TR202013709A1 - İlaç yüklü nanokapsül katkili pmma sementi̇ - Google Patents
İlaç yüklü nanokapsül katkili pmma sementi̇Info
- Publication number
- TR202013709A1 TR202013709A1 TR2020/13709A TR202013709A TR202013709A1 TR 202013709 A1 TR202013709 A1 TR 202013709A1 TR 2020/13709 A TR2020/13709 A TR 2020/13709A TR 202013709 A TR202013709 A TR 202013709A TR 202013709 A1 TR202013709 A1 TR 202013709A1
- Authority
- TR
- Turkey
- Prior art keywords
- nanocapsules
- pmma
- cement
- nanocapsule
- sensitive
- Prior art date
Links
- 229920003229 poly(methyl methacrylate) Polymers 0.000 title claims abstract description 29
- 239000004926 polymethyl methacrylate Substances 0.000 title claims abstract description 29
- 239000004568 cement Substances 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 229940079593 drug Drugs 0.000 title claims abstract description 15
- 239000002088 nanocapsule Substances 0.000 title claims description 39
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 229920000642 polymer Polymers 0.000 claims description 24
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 24
- 108010059993 Vancomycin Proteins 0.000 claims description 21
- 229960003165 vancomycin Drugs 0.000 claims description 21
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 claims description 21
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 16
- 229920002674 hyaluronan Polymers 0.000 claims description 16
- 229960003160 hyaluronic acid Drugs 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 12
- 241000894006 Bacteria Species 0.000 claims description 5
- 238000011068 loading method Methods 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims description 3
- 229930182566 Gentamicin Natural products 0.000 claims description 3
- 229960002518 gentamicin Drugs 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 229960000707 tobramycin Drugs 0.000 claims description 3
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 claims description 3
- 108010053950 Teicoplanin Proteins 0.000 claims description 2
- DDTDNCYHLGRFBM-YZEKDTGTSA-N chembl2367892 Chemical compound CC(=O)N[C@H]1[C@@H](O)[C@H](O)[C@H](CO)O[C@H]1O[C@@H]([C@H]1C(N[C@@H](C2=CC(O)=CC(O[C@@H]3[C@H]([C@H](O)[C@H](O)[C@@H](CO)O3)O)=C2C=2C(O)=CC=C(C=2)[C@@H](NC(=O)[C@@H]2NC(=O)[C@@H]3C=4C=C(O)C=C(C=4)OC=4C(O)=CC=C(C=4)[C@@H](N)C(=O)N[C@H](CC=4C=C(Cl)C(O5)=CC=4)C(=O)N3)C(=O)N1)C(O)=O)=O)C(C=C1Cl)=CC=C1OC1=C(O[C@H]3[C@H]([C@@H](O)[C@H](O)[C@H](CO)O3)NC(C)=O)C5=CC2=C1 DDTDNCYHLGRFBM-YZEKDTGTSA-N 0.000 claims description 2
- 229960001608 teicoplanin Drugs 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 2
- 229920001992 poloxamer 407 Polymers 0.000 claims 1
- 230000003115 biocidal effect Effects 0.000 description 12
- 239000003242 anti bacterial agent Substances 0.000 description 9
- 208000015181 infectious disease Diseases 0.000 description 9
- 229940088710 antibiotic agent Drugs 0.000 description 8
- 238000001356 surgical procedure Methods 0.000 description 7
- 241000191967 Staphylococcus aureus Species 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 125000002091 cationic group Chemical group 0.000 description 4
- 229920001519 homopolymer Polymers 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 125000006850 spacer group Chemical group 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 108010003272 Hyaluronate lyase Proteins 0.000 description 3
- 206010031252 Osteomyelitis Diseases 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 206010060968 Arthritis infective Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000399 orthopedic effect Effects 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- -1 PIuronic®F127 Polymers 0.000 description 1
- 229920002415 Pluronic P-123 Polymers 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 238000013196 antibiotherapy Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002639 bone cement Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 125000000600 disaccharide group Chemical group 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 230000007474 system interaction Effects 0.000 description 1
- 231100000901 systemic toxic effect Toxicity 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000008542 thermal sensitivity Effects 0.000 description 1
- 229920000428 triblock copolymer Polymers 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
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- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Composite Materials (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Manufacturing Of Micro-Capsules (AREA)
Abstract
Buluş, ilaç yüklü nanokapsül katkılı polimetilmetakrilat (PMMA) sementi ve üretim yöntemi ile ilgilidir.
Description
TARIFNAME
iLAç YUKLU NANOKAPSUL KATKILI PMMA SEMENTI
Teknik Alan
Bulus, ilaç yüklü nanokapsül katkili polimetilmetakrilat (PMMA) sementi ve üretim yöntemi ile
Bulus özellikle, ortopedik cerrahide özellikle 0steomyelit ve periprostetik eklem enfeksiyonu gibi
antibiyotik katkili polimetilmetakrilattan (PMMA) elde edilen kemik sementinin kullanildigi her
alanda kullanilmak üzere, ilaç yüklü nanokapsül katkili PMMA sementi ve üretim yöntemi ile
Teknigin Bilinen Durumu
Osteomyelit denilen kemik enfeksiyonu cerrahisinde iltihapli alan temizlendikten sonra bölgeye
birakilan antibiyotik katkilanmis sement, küçük boncuklar haline getirilerek bir cerrahi sütura kolye
gibi dizilmekte ve temizlenen kemik medullasina birkaç hafta sonra tekrar bir ameliyatla alinmak
üzere birakilmaktadir. Ayni prensiple, periprostetik eklem enfeksiyonu cerrahisinde protez,
uygulanmis oldugu bölgeden çikarilip bölge makroskobik olarak yikandiktan sonra yeniden bir
protez uygulanmadan önce bölgenin mikroorganizmalardan mikroskobik düzeyde de
temizlenmesi için bölgeye protezin seklini taklit eden antibiyotik yüklü PMMA'dan elde edilen
sementlerden spacer denilen bosluk gidericiler hazirlanarak uygulanmaktadir. Kan tablosu ve
yaranin disaridan görüntüsü tamamen düzelinceye kadar bu spacer bölgede kalmaktadir.
Böylelikle enfeksiyonla lokal olarak da mücadele edilmesi saglanmis olmaktadir. Bahsedilen
süreçlerde lokal mücadele özellikle sistemik antibiyoterapinin süresi ve antibiyotige karsi direnç
gelismesinde kilit rol oynamaktadir. Mevcut teknik alanda kullanilmakta olan uygulamalar birtakim
problemleri de beraberinde getirmektedir. Asagida, bahsedilen problemler maddeler halinde
özetlenmistir:
o Antibiyotigin kontrollü bir salimi olmadigi için ilk birkaç günde yüksek düzeyde, sonraki
günlerde ise terapotik düzeyin çok altinda dozlarda salimi sonucu enfeksiyonla
mücadelede yetersiz kalmasi (Boelch vd. 2019, van Vugt vd. 2019),
. Kültürde elde edilen antibiyogramda duyarli her antibiyotigin sementle karisima uygun
olmamasi, semente antibiyotik olarak ancak belli etkin maddelerin eklenebilmesi (van
Vugt vd. 2019),
- Antibiyotigin semente ancak belli oranda eklenebilmesi (yüksek doz antibiyotik eklenmesi
ile sistemik toksik etkilerin olusabilmesi veya antibiyotik miktarinin belli bir degerin
üzerinde eklenmesiyle sementin mukavemetinin azalmasi) (Boelch vd. 2017, Nodzo vd.
2017, Boelch vd. 2019),
0 Iki asamali revizyon cerrahilerinde spacer ile beklenen süre ortalama 3-10 ay arasi
degismesi, antibiyotik saliminin ilk birkaç günden sonra terapotik düzeyin altina
düsmesiyle spacerin artik enfeksiyon olusumuna neden olabilecek bir yabanci cisim gibi
davranmasi (Nodzo vd. 2017, Wouthuyzen-Bakker vd. 2019). (In-vitro yapilan
çalismalardaki ölçülebilir en düsük antibiyotik konsantrasyon süresi ile asamali yapilan
revizyon ameliyatlarindaki enfeksiyon için bekleme süresine bakildiginda ortalama 3-9
0 Sistemik antibiyoterapi ile desteklenen tedavi sürecinde lokal tedavinin yetersiz kalmasi
durumunda sistemik antibiyoterapi için daha uzun süre ve farkli antibiyotikler kullanilacak
olmasindan dolayi hastada görülebilecek yan etkilerin ve tedavi maliyetlerinin artmasi
(Boelch vd. 2019, van Vugt vd. 2019),
o Enfeksiyonla mücadelede basarisiz olunmasi durumunda ek cerrahi girisimlere bagli
olarak ko-morbiditelerin ve hastane maliyetlerinin artmasi (Gandhi vd. 2018, Siddiqi vd.
2019)
Sonuç olarak, söz konusu teknik alanda, yukarida bahsedildigi üzere birçok problem ve
olumsuzluk yasanmakta, mevcut uygulamalar, bu problemler ve olumsuzluklarin çözümünde
yetersiz kalmaktadir. Bu durum, teknik alanda bir gelistirme ve yenilik yapmayi zorunlu
kilmaktadir.
Bulusun Kisa Açiklamasi
Mevcut bulus, yukarida bahsedilen gereksinimleri karsilayan, tüm dezavantajlari ortadan kaldiran
ve ilave bazi avantajlar getiren, ilaç yüklü nanokapsül katkili PMMA sementi ve üretim yöntemi ile
Bulusun bir amaci, kontrollü salim sistemi ile etkin dozun standardize edilerek, teknigin bilinen
durumunda yer alan yöntemlere kiyasla daha uzun süre hastanin, ayni terapotik dozda VCM ile
enfeksiyonlara karsi korunmasini saglamaktir.
Bulusun bir diger amaci, teknigin bilinen durumu uygulamalarindaki sementlere oranla sement
mukavemetinin artirilmasini saglamaktadir. Bulusta, aktive edilmis kapsülleyici özellikte bir
polimer kullanilarak yüksek mukavemet elde edilmektedir.
Bulusun bir diger amaci, enfeksiyonla daha etkili mücadele saglayarak antibiyotik direnç riskini
en aza indirmektir.
Bulusun bir diger amaci, sentezlenen nanokaps'uller ile mevcut sement uygulamalarina oranla
kullanilacak antibiyotik miktarinin azaltilmasi ve antibiyotik verimliliginin arttirilmasidir.
Bulusun bir diger amaci, enfeksiyon olusumundan dolayi, ortam sicakliginin artmasi nedeniyle
termal duyarli nanokapsüllerden kontrollü Vankomisin (VCM) saliminin saglanmasidir.
Bulusun bir diger amaci, ortamda Staphylococcus aureus bakterisi bulunmasi durumunda, bakteri
duyarli akilli nanokapsüllerden Vankomisin (VCM) salim miktarinin artirilmasi ve buna bagli
olarak, enfeksiyonla mücadelede etkin antibiyotik konsantrasyonuna ulasilmasidir.
Bulusun yapisal ve karakteristik özellikleri ve tüm avantajlari detayli açiklama sayesinde daha net
olarak anlasilacaktir. Bu nedenle degerlendirmenin de söz konusu detayli açiklama göz önüne
alinarak yapilmasi gerekmektedir.
Bulusun Detayli Açiklamasi
Bu detayli açiklamada, bulus konusunun tercih edilen uygulamalari, sadece konunun daha iyi
anlasilmasina yönelik olarak ve hiçbir sinirlayici etki olusturmayacak sekilde açiklanmaktadir.
Bulus, ilaç yüklü nanokaps'ul katkili PMMA sementi ve 'üretim yöntemi ile ilgilidir. Bulusta
nanokapsül üretiminde esas madde olarak kapsülleyici özellikte bir polimer kullanilmaktadir. Söz
konusu kapsülleyioi 'özellikte bir polimerler, iletken özellikte triblok kopolimerdir ve tamamen
biyouyumludur. Kullanilan kapsülleyici polimerler, bulusta amin ve karboksil gibi fonksiyonel
gruplarla aktive edilerek kullanilmaktadir.
Bulus kapsaminda nanokaps'L'il üretimi, termal duyarli ve bakteri duyarli olarak ikiye ayrilmaktadir.
Bakteri duyarli nanokaps'ül 'üretiminde, kapsülleyici özellikte polimerlere ek olarak, etkinligi
saglamak için Hyaluronik asit (HA) kullanilmaktadir. Söz konusu Hyaluronik asit (HA),
Staphylococcus aureus bakterisinin salgiladigi hyalurinidaz enziminin substratidir. Antibiyotik
yüklü nanokapsüllerden ilaç salim hizinin artirilmasi Hyaluronik asit (HA) sayesinde olmaktadir.
Staphylococcus aureus bakterisinin salgiladigi Hyaluronidaz enziminin substrati olan Hyaluronik
asit (HA) baglayici özellik tasiyan bir tür polimerdir ve anyonik, uzun polisakkaritler içeren
glikozaminoglikanlardandir. Bunlar tekrarlayan disakkarid ünitelerinden olusmus, lineer polimer
olan heteropolisakkarid genel adi ile bilinirler. Termal duyarli nanokaps'ül üretiminde ise,
kapsülleyici özellikte polimerlere ek olarak, cam, metaller, polimerler ve metalik oksitler dâhil
olmak üzere çesitli substratlar üzerinde fiziksel adsorpsiyon ve elektrostatik adsorpsiyon yoluyla
kolayca yüklü filmler olusturabilen katyonik homopolimerler kullanilmaktadir. Termal duyarli
nanokapsül üretiminde temel malzeme olan bahsi geçen katyonik homopolimerler, polimer
nanokapsül duvarinin sicakliga bagli olarak açilip kapanmasini ve ilacin difüzyon hizinin
ayarlanmasini saglamaktadir.
Polimetilmetakrilat (PMMA), ortopedik cerrahide uzun yillardir kemik yapida bosluk doldurucu
veya tutunma araci olarak kullanilan sement, çimento gibi isimlerle adlandirilan karisimdir. Bulusa
konu olan ilaç yüklü nanokapsül katkili PMMA sementinde, PMMA, Vankomisin (VCM) ile
karistirilmaktadir. Vankomisin yerine bulus konusu yöntem sayesinde tobramisin, gentamisin,
antibiyoterapi etkisi olusturulmaktadir.
Bulus konusu ilaç yüklü nanokapsül katkili PMMA sementi üretim yönteminde, aktif kapsülleyici
özellikte polimerler hazirlanmaktadir. Bir sonraki islem adiminda termal duyarli nanokapsüller
kapsülleyici özellikte polimerler/katyonik homopolimerler kullanilarak sentezlenmektedir.
Ardindan, bakteri duyarli kapsülleyici özellikte polimerler/hyaluronik asit (HA) bazli akilli
nanokapsüller sentezlenmektedir. Sentezlenen söz konusu termal duyarli ve bakteri duyarli
nanokapsüller 4°C ila 40“C sicaklik arali ginda termal duyarliliga sahiptir. Bunlara ek olarak, doz
kontrolünü saglamak amaciyla ortamda Staphylococcus aureus türlerinin bulunmasi durumunda
patojen stafilokoklarin yaklasik % 90'inda var olan Hyaluronidaz enziminin substratini içeren akilli
kapsülleyici özellikte polimerler/hyaluronik asit nanokapsülleri olacaktir. Ortamda bakteri oldugu
durumlarda salgilanan Hyaluronidaz enziminden kaynakli nano ilaç salim sistemi etkilesimi
sonucu antibiyotik salimini artmaktadir.
Termal olarak duyarli nanokapsülün boyutu arttikça, yüksek duvar geçirgenligine ve düsük
sicakliga sahip olmaktadir. Sicaklik arttikça nanokapsül boyutu ve geçirgenligi de azalmaktadir.
Ilaç yüklü nanokapsül katkili PMMA sementi hazirlanma asamasinda sicaklik kisa süreligine 60
°C ila 80 “C arali gina ulastigi için bu duruma karsi nanokapsül, geçirgenligini azaltarak
Vankomisin (VCM) salimini minimize etmektedir. Bu yönüyle de termal duyarli nanokapsül
kullanimi bir avantaj saglamaktadir. Nanokapsüllerin elde edilmesinin ardindan, Vankomisinin
(VCM) kapsüllenmesi, nanokapsüllerin sulu çözeltide düsük sicaklikta inkübe edilmesi ve
ardindan suyun uzaklastirilmasiyla Iiyofilize edilerek diyaliz tüpü içerisinde, söz konusu
nanokapsüllere yüklenmesi islemi gerçeklestirilmektedir. Vankomisinin (VCM) yüklü termal
duyarli nanokapsüllerin ortalama boyutu, 70-230 nm araligindadir. Bu aralik, hücre içi
uygulamalardaki boyut dikkate alinarak belirlenmistir.
Kapsülleyici özellikte polimer/Hyaluronik asit (HA) nanokapsüllerinde Hyaluronik asit (HA) ve
Vankomisinin (VCM) arasinda gerçeklesecek elektrostatik etkilesimlerden dolayi, kapsi'JIIeyici
özellikte polimerler/katyonik homopolimer nanokapsüllerine kiyasla daha yüksek bir kapsülleme
kabiliyeti ve salim hizi kontrolü saglanmasi hedeflenmektedir. Elde edilen ilaç y'ukl'u nano
kapsüller, standart Polimetilmetakrilat (PMMA) polimerine homojen olarak katkilanmaktadir.
Burada bahsedilen karistirma isleminde, tercihen 1 gr Vankomisinin (VCM) yüklü nanokaps'ül ve
40 mg PMMA kullanilmaktadir. Son asamada elde edilen toz karisim monomer ile 100
devir/dakika olacak sekilde karistirilmaktadir. Kapsülleyici polimer olarak Pluronik bazli
polimerlerden PIuronic®F127, Pluronic P123 veya Pluronic F68 gibi polimerler kullanilmaktadir.
Yukarida bahsedilen teknik problemleri çözmek ve asagidaki detayli anlatimdan anlasilacak tüm
avantajlari gerçeklestirmek 'üzere mevcut bulus; ilaç yüklü nanokaps'ül katkili PMMA sementi
üretim yöntemi olup;
a) Aktif kapsülleyici özellikte polimerlerin hazirlanmasi,
b) Termal duyarli nanokaps'üllerin sentezlenmesi,
c) Bakteri duyarli nanokapsüllerin sentezlenmesi,
d) Vankomisinin vei'veya tobramisin ve/veya gentamisin ve/veya Iinezolid vei'veya
teikoplaninin söz konusu nanokapsüllere yüklenmesi,
e) (d) adiminda elde edilen yüklü nanokapsüllerin standart Polimetilmetakrilat (PMMA)
polimerine yüklenmesi islem adimlarini içermesi ile ilgilidir.
Claims (1)
- ISTEMLER Ilaç yüklü nanokapsül katkili PMMA sementi 'üretim yöntemi olup, özelligi; a) Aktif kapsülleyici özellikte polimerlerin hazirlanmasi, b) Termal duyarli nanokaps'üllerin sentezlenmesi, c) Bakteri duyarli nanokaps'üllerin sentezlenmesi, d) Vankomisinin ve/veya tobramisin ve/veya gentamisin ve/veya Iinezolid vei'veya teikoplaninin söz konusu nanokaps'üllere yüklenmesi, e) (d) adiminda elde edilen yüklü nanokapsüllerin standart Polimetilmetakrilat (PMMA) polimerine yüklenmesi islem adimlarini içermesidir. istem 1=e uygun bir 'üretim yöntemi olup, özelligi; Pluronic®F127 ve poly(s-Iysine) (s- PL)”den termal duyarli nanokapsüllerin sentezlenmesi islem adimini içermesidir. istem 1'e uygun bir üretim yöntemi olup, özelligi; PIuronic®F127 ve Hyaluronik asitrten bakteri duyarli nanokapsi'illerin sentezlenmesi islem adimini içermesidir. istem 1'e uygun bir 'üretim yöntemi olup, özelligi; 1 gr Vankomisin yüklü nanokapsül'un ve 40 mg Polimetilmetakrilat (PMMA) polimerine katkilanmasi islem adimini içermesidir.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2020/13709A TR202013709A1 (tr) | 2020-08-31 | 2020-08-31 | İlaç yüklü nanokapsül katkili pmma sementi̇ |
| US17/905,867 US20230346712A1 (en) | 2020-08-31 | 2021-08-27 | Medicine loaded nano-capsule additive pmma cement |
| PCT/TR2021/050871 WO2022046017A1 (en) | 2020-08-31 | 2021-08-27 | Medicine loaded nano-capsule additive pmma cement |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2020/13709A TR202013709A1 (tr) | 2020-08-31 | 2020-08-31 | İlaç yüklü nanokapsül katkili pmma sementi̇ |
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|---|---|---|---|---|
| DE102007050762B3 (de) * | 2007-10-22 | 2009-05-07 | Heraeus Medical Gmbh | Pastenförmiger Polymethylmethacrylat-Knochenzement und seine Verwendung |
| KR101405104B1 (ko) * | 2011-12-26 | 2014-06-10 | 한남대학교 산학협력단 | 약물의 서방형 방출 특성을 가지는 골 시멘트 |
| KR101470850B1 (ko) * | 2013-04-03 | 2014-12-09 | 코스맥스 주식회사 | 거대 다공성 폴리메틸메타아크릴레이트 제조방법 |
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