, tobramycin, vancomycin, azithromycin, doxycycline, tetracycline, oxytetracycline, minocycline, aureomycin, guamecycline, demeclocycline, metacycline, etimicin, netilmicin, sisomicin, amikacin, arbekacin, dibekacin, aztreonam, meropenem, imipenem, thienamycin, panipenem, ertapenem, neomycin, paromomycin, or spectinomycin;

the calcium ion antagonist comprises nimodipine, nifedipine, nicardipine, nitrendipine, verapamil, amlodipine, diltiazem, flunarizine, prenvlamine, gallopamil, or tiapamil;

the non-steroidal anti-inflammatory drug comprises indomethacin, aspirin, paracetamol, naproxen, diclofenac, ibuprofen, nimesulide, rofecoxib, or celecoxib;

the immunosuppressive agent comprises cyclosporin, alprostadil, cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, or mizoribine;

the anesthetic comprises halothane, sevoflurane, isoflurane, enflurane, propofol, fentanyl, urethane, lidocaine, procaine, tetracaine, bupivacaine, pelltobarbitalum natricum, chloral hydrate, ketamine, morphine, or chloralose;

the cardiovascular or vasodilation drug comprises dabigatran etexilate, alogliptin, polysaccharide sodium, ginkgolides, gingko flavonoid, Ginkgo biloba extract, asarone, olmesartan medoxomi, repaglinide, lipoic acid, breviscapine, urapidil, niacin, captopril, losartan, puerarin, tanshinone IIA, sarpogrelate hydrochloride, fluvastatin, pravastatin, simvastatin, lovastatin, simvastatin, mevastatin, cerivastatin, rosuvastatin, atorvastatin calcium, or rosuvastatin calcium;

the gastrointestinal drug comprises omeprazole, lansoprazole, ilaprazole, pantoprazole, rabeprazole, terazosin, esomeprazole, tenatoprazole, leminoprazole, tenatoprazole, disuprazole, or lafutidine;

the antidepressant drug comprises agomelatine, fluoxetine, paroxetine, duloxetine, sertraline, fluvoxamine, citalopram, escitalopram, venlafaxine, mirtazapine, imipramine, amitriptyline, clomipramine, doxepin, remeron, venlafaxime, phenelzine, isocarboxazid, or tranylcypromine,

the polynucleotide or oligonucleotide comprises a fragment having genetic functions and consisting of the basic groups of such as A, T, C, G or U,

the biological agent comprises a conventional mono-antibody drug, insulin, gamma globulin, antitoxic serum, interferon, interleukin, tumor necrosis factor, active factor of skin, epidermal growth factor, influenza vaccine, hepatitis A vaccine, cancer vaccine, recombinant human acidic fibroblast growth factor, or vascular endothelial growth factor 2 monoclonal antibody,

the cosmetically active substance comprises ursolic acid, superoxide dismutase, biological protein T4N5, vitamin D2, methyl nicotinate, refined snake oil, hyaluronic acid, essential oil, or ceramide,

the substance with healthcare function comprises glycyrrhizin, glycyrrhizic acid, disodiumglycyrrhizinate, methyl glycyrrhizinate, diammoniumglycyrrhizinate, vitamin E, resveratrol, coenzyme Q10, silymarin, anthocyanins, proanthocyanidins, lutein, folic acid, folinic acid, curcumin, emodin, tea polyphenols, epigallocatechin gallate, catechin, blueberry extract, glutathione, or oxymatrine.

13. The loaded liposome of claim 11, wherein the loaded liposome is in a form suitable for injection, lyophilized injection, oral administration, or topical administration.

14. The loaded liposome of claim 11, wherein the drug comprises paclitaxel, docetaxel, or irinotecan hydrochloride, the liposome comprises phospholipid and a ginsenoside of Formula I, the ginsenoiside comprises ginsenoside Rg5, and the mass ratio of the phospholipid to the ginsenoside Rg5 is in the range of 0.5:

1 to 100;

1, 0.5;

1 to 20;

1, or 0.5;

1 to 4;

1.

15. The loaded liposome of claim 14, wherein the liposome further comprises a cholesterol;

the mass ratio of the phospholipid to ginsenoside Rg5 is in the range of 1;

0.01 to 1;

3, 1;

0.05 to 1;

0.9, or 1;

0.1 to 1;

0.9; and

the mass ratio of ginsenoside Rg5 to the cholesterol is in the range of 0.1;

1 to 100;

1, 0.5;

1 to 50;

1, or 0.5;

1 to 10;

1.

16. The loaded liposome of claim 14, wherein the mass percentage of ginsenoside Rg5 in the blank liposome is in the range of 0.01% to 80%, 10% to 80%, 10% to 40%, or 20% to 40%;

the mass percentage of the phospholipid in the blank liposome is in the range of 5% to 99.9%, 10% to 70%, 30% to 70%, or 30% to 60%; and

the mass percentage of the cholesterol in the blank liposome is in the range of 0% to 50%, 0.5% to 50%, 5% to 40%, or 5% to 30%.

17. The loaded liposome of claim 14, further comprising and encapsulating within the liposome'"'"'s membrane an antioxidant, a cryoprotectant, or soybean oil and/or sodium oleate;

wherein the mass percentage of the antioxidant (when present) in the blank liposome is no more than 25% or is in the range of 0.001% to 15%, 0.01% to 10%, or 0.01% to 5%;

the mass percentage of the cryoprotectant (when present) in the blank liposome is no more than 80% or is in the range of 0.5% to 60%, 5% to 60%, or 30% to 60%; and

the mass percentage of the soybean oil and/or sodium oleate (when present) in the blank liposome is in the range of 1% to 90%, 15% to 80%, 20% to 70%, 20% to 30%, or 60% to 70%.

18. The loaded liposome of claim 17, wherein the phospholipid comprises soyabean lecithin, egg lecithin, or dimyristoyl phosphatidylcholine;

the antioxidant comprises ascorbic acid, vitamin E, vitamin C, or threonine;

the cryoprotectant comprises glucose, mannitol, xylitol, sucrose, lactose, trehalose, or propanediol.

19. A process for preparing a loaded liposome of claim 11, wherein when the liposome includes a cryoprotectant, the process for preparing the loaded liposome comprises any of Methods A, B, C, and D, wherein when the liposome does not contain or include a cryoprotectant, the process for preparing the loaded liposome comprises any one of Methods A1, B1, C1, and D1;

Method A comprises;

(1) mixing the lipid, the ginsenoside of Formula I, and the active substantive, and optionally, a cholesterol, a hydrophobic antioxidant, soybean oil and/or sodium oleate, a hydrophobic surfactant, a hydrophobic heat-sensitive excipient, a hydrophobic pH sensitive material, and/or a hydrophobic ion additive in an organic solvent to obtain a clear solution; and

(2) removing the organic solvent of the clear solution obtained in step (1), filming, mixing the film with an aqueous solution containing a cryoprotectant and optionally a hydrophilic antioxidant, a hydrophilic surfactant, a hydrophilic heat-sensitive excipient, a hydrophilic pH sensitive material, and/or a hydrophilic ion additive to give a mixture, filtering the mixture after an operation of ultrasound, high pressure homogenization of the mixure or pushing the mixture through a membrane to obtain an aqueous solution containing the liposome loaded with the active substance, drying to give the loaded liposome;

Method B comprises;

(1) mixing the lipid and the ginsenoside of Formula I, optionally, a cholesterol, a hydrophobic antioxidant, soybean oil and/or sodium oleate, a hydrophobic surfactant, a hydrophobic heat-sensitive excipient, a hydrophobic pH sensitive material, and/or a hydrophobic ion additive in an organic solvent to obtain a clear solution; and

(2) removing the organic solvent of the clear solution obtained in step (1), filming, mixing the film with an active substance and an aqueous solution containing a cryoprotectant and optionally a hydrophilic antioxidant, a hydrophilic surfactant, a hydrophilic heat-sensitive excipient, a hydrophilic pH sensitive material, and/or a hydrophilic ion additive to give a mixture, obtaining a solution of a loaded liposome after an operation of ultrasound, high pressure homogenization of the mixture or pushing the mixture through a membrane, dialyzing and filtering to obtain an aqueous solution containing the liposome loaded with the active substance, drying to give the loaded liposome;

Method C comprises;

(1) mixing the lipid and the ginsenoside of Formula I, and optionally, a cholesterol, a hydrophobic antioxidant, soybean oil and/or sodium oleate, a hydrophobic surfactant, a hydrophobic heat-sensitive excipient, a hydrophobic pH sensitive material, and/or a hydrophobic ion additive in an organic solvent to obtain a clear solution in an organic solvent to obtain a clear solution, and

(2) removing the organic solvent of the clear solution obtained in step (1), filming, mixing the film with an aqueous solution containing ammonium sulfate and a cryoprotectant, and optionally a hydrophilic antioxidant, a hydrophilic surfactant, a hydrophilic heat-sensitive excipient, a hydrophilic pH sensitive material, and/or a hydrophilic ion additive to give a mixture, obtaining a solution of a blank liposome after an operation of ultrasound, high pressure homogenization of the mixture or pushing the mixture through a membrane, dialyzing, then mixing with an active substance, filtering to obtain an aqueous solution containing a liposome loaded with the active substance, drying to give the loaded liposome;

Method D comprises;

(1) mixing the lipid and the ginsenoside of Formula I, and optionally, a cholesterol, a hydrophobic antioxidant, soybean oil and/or sodium oleate, a hydrophobic surfactant, a hydrophobic heat-sensitive excipient, a hydrophobic pH sensitive material, and/or a hydrophobic ion additive in an organic solvent to obtain a clear solution, and

(2) removing the organic solvent of the clear solution obtained in step (1), filming, mixing the film with citric acid and an aqueous solution containing a cryoprotectant and optionally a hydrophilic antioxidant, a hydrophilic surfactant, a hydrophilic heat-sensitive excipient, a hydrophilic pH sensitive material, and/or a hydrophilic ion additive to give a mixture, obtaining a solution of a blank liposome after an operation of ultrasound, high pressure homogenization of the mixture or pushing the mixture through a membrane, mixing the solution with an active substance and an aqueous solution of disodium hydrogen phosphate, filtering to obtain an aqueous solution containing a liposome loaded with the active substance, drying to give the loaded liposome;

Method A1 comprises

(1) mixing the lipid, the ginsenoside of Formula I and an active substantive, and optionally, a cholesterol, a hydrophobic antioxidant, soybean oil and/or sodium oleate, a hydrophobic surfactant, a hydrophobic heat-sensitive excipient, a hydrophobic pH sensitive material, and/or a hydrophobic ion additive in an organic solvent to obtain a clear solution, and

(2) removing the organic solvent of the clear solution obtained in step (1), filming, mixing the film with water to obtain an aqueous mixture, optionally adding to the aqueous mixture a hydrophilic antioxidant, a hydrophilic surfactant, a hydrophilic heat-sensitive excipient, a hydrophilic pH sensitive material, and/or a hydrophilic ion additive, filtering the mixture after an operation of ultrasound, high pressure homogenization of the mixture or pushing the mixture through a membrane to obtain an aqueous solution containing a liposome loaded with the active substance, drying to give the loaded liposome;

Method B1 comprises;

(1) mixing the lipid and the ginsenoside of Formula I, and optionally, a cholesterol, a hydrophobic antioxidant, soybean oil and/or sodium oleate, a hydrophobic surfactant, a hydrophobic heat-sensitive excipient, a hydrophobic pH sensitive material, and/or a hydrophobic ion additive in an organic solvent to obtain a clear solution, and

(2) removing the organic solvent of the clear solution obtained in step (1), filming, mixing the film with an active substance and optionally an aqueous solution containing a hydrophilic antioxidant, a hydrophilic surfactant, a hydrophilic heat-sensitive excipient, a hydrophilic pH sensitive material, and/or a hydrophilic ion additive, obtaining a solution containing a liposome loaded with an active substance after an operation of ultrasound, high pressure homogenization or pushing through a membrane, dialyzing and filtering to obtain an aqueous solution containing the liposome loaded with the active substance, drying to give the loaded liposome;

Method C1 comprises;

(1) mixing the lipid and the ginsenoside of Formula I, and optionally, a cholesterol, a hydrophobic antioxidant, soybean oil and/or sodium oleate, a hydrophobic surfactant, a hydrophobic heat-sensitive excipient, a hydrophobic pH sensitive material, and/or a hydrophobic ion additive in an organic solvent to obtain a clear solution, and

(2) removing the organic solvent of the clear solution obtained in step (1), filming, mixing the film with an aqueous solution containing ammonium sulfate and optionally a hydrophilic antioxidant, a hydrophilic surfactant, a hydrophilic heat-sensitive excipient, a hydrophilic pH sensitive material, and/or a hydrophilic ion additive, obtaining a solution of a blank liposome after an operation of ultrasound, high pressure homogenization or pushing through a membrane, dialyzing, then mixing the solution with an active substance, filtering to obtain an aqueous solution containing a liposome loaded with the active substance, drying to give the loaded liposome;

Method D1 comprises;

(1) mixing the lipid and the ginsenoside of Formula I, and optionally, a cholesterol, a hydrophobic antioxidant, soybean oil and/or sodium oleate, a hydrophobic surfactant, a hydrophobic heat-sensitive excipient, a hydrophobic pH sensitive material, and/or a hydrophobic ion additive in an organic solvent to obtain a clear solution,

(2) removing the organic solvent of the clear solution obtained in step (1), filming, mixing the film with an aqueous solution containing citric acid and optionally a hydrophilic antioxidant, a hydrophilic surfactant, a hydrophilic heat-sensitive excipient, a hydrophilic pH sensitive material, and/or a hydrophilic ion additive, obtaining a solution of a blank liposome after an operation of ultrasound, high pressure homogenization or pushing through a membrane, then mixing the blank liposome solution with an active substance and an aqueous solution of disodium hydrogen phosphate, filtering to obtain an aqueous solution containing a liposome loaded with the active substance, drying to give the loaded liposome;

wherein in the method A, B, C, D, A1, B1, C1 or D1, each condition or parameter is as defined in claim 10;

the mass ratio of the active substance to the ginsenoside of Formula I is 1;

0.1 to 1;

10 or 1;

2 to 1;

6; and

the lipid, the ginsenoside of Formula I, the cholesterol, the antioxidant, the soybean oil and/or sodium oleate, the cryoprotectant, the surfactant, the heat-sensitive excipient, the pH sensitive material, the ion additive, and the active substantive are each as defined above in claims 1-10 and 11-18.

20. The process of claim 19, wherein in Method B, C, B1, or C1, the operation of dialysis comprises putting a blank liposome solution or a loaded liposome solution in an aqueous solution of glucose or pure water to give a mixed solution, and then dialyzing the mixed solution for 5 to 20 hours or for about 12 hours;

or in Method B, C, B1 or C1, the operation of dialysis is carried out before the operation of ultrasound, high pressure homogenization or pushing through a membrane;

or in Method C or C1, the mass fraction of the ammonium sulfate in the aqueous solution of ammonium sulfate and the cryoprotectant or the aqueous solution of ammonium sulfate is in the range of 1% to 15%, or of 6.6%;

in Method C or C1, there comprises an operation of warm-keeping before filtering, for keeping the solution at 30°

C. to 80°

C. for 5 minutes to 1 hour;

in Method D or D1, the mass concentration of citric acid in its aqueous solution is in the range of 1% to 15% or is about 5.76%, the mass concentration of disodium hydrogen phosphate in its aqueous solution is in the range of 5% to 20% or is about 7.1%;

in Method D or D1, there comprises an operation of warm-keeping before filtering, the operation of warm-keeping preferably comprises keeping warm at 30°

C. to 80°

C. for 5 minutes to 1 hour;

in Method A, B, C, D, A1, B1, C1 or D1, the active substance is used in the form of its aqueous solution or organic solution based on the active substance'"'"'s lipid solubility or water solubility, and the active substance'"'"'s mass volume percentage in the aqueous solution or the organic solution is in the range of 1% to 20%.

21. A process for preparing a loaded liposome of claim 11, comprising Method {circle around (1)}, Method {circle around (2)}, Method {circle around (3)}, Method {circle around (4)}, Method {circle around (5)}, or Method {circle around (6)}, wherein

Method {circle around (1)} comprises:

adding soybean lecithin, ginsenoside Rg5 and paclitaxel into acetonitrile and stirring to form a clear solution;

wherein a mass ratio of the soybean lecithin, ginsenoside Rg5 and paclitaxel is 10;

6;

3, a ratio of the volume of the acetonitrile to the mass of the ginsenoside Rg5 is 100 mL/3 g;

removing the organic solvent in a thermostatic water bath at 50 to 60°

C. to form a film, and adding purified water, a ratio of the volume of the purified water to the mass of the ginsenoside Rg5 is 100 mL/3 g, carrying out an operation of ultrasound until the particle size of the liposome is between 0.1 and 0.3 micron, filtering through a 0.22 micron microporous membrane thereby obtaining an aqueous solution containing ginsenoside Rg5 paclitaxel liposome, freeze drying the aqueous solution containing ginsenoside Rg5 paclitaxel liposome, introducing protective gas, sealing to give the ginsenoside Rg5 paclitaxel liposome;

Method {circle around (2)} comprises;

adding egg lecithin, ginsenoside Rg5, paclitaxel and threonine into methanol and stirring to form a clear solution, wherein a mass ratio of the egg lecithin, ginsenoside Rg5, paclitaxel, cholesterol and threonine is 13;

12;

4;

5;

5, a ratio of the volume of the methanol to the mass of the ginsenoside Rg5 is 100 mL/3 g, removing the organic solvent in a thermostatic water bath at 60 to 70°

C. to form a film, and adding 5% glucose aqueous solution, a ratio of the volume of the glucose aqueous solution to the mass of the ginsenoside Rg5 is 100 mL/3 g, carrying out an operation of ultrasound until the particle size of the liposome is between 0.1 and 0.3 micron, filtering through a 0.22 micron microporous membrane thereby obtaining an aqueous solution containing ginsenoside Rg5 paclitaxel liposome, freeze drying the aqueous solution containing ginsenoside Rg5 paclitaxel liposome, introducing a protective gas, sealing to give the ginsenoside Rg5 paclitaxel liposome;

Method {circle around (3)} comprises;

adding egg lecithin, ginsenoside Rg5, paclitaxel, soybean oil and vitamin C into chloroform and stirring to form a clear solution, wherein a mass ratio of the egg lecithin, ginsenoside Rg5, paclitaxel, soybean oil and vitamin C is 8;

6;

1.5;

4;

0.5, a ratio of the volume of the chloroform to the mass of the ginsenoside Rg5 is 100 mL/3 g, the organic solvent is removed at 30 to 60°

C. to form a film, and adding 10% trehalose aqueous solution, a ratio of the volume of the trehalose aqueous solution to the mass of the ginsenoside Rg5 is 100 mL/3 g, carrying out an operation of homogenization by a high pressure homogenizer until the particle size of the liposome is between 0.1 and 0.3 micron, filtering through a 0.22 micron microporous membrane thereby obtaining an aqueous solution containing ginsenoside Rg5 paclitaxel liposome, freeze drying the aqueous solution containing ginsenoside Rg5 paclitaxel liposome, introducing a protective gas, and sealing to give the ginsenoside Rg5 paclitaxel liposome;

Method {circle around (4)} comprises;

adding egg lecithin, ginsenoside Rg5, paclitaxel, soybean oil, cholesterol and vitamin E into chloroform and stirred to form a clear solution, wherein a mass ratio of the egg lecithin, ginsenoside Rg5, paclitaxel, soybean oil, cholesterol and vitamin E is 14;

12;

4;

8;

0.5;

0.1, a ratio of the volume of the chloroform to the mass of the ginsenoside Rg5 is 100 mL/3 g, removing the organic solvent at 30 to 60°

C. to form a film, and adding 5% saccharose aqueous solution, a ratio of the volume of the saccharose aqueous solution to the mass of the ginsenoside Rg5 is 100 mL/3 g, carrying out an operation of homogenization by a high pressure homogenizer until the particle size of the liposome is between 0.1 and 0.3 micron, filtering through a 0.22 micron microporous membrane thereby obtaining an aqueous solution containing ginsenoside Rg5 paclitaxel liposome, then freeze drying the aqueous solution containing ginsenoside Rg5 paclitaxel liposome, then introducing protective gas, sealing to give the ginsenoside Rg5 paclitaxel liposome;

Method {circle around (5)} comprises;

adding egg lecithin, ginsenoside Rg5, docetaxel, soybean oil, and vitamin C into chloroform and stirred to form a clear solution, wherein a mass ratio of the egg lecithin, ginsenoside Rg5, docetaxel, soybean oil, and vitamin C is 8;

6;

3;

4;

5, a ratio of the volume of the chloroform to the mass of the ginsenoside Rg5 is 100 mL/3 g, removing the organic solvent at 30 to 60°

C. to form a film, and adding 10% trehalose aqueous solution, a ratio of the volume of the trehalose aqueous solution to the mass of the ginsenoside Rg5 is 100 mL/3 g, carrying out an operation of ultrasound until the particle size of the liposome is between 0.1 and 0.3 micron, filtering through a 0.22 micron microporous membrane thereby obtaining an aqueous solution containing ginsenoside Rg5 docetaxel liposome, freeze drying the aqueous solution containing ginsenoside Rg5 docetaxel liposome, introducing protective gas, sealing to give the ginsenoside Rg5 docetaxel liposome;

Method {circle around (6)} comprises;

adding egg lecithin, ginsenoside Rg5, irinotecan hydrochloride and soybean oil into chloroform and stirring to form a clear solution, wherein a mass ratio of the egg lecithin, ginsenoside Rg5, irinotecan hydrochloride and soybean oil is 8;

6;

2;

4;

5, a ratio of the volume of the chloroform to the ginsenoside Rg5 is 100 mL/3 g, removing the organic solvent at 30 to 60°

C. to form a film, and adding 10% trehalose aqueous solution, a ratio of the volume of the trehalose aqueous solution to the mass of the ginsenoside Rg5 is 100 mL/3 g, carrying out an operation of ultrasound until the particle size of the liposome is between 0.1 and 0.3 micron, filtering through a 0.22 micron microporous membrane to obtain an aqueous solution containing ginsenoside Rg5 docetaxel liposome, freeze drying the aqueous solution to contain ginsenoside Rg5 docetaxel liposome, introducing protective gas, and sealing to give the ginsenoside Rg5 docetaxel liposome.