# US 2013/0280330 A9 · Microsphere drug carrier, preparation method, composition and use thereof

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- Number: US 2013/0280330 A9
- Document ID: US20130280330A9
- Status: Published application
- Kind: A9
- Application number: 13/384,747
- Filed: 2010-07-30
- Published: 2013-10-24
- Earliest claimed: 2009-07-31
- Assignees: Xi'an Libang Medical Technology Co., Ltd.
- Inventors: Renle Hu; Jiucheng Wang; Tao Chen; Hua Liang; Duohao Ding; Yaqi Jiao
- Web page: https://patentgrep.com/patent/US20130280330A9

## CPC

- A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 9/0056: {Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/565: not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 5/16: for decreasing, blocking or antagonising the activity of the thyroid hormones
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/06: Antiarrhythmics
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 19/10: for osteoporosis
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- A61P 31/08: for leprosy
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 33/04: Amoebicides
- A61P 33/06: Antimalarials
- A61P 33/10: Anthelmintics
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C08G 63/664: derived from hydroxy carboxylic acids
- C08G 63/6852: {derived from hydroxy carboxylic acids}
- Y10T 428/2982: Particulate matter [e.g., sphere, flake, etc.]
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

A nanosphere or microsphere drug carrier, formulations comprising the drug carrier and the preparation method of the formulations and the use of the carrier are disclosed. The carrier comprises a biodegradable methoxy end-capped polyethylene glycol-polylactide block copolymersor a derivative thereof represented by formula (I) as the main carrier material: CH3O—[CH2—CH2—O]m—[C(O)—CH(CH3)—O]n—R (I).

## Claims

### Claim 1

A methoxy end-capped polyethylene glycol-polylactic acid block copolymer represented by the following formula (I):
wherein:
m=4˜454, preferably 20˜454, more preferably 120˜230 or 20˜45, and most preferably 45;
n=4˜2778, preferably 60˜1400, more preferably 300˜1400 or 60˜150, and most preferably 400˜555;
substituent group R is selected from:
a. a neutral terminal group
—H, —CH3, —CH2CH3, —CH2(CH2)xCH3, wherein x=1-8;
b. a negatively charged terminal group
one negative charge: —COCH2CH2CO2H
two negative charges: —COCH2CH2CONHCH(CO2H)(CH2)2CO2H
four negative charges:
—COCH2CH2CONHCH[CONHCH(CO2)(CH2)2CO2H](CH2)2[CONHCH(CO2)(CH2)2CO2H]; and
c. a positively charged terminal group
one positive charge: —COCH2CH2NH2
two positive charges: —COCH2CH2NHCOCH(NH2)(CH2)4NH2
four positive charges:
—COCH2CH2NHCOCH[NHCOCH(NH2)(CH2)4NH2](CH2)4NH[COCH(NH2)(CH2)4NH2].

### Claim 2 (depends on 1)

The drug carrier according to claim 1, wherein the HLB value of the methoxy end-capped polyethylene glycol-polylactic acid block copolymer or derivative thereof is 0.01˜19.84.

### Claim 3 (depends on 1)

The drug carrier according to claim 1, wherein the drug carrier further includes one or more other high molecular materials for regulating the drug release rate; preferably, the other high molecular material is polylactic acid, polyglycolic acid, poly(lactic-co-glycolic acid), or polycaprolactone; preferably, the mass ratio of the other high molecular material to the biodegradable copolymer or derivative thereof represented by formula (I) is 0%˜50%.

### Claim 4 (depends on 1)

A nanosphere or microsphere drug formulation, wherein the drug formulation includes the drug carrier according to claim 1.

### Claim 5 (depends on 1, 4)

The nanosphere or microsphere drug formulation according to claim 4, wherein the nanosphere or microsphere is the nanosphere or microsphere prepared by the drug carrier of claim 1 enwrapping an active pharmaceutical ingredient.

### Claim 6 (depends on 5)

The nanosphere or microsphere drug formulation according to claim 5, wherein the active pharmaceutical ingredient is selected from one or more of the following: antituberculosis drugs, antileprosy drugs, antiviral drugs, antimalarial drugs, antiamebic drugs, antitrichomonal drugs, antifilarial drugs, anthelminthic drugs, broad-spectrum antibiotics, antifungal drugs, analgesic drugs, analgesic-antipyretic drugs, antigout drugs, antiepileptic drugs, antiparkinsonism drugs, antipsychotic drugs, antianxiety drugs, antidepressant drugs, drugs affecting brain blood vessels, cerebral metabolism and nootropic drugs, calcium antagonists, drugs for treating chronic cardiac insufficiency, antiarrhythmic drugs, peripheral vasodilators, blood lipid regulating and antiarteriosclerotic drugs, drugs for promoting proliferation of leukocyte, antiplatelet drugs, hormons drugs, contraceptive drugs, hypoglycemic drugs, thyroid hormones drugs and antithyroid drugs, antineoplastic drugs, drugs affecting immunity, slimming drugs, anti-osteoporotic drugs and drugs against prostatic hyperplasia;
preferably, the active pharmaceutical ingredient is selected from one or more of the following: Rifampin, Amlodipine, Stavudine, Azithromycin, Naproxen, Ropinirole, Paroxetine, Cinnarizine, Lovastatin, Fulvestrant, Orlistat, Fluconazol, Tramadol hydrochloride, Carbamazepine, Clarithromycin, Meloxicam, Probenecid, Thioridazine hydrochloride, Timiperone, Chlorprothixene, Risperidone, Alprazolam, Trazodone, Famciclovir, Amitriptyline hydrochloride, Nimodipine, Donepezil, Captopril, Norethindrone, Gliclazide and Melphalan;
more preferably, the active pharmaceutical ingredient is Fulvestrant, Naproxen, or Carbamazepine.

### Claim 7 (depends on 4)

The nanosphere or microsphere drug formulation according to claim 4, wherein the particle size of the drug carrier nanosphere or microsphere is 100 nm˜1 mm; the drug loading rate is 0.01%˜30%, preferably 5%˜30%, more preferably 10%˜30%, and most preferably 20%˜30%.

### Claim 8 (depends on 1, 4)

A method for preparing the nanosphere or microsphere drug formulation according to claim 4, wherein the method includes:
a. dispersing the active pharmaceutical ingredient in a solvent system containing the dissolved carrier material according to claim 1;
b. adding into a nonsolvent system to form nanospheres or microspheres;
c. solidifying, collecting, washing and drying;
preferably, the solvent suitable for the carrier material is one or more of dichloromethane, chloroform, tetrahydrofuran, ethanol, and ethyl acetate;
preferably, the concentration of the carrier material in the solvent system is 0.1%˜50% (g/ml);
preferably, the concentration of the active pharmaceutical ingredient in the solvent system which contains the dissolved carrier material is 0.01%˜80% (g/ml);
preferably, the nonsolvent system is ethyl ether, petroleum ether, n-hexane, cyclohexane, or acetone;
preferably, the volume ratio of the solvent system to the nonsolvent system is 1:10˜10:1;
preferably, the nonsolvent system is slowly added and dispersed under stirring or high speed shearing or high pressure homogenizing or using microjet pump; more preferably, the stirring rate is 100˜1000 rpm, the shearing rate is 1000˜10000 rpm, the pressure of the high pressure homogenizer is 200˜2000 bar for from one to 10 times, the pressure of the microjet pump is 100˜2000 bar for from one to 10 times; and/or
preferably, adding one or more of polyisobutyl ester, polyethylene, and butyl rubber into the nonsolvent system as an antisticking agent; more preferably, the mass ratio of the antisticking agent to the carrier material is 10:0˜10:2.

### Claim 9 (depends on 1, 4)

A method for preparing the nanosphere or microsphere drug formulation according to claim 4, wherein the method includes:
a. dissolving the active pharmaceutical ingredient and the carrier material of claim 1 in an organic solvent to make an oil phase;
b. adding the oil phase in an aqueous phase and emulsifying to obtain an O/W type emulsion;
c. stirring and warming up the O/W type emulsion to completely volatilize the organic solvent in the O/W type emulsion;
d. filtering, washing, collecting and drying;
preferably, the solvent suitable for the carrier material is one or more of dichloromethane, chloroform, tetrahydrofuran, ethanol, and ethyl acetate;
preferably, the mass ratio of the drug to the carrier material is 1:50-1:3; a preferable concentration of the carrier material in the oil phase is 1%˜50% (g/ml);
preferably, the aqueous phase is one of or a mixed solution of two or more of surfactant solution, monosaccharide or polysaccharide solution, polylol solution, cellulose solution, and colloidal solution, and the pH value of the aqueous phase is in the range of 3.0˜10.5;
preferably, the pH adjusting agent used is selected from an inorganic acid, an organic acid, an inorganic base, an organic base and a buffer salt;
preferably, the volume ratio of the oil phase to the aqueous phase is 1:300˜1:5; and/or
preferably, emulsifying with mechanical agitation or high speed shearing or high pressure homogenizing or microjet pump; more preferably, the stirring rate of the mechanical agitation is 100˜1000 rpm, the shearing rate is 1000˜10000 rpm, the pressure of the high pressure homogenizer and the pressure of the microjet pump are 100˜1500 bar for from one to 10 times.

### Claim 10 (depends on 1, 4)

A method for preparing the nanosphere or microsphere drug formulation according to claim 4, wherein the method includes:
a. dissolving or dispersing the drug in a solvent system containing the dissolved carrier material according to claim 1;
b. spraying into the drying tower of a spray drying equipment in the form of spray, and drying, isolating, and collecting;
wherein the solvent suitable for the carrier material is one or more of dichloromethane, chloroform, tetrahydrofuran, ethanol, and ethyl acetate;
preferably, the concentration of the carrier material in the solvent system is 0.1%˜50% (g/ml);
preferably, the concentration of the drug dissolved or dispersed in the solvent system of the carrier material is 0.01%˜50% (g/ml); preferably, the inlet air temperature is 30° C.˜80° C.;
preferably, the carrier material further comprises a plasticizer; more preferably, the plasticizer is one or more of dimethyl phthalate, diethyl phthalate, dibutyl benzoate, dibutyl sebacate, tributyl citrate, tributyl acetylcitrate, and glyceryl triacetate; the mass ratio of the plasticizer to the carrier material is 0%˜50%; and/or
preferably, the solvent system further comprises an antisticking agent, the antisticking agent is one or more of cholesterol, glycerol monostearate, talc powder, silica gel, and magnesium stearate, the mass ratio of the antisticking agent to the carrier material is 0%˜100%.

### Claim 11

Use of a biodegradable methoxy end-capped polyethylene glycol-polylactic acid block copolymer or a derivative thereof represented by the following formula (I) in the preparation of a drug carrier,
wherein:
m=4˜454, preferably 20˜454, more preferably 120˜230 or 20˜45, and most preferably 45;
n=4˜2778, preferably 60˜1400, more preferably 300˜1400 or 60˜150, and most preferably 400˜555;
substituent group R is selected from:
a. a neutral terminal group
—H, —CH3, —CH2CH3, —CH2(CH2)xCH3 wherein x=1-8;
b. a negatively charged terminal group
one negative charge: —COCH2CH2CO2H
two negative charges: —COCH2CH2CONHCH(CO2H)(CH2)2CO2H
four negative charges:
—COCH2CH2CONHCH[CONHCH(CO2)(CH2)2CO2H](CH2)2[CONHCH(CO2)(CH2)2CO2H]; and
c. a positively charged terminal group
one positive charge: —COCH2CH2NH2
two positive charges: —COCH2CH2NHCOCH(NH2)(CH2)4NH2
four positive charges:
—COCH2CH2NHCOCH[NHCOCH(NH2)(CH2)4NH2](CH2)4NH[COCH(NH2)(CH2)4NH2].

### Claim 12

A methoxy end-capped polyethylene glycol-polylactic acid block copolymer derivative represented by the following formula (I):
wherein:
m=4˜454, preferably 20˜454, more preferably 120˜230 or 20˜45, and most preferably 45;
n=4˜2778, preferably 60˜1400, more preferably 300˜1400 or 60˜150, and most preferably 400˜555;
substituent group R is selected from:
a. a negatively charged terminal group
one negative charge: —COCH2CH2CO2H
two negative charges: —COCH2CH2CONHCH(CO2H)(CH2)2CO2H
four negative charges:
—COCH2CH2CONHCH[CONHCH(CO2)(CH2)2CO2H](CH2)2[CONHCH(CO2)(CH2)2CO2H]; and
b. a positively charged terminal group
one positive charge: —COCH2CH2NH2
two positive charges: —COCH2CH2NHCOCH(NH2)(CH2)4NH2
four positive charges:
—COCH2CH2NHCOCH[NHCOCH(NH2)(CH2)4NH2](CH2)4NH[COCH(NH)(CH2)4NH2].