의료용 고분자 - kocwcontents.kocw.net/kocw/document/2014/pusan/kimhongsung/3.pdf ·...

의료용 고분자 Medical Polymers

2014

Professor, Ph.D. Kim, Hong Sung Biomaterials, Applied Life Science, Pusan National University

http:// 203.232.243.139/bm/, Polymeric Biomaterials Lab., Medical Polymers & Functional Scaffolds, [email protected]

3 / 13

Targeting of drug to the colon • oral administration

To avoid digestive process Modified biodegradable polysaccharide as vehicles crosslinked Guar gum(GG)

• trisodium trimetaphosphate (aionic) • drug: hydrocortisone, indomethacin, etc • in cecum, enzyme degradation (α- galactosidase, β- mannanase)

Medical Polymers, Functional Polymers, and Biomaterials

1. Drug conc. vs. Swelling : inverse relationship (Report 1) 2. PVA-GG IPN microspheres – glutaraldehyde crosslink – drug: nifedipine

• release factor: crosslink, drug conc., loading method (formation) • independent of stir speed

상호 침투형 고분자그물구조 서로 결합성이 없는 두 고분자를 각각 가교시켜 서로 얽힌

그물형태를 가지도록 한 구조

서로 다른 물성의 폴리머를 혼합하여

균일한 특성을 나타내게 하는 방법

PVA-crosslink GG에 있어서는

- PVA의 팽윤성에 따른 약물보유력과

- GG의 팽윤성에 의한 약물방출성을 조화시킨 것.


from fungi, Aureobasidium pullulans α- glucan, heteropolysaccharides α-(1-4) and α-(1-6) glucosidic linkages High liver affinity

interferon(IFN)-pullulan conjugation • targeting to liver • efficient antiviral activity • cyanuric chloride method (Report 2) Coupling agent in the immobilization of microorganisms and enzymes1,2

1. J.L. Gainer et al. Biotechnol. Bioeng. Symp. 10, 35, (1980) 2. W.J. Smith Proc. Ann. Biochem. Eng. Symp. 6, 34, (1976)

• enhanced accumulation & retention, reproducible Medical Polymers, Functional Polymers, and Biomaterials

Chelating residue-Pullulan conjugate with IFN (IFN-DTPA-Pullulan conjugate) • diethylenetriamine pentaacetic acid(DTPA) • Zn++ coordination

Hydrophobized PS nanoparticles • HER2 oncoprotein containing epitope peptide • hydrophobized PS: cholesteryl-bearing pullulan (CHP) cholesteryl-bearing mannan (CHM)

• enhanced production of IgG antibodies • rejected HER2-transfected tumors


EDTA

Capsulation of liposome coated with CHP

• drug: adriamycin (ADM): 림프종항암제

• stability in blood stream as carrier • 1-aminolactose (1-AL; 종양인식인자) assembled to outer layer of CHP • good carrier for active targeting of tumor cells

Hydrogel nanoparticle of CHP • diameter 20~30nm, stable colloid • complexed insulin


Polymers: HPMC, PVP, PVA, Pullulan

Drug: nifedipine (칼슘길항제) • 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)- 3,5-pyridinedicarboxylic acid dimethylester

• 세포 내 칼슘유입차단으로 근세포 이완작용-혈관확장-혈압강하

in fused nicotinamide • drug conc. increases twice intrinsic solubility • order: HPMC > PVP > PVA • pullulan is insoluble in fused solv. • drug as crystalline state in solid dispersion

HPMC – diclofenac dose Medical Polymers, Functional Polymers, and Biomaterials

α-(1→6) linked glucan with branch (5%) hemostasis, adsorption on surface of

vascular endothelium and various cells native dextrin: immunogenic

• low mol. weight fraction: non-immunogenic • antigenic determinant: 2~7 glucose units


1. pH-sensitive dextrin hydrogel with 4-nitrophenyl chloroformate • conjugation of dextrin with 4-aminobutyric acid; H2N(CH2)3COOH • incorporation of carboxylpropyl groups • crosslinked with 1,10-diaminodecane; H2N(CH2)10NH2 • higher and fast swelling in high pH • swelling reversibility in pH 2~7.4

cyclic oligosaccharide • 6~13 α-1,4-linked D-glucopyranose • hydrophilic ends (OH) • potential sites for chemical modification • inclusion complex with drug (host-guest complex) • stabiliy, solubility, bioavailability for oral admin. • native α,β,γ –CDs • enzymatic degradation mainly in colon • no acute toxicity • protect included molecule • β,γ –CDs: 7, 8 glucoside ring


α –CDs

increase conc. of drug • poor water-solubility drug: opoid analgesic; buprenorphine • modify release from patch; poly(acrylic acid),

polyisobutylene, polyisoprene

decrease side effects • reduce bitterness of femoxetine (serotonin(혈중혈관수축성분) inhibitor) • reduce local irritation of pirprofen (anti-inflammatory agent for rheumatoid

arthritis)

• decrease ulcerous effect of phenybutazone, indomethacin

enhance bioavailability of drug • every admin. route • modified CDs for direct formation of targeting agents


Noradrenaline Dopamine

A. Microspheres and Microcapsules native/modified starch in food, paper, textile, medicine industry crosslinked starch:

• biodegradable, high mechanical, chemical stable Starch microspheres

• crosslinked with epichlorohydrin: O • 3 dimensional matrices Cl-CH2-CH2-CH2


interfacial crosslinking process • Vapor phase linking (bp.117°C); remarkable • Microcapsules of hydrosoluble starch

crosslinking point: C2, C3, C6

block activity of α-amylase


1. Silicone polymer–grafted starch microparticles • 3-(triethoxysilyl)-propyl-terminated polydimethylsiloxane (TSPDMS) • efficacious orally and intranasally • Not appear to retard release of antigen or to protect antigen

from degradation • Predominance of Th2 antibody response


2. Degradable starch microspheres with hyperthermia • In rabbits VX2 tumor, injection • marked decrease of tumor in blood flow and pH • Increase maximum temp. with normal muscle, suppress 330% times in tumor growth at 3 weeks • Damage to normal muscle tissue was mild

3. Magnetic starch microspheres (MSM) • Contrast agent for MR imaging • Iron oxide core coating with starch and polyalkylene oxide • increase detection hepatic metastases, diameter of smallest lesions depicted were 1 mm

1. Hydroxyethyl Starches (HES) • Made by hydrolysis and hydroxyethylation • Higher degree of substitution, Less metabolized • Detrimental effect on hemostatic mechanism High Mw HES lead to decrease fibronectin conc. Infusing larger volumes of HES, occur hemorrhagic

complication, but avoid with low in vivo Mw Prolong partial thromboplastin times Decrease factor VIII activities & fibrinogen levels, Decrease platelet aggregation

• Low in vivo Mw has short half-life • As volume expander, reduce chemotaxis of

polymorphoneuclear leukocyte (PMNs)


• New development; • Mw 130kD (convent. 200kD), DS 0.4 (convent. 0.5) • compromised blood coagulation

1. Fibrinogen 2. Prothrombin 3. Thromboplastin 4. Calcium ion 5. Accelerin 7. SPCA 8. globulin A 9. globulin B 10. Thrombinase 11. PTA 12. Hageman Factor 13. Fibrin Stable Factor


2. Acetyl Starches (ACS) • New synthetic colloid • for plasma volume expansion • undergoing phase 2 clinical trials • rapid and complete enzymatic degradation

3. Carboxymethyl Starch (CMS) • binding of vancomycin Glycopeptide계 antibiotics from Streptomyces orientalis

• 황색포도상구균, 장내구균

• no effect on in vitro antimicrobial activity Medical Polymers, Functional Polymers, and Biomaterials

임상실험 단계

1 상: 제한된 건강한 대상자 안전성 용량, 대사 조사

2상: 제한된 환자 약리효과, 용량, 유효성

3상: 다수 환자 통계적 효능, 부작용 ---- 판매허가 -----

4상: 장기투여, 희귀작용, 부작용, 목적외 약리작용 추적검사


1940 penicillin

methicillin 1960

MRSA vancomycin

1996 VRSA

• MRSA: Methicillin Resistance Staphylococcus Aureus; 메티실린내성균 • VRSA: Vancomycin Resistance Staphylococcus Aureus; 반코마이신내성균

sulfated PS from brown marine algae • antibacterial, antiviral, antitumor,

immunosuppressive, antilipemic, antihemostatic

anticoagulant activity • thromboplastin time, prothrombin time,

thrombin clotting time polydisperse heteromolecules

• fucose, xylose, glucuronic acid, galactose, mannose


proteins or glycoproteins of nonimmune origin binding specific sugar resides mediating biological processes

• cell-cell or host-pathogen interaction, serum glycoprotein, innate immune responses

200 kind of 3-D structures interact with carbohydrate:

• acetylamino-, amino-, sialic acid, hexoses, pentose interfere with bacterial & viral attachment to

epithelial cell surfaces with alimentary canal


galactose-terminated glycoproteins • membrane lectin of cell, capable of internalization

of ligands, as recognized glycoconjugate • for carrier of antiparasitic and antiviral drug, and metabolite inhibitors

anchoring in DDS for eye mucosal surface • no tissue necrosis, edema, Evans blue infiltration • minimal acute irritancy


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