1-9 A-D E-G H-M N-P Q-S T-Z

CALCIUM GLYCEROPHOSPHATE (KALSİYUM GLİSEROFOSFAT)


CALCIUM GLYCEROPHOSPHATE (KALSİYUM GLİSEROFOSFAT)

Synonyms:
CALCIUM GLYCEROPHOSPAHE; CALSIUMGLICEROPHOSPHATE; CALSIUM GLICEROPHOSPHAT; CALCIUM GLICERIFOSFAT; CALSIUM GLYCERIPHOSPAT; calsiumgliserofosfat; calcium glycero; calcıum glycerophosphate; calsium, gly, ceryphosphat; Calcium, calsium, fosfat, phosphat, glycerophosphat; Neurosin; Calcium Glycerophosphate; calcium glycerophosphate; kalsiyum gliserofosfat; Calucium Glycerophosphate; Calcium Glycerylphosphate; Glycerol phosphate calcium salt; Calcium Glycerinophosphate; Calciumglycerophosphate, Fcc; Glycerol Phosphate Calcium Salt; Calcium Glycerophosphate Powder;Beta- Glycerophosphate Calcium Salt; Glycerophosphoric Acid Calcium Salt; calcium 1,3-dihydroxypropan-2-yl phosphate; calcium glycerino-phosphoricum; calcium glycerophosphoricum; 1,2,3- propanetriol, 2-(dihydrogen phosphate), calcium salt (1:1); 1,2,3-Propanetriol, mono(dihydrogen phosphate) calcium salt ; 1,2,3-Propanetriol, mono(dihydrogen phosphate), calcium salt; ß-glycerophosphoric acid calcium salt; calcium ß-glycerophosphate; Calcium beta-glycerophosphate; KEGG COMPOUND; Calcium Glycerophosphate; kalsiyum gliserofosfat; 1,2,3-Propanetriol, mono(dihydrogen phosphate) calcium salt; 1,2,3-Propanetriol, mono(dihydrogen phosphate), calcium salt; Calcium beta-glycerophosphate; calcium ß-glycerophosphate; ß-glycerophosphoric acid calcium salt; Glycerol phosphate calcium salt; Calcium glycerophosphat; Sn-glycerol-2-phosphate; Alkyl phosphate; Phosphoric acid ester; Organic phosphoric acid derivative; Organic calcium salt; Organic oxygen compound; Organic oxide; Hydrocarbon derivative; Organic salt; Primary alcohol; Calcium glycerylphosphate; calcium glycerophosphate; CALCIUM GLYCEROPHOSPAHE; CALSIUMGLICEROPHOSPHATE; CALSIUM GLICEROPHOSPHAT; CALCIUM GLICERIFOSFAT; CALSIUM GLYCERIPHOSPAT; calsiumgliserofosfat; kalsiyum glisero; calcıum gliserofosfat; calsium, gly, ceryphosphat; Kalsiyum, calsium, fosfat, fosfat, gliserofosfat; Neurosin; Kalsiyum Gliserofosfat; kalsiyum gliserofosfat; kalsiyum gliserofosfat; Calucium Glycerophosphate; Kalsiyum Gliserilfosfat; Gliserol fosfat kalsiyum tuzu; Kalsiyum Gliserinfosfat; Kalsiyum gliserofosfat, Fcc; Gliserol Fosfat Kalsiyum Tuzu; Kalsiyum Gliserofosfat Tozu, Beta-Gliserofosfat Kalsiyum Tuzu; Gliserofosforik Asit Kalsiyum Tuzu; kalsiyum 1,3-dihidroksipropan-2-il fosfat; kalsiyum gliserin-fosforrikum; kalsiyum gliserofosforik; 1,2,3-propanetriol, 2- (dihidrojen fosfat), kalsiyum tuzu (1: 1); 1,2,3-Propanetriol, mono (dihidrojen fosfat) kalsiyum tuzu; 1,2,3-Propanetriol, mono (dihidrojen fosfat), kalsiyum tuzu; ß-gliserofosforik asit kalsiyum tuzu; kalsiyum ß-gliserofosfat; Kalsiyum beta-gliserofosfat; KEGG BİLEŞİMİ; Kalsiyum Gliserofosfat; kalsiyum gliserofosfat; 1,2,3-Propanetriol, mono (dihidrojen fosfat) kalsiyum tuzu; 1,2,3-Propanetriol, mono (dihidrojen fosfat), kalsiyum tuzu; Kalsiyum beta-gliserofosfat; kalsiyum ß-gliserofosfat; ß-gliserofosforik asit kalsiyum tuzu; Gliserol fosfat kalsiyum tuzu; Kalsiyum gliserofosfat; Sn-gliserol-2-fosfat; Alkil fosfat; Fosforik asit esteri; Organik fosforik asit türevi; Organik kalsiyum tuzu; Organik oksijen bileşiği; Organik oksit; Hidrokarbon türevi; Organik tuz; Birincil alkol; Kalsiyum gliserilfosfat; kalsiyum gliserofosfat; CALCIUM GLYCEROPHOSPAHE; CALSIUMGLICEROPHOSPHATE; CALSIUM GLICEROPHOSPHAT; CALCIUM GLICERIFOSFAT; CALSIUM GLYCERIPHOSPAT; calsiumgliserofosfat; calcium glycero; calcıum glycerophosphate; calsium, gly, ceryphosphat; Calcium, calsium, fosfat, phosphat, glycerophosphat; Neurosin; Calcium Glycerophosphate; calcium glycerophosphate; kalsiyum gliserofosfat; Calucium Glycerophosphate; Calcium Glycerylphosphate; Glycerol phosphate calcium salt; Calcium Glycerinophosphate; Calciumglycerophosphate, Fcc; Glycerol Phosphate Calcium Salt; Calcium Glycerophosphate Powder;Beta- Glycerophosphate Calcium Salt; Glycerophosphoric Acid Calcium Salt; calcium 1,3-dihydroxypropan-2-yl phosphate; calcium glycerino-phosphoricum; calcium glycerophosphoricum; 1,2,3- propanetriol, 2-(dihydrogen phosphate), calcium salt (1:1); 1,2,3-Propanetriol, mono(dihydrogen phosphate) calcium salt ; 1,2,3-Propanetriol, mono(dihydrogen phosphate), calcium salt; ß-glycerophosphoric acid calcium salt; calcium ß-glycerophosphate; Calcium beta-glycerophosphate; KEGG COMPOUND; Calcium Glycerophosphate; kalsiyum gliserofosfat; 1,2,3-Propanetriol, mono(dihydrogen phosphate) calcium salt; 1,2,3-Propanetriol, mono(dihydrogen phosphate), calcium salt; Calcium beta-glycerophosphate; calcium ß-glycerophosphate; ß-glycerophosphoric acid calcium salt; Glycerol phosphate calcium salt; Calcium glycerophosphat; Sn-glycerol-2-phosphate; Alkyl phosphate; Phosphoric acid ester; Organic phosphoric acid derivative; Organic calcium salt; Organic oxygen compound; Organic oxide; Hydrocarbon derivative; Organic salt; Primary alcohol; Calcium glycerylphosphate; calcium glycerophosphate; CALCIUM GLYCEROPHOSPAHE; CALSIUMGLICEROPHOSPHATE; CALSIUM GLICEROPHOSPHAT; CALCIUM GLICERIFOSFAT; CALSIUM GLYCERIPHOSPAT; calsiumgliserofosfat; kalsiyum glisero; calcıum gliserofosfat; calsium, gly, ceryphosphat; Kalsiyum, calsium, fosfat, fosfat, gliserofosfat; Neurosin; Kalsiyum Gliserofosfat; kalsiyum gliserofosfat; kalsiyum gliserofosfat; Calucium Glycerophosphate; Kalsiyum Gliserilfosfat; Gliserol fosfat kalsiyum tuzu; Kalsiyum Gliserinfosfat; Kalsiyum gliserofosfat, Fcc; Gliserol Fosfat Kalsiyum Tuzu; Kalsiyum Gliserofosfat Tozu, Beta-Gliserofosfat Kalsiyum Tuzu; Gliserofosforik Asit Kalsiyum Tuzu; kalsiyum 1,3-dihidroksipropan-2-il fosfat; kalsiyum gliserin-fosforrikum; kalsiyum gliserofosforik; 1,2,3-propanetriol, 2- (dihidrojen fosfat), kalsiyum tuzu (1: 1); 1,2,3-Propanetriol, mono (dihidrojen fosfat) kalsiyum tuzu; 1,2,3-Propanetriol, mono (dihidrojen fosfat), kalsiyum tuzu; ß-gliserofosforik asit kalsiyum tuzu; kalsiyum ß-gliserofosfat; Kalsiyum beta-gliserofosfat; KEGG BİLEŞİMİ; Kalsiyum Gliserofosfat; kalsiyum gliserofosfat; 1,2,3-Propanetriol, mono (dihidrojen fosfat) kalsiyum tuzu; 1,2,3-Propanetriol, mono (dihidrojen fosfat), kalsiyum tuzu; Kalsiyum beta-gliserofosfat; kalsiyum ß-gliserofosfat; ß-gliserofosforik asit kalsiyum tuzu; Gliserol fosfat kalsiyum tuzu; Kalsiyum gliserofosfat; Sn-gliserol-2-fosfat; Alkil fosfat; Fosforik asit esteri; Organik fosforik asit türevi; Organik kalsiyum tuzu; Organik oksijen bileşiği; Organik oksit; Hidrokarbon türevi; Organik tuz; Birincil alkol; Kalsiyum gliserilfosfat; kalsiyum gliserofosfat;

Chemical Identifiers
Linear Formula C3H7CaO6P
Pubchem CID 120096
MDL Number N/A
EC No. 248-328-5
IUPAC Name calcium; 2,3-dihydroxypropyl phosphate
Beilstein Registry No. N/A
SMILES C(C(COP(=O)([O-])[O-])O)O.[Ca+2]
InchI Identifier InChI=1S/C3H9O6P.Ca/c4-1-3(5)2-9-10(6,7)8;/h3-5H,1-2H2,(H2,6,7,8);/q;+2/p-2
InchI Key IWIRHXNCFWGFJE-UHFFFAOYSA-L

Application Calcium glycerylphosphate (or calcium glycerophosphate) is a mineral supplement.
CAS Number 27214-00-2
IUPAC Name Calcium 1,3-dihydroxypropan-2-yl phosphate
Molecular Formula C3H7CAO6P

Product Details
Product Specification
Application Calcium glycerylphosphate (or calcium glycerophosphate) is a mineral supplement.
CAS Number 27214-00-2
IUPAC Name Calcium 1,3-dihydroxypropan-2-yl phosphate
Molecular Formula C3H7CAO6P
Product Description
Solution S is not more opalescent than reference suspension.
Neurosin; Calcium Glycerophosphate; Calucium Glycerophosphate; Calcium Glycerylphosphate; Calcium Glycerinophosphate; Calciumglycerophosphate, Fcc; Glycerol Phosphate Calcium Salt; Calcium Glycerophosphate Powder;Beta- Glycerophosphate Calcium Salt; Glycerophosphoric Acid Calcium Salt

Calcium glycerophosphate is found in OTC dental products such as toothpastes for the prevention of dental caries. As OTC products these do not have an official indication.
In prescription products it is indicated as a Calcium or phosphate donor for replacement or supplementation in patients with insufficient Calcium or phosphate.
Pharmacodynamics
It is thought that calcium glycerophosphate may act through a variety of mechanisms to produce an anti-caries effect 2. These include increasing acid-resistance of the enamel, increasing enamel mineralization, modifying plaque, acting as a pH-buffer in plaque, and elevating Calcium and phosphate levels.
When used as an electrolyte replacement, calcium glycerophosphate donates Calcium and inorganic phosphate. Calcium glycerophosphate is preferable to calcium phosphate due to its increased solubility. Compared to combination calcium gluconate and potassium phosphate, calcium glycerophosphate produces greater phosphate retention which allows for increased Calcium retention and ultimately greater incorporation of the ions into bone structure 1.
Mechanism of action
Calcium glycerophosphate in combination with sodium monofluorophosphate was found to reduce the acid solubility of enamel. This is thought to be due to increased uptake of fluoride in a non-alkali soluble form at the expense of a fraction remaining in the alkali-soluble form of calcium fluoride 2. It is also thought that calcium glycerophosphate enhances the remineralization effect of sodium monofluorophosphate leading to greater remineralization of enamel but the mechanism behind this is unknown.
Calcium glycerophosphate reduces the decrease in plaque pH produced by sucrose solutions 2. This may be due to the buffering action of donated phosphate which acts as an acceptor to three hydrogen ions to form biphosphate, dihydrogen phosphate, and finally phosphoric acid. As bisphosphate and dihydrogen phosphate are amphoteric, these molecules can act as buffers against both acids and bases.
Studies on plaque-modification by calcium glycerophosphate have been inconsistent 2. Redections in plaque weight and plaque area have been noted in separate studies but neither has been confirmed and no causative link has been established in regards to calcium glycerophosphate's anti-caries effect.
Calcium glycerophosphate donates Calcium and inorganic phosphate resulting in elevated levels of the ions in plaque 2. These ions are important components of the mineral structure of teeth. As such, their presence supports maintenance of healthy tooth structure and mineralization.
In electrolyte replacement calcium glycerophosphate again acts as a donor of Calcium and phosphate. See Calcium Phosphate for pharmacological descriptions of calcium and phosphate.

GÜVENLİK BİLGİ FORMU
A.B. (EC) 1907/2006# no`lu REACH tüzüğüne ve T.C. 27092 no`lu mevzuatına göre hazırlanmıştır.
Kaçıncı düzenleme olduğu 6.1
Yeni düzenleme tarihi 18.04.2019
Hazırlama Tarihi 22.06.2019
BÖLÜM 1: Maddenin/karışımın ve şirketin/dağıtıcının kimliği
1.1 Ürün adı
Ürün ismi : Glycerol phosphate calcium salt
Ürün Numarası : G6626
Marka : Sigma
REACH No. : Ürün veya kullanımı alanı kayıttan muaf tutulduğundan dolayı, kayıt numarası bu ürün için uygun değildir.
CAS-No. : 58409-70-4
1.2 Madde veya karışımın belirlenmiş kullanımları ve tavsiye edilmeyen kullanımları
Belirlenmiş kullanımları : Laboratuar kimyasalları, Maddelerin imalatı
1.3 Güvenlik bilgi formu tedarikçisinin bilgileri
Şirket : Sigma-Aldrich Chemie GmbH
Eschenstrasse 5
D-82024 TAUFKIRCHEN
Telefon : +49 (0)89 6513-1130
Faks : +49 (0)89 6513-1161
1.4 Acil durum telefon numarası
Acil telefon : 0800 181 7059 (CHEMTREC Deutschland)
+49 (0)696 43508409 (CHEMTREC
weltweit)
BÖLÜM 2: Zararlılık tanımlanması
2.1 Madde veya karışımın sınıflandırılması
(EC) No 1272/2008 Yönetmeliğine göre tehlikeli madde ya da karışım değildir.
2.2 Etiket unsurları
(EC) No 1272/2008 Yönetmeliğine göre tehlikeli madde ya da karışım değildir.
2.3 Diğer zararlar - yok
BÖLÜM 3: Bileşimi/İçindekiler hakkında bilgi
3.1 Maddeler
Formül : C3H7CaO6P
Molekül ağırlığı : 210,14 g/mol
CAS-No. : 58409-70-4

EC-No. : 261-240-1
Yürürlükte bulunan düzenlemeler doğrultusunda; herhangibir komponentin ifşa edilmesine gerek duyulmamıştır.
BÖLÜM 4: İlk yardım önlemleri
4.1 İlk yardım önlemlerinin açıklaması
Solunması halinde
Solunması halinde, kazazedeyi açık havaya çıkartınız. Solunum durmuşsa suni solunum
yapınız.
Deriyle teması halinde
Sabun ve bol miktarda su ile yıkayınız.
Gözle teması halinde
Tedbir olarak gözlere su tutunuz.
Yutulması halinde
Bilinci yerinde olmayan bir kişiye asla ağız yoluyla bir şey vermeyiniz. Ağzı suyla
çalkalayınız.
4.2 Akut ve sonradan görülen önemli belirtiler ve etkiler
Bilinen semptomlar ve etkileri etiket üzerinde belirtilmiştir(bak bölüm 2.2ve /veya
bölüm11)
4.3 Tıbbi müdahale ve özel tedavi gereği için ilk işaretler
Uygun veri yoktur
BÖLÜM 5: Yangınla mücadele önlemleri
5.1 Yangın söndürücüler
Uygun yangın söndürücüler
Su spreyi, alkole dayanıklı köpük, kuru kimyasal veya karbondioksit kullanınız.
5.2 Madde veya karışımdan kaynaklanan özel zararlar
Karbon oksitler, Fosfor oksitleri, Kalsiyum oksit
5.3 Yangın söndürme ekipleri için tavsiyeler
Yangın söndürmek için gerektiğinde oksijen tüplü komple maske kullanınız.
5.4 Ek bilgi
Uygun veri yoktur
BÖLÜM 6: Kaza sonucu yayılmaya karşı önlemler
6.1 Kişisel önlemler, koruyucu donanım ve acil durum prosedürleri
Toz oluşmamasına dikkat ediniz. Buhar, duman veya gazını solumaktan kaçınınız.
Kişisel korunma için 8. bölüme bakınız.
6.2 Çevresel önlemler
Çevre için özel tedbirler alınması gerekmez.
6.3 Muhafaza etme ve temizleme için yöntemler ve materyaller
Süpürünüz ve küreyiniz. Atıkları kapalı ve bu iş için uygun kapalı kaplarda saklayınız.
6.4 Diğer bölümlere atıflar
Atık bertarafı için 13. bölüme bakınız

BÖLÜM 7: Elleçleme ve depolama
7.1 Güvenli elleçleme için önlemler
Toz oluşan yerlerde uygun egzos havalandırma sistemi olmalıdır.
Önlemler için bakınız: bölüm 2.2.
7.2 Uyuşmazlıkları da içeren güvenli depolama için koşullar
Soğuk bir yerde saklayınız. Kabı sıkıca kapalı olarak kuru ve iyi havalandırılmış yerlerde
saklayınız.
7.3 Belirli son kullanımlar
Bölüm 1.2'de tanımlanan kullanım haricinde hiçbir kullanım öngörülmemiştir.
BÖLÜM 8: Maruz kalma kontrolleri/kişisel korunma
8.1 Kontrol parametreleri
Çalışma alanı kontrol parametreleri ile bileşenler
Maruz kalma limiti bulunan hiçbir madde içermez.
8.2 Maruz kalma kontrolleri
Uygun mühendislik kontrolleri
Genel endüstriyel hijyen uygulaması.
Kişisel koruyucu ekipmanlar
Göz/yüz koruması
NIOSH (US) veya EN 166 (EU) gibi standartlara uygun olarak test edilmiş ve onaylanmış göz koruma ekipmanı kullanınız.
Cildin korunması
Taşırken eldiven takınız. Eldivenler kullanım öncesi kontrol edilmelidir. Bu ürün ile ten temasını önlemek için, doğru eldiven çıkartma yöntemi (eldivenin dış yüzeyine dokunmadan) kullanınız. Kontamine olmuş eldivenler iyi laboratuvar uygulamaları ve uygunluk kurallarına paralel olarak bertaraf edilmelidir. Ellerinizi yıkayıp kurulayın.
Seçilen koruma eldivenleri, AB 2016/425 Yönetmeliğine ve bu yönetmelikten yola çıkılarak hazırlanan EN 374 standardına uygun olmalıdır.
Vücut korunması
Tehlikeli maddenin çeşidi, konsantrasyonu ve miktarına ve de işyeri koşullarına göre uygun vücut koruması seçiniz., Korunma malzemelerinin türü, her iş yerine göre, tehlikeli maddenin miktarı ve konsantrasyonuna bağlı olarak belirlenmelidir.
Solunum sisteminin korunması
Solunum korumasına gerek yoktur. Rahatsız edici toz düzeylerinden korunmak (EN 143) tipi toz maskeleri kullanınız. NIOSH (Amerika Birleşik Devletleri) veya CEN (Avrupa Birliği) gibi ilgili cihazları ve gereçler kullanınız.
Çevresel maruziyet kontrolü
Çevre için özel tedbirler alınması gerekmez.
BÖLÜM 9: Fiziksel ve kimyasal özellikler
9.1 Temel fiziksel ve kimyasal özellikler hakkında bilgi
a) Görünüm Fiziksel hali: katı
b) Koku Uygun veri yoktur
c) Koku Eşiği Uygun veri yoktur
d) pH Uygun veri yoktur
e) Erime noktası/Donma noktası
Uygun veri yoktur
f) İlk kaynama noktası ve kaynama aralığı
Uygun veri yoktur
g) Parlama noktası Uygun veri yoktur
h) Buharlaşma oranı Uygun veri yoktur
i) Alev alma sıcaklığı (katı, gaz) Uygun veri yoktur
j) Üst/alt alev alabilirlik veya patlama sınırları
Uygun veri yoktur
k) Buhar basıncı Uygun veri yoktur
l) Buhar yoğunluğu Uygun veri yoktur
m) Nispi yoğunluk Uygun veri yoktur
n) Su içinde çözünürlüğü
Uygun veri yoktur
o) Dağılım katsayısı ( noktanol/su)
Uygun veri yoktur
p) Kendiliğinden tutuşma sıcaklığı
Uygun veri yoktur
q) Bozunma sıcaklığı Uygun veri yoktur
r) Viskozite Uygun veri yoktur
s) Patlayıcılık özellikleri Uygun veri yoktur
t) Oksitleyici özellikler Uygun veri yoktur
9.2 Diğer bilgiler
Uygun veri yoktur
BÖLÜM 10: Kararlılık ve tepkime
10.1 Tepkime
Uygun veri yoktur
10.2 Kimyasal kararlılık
Önerilen depolama koşullarında kararlıdır.
10.3 Zararlı tepkime olasılığı
Uygun veri yoktur
10.4 Kaçınılması gereken durumlar
Uygun veri yoktur
10.5 Kaçınılması gereken maddeler
Oksitleyici maddeler
10.6 Zararlı bozunma ürünleri
Yangın ortamında, tehlikeli bozunma ürünleri oluşur. - Karbon oksitler, Fosfor oksitleri, Kalsiyum oksit

Diğer bozunma ürünleri - Uygun veri yoktur
Yangın sırasında bakınız: Bölüm 5
BÖLÜM 11: Toksikolojik bilgiler
11.1 Toksik etkiler hakkında bilgi
Akut toksisite
Uygun veri yoktur
Cilt aşınması/tahrişi
Uygun veri yoktur
Ciddi göz hasarı/göz tahrişi
Uygun veri yoktur
Solunum yolları veya cilt hassaslaşması
Uygun veri yoktur
Eşey hücre mutajenitesi
Uygun veri yoktur
Kanserojenite
IARC: % 0.1 ya da daha büyük oranda bulunan bu ürünün hiçbir içeriği IARC tarafından
muhtemel, olası veya onaylanmış kanserojen olarak tanımlanmamıştır.
Üreme sistemi toksisitesi
Uygun veri yoktur
Belirli Hedef Organ Toksisitesi - Tek maruz kalma
Uygun veri yoktur
Belirli Hedef Organ Toksisitesi - Tekrarlı maruz kalma
Uygun veri yoktur
Aspirasyon toksisitesi
Uygun veri yoktur
Ek Bilgi
RTECS: uygun veri yoktur
Merkezi sinir sistemi depresyonu, Mide bulantısı, Baş ağrısı, Kusma, narkoz, Kalpte hasar.
BÖLÜM 12: Ekolojik bilgiler
12.1 Toksisite
Uygun veri yoktur
12.2 Kalıcılık ve bozunabilirlik
Uygun veri yoktur
12.3 Biyobirikim potansiyeli
Uygun veri yoktur
12.4 Toprakta hareketlilik
Uygun veri yoktur
12.5 PBT ve vPvB değerlendirmesinin sonuçları
PBT/vPvB değerlendirmesi; kimyasal güvenlik değerlendirmesi gerekmediği/uygulanmadığı için bulunmamaktadır.
12.6 Diğer olumsuz etkiler
Uygun veri yoktur
BÖLÜM 13: Bertaraf etme bilgileri
13.1 Atık işleme yöntemleri
Ürün
Artıkları ve tekrar kazanımı mümkün olmayan çözeltileri, bir atık firmasına vermeyi teklif
ediniz.
Kontamine ambalaj
Kullanılmamış ürün olarak imha ediniz.
BÖLÜM 14: Taşımacılık bilgileri
14.1 UN Numarası
ADR/RID: - IMDG: - IATA: -
14.2 Uygun UN taşımacılık adı
ADR/RID: Tehlikeli mal değildir
IMDG: Not dangerous goods
IATA: Not dangerous goods
14.3 Taşımacılık zararlılık sınıf(lar)ı
ADR/RID: - IMDG: - IATA: -
14.4 Ambalajlama grubu
ADR/RID: - IMDG: - IATA: -
14.5 Çevresel zararlar
ADR/RID: hayır IMDG Deniz kirletici: hayır IATA: hayır
14.6 Kullanıcı için özel önlemler
Uygun veri yoktur
BÖLÜM 15: Mevzuat bilgileri
15.1 Madde veya karışıma özgü güvenlik, sağlık ve çevre mevzuatı
Bu madde güvenlik bilgi formu 1907/2006 No'lu AB Düzenlemesi gereklerine uymaktadır.
15.2 Kimyasal Güvenlik Değerlendirmesi
Bu ürün için bir kimyasal güvenlik değerlendirmesi uygulanmamıştır.
BÖLÜM 16: Diğer bilgiler
Ek bilgi
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Neurosin; Calcium Glycerophosphate; Calucium Glycerophosphate; Calcium Glycerylphosphate; Calcium Glycerinophosphate; Calciumglycerophosphate, Fcc; Glycerol Phosphate Calcium Salt; Calcium Glycerophosphate Powder;Beta- Glycerophosphate Calcium Salt; Glycerophosphoric Acid Calcium Salt

Calcium glycerophosphate
IDENTIFICATION
Name
Calcium glycerophosphate
Accession Number
DB11264 (DBSALT002553)
Type
Small Molecule
Groups
Approved
Description
Calcium glycerophosphate is a Calcium salt of glycerophosphoric acid that forms a white, fine, slightly hygroscopic powder. The commercial product is a mixture of calcium beta-, and D-, and L -alpha-glycerophosphate. By FDA, calcium glycerophosphate is considered a generally recognized as safe (GRAS) food ingredient as a nutrient supplement (source of calcium or phosphorus), or in food products such as gelatins, puddings, and fillings. It is also present in dental or oral hygiene products due to its cariostatic effects. It is suggested that calcium glycerophosphate promotes plaque-pH buffering, elevation of plaque Calcium and phosphate levels and direct interaction with dental mineral 2.

Structure
Thumb
Synonyms
1,2,3-Propanetriol, mono(dihydrogen phosphate) calcium salt
1,2,3-Propanetriol, mono(dihydrogen phosphate), calcium salt
Calcium beta-glycerophosphate
calcium ß-glycerophosphate
ß-glycerophosphoric acid calcium salt

Mixture Products
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NAME INGREDIENTS DOSAGE ROUTE LABELLER MARKETING START MARKETING END
Betacol Calcium glycerophosphate (50 mg) + Choline bitartrate (2.5 mg) + Betaine hydrochloride (61 mg) + Potassium bicarbonate (41 mg) Capsule Oral Therapeutic Foods Co. 1989-12-15 1996-09-09 Canada
Calcium Inj Calcium glycerophosphate (10 mg) + Calcium levulinate (15 mg) Liquid Intramuscular; Intravenous; Subcutaneous Kripps Pharmacy Ltd. 1981-12-31 Not applicable Canada
Formula 2025 Tab Calcium glycerophosphate (34 mg) + Calcium (51 mg) Tablet Oral Standard Process Inc. Not applicable Not applicable Canada
Perioe lucky fresh - breath care Calcium glycerophosphate (.13 g/100g) + Sodium fluorophosphate (.76 g/100g) Paste Dental Lg Household & Health Care Ltd. 2010-04-28 Not applicable Us
Perioe lucky fresh - cavity care Calcium glycerophosphate (0.13 g/100g) + Pyridoxine hydrochloride (0.03 g/100g) + Sodium fluorophosphate (0.76 g/100g) Paste Dental Lg Household & Health Care Ltd. 2010-04-26 Not applicable Us
Showing 1 to 5 of 5 entries

1

Categories
Carbohydrates
Lipids
Membrane Lipids
Phospholipids
Sugar Phosphates
UNII
Y56W30YB7O
CAS number
27214-00-2
Weight
Average: 210.135
Monoisotopic: 209.9606158
Chemical Formula
C3H7CaO6P
InChI Key
UHHRFSOMMCWGSO-UHFFFAOYSA-L
InChI
InChI=1S/C3H9O6P.Ca/c4-1-3(2-5)9-10(6,7)8;/h3-5H,1-2H2,(H2,6,7,8);/q;+2/p-2
IUPAC Name
calcium 2-(phosphonooxy)propane-1,3-diol
SMILES
[Ca++].OCC(CO)OP([O-])([O-])=O
PHARMACOLOGY
Indication
Calcium glycerophosphate is found in OTC dental products such as toothpastes for the prevention of dental caries. As OTC products these do not have an official indication.
In prescription products it is indicated as a Calcium or phosphate donor for replacement or supplementation in patients with insufficient Calcium or phosphate.
Pharmacodynamics
It is thought that calcium glycerophosphate may act through a variety of mechanisms to produce an anti-caries effect 2. These include increasing acid-resistance of the enamel, increasing enamel mineralization, modifying plaque, acting as a pH-buffer in plaque, and elevating Calcium and phosphate levels.
When used as an electrolyte replacement, calcium glycerophosphate donates Calcium and inorganic phosphate. Calcium glycerophosphate is preferable to calcium phosphate due to its increased solubility. Compared to combination calcium gluconate and potassium phosphate, calcium glycerophosphate produces greater phosphate retention which allows for increased Calcium retention and ultimately greater incorporation of the ions into bone structure 1.
Mechanism of action
Calcium glycerophosphate in combination with sodium monofluorophosphate was found to reduce the acid solubility of enamel. This is thought to be due to increased uptake of fluoride in a non-alkali soluble form at the expense of a fraction remaining in the alkali-soluble form of calcium fluoride 2. It is also thought that calcium glycerophosphate enhances the remineralization effect of sodium monofluorophosphate leading to greater remineralization of enamel but the mechanism behind this is unknown.
Calcium glycerophosphate reduces the decrease in plaque pH produced by sucrose solutions 2. This may be due to the buffering action of donated phosphate which acts as an acceptor to three hydrogen ions to form biphosphate, dihydrogen phosphate, and finally phosphoric acid. As bisphosphate and dihydrogen phosphate are amphoteric, these molecules can act as buffers against both acids and bases.
Studies on plaque-modification by calcium glycerophosphate have been inconsistent 2. Redections in plaque weight and plaque area have been noted in separate studies but neither has been confirmed and no causative link has been established in regards to calcium glycerophosphate's anti-caries effect.
Calcium glycerophosphate donates Calcium and inorganic phosphate resulting in elevated levels of the ions in plaque 2. These ions are important components of the mineral structure of teeth. As such, their presence supports maintenance of healthy tooth structure and mineralization.
In electrolyte replacement calcium glycerophosphate again acts as a donor of Calcium and phosphate. See Calcium Phosphate for pharmacological descriptions of calcium and phosphate.
ADDITIONAL DATA AVAILABLE
Adverse Effects
Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.
ADDITIONAL DATA AVAILABLE
Contraindications
Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.
ADDITIONAL DATA AVAILABLE
Blackbox Warnings
Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available
INTERACTIONS
Drug Interactions
Not Available
Food Interactions
Not Available
REFERENCES
General References
Draper HH, Yuen DE, Whyte RK: Calcium glycerophosphate as a source of calcium and phosphorus in total parenteral nutrition solutions.
KEGG Drug
D01488
KEGG Compound
C12935
PubChem Substance
347911170
ChemSpider
56554
ChEBI
31336
ChEMBL
CHEMBL3707206

Calcium_glycerophosphate
MSDS
Download (46.9 KB)
CLINICAL TRIALS
Clinical Trials

PHASE STATUS PURPOSE CONDITIONS COUNT
1 Completed Prevention Dental Decay 1
PHARMACOECONOMICS
Dosage forms
Show entries

FORM ROUTE STRENGTH
Capsule Oral
Liquid Intramuscular; Intravenous; Subcutaneous
Tablet Oral
Paste Dental
Patents
Not Available
PROPERTIES
State
Solid
Experimental Properties
PROPERTY VALUE SOURCE
melting point (°C) Decomposes at 170 MSDS
water solubility Soluble MSDS
Predicted Properties
PROPERTY VALUE SOURCE
Water Solubility 50.9 mg/mL ALOGPS
logP -1 ALOGPS
logP -2 ChemAxon
logS -0.71 ALOGPS
pKa (Strongest Acidic) 1.13
pKa (Strongest Basic) -3
Physiological Charge -2
Hydrogen Acceptor Count 5
Hydrogen Donor Count 2
Polar Surface Area 112.88 Å2
Rotatable Bond Count 4
Refractivity 29.15 m3·mol-1
Polarizability 12.63 Å3
Number of Rings 0
Bioavailability 1
Rule of Five Yes
Ghose Filter No
Veber's Rule No
MDDR-like Rule No
Predicted ADMET features
Not Available
SPECTRA
Mass Spec (NIST)
Not Available
Spectra
Not Available
TAXONOMY
Description
This compound belongs to the class of organic compounds known as glycerophosphates. These are compounds containing a glycerol linked to a phosphate group.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Glycerophospholipids
Sub Class
Glycerophosphates
Direct Parent
Glycerophosphates
Alternative Parents
Alkyl phosphates / Organic calcium salts / Primary alcohols / Organic oxides / Hydrocarbon derivatives
Substituents
Sn-glycerol-2-phosphate / Alkyl phosphate / Phosphoric acid ester / Organic phosphoric acid derivative / Organic calcium salt / Organic oxygen compound / Organic oxide / Hydrocarbon derivative / Organic salt / Primary alcohol
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
calcium salt (CHEBI:31336)
Names
IUPAC name
Calcium 1,3-dihydroxypropan-2-yl phosphate
Identifiers
CAS Number
27214-00-2 ?
3D model (JSmol)
Interactive image
ChEBI
CHEBI:31336 ?
ChemSpider
56554 ?
ECHA InfoCard 100.055.654
E number E383 (antioxidants, ...)
PubChem CID
62820
CompTox Dashboard (EPA)
DTXSID1048962 Edit this at Wikidata
InChI
SMILES
Properties
Chemical formula
C3H7CaO6P
Molar mass 210.135 g·mol-1
Pharmacology
ATC code
A12AA08 (WHO)

Calcium glycerylphosphate (or calcium glycerophosphate) is a mineral supplement.

Major
Calcium
ß-hydroxy-ß-methylbutyrate carbonate chloride +cholecalciferol citrate glubionate glucoheptonate gluconate# glycerylphosphate hydroxyapatite lactate gluconate lactate pangamate phosphate
Magnesium
aspartate chloride citrate gluconate glycinate lactate levulinate malate orotate oxide pidolate sulfate taurate
Phosphorus
adenosine triphosphate disodium hydroxyapatite monosodium phosphate
Potassium
bicarbonate bitartrate chloride citrate gluconate
Sodium
chloride sulfate
Sulfur
L-cysteine L-cystine L-glutathione L-methionine methylsulfonylmethane N-acetyl-L-cysteine R-?-lipoic acid S-adenosyl methionine taurine
Trace
Copper
gluconate
Iodine
potassium iodide
Iron
(II) fumarate (II) sulfate
Selenium
selenate selenite
Zinc
acetate L-aspartate L-carnosine gluconate oxide proteinate sulfate
Ultratrace
Chromium
(III) picolinate (III) chloride
Fluorine
fluoride# monofluorophosphate
Lithium
aspartate carbonate orotate
Vanadium
(IV) sulfate
Feed Additives Calcium Phosphate (16.5%/17%/18%) China Supplier
Product Specification
Product Number: G6626
CAS Number: 58409-70-4
MDL: MFCD00037173
Formula: C3H7CaO6P
Formula Weight: 210.14 g/mol
TEST Specification
Appearance (Color) White to Off-White
Appearance (Form) Powder
Solubility (Color) Colorless to Faint Yellow
Solubility (Turbidity) Clear
50 mg/ml, 0.5 M HCl
Infrared spectrum Conforms to Structure
Loss on Drying < 12.0 % _
Solvent Content (by GC) < 4.0 % _
Calcium (Dry Basis) 15.0 - 22.8 %
Purity (TLC) > 98 % _
Specification: PRD.1.ZQ5.10000029414
Sigma-Aldrich warrants, that at the time of the quality release or subsequent retest date this product conformed to the information contained in
this publication. The current Specification sheet may be available at Sigma-Aldrich.com. For further inquiries, please contact Technical Service.
Purchaser must determine the suitability of the product for its particular use. See reverse side of invoice or packing slip for additional terms
and conditions of sale.
Product Name:
Effects of calcium glycerophosphate and sodium fluoride on the induction in vivo of caries-like changes in human dental enamel
Author links open overlay panelW.M.EdgaraD.A.M.Geddesa*G.N.JenkinsaA.J.Rugg-GunnaR.Howella†
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https://doi.org/10.1016/0003-9969(78)90190-5Get rights and content
Abstract
Optical changes interpreted as demineralization on the enamel surfaces of 8 volunteers who did not clean their teeth for 18 days, while rinsing 9 times each day with 50 per cent sucrose solution, were not reduced by the addition of calcium glycerophosphate (1 per cent w/v) in the rinse. No changes were observed in plaque accumulation or in the plaque pH fall after sucrose attributable to calcium glycerophosphate. Topical applications of sodium fluoride (2 per cent) tended to inhibit the development of similarly-induced changes but the effect was not statistically significant with the small number of subjects.

Calcium glycerophosphate for treating and preventing respiratory diseases or conditions
Abstract
Calcium glycerophosphate is found to be effective in treating and preventing a disease, disorder and/or condition of the respiratory system The disease, disorder and/or condition is related to an obstructive or a restnctive condition of the respiratory airway The disease, disorder and/or condition can be a respiratory airway inflammatory disease, a respiratory airway stenosis or a nasal cavity inflammatory disease, such as an asthma, a chronic obstructive pulmonary disease (COPD), an emphysema, a reactive airway disease (RADS), rhinitis, bronchitis, bronchiolitis, congestion, sinusitis, tonsillitis, or laryngitis, post-nasal drip (PND) and a related complication thereof, inflamed degranulating and non-degranulating mast cell activity, any irritation occasioning mucus secretion from goblet cells breathing difficulty, restriction, obstruction, airways constriction or closure or mucus interference with air passage, sleep apnea, snoring, inflammatory or non-inflammatory responses to an airborne or non-airborne allergen or irritant.
Classifications
A61K45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
View 1 more classifications
WO2009029705A1
WIPO (PCT)
Download PDF Find Prior Art Similar
Other languages French Inventor Alan E. Kligerman
Worldwide applications
2008 JP CN EP CA WO
Application PCT/US2008/074589 events
2007-08-30
Priority to US96893807P
2007-08-30
Priority to US60/968,938
2008-08-28
Application filed by Prelief Inc.
2009-03-05
Publication of WO2009029705A1
2010-03-01
Priority claimed from US12/714,700
Info Patent citations (3) Cited by (2) Legal events Similar documents Priority and Related Applications External links EspacenetGlobal DossierPatentScopeDiscuss
Description
Calcium Glycerophosphate for Treating and Preventing Respiratory Diseases or Conditions
BACKGROUND OF THE INVENTION
[0001] Diseases, disorders and/or conditions of the respiratory system occur commonly in both affluent countries and developing countries. They account for a significant proportion of all days of sickness related absence from work. The morbidity related to respiratory diseases, disorders and conditions has not decreased.
[0002] Therefore, there is a need to develop a relatively inexpensive means for treating and preventing diseases, disorders and/or conditions of the respiratory system. Preferably, such a means is non-toxic, non-hazardous and without significant side effects.
BRIEF SUMMARY OF THE INVENTION
[0003] It is now discovered that calcium glycerophosphate is effective in treating and preventing a disease, disorder and/or condition of the respiratory system. [0004] In one general aspect, the present invention relates to a method of treating or preventing a disease, disorder and/or condition of the respiratory system in a subject. The method comprises administering to the respiratory system of the subject an effective amount of calcium glycerophosphate in a composition formulated for oral or nasal administration. [0005] In another general aspect, the present invention relates to a composition for treating or preventing a disease, disorder and/or condition of the respiratory system in a subject. The composition comprises an effective amount of calcium glycerophosphate and is formulated for oral or nasal administration to the respiratory system of the subject by a nasal drop, a nasal spray, a gel, a nasal lavage, a quick-dissolving tablet, an inhaled powder, an oral inhalation solution or suspension, a syrup, a mechanized intermittent fluid pulser (such as Water-Pik®), an inhaler, a respirator, a transpirator, an atomizer, a vaporizer, a nebulizer, an air mask, an insufflator, a means for direct physical or mechanical application (such as a cotton swab), etc.
[0006] In yet another general aspect, the present invention relates to a device for treating or preventing a disease, disorder and/or condition of the respiratory system in a subject. The device comprises an effective amount of calcium glycerophosphate and a means for administering the effective amount of calcium glycerophosphate to the respiratory system of the subject. [0007] Other aspects, features and advantages of the invention will be apparent from the following disclosure, including the detailed description of the invention and its preferred embodiments and the appended claims.
DETAILED DESCRIPTION OF THE INVENTION [0008] Calcium glycerophosphate has already been shown to behave as an anti-inflammatory substance on epidermal and epithelial cells and as a wound healer on epidermal cells as well as in the gums and mucosal soft tissue elsewhere in the body, e.g., vaginal. Investigation has been expanded to its use on the nasal mucosa and other parts of the respiratory system. [0009] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set in the specification. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth fully herein. It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. [0010] As used herein, the term "subject" refers to a mammal, who has been the object of treatment, observation or experiment. Examples of a subject can be a human, a livestock animal (beef and dairy cattle, sheep, poultry, etc.), or a companion animal (dog, cat, horse, etc). [0011] As used herein, the term "respiratory system" refers to all parts of the airway, i.e., the passageway for air during respiration, from the nose to the pulmonary alveoli. The respiratory system includes organs that are involved in breathing, such as the nose, throat, larynx, trachea, bronchi, and lungs.
[0012] As used herein, the term a "disease, disorder and/or condition of a/the respiratory system" refers to any disease, disorder and/or condition that is related to an obstructive or restrictive condition of a respiratory system. An obstructive condition of a respiratory system includes any condition which impedes the rate of air flow into and out of the lung. A restrictive condition of a respiratory system includes any condition which causes a reduction in the functional volume of the lung. The obstruction or restriction of the airway may cause symptoms such as wheezing, shortness of breath, difficulty breathing, chest tightness, and coughing. The disease, disorder and/or condition of the respiratory system can be, for example, an airway inflammatory disease, an airway stenosis, or a nasal cavity inflammatory disease.
[0013] Examples of the disease, disorder and/or condition of the respiratory system include, bu are not limited to, an asthma; a chronic obstructive pulmonary disease (COPD); an emphysema, a reactive airway disease (RADS); rhinitis; bronchitis; bronchiolitis; congestion; sinusitis; tonsillitis; laryngitis; post-nasal drip (PND) and any and all complications dependent on same; inflamed degranulating and non-degranulating mast cell activity; any irritation occasioning mucus secretion from goblet cells or elsewhere, resulting in breathing difficulty, restriction and/or obstruction; airway constriction or closure or mucus interference with air passage; sleep apnea; snoring; inflammatory or non-inflammatory responses to any airborne or other allergen or irritant; nasal or other airway inflammation or irritation caused by any other body area problem; physical damage to the respiratory system such as nosebleed, surgery healing, traumatic injury; any respiratory disease, disorder and/or condition caused by an airborne or seasonal allergen or irritant, any swelling of tissue occasioned by any of the above, etc.
[0014] As used herein, the term "asthma" refers to a chronic condition, which in most cases is characterized by reversible airway obstructions and/or constrictions. The airway becomes inflamed and is lined with excessive amounts of mucus, often in response to one or more triggers for asthma. The triggers for asthma include, but are not limited to, an environmental stimulant, such as an allergen (ragweed, house dust, animal hair, pollen, etc.), cold air, warm air, moist air, change in temperature or humidity, upper respiratory infections, exercise, exertion, physical or emotional stress, smoke, viral illnesses such as those caused by common cold. The term "asthma" includes those caused by any cause of asthma whose primary effect is cellular inflammation and/or irritation, whether involving mast cells or not, degranulation or not, mucus exudation or not, whether exacerbant is identified or not, or whether the cause is airborne or not. The term 'asthma' is to be the widest-encompassing and is to include breathing difficulty of all degrees from the barely perceptible to acute.
[0015] Examples of asthma include, but are not limited to bronchial asthma, infantile asthma, allergic asthma, atopic asthma, steroid refractory asthma, non-allergic asthma, endogenous asthma, exogenous asthma, aspirin asthma, cardiac asthma, exercise-induced asthma, infectious asthma, any asthma triggered by airway restriction or constriction.
[0016] As used herein, the term "chronic obstructive pulmonary disease" or "COPD", also known as chronic obstructive airway disease (COAD), refers to a progressive respiratory disease characterized by limitation of airflow in the airway that is not fully reversible. COPD often involves permanent or temporary narrowing of small bronchi, in which forced expiratory flow is slowed.
Examples of COPD include chronic bronchitis, emphysema and a range of other disorders to which no etiologic or other more specific term can be applied. COPD is most often due to tobacco smoking but can be due to other airborne irritants, such as coal dust, asbestos or solvents, as well as preserved meats containing nitrites.
[0017] As used herein, the term "reactive airway disease (RAD)" refers to an asthma-like syndrome developed after a single exposure to high levels of a trigger, such as irritating vapor, fume, or smoke. In a particular embodiment of the present invention, the term RAD includes an asthma-like syndrome in infants that may later be confirmed to be asthma when they become old enough to participate in diagnostic tests.
[0018] As used herein, the term "rhinitis" refers to any disease, disorder and/or condition caused by inflammation of the nasal mucous membrane. Examples of rhinitis include, but are not limited to, allergic rhinitis, pollinosis, acute rhinitis, chronic rhinitis, hypertrophic rhinitis, deflected septum and the like. Symptoms of rhinitis include, but are not limited to, a runny nose, nasal congestion and post-nasal drip. According to recent studies completed in the United States, more than fifty million Americans are current sufferers of rhinitis. Rhinitis has been found to adversely affect more than just the nose, throat, and eyes. It has been associated with sleeping problems, problems with the ears, and has even been linked to learning problems. Causes that may bring about the presence of rhinitis include food reactions, anatomic defects, immunodeficiency diseases, ciliary dyskinesia, environmental triggers, emotional triggers, occupational triggers, hormonal triggers, etc. [0019] As used herein, the term "calcium glycerophosphate" or "CGP," also known as "glycerophosphate calcium," refers to a chemical compound having a molecular formula of C3H7CaO6P in its anhydrous form. "CGP" can also exist as a hydrate, including the monohydrate and the dihydrate. Examples of calcium glycerophosphate include, but are not limited to, any one, or any combination of two or more of the three isomers of CGP, namely ß-glycerophosphoric acid calcium salt ((HOCH2)2CHOPC>3Ca) and D(+) and L(-)-?-glycerophosphoric acid calcium salt (HOCH2CH(OH)CH2OPO3Ca). [0020] Calcium glycerophosphate can be synthesized using methods known in the art. Calcium glycerophosphate can also be obtained from various commercial sources. The commercially available CGP preparations include, but are not limited to, those available from AkPharma Inc. (Pleasantville, NJ 08232), Astha Laboratories Pvt, Ltd, (B-4, Industrial Estate, Sanathnagar, Hyderabad- 18, India), and Seppic Inc. (30 Two Bridges Road, Fairfield, NJ 07004). [0021] As used herein the term "treatment", "treat" or "therapy" refers to the prevention of deterioration of a disease, disorder or condition when a patient contracts such a disease, disorder or condition, preferably, at least maintenance of the status quo, and more preferably, alleviation, still more preferably, resolution of the disease, disorder or condition. [0022] As used herein the term "prophylaxis", "prevent" or "prevention" refers to, when referring to a disease, disorder or condition, a type of treatment conducted before such a disease, disorder or condition occurs such that the disease, disorder or condition will not occur, will be delayed to occur, or will occur but will deteriorate to a less degree. [0023] As used herein, the term "treat" or "prevent" in the broadest sense, with respect to a disease, disorder or condition, refers to any medical act thereto, and include any act for diagnosis, therapy, prevention, prognosis and the like.
[0024] When used for treating or preventing a disease, disorder and/or condition of the respiratory system, calcium glycerophosphate can be used as a reliever which is used during an episode or an attack of the disease, disorder and/or condition, such as an episode of an asthma, for alleviation of the episode or attack. Calcium glycerophosphate can also be used as a controller which is used for long-term control to prevent the occurrence of the episode or attack. Controlling or preventing an attack is substantially the therapy of a disease, disorder and/or condition of the respiratory system per se, because it is equally important to control and prevent an attack as to relieve or alleviate the attack. Those skilled in the art will be able to use an appropriate dosage of calcium glycerophosphate for either therapy or prevention of a disease, disorder and/or condition of the respiratory system.
[0025] The term "effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. The administration of an effective amount of calcium glycerophosphate to a subject results in a clinically observable beneficial effect. The clinically observable beneficial effect can be a situation in which an observable disease, disorder and/or condition of the respiratory system is prevented from further development or aggravation or will develop to a lesser degree, than without administration of the composition of the present invention. The clinically observable beneficial effect can also be a situation in which a disease, disorder and/or condition of the respiratory system is prevented from occurring or subsequently occurs to a lesser degree than without administration of the composition of the present invention, when the composition is administered to a subject before the disease, disorder and/or condition of the respiratory system is observable. In one embodiment of the invention, an effective amount of calcium glycerophosphate alleviates or improves a disease, disorder and/or condition of the respiratory system in a subject to a degree that is about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of that which would have been had the subject not received an effective amount of calcium glycerophosphate.
{0026] Methods are known in the art for determining therapeutically and prophylactically effective doses of calcium glycerophosphate according to embodiments of the present invention. A useful assay for confirming an effective amount (e.g., a therapeutically effective amount) for a predetermined application is to measure the degree of recovery from a target disease. An amount actually administered depends on an individual to be treated. The amount is preferably optimized so as to obtain a desired effect without significant side effects. The determination of a prophylactically or therapeutically effective dose is within the ability of those skilled in the art. A prophylactically or therapeutically effective dose of any compound can be estimated using either a cell culture assay or any appropriate animal model. The animal model is used to achieve a desired concentration range and an administration route. Thereafter, such information can be used to determine a dose and route useful for administration into humans. [0027] The therapeutic effect and toxicity of a compound may be determined by standard pharmaceutical procedures in cell cultures or experimental animals (e.g., ED50, a dose therapeutically effetive for 50% of a population; and LD50, a dose lethal to 50% of a population). The dose ratio between therapeutic and toxic effects is a therapeutic index, and it can be expressed as the ratio of ED50/LD50. Pharmaceutical compositions which exhibit high therapeutic indices are preferable. The data obtained from cell culture assays and animal studies can be used for formulating a dosage range for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED5O, with little or no toxicity. Such a dosage may vary within this range depending upon the dosage form employed, the susceptibility of a patient, and the route of administration. Guidance for specific doses and delivery methods is provided in publications known in the art. The exact dose is chosen by an individual physician in view of the condition of a patient to be treated. Doses and administration are adjusted to provide a sufficient level of the active portion, or to attain a desired effect.
[0028] The effective amount of CGP can be any dosage amount, from micro-doses to megadoses. Mega-doses of CGP can be effectively used, because CGP is non-toxic, non-hazardous and has no known side effects. Micro-doses of CGP can be effectively used, because both Ca2+ and the glycerophosphate anion are signaling molecules that can have a biological effect at very low levels. [0029] In embodiments of the present invention, the effective amount of CGP is administered to the subject in a composition containing about 0.05% - 15% (w/w), preferably about 0.5% - 10% (w/w); most preferably about 1% - 5% (w/w) of CGP. It has been discovered that at higher levels tested, e.g., about 7.5% (w/w) or above, calcium glycerophosphate may help in stanching nosebleeds, possibly due to the effect of calcium on blood clotting. However, the amount of CGP in the composition is not limited to about 0.05% - 15% (w/w).
[0030] In one general aspect, an embodiment of the present invention relates to a method of treating or preventing a disease, disorder and/or condition of a respiratory system in a subject. The method comprises administering to the respiratory system of the subject an effective amount of calcium glycerophosphate, wherein calcium glycerophosphate is administered to the respiratory system of the subject in a composition formulated for oral or nasal administration. The composition formulated for oral or nasal administration can be a liquid, solid, gel, syrup, powder, or mist formulation.
[0031] Calcium glycerophosphate can be administered to the respiratory system of the subject by one or more means of oral or nasal administration depending on the type of diseases, disorders and/or conditions of the respiratory system. For example, in the case of asthma, COPD and the like, atomizer type inhalators such as MDI, BDI, or nebulizers and the like may be used for inhalation. For example, in the case of rhinitis, absorption and inhalation may be used for administration.
Examples of applicable means of oral or nasal administration include, but are not limited to, a nasal drop, a nasal spray, a nasal lavage, a quick-dissolving tablet, an inhaled powder, an oral inhalation solution or suspension, a syrup, a mechanized intermittent fluid pulser (such as Water-Pik®), an inhaler, a respirator, a transpirator, an atomizer, a vaporizer, an air mask, an insufflator, a means for direct physical or mechanical application, such as a cotton swab, etc.
[0032] Inhalation is conventionally used as a method for administration via the nasal cavity, airway and nasal pathways and the like. In intra-airway administration formulations, transairway absorption formulations or pernasal absorption formulations, it is usually preferable to make a drug solution in a mist form or as fine powder (dry powder). Generally, a drug solution formed may be inhaled by means of a nebulizer, those processed into powder may be inhaled by means of a gas- atomizing type, MDI (metered dose inhaler) or expiration inhalation system, DPI (dry powder inhaler) with the drug loaded therein.
[0033] With respect to powder inhalers, there are two types presently used for rapid and deep inhalation, "dry powder inhaler (DPI)" and delayed inhaling type "metered dose inhaler (MDI)". DPI are further classified into three categories: multi-dose reservoir, such as the product TURBUHALER®, available from AstraZeneca; multi-unit dose, such as the product ACCUHALERTM/ FLOVENT DISKUSTM, available from GSK; and unit dose, available from many manufacturers. [0034] Inhaler refers to a kit comprising a mouth piece and cartridge (tube), and are usually employed by sealing both termini of the tube with aluminum foil. Prior to use, the tube is equipped with the mouth piece to pierce the aluminum foil, thereby allowing inspiration of powdered drug inside. [0035] On the other hand, absorption of a drug solution may be achieved by means of a nebulizer or respirator, an artificial respirator. A nebulizer causes a drug aerosol to flow in the air at slow speed, thus makes it easier for one to absorb the drug.
[0036] How often and how long calcium glycerophosphate is administered to a subject depends on the disease, disorder and/or condition of the respiratory system to be treated or prevented, as well as factors associated with the subject, e.g., age, weight, health, etc. Calcium glycerophosphate can be administered on a regimen of one to multiple times per day. Calcium glycerophosphate can be administered to the subject at intervals during the day, such as upon arising, after breakfast, lunch, dinner, and upon retiring. Calcium glycerophosphate can be administered during an episode or an attack of the disease, disorder and/or condition of the respiratory system to provide a relief of symptoms, such as wheezing, shortness of breath, difficulty breathing, chest tightness, and coughing. Calcium glycerophosphate can also be administered to a subject prior to an episode or an attack to control or prevent the episode or attack and the symptoms associated with the episode or attack.
[0037] Dosages of calcium glycerophosphate are not limited to a particular value. The dosage appropriately varies depending on the targeted disease, condition (extent), age, the presence or absence of complication(s), etc. For example, the dosage is usually, per adult, per administration, about 100 µg to about 1000 mg, preferably about 500 µg to about 100 mg, and most preferably about 1 mg to about 40 mg of anhydrous CGP. As used herein, "anhydrous CGP" refers to a CGP preparation that contains at least about 88% (w/w) of CGP that is free of residual or acquired moisture. The anhydrous CGP used in embodiments of the present invention complies with Food Chemicals Codex (FCC) specifications, in which loss on drying (LOD) is not to exceed 12%. As used herein, "per administration" can be, per inhalation per nostril, per spray, per tablet, etc. In one embodiment of the present invention, the dosage is about 400 mg solution/suspension formulation containing about 2% by weight of dry CGP per administration, hi another embodiment of the present invention, the dosage is about 400 mg solution/suspension formulation containing about 3.75% by weight of dry CGP per administration. The dry CGP contains about 95-98% anhydrous CGP balancing with moisture. However, the dosage of CGP is not limited to the above ranges and can be any range without causing physical endangerment. [0038] While not wishing to be bound by theory, calcium glycerophosphate can be used to treat or prevent a disease, disorder and/or condition of the respiratory system at least in part due to the anti-inflammatory effect of CGP. Inflamed airway epithelium results in a disease, disorder and/or condition of the respiratory system. Various observations suggest that a glycerophosphate salt functions to promote epidermal cell renewal, see for example, US2004/0037766. The quick repair and replacement of epidermal cells provide, among other things, enhanced ceramide synthesis, which hastens repair of the skin's surface and provides tighter cell-to-cell adhesion, which may prevent invasion between vulnerable cell walls of irritating substances. This is to be distinguished from the possible function of the calcium ion to modify the permeability of cell membranes, per se, i.e., the ability of calcium ion to decrease membrane porosity at a large concentration. The reduction, interdiction, suppression or prevention of inflammation of the respiratory system provides symptom relief or prevention. The beneficial effect of CGP may also be due to, at least in part, its ability to prevent or reduce acid-caused irritation and cytotoxicity in the upper and lower respiratory tract, and/or its ability to promote higher ciliary activity, e.g., via regulating the phosphorylation state of certain ciliary proteins. It is believed that the newly discovered beneficial effect of CGP on the respiratory system according to embodiments of the present invention is achieved synergistically between the calcium ion and the glycerophosphate. This synergistic effect is distinct from the function of the calcium ion or the glycerophosphate alone. [0039] Calcium glycerophosphate is non-toxic, non-hazardous and has no known side effects. Therefore, methods according to embodiments of the present invention are particularly desirable for pediatric patients, elderly patients, pregnant women, or patients who have frequent need of relief medications and/or preventive medications for a disease, disorder and/or condition of the respiratory system. Oral or nasal administration of the composition according to the present invention is noninvasive and can be repetitively provided. [0040] In particular embodiments, calcium glycerophosphate can be administered in combination with one or more other relief and/or preventive agents for a disease, disorder and/or condition of the respiratory system. Thus, embodiments of the present invention relate to compositions comprising calcium glycerophosphate and one or more other relief and/or preventive agents for a disease, disorder and/or condition of the respiratory system, and methods of using the compositions for treating or preventing a disease, disorder and/or condition of a respiratory system in a subject. Calcium glycerophosphate and the other agent can be administered simultaneously or sequentially, one following the other. The other agents can be administered to the subject via routes of administration customarily used for such other drugs. However, it is not necessary to administer the other relief and/or preventive agent in a substantial percentage of instances according to embodiments of the present invention. Calcium glycerophosphate, as the sole active pharmaceutical ingredient, is effective to treat or prevent a disease, disorder and/or condition of the respiratory system. [0041] Examples of such relief and/or preventive agents include, but are not limited to, a beta-2 agonist, an alpha agonist, a bronchodialator, a glucocorticoid, a leukotriene modifier, a mast cell stabilizer, an antimuscarinic/anticholinergic, a methylxanthine, an antihistamine, omalizumab, methotrexate, and tianeptine, albuterol, cromolyn, or the like. [0042] Other embodiments of the present invention relate to compositions comprising calcium glycerophosphate and one or more analgesics, and methods of using the compositions for treating or preventing a disease, disorder and/or condition of a respiratory system in a subject. Examples of the compositions include, but are not limited to, a pharmaceutical product for treating a cold, hayfever, any respiratory disease, disorder and/or condition caused by an airborne or seasonal allergen or irritant, etc., comprising CGP as the nasal cleaner/decongestant (NasoCellTM) and a common over the counter (OTC) analgesic such as ibuprofen, acetominophen, aspirin, naproxen, capsaicin, etc. The amount of CGP in the composition can be appropriate to supply in a single dosage, which may be 2 to 4 sprays of the NasoCell, to provide nasal cleaning and/or decongestant. The amount of the analgesic in the composition can be effective to relieve common headaches, sinus aches, eye aches, etc. that are associated with colds, hay fever, etc. [0043] Nasal administration of the composition according to the present invention can provide more rapid relief of the symptoms associated with cold, hayfever, etc. Administration via nasal membrane absorption can be more quantitatively effective and more chronologically prompt to reach the bloodstream than the same analgesic ingested that must go through the gastric system for subsequent absorption with possible compositional compromise by the digestive process. In addition, the hypotonicity of the NasoCell allows the composition to adhere more readily to the epithelial nasal cells, thus be absorbed more readily through the cell walls and into the bloodstream. [0044] The compositions according to the present invention offer the unique combination of effective nasal cleaning, nasal clearing, anti-inflammation, anti-swelling, and pain relief, without any of the psychogenic effects associated with the presently marketed drugs, such as diphenhydramine, ephedrine, pseudoephedrine, etc., nor any of the undesirable, typical anticholinergic side effects at the site or elsewhere in the body. The composition is safe to use liberally even when driving or operating machinery. [0045] In another general aspect, an embodiment of the invention provides a composition for treating or preventing a disease, disorder and/or condition of the respiratory system in a subject. The composition comprises an effective amount of calcium glycerophosphate, wherein the composition is formulated for oral or nasal administration to the respiratory system of the subject by a nasal drop, a nasal spray, a nasal lavage, a quick-dissolving tablet, an inhaled powder, an oral inhalation solution or suspension, an inhaler, a respirator, a nebulizer, a transpirator, an atomizer, a vaporizer, an air mask, an insufflator, a means for direct physical or mechanical application, such as a cotton swab, etc. [0046] The composition according to embodiments of the present invention may be produced using a method similar to methods known in the art, e.g., conventional mixing, dissolution, rendering to granules, preparation of a sugar-coated agent, elutriation, emulsification, capsulation, inclusion, or freeze drying. One or more excipients can be added to the composition. Excipients which can be used are those that are inactive against calcium glycerophosphate, and as long as the use is recognized as a pharmaceutical additive, no limitation is made for such excipient. Examples of appropriate excipients include, but are not limited to, monosaccharides such as galactose, mannose, sorbose; disaccharides such as lactose, sucrose and trehalose and the like; polysaccharides such as starch, raffinose, dextran and the like; sugar alcohols (including glycerol, erythritol, arabitol, xylitol, sorbitol, mannitol); glycols (including ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol); cellulose-like polymers (including hydroxy cellulose, hydroxy propyl cellulose); insoluble additives (crystalline cellulose, chitosan, calcium carbonate, talc, titanium oxide or silica (silicon oxide), and mixtures thereof.
[0047] The composition according to embodiments of the present invention can be formulated to have a pH of about 4.5 - 10, such as about 4.5 - 6.0, about 6.0 - 8.0, or about 8.0 - 10.0. Note that nasal pH varies considerably, from 4.5 - 6.5 in normal nasal cells, to as high as 8.3 in rhinitis. However, the pH of the composition according to embodiments of the present invention is not limited to the range of about 4.5 - 10, or that of the nasal pH.
[0048] The composition according to embodiments of the present invention can further contain a preservative. Preferably the preservative is food grade or pharmaceutical grade. Examples of appropriate preservatives include, but are not limited to, methylparaben, ethylparaben, butylparaben, propylparaben, sorbic acid and any other preservative that is typically used in water-based cosmetics, such as creams and lotions and some bath products. The preservative is preferably present at an amount that is sufficient to prevent the composition from supporting the growth of microbes, such as bacteria, fungi, or yeasts. [0049] The composition according to embodiments of the present invention can also include an adhesion molecule or material that allows the composition to adhere to an airway tissue for an extended period of time, thus results in an extended release of CGP into the airway. Adherence is accomplished by a number of interactions, physical or chemical, such as electrostatic interaction, hydrogen bonding or hydrophobic interaction. In preferred embodiment, the adhesion molecule or material extends the contact time of CGP in the nasal cavity. Any suitable adhesion molecule or material known to a person skilled in the art can be used in a composition according to embodiments of the present invention. In one embodiment, the adhesion molecule or material is a polysaccharide. In a preferred embodiment, the adhesion molecule is chitosan, a cationic polysaccharide derived from the shells of crustaceans. A versatile transmucosal delivery system based on chitosan is commercially available from West Drug Delivery of Lionville, PA 19353 (US), and can be used in the present invention.
Glycerol phosphate calcium salt
Synonym: Calcium glycerophosphate
CAS Number 58409-70-4 Linear Formula C3H7O6PCa Molecular Weight 210.14 EC Number 261-240-1 PubChem Substance ID 24895263
Glycerol phosphate calcium salt
SDS Specification Sheet (PDF)
Calcium glycerophosphate is a source of highly bioavailable calcium and phosphorus. This mineral salt has nutritional, organoleptic and technological superior quality. These qualities are due to the specific characteristics of the organic anion glycerophosphate.
Advantages to use GIVOCALTM
A "3 in 1" salt
It supplies calcium, glycerol and phosphorus
Double interest
This type of calcium salt has a physiologic and metabolic interest due to the glycerophosphate, which is absent in inorganic calcium salts
A superior way
As part of nutraceuticals or health food, GIVOCALTM is a highly bioavailable source of calcium
Scientific evidences
Calcium glycerophosphate shows excellent absorption. Some other clinical studies show positive effects on bone and teeth development
A chelate
Glycerophosphate is an excellent vector for delivering calcium into the GI tract
Bioavailability
Most calcium compounds given orally are soluble in gastric acid but are converted into insoluble calcium carbonate in the duodenum resulting in only a fraction of the calcium is available for absorption. Absorption of calcium salts therefore depends greatly on their solubility and stability in a wide pH range.
A study on the capacity of acidity neutralization made on several calcium salts shows that GIVOCALTM has the smallest buffer power and therefore is the best solubilized in the stomach among all salts studied. It also stays solubilized in the small intestine.
These results were confirmed by an in vitro study made on the gastrointestinal model TIM-1 of TNO laboratory (The Netherlands) which compared the absorption of GIVOCALTM and calcium carbonate. With the same amount of calcium ingested (introduced into the system), GIVOCALTM permits a better absorption of calcium: 4 times more calcium is absorbed with GIVOCALTM than with calcium carbonate (internal results).
Moreover, a recent study made on rats shows that, with the same amount of calcium ingested, GIVOCALTM has twice as less of calcium excretion than calcium carbonate (internal results). These results suggest that GIVOCALTM has a higher bioavailability than calcium carbonate.
Other in vitro or in vivo studies show that GIVOCALTM allows a good assimilation of calcium by the bone tissue, has a cariostatic effect on teeth and shows a beneficial action on the nervous system (internal results).
Technical information
Composition :
- Ca/P ratio: 1.3
- 19.1% Ca content
- 14.6% P content
Taste & Odour: Neutral
Solubility: Water soluble
Appearance: Fine white powder
ISALTIS
Partner
Isaltis is a leading manufacturer of high quality mineral salts.
Isaltis owns two GMP sites in France, Bernady and Givaudan Lavirotte, where are manufactured glycerophosphate, gluconate, glucoheptonate, citrate and lactate salts.
Purity Does not come with a purity or COA.
Purity Expiration 01/31/23dd
Alternate Name(s) Glycerophosphoric acid calcium salt
Size 1G
Molecular Formula C3H9O6P.Ca
COA of Current Lot You must login to your account to view the COA
Calcium content :19.
Ca/P ratio: 1.3
Phosphorus content :14.8%
Solubility :20 g/l in water(at 15°C)
Organoleptic: Tasteless and odorless
Particle size :95 % < 100 µm
Aspect :White crystalline powder
Water content :10 %
Glycerophosphate anion is a vector for calcium
Calcium is better absorbed in ionised form
Calcium is absorbed in the small intestine
Calcium absorption is regulated by 4 physico-chemical parameters
Ca salt solubility into stomach acid compartment
Ca precipitation in the small intestine after neutralisation by pancreatic secretion
Ca complexation with anions (phytates, oxalates) in the small intestine
Digestive use coefficient : 50 -25 %
Comparative studes at different pH
3 mg/ml Ca + 2,35 mg/ml phosphate anios for salts without P
pH adjusted with HCl or NaOH from 2 to 9
Calcium glycerophosphate is soluble in all the pH scale
A comparative study with an equivalent of 200 mg of calcium element
Calcium glycerophosphate has the smallest buffer power that means it is best solubilised in stomach
Calcium carbonate
CaCO3 is soluble at acid pH but it rapidly neutralises gastric acidity
CaCO3 develops a neutral area in the stomach where it becomes insoluble
CaCO3 is usually used as an antiacid compound
When CaCO3 arrives in the small intestine it is neutralised
Tricalcium phosphate (Ca3(PO4)2)
Ca3(PO4)2 is soluble in pH < 4 but it has a high buffer power
When pancreatic secretions enter in contact, Ca3(PO4)2 precipitates
An excess of phosphates induces extrabone calcifications
Physiological time of metabolic interest of CaCO3 & Ca3(PO4)2 are very brief
Calcium carbonate has an alkaline effect and modifies the electrolyte equilibrium. It also might induce flatulencies, constipations, nausea.
Tricalcium phosphate modifies the electrolyte equilibrium
Calcium lactate & glycerophosphate are non irritant for digestive tract
The biological ratio between Ca & has to be 1 to 1,5
Calcium glycerophosphate: Ca/P = 1,3
Calcium carbonate: no P / Risk hypophosophatenia
Tricalcium phosphate: Ca/P = 1,3
Glycerophosphate is an intermediate of the cellular metabolism
Potentiality to become integrated into well-known mechanisms
Has an esssential place into the biosynthesis of triglycerides and phospholipids
L-glycerol-3-phosphate is the main acceptor of actylated group which are characteristics of lipidic structures.
It is then important for the lipids storage in the adipous tissue, for blood lipoortein structure (triglycerides and phospholipids) or biological membranes structure
Glycerophosphate acts very directly into the general ways of glycolic metabolic regulation and cell energy
Mitochondria
Glycerophosphate is able to become integrated into the cellular metabolism in the way of classical reactions
Subjects: in vitro study protocol using rat nerve cells
Design:
Survival of neurons
Differentiation of neurons cocultured with astrocytes
Results:
Calcium glycerophosphate enhances neuron survival in tissue culture
Calcium glycerophosphate has more activity in promoting the survival & differenciation of neurons
Astrocytes cocultured with calcium glycerophosphate were more shaped and thus formed a greater number of interneuronal connections
Calcium glycerophosphate stimulates the energetic way (degradation of glucose to pyruvate through its transofrmation into G3P)
Subjects: mice
Design:
Comparative absorption of diferent calcium salts
Diet supplemented with 0,5% calcium
Measurements of the femur resistance to fracture
Duration: 6 weeks
Results: calcium glycerophosphate leads to a better fixation of calcium by the femoral bone in comparison to other commonly employed calcim salts and increases the hardness of bone TNO dynamic models are unique tools to study stability, release, dissolution, absorption & bioconversion of nutrients, chemicals, bioactive pharmaceutical compounds in gastrointestinal tract
Subjects: TIM -1 (dynamic gastrointestinal model) Simulation of gastrointestinal conditions
Design: to determine the digestibility of calcium glycerophosphate & calcium carbonate durign passage through the stomach and small intestine
Simulation dynamic conditions in gastric small intestinal tract
Body temperature & pH curves
Concentration of electrolytes
Activity of enzymes in the stomach & small intestine
Concentration of the bile salts
Kinetics of passage of the chime through the stomach and small intestine
Absorption of low molecular molecules and water
Experiments performed under the average physiological conditions of the gastrointestinal tract as described for young adults
The Influence of Calcium Glycerophosphate (GPCa)
Abstract: In this paper we describe the synthesis of poly(ester ether urethane)s (PEEURs) by using selected raw materials to reach a biocompatible polyurethane (PU) for biomedical applications. PEEURs were synthesized by using aliphatic 1,6-hexamethylene diisocyanate (HDI), poly(ethylene glycol) (PEG), ?,?-dihydroxy(ethylene-butylene adipate) (Polios), 1,4-butanediol (BDO) as a chain extender and calcium glycerolphosphate salt (GPCa) as a modifier used to stimulate bone tissue regeneration. The obtained unmodified (PURs) and modified with GPCa (PURs-M) PEEURs were studied by various techniques. It was confirmed that urethane prepolymer reacts with GPCa modifier. Further analysis of the obtained PURs and PURs-M by Fourier transform infrared (FTIR) and Raman spectroscopy revealed the chemical composition typical for PUs by the confirmed presence of urethane bonds. Moreover, the FTIR and Raman spectra indicated that GPCa was incorporated into the main PU chain at least at one-side. The scanning electron microscopy (SEM) analysis of the PURs-M surface was in good agreement with the FTIR and Raman analysis due to the fact that inclusions were observed only at 20% of its surface, which were related to the nonreacted GPCa enclosed in the PUR matrix as filler. Further studies of hydrophilicity, mechanical
properties, biocompatibility, short term-interactions, and calcification study lead to the final conclusion that the obtained PURs-M may by suitable candidate material for further scaffold fabrication. Scaffolds were prepared by the solvent casting/particulate leaching technique (SC/PL) combined with thermally-induced phase separation (TIPS). Such porous scaffolds had satisfactory pore sizes (36-100 µm) and porosity (77-82%) so as to be considered as suitable templates for bone tissue regeneration.
Keywords: polyurethane; bone tissue engineering; calcium glycerolphosphate salt; mechanical
properties; contact angle; SEM; EDX; calcification; solvent casting/particulate leaching; TIPS
Polymers 2017, 9, 329 2 of 21
1. Introduction
Tissue scaffolds, designed for tissues regeneration, are three-dimensional porous structures, which serve as biological tissue substitutes that enable the functional performance of the regenerated tissue to be restored, maintained or improved[1]. Tissue engineering (TE) applies both natural and synthetic polymers [2], metals [3], ceramics [4] and bioactive glasses [5]. Biomaterials used for the purpose of tissue engineering (TE) have to meet strict requirements such as biocompatibility. Moreover, these materials may reveal some bioactive behavior, which could stimulate proper tissue regeneration [6]. The 3D scaffold has to provide an adequate support for the regenerated tissue, thus the mechanical characteristics of the used biomaterials are an important feature. In addition the gradual degradation of the scaffold is necessary for proper tissue restoration [7,8]. However, in order to meet the requirements of an ideal tissue scaffold material and to combine the best mechanical properties with bioactivity and ability to degrade in the human body environment, new composite materials, which are the combination of polymers with different types of fillers, are being developed [1,8].
Polyurethanes (PU) according to their superior characteristics of proper physicochemical, mechanical, and biological properties seem to meet all of these requirements for use in TE as materials for scaffold fabrication [1,6].
PUs have been widely developed in the field of biomedical devices, thus their modification is well known [1,6,9]. The most common PU modifications for bone tissue engineering take place mainly by the introduction of the filler into the PU matrix. The most often reported fillers are calcium phosphates like hydroxyapatite [4,10,11], nanohydroxyapatite [12,13], and ß-tricalcium phosphate [14,15]. Recently anew solution for PU modification was proposed in the form of calcium glycerophosphate [16], bioactive glass [5] or carbon nanotubes [17].
Calcium glycerophosphate is the calcium salt of glycerophosphoric acid. This compound has been approved for use by the Ministry of Health [18] as a nutrient, a component of dietary supplements or mineral food products, and has been considered as a safe ingredient/food additive by the US Food and Drug Administration [19]. In addition to the previously listed applications, calcium glycerophosphate is also used as an ingredient in toothpaste [20], dental varnishes [21], as well as electrolytes used for mineralization of hydrogels for bone regeneration [22] or surface modification of titanium bone implants [3].
There are several examples in the literature, describing the synthesis of PU composites with the use of fillers mentioned above leading to the desired changes in mechanical properties of the material, as well as contributing to its bioactivity improvement [4,10-17].The effect of calcium glycerolphosphate salt (GPCa) as a filler on tissue scaffolds properties which received biodegradable polyurethane foams for bone graft substitutes was recognized by Gorna et al. [16]. The PU system studied by Gorna et al.
was derived from 1,6-hexamethylene diisocyanate, poly(ethylene oxide)diol, poly(?-caprolactone)diol, amine-based polyol or sucrose-based polyol, water as a chain extender and foaming agent, catalysts, citric acid as a calcium complexing agent, lecithin or solutions of vitamin D3 as surfactants, and various inorganic fillers. One of the fillers used was GPCa, others were calcium carbonate and hydroxyapatite [16]. Recently, Kavanaugh et al. [23] proved as well that segmented polyurethanes prepared with ß-glycerol phosphate as a biologically active chain extender, supported human mesenchymal stem cell adhesion, growth, and osteogenic differentiation. The PU system studied by Kavanaugh et al. was synthesized by using poly(?-caprolactone)diol, 4,4'-methylene bis(cyclohexyl isocyanate), and biologically active compounds such as ascorbic acid, L-glutamine, ß-glycerol phosphate, and dexamethasone as chain extenders [23]. In brief, the use of ß-glycerol phosphate as a chain extender has improved the biological activity of polyurethane applicable as a material for bone regeneration. Furthermore, glycerophosphates have high potential for mineralization, proper adhesion and proliferation and therefore the attempted GPCa chain PU contrasts with the approach by Gornal et al. [16] where it was used as a filler.
In this paper we describe the synthesis and characterization of the PEEURs designed for bone tissue regeneration. PEEURs were synthesized by using 1,6-hexamethylene diisocyanate (HDI), poly(ethylene glycol) (PEG), ?,?-dihydroxy(ethylene-butylene adipate) (Polios), 1,4-butanediol (BDO) as a chain extender and GPCa as a modifier used to stimulate bone tissue regeneration. The obtained unmodified (PUR) and GPCa modified (PURs-M) PEEURs were studied with various techniques in order to confirm the reactivity of GPCa with the urethane prepolymer, to study its chemical composition, surface morphology, hydrophilic character, mechanical properties, in vitro biocompatibility and short-term interactions with selected acidic, basic and oxidative environment.
Moreover the calcification study was performed to establish if the GPCa modifier improved the bioactive character of the obtained PUR-M materials. Furthermore, with the use of selected samples, porous scaffolds were obtained by using the SC/PL technique combined with TIPS. According to performed studies the obtained PURs-M may be a suitable candidate for bone tissue engineering and further studies are being developed by our team in this field.
2. Experimental
2.1. Poly(ester ether urethane)s Synthesis
PEEURs were synthesized by the standard two step polymerization procedure with urethane prepolymer intermediate [1,6]. The urethane prepolymer was obtained in the reaction of polyester ?,?dihydroxy(ethylene-butylene adipate) (PEBA, trade name Polios 55/20; Purinova, Bydgoszcz, Poland)
(63 wt %),poly(ethylene glycol) (PEG) (14 wt %) and aliphatic 1,6-hexamethylene diisocyanate (HDI) ( Poznan, Poland) (23 wt % ). In the second step the chain extender-1,4-butanediol (BDO) (POCH, Gliwice, Poland)-Was added to the urethane prepolymer to obtain PEEUs with a molar ratio of free isocyanate groups (NCO) (in the urethane prepolymer) to hydroxyl groups (OH) of the chain extender BDO equal to NCO/OH= 0.9:1.
The synthesis of modified PEEURs (PUR-M) was as follows: In the first step the urethane prepolymer was obtained in the reaction between PEBA, PEG, and HDI. In the second step the 10 wt % of GPCa ( calculated per mass of the prepolymer was added at 80 °C and stirred for 4 h (the mass ratio of urethane prepolymer to GPCa was equal to 1:0.25). In the next step the chain extender BDO was added to obtain PUR-M with a molar ratio of free isocyanate groups (NCO) (in the urethane prepolymer) to hydroxyl groups (OH) of chain extender BDO equal to
NCO/OH = 0.9:1. Reaction of unmodified and modified polyurethanes is presented in Figure 1.
(a)
Polymers 2017, 9, 329 4 of 21
(b)
Figure 1. Synthesis of unmodified (a) and calcium glycerolphosphate (GPCa)-modified (b) poly(ester
ether urethane)s (PEEURs).
2.2. Characterization Methods
2.2.1. Indications of Free Isocyanate Groups (FNCO) by the Acidimetric Method
Indication of free isocyanate groups is a standard procedure in the case of PURs obtained by a two-step polymerization method. Its aim is to establish the time, after which the requiredamount of unreacted diisocyanate groups (NCO) in the prepolymerization reaction takes place. The determination of free isocyanate groups (FNCO, %) was performed according to the PN-EN 1242:2006 standard.
2.2.2. Fourier Transform Infrared Spectroscopy (FTIR)
The FTIR of the solid PUR and PUR-M was performed by an FTIR Nicolet 8700 Spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) with Specac's Golden Gate module and single reflection diamond ATR unit to determine the influence of the processing technique on the composition of the obtained materials. The studied spectral range was from 4000 to 500 cm-1 averaging 254 scans per sample with a resolution of 4 cm-1.
2.2.3. Raman Spectroscopy
Raman spectra were performed by using Monovista CRS + spectrometer provided by S&I Ltd., (Warstein, Germany) which was operated by VistaControl 4.1 software (S&I Ltd., (Warstein, Germany). Data about the polymers' structure was obtained by using a 532 nm green laser with the scanning power reduced to 10 mV. The best suitable grating was set to 1800 grooves per mm and was chosen to provide resolution of about 0.5 cm-1. The slit was set to standard 100 micrometers and the objective used to scan in Point by Point, 2D mode was a long focal-length Olympus with 100 magnification rate. All spectra were obtained by gaining two accumulations within 10 s time frame.
Each scanning point from which the Raman spectra were taken had approximately1 µm2 surface.
2.2.4. Scanning Electron Microscopy with Energy Dispersive X-ray Spectroscopy (SEM/EDX)
SEM was performed with the use of a Zeiss Scanning Electron Microscope EVO-40(Jena, Germany) (different magnifications were used: 3000×, 1000×, and 250×). The SEM instrument was integrated with an energy dispersive X-ray (EDX) microanalyzer (Jena, Germany) for elemental analysis. Prior to the study PURs were covered with a conductive layer of gold by sputter coater Quorum 150T E. To study the morphology of the obtained PURs, PURs-M and the scaffolds ImageJ® software (U.S. National Institutes of Health, Bethesda, MA, USA) was used.
2.2.5. Static Contact Angle Determination
Polymers 2017, 9, 329 5 of 21
The contact angle as well as the surface free energy of the materials' surfaces weredeterminedat room temperature by using a Kruss Goniometer G10 (KRÜSS GmbH, Hamburg, Germany) with drop shape analysis software. The water contact angle of the 10 samples was evaluated by static contact angle measurements using the sessile drop method. Surface free energy was calculated by using measurements performed according to the Acid-Base method (AB) [24] by static contact angle studied with the use of three liquids: Water, ethylene glycol, and formamide.
2.2.6. Mechanical Properties
Tensile strength (TSB) and elongation at break (?b) were studied using the universal testing machine Zwick & Roell Z020 (Zwick Roell Polska Sp. z o.o. Sp.K., Wroclaw, Poland) according to PNEN ISO 527-2:2012 with a crosshead sped of 500 mm/min. Samples of sixwere used for this study.
Hardness was measured by using the Shore method according to PN-EN ISO 868:2004. Obtained data were presented with Shore degree (°Sh D and °Sh A). Samples of 10 were used for this study.
2.2.7. Short-Term Interactions Study Performed in Selected Environments PURs were cut into round samples of 0.5 cm2 area. Prepared samples were dried and weighed in a thermobalance (Radwag, Radom, Poland) (RADWAG MAX50/SX) set at 60 °C. Then, 6 samples of each studied PUR materials were placed in a 24-well cell culture plate filled with selected media:
Oxidative solution of 0.1 M CoCl2/20% H2O2; acidic solution of 2 N HCl or basic solution of 5 M NaOH. Samples were incubated in the selected media at 37 °C. The mass change of the samples was examined after 15 days for oxidative, acidic, and basic media. Samples mass change measurement was as follows: Samples were taken out from the container and put into a paper sheet to reduce the medium excess. Then, samples were placed in the thermobalance (set at 60 °C) where they were weighed to constant mass. The results are the arithmetic mean of six measurements.The changes at the PUR and PUR-M surface were monitored by optical microscopy (OM) performed with the use of a Bresser microscope(Bresser GmbH, Rhede, Germany) at a magnification of 20×.
2.2.8. In Vitro Cytocompatibility
The cytotoxicity assay was performed by using selected PUR and PUR-M samples. To examine the cytotoxicity of the obtained materials, the extract was prepared and tested with the use of a C2C12 cell line according to ISO 10993-5:2009 standard. In order to obtain extract the sterile PUR or PUR-M samples were incubated at the ratio 1:100 (w/v) in cell culture medium (Dulbecco's Modified Eagle's Medium, DMEM) (Gibco, Gaithersburg, MD, USA) supplemented with 10% fetal bovine serum (FBS) (Gibco), L-glutamine (1% solution in medium) (Gibco), 1% antibiotic-antimycotic mixture for 24 h at 37 °C under continuous steering.
Cell Viability Assay
MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used for assessing cell metabolic activity. C2C12 cells were split into 24-well plates at 30,000 cells per well and grown for 24 h in 500 µL of culture medium. Cells were incubated for 72 h with the matrices' extracts.
Then, the MTT assay of viable cells was used in accordance with the manufacturer's
recommendations The reaction product was quantitatively
determined by an Absorbance Reader BioTek EL*800 (BioTek Instruments, Inc., Winooski, VT, USA)
at a wavelength of 570 nm. The viability of the untreated cells was counted as 100.
2.2.9. Calcification Study
Golomb and Wagner's Compound was used to perform the calcification study. The calcification metastable solution consisted of 3.87 millimole (mM) CaCl2, 2.32 mM K2HPO4, yielding a ratio of calcium to phosphate (Ca/PO4) = 1.67, and 0.05 M Tris Buffer (in this study C4H11NO3) dissolved in one mL of reverse osmosis (RO) water[25]. PUR and PUR-M samples were cut into round samples of Polymers 2017, 9, 329 6 of 21
0.5 cm2 area. Prepared samples were dried and weighed in a thermobalance (RADWAG MAX50/SX) set at 60 °C. Then, 6 samples of each studied PUR materials were placed in a 24-well cell culture plate filled with Golomb and Wagner's Compound. The progress of the calcification was studied by SEM and EDX after 21 days.
2.2.10. Scaffold Fabrication
PUR or PUR-M was dissolved in 1,4-dioxane (POCH, Gliwice, Poland) at a concentration of 20% w/v. Then, sodium chloride, of crystal size in the range of 0.6-0.4 µm, was added to the polyurethane solution until complete saturation of the solution occurred. Formulated PUR (or PUR-M)-salt saturated solution was transferred into the stainless steel mold of the size 2.5 cm × 2.5 cm × 2.5 cm and placed at -20 °C for 24 h to direct the solvent crystallization and to fabricate scaffolds of local anisotropy where the porosity of the scaffolds was of controlled pore size and porosity [26-29]. Then scaffolds were removed from the mold and immersed in warm (40-50 °C) bidistilled water, where for 7 days the sodium chloride crystals were washed out. The water was changed twice a day. Finally, the samples were dried at 60 °C for 24 h.
3. Results and Discussion
The impact of the prepolymer modification time on the decrease of the free isocyanate groups in it is outlined below.
prepolymeryzation (h)
Content of the free isocyanate groups
in the unmodified prepolymer (NCO )
Content of the free isocyanate
groups in the modified prepolymer
Polymers 2017, 9, 329 7 of 21
Figure 2. FTIR spectra of PUR (black) and PUR-M (red).
Analysis of FTIR spectra (Figure 2) revealed the presence of functional groups characteristic for PURs composition; i.e., urethane linkages (see Table 2). Thus, conditions designed to carry out PURs synthesis were suitable and provided PUR product. The expanded base of the NH stretching band (3392 and 3326 cm-1) for PURs suggested the presence of "free" and hydrogen bonded HS in the obtained material respectively [30,31]. In the case of PUR-M the expanded base of the NH stretching band was observed as well, but its intensity relating to the "free" NH (3389 cm-1) in the PUR-M composition was decreased. Conversely to the PURs the PUR-M revealed the well-shaped NH stretching band related to the moderate and strong hydrogen bonds present in the HS of PUR chains [32,33]. The observed C=O stretching band confirmed the presence of ester and urethane linkages, which were "free" (1728 cm-1) and hydrogen bonded (1680 cm-1) for both PUR and PUR-M [32,33]. It can be pointed out here that the PUR-M appears to have a large number of hydrogen bonded urethane linkages in comparison to PURs. Performed FTIR analysis confirmed the presence of urethane linkages. Furthermore, the FTIR spectra of PUR-M showed that GPCa modification represents a higher level of hydrogen bonds between HS in PUR chains. Some differences in band intensities (1462-945 cm-1) between PURs and PURs-M were observed which might be related as well to the presence of GPCa molecules in the PUR system [34].
Table 2. Spectral data and band assignments of FTIR analysis presented in Figure 2.
PUR PUR-M Band Description Wavelength (cm-1)
3315, 3326 stretching vibrations of N-H in urethane groups (as for II amides), P-O-Ca stretch
2925, 2883
the strongest polarized stretching vibrations of asymmetric and symmetric CH2
groups present in PUR chains. Analogic CH2 in H2C-O-P-O stretch phonons
included
Raman spectroscopy results were complimentary to the FTIR study (Tables 4 and 5). Thus, it confirmed the presence of strongly hydrogen bonded urethane groups in the PUR-M structure as well as introduction of the GPCa modifier into the main chain of PUR at least at one-side.
3.3. Scanning Electron Microscopy with Energy Dispersive X-ray Spectroscopy(SEM/EDX)
ed the values of the contact angles and total surface free energy studied for the obtained PUR and PUR-M.
The obtained PURs and PURs-M had water contact angles in the range from 72° (PUR) to 57° (PU-M) (Table 5). The contact angles studied in formamide and ethylene glycol were slightly lower in comparison to the values of the water contact angle. Addition of GPCa caused a decrease of the contact angle independently of the solvent used in the study. The total surface free energy is higher for PURs-M (59 mN/m) than for PURs (32 mN/m). This trend was observed independently of the
method used for its examination (Table 5).
Table 5. Contact angle and total surface free energy of obtained PURs and PURs-M.
Symbol
Contact angle (°) Surface energy (mN/m)
Formamide Ethylene glycol Water Acid-part Base-part Total surface
free energy
Performed in vitro cell studies revealed good biocompatibility of the obtained PUR and PUR-M materials independent of the extract concentration. In the case of extract concentrations in the range of 25-75% as light improvement of cell growth was noted for PURs-M in comparison to the controls.
Only in the case of undiluted extracts (100%) was the cell viability of PURs and PURs-M slightly lower in comparison to the controls, but still in the range of good biocompatibility.
Figure 6. The effect of PUR and PUR-M extracts on the in vitro growth of C2C12 cells studied by MTT assay after 72 h (* p < 0.05).
3.7. Short-Term Interactions Study Performed in Selected Environments
Table 6 shows the mass loss of PURs and PURs-M noted after the short-term interactions study (15 days) performed with the selected media of acidic, basic, and oxidative environment.
Indicated mass loss was noted for both PUR and PUR-M materials (Table 6). Thus, both types of obtained materials may be considered as possibly degradable. In a strongly basic environment both materials had similar values of mass loss, which was over 50%. The GPCa modification (PURs-M) caused the increase of degradation rate of about 4% in comparison to PURs. In the case of acidic environment the mass loss was over 30% for both PURs and PURs-M, and this mass loss was higher Polymers 2017, 9, 329 12 of 21
by 3% for PURs than for PURs-M. In the oxidative environment PURs-M were slightly more stable than PURs, but the mass loss did not exceed 5%.
Table 6. The mass loss of the PURs and PURs-M after 15 days of short-term interactions study performed with selected media of the acidic, basic, and oxidative environment.
Sample Extracted mass (%)
3.9. Fabrication of PUR and PURs-M Scaffolds
Obtained PURs and PURs-M met the requirements of biomaterials used for bone tissue
engineering. Their mechanical, physicochemical biological characteristic was suitable for bone tissue
engineering. Thus, in the next step we made an attempt to fabricate, with the use of PURs and PURsM, the porous scaffold by using SC/PL combined with TIPS. Figure 12 shows the SEM micrographs
of the obtained porous scaffolds.
The main conclusion coming from the analysis of Figure 13 is the fact that the obtained PURs-M possesses better biocompatibility than PURs. Thus, it confirms the beneficial effects of the employed GPCa modifier. The proliferation of cells of the PUR-M extracts was observed at concentrations between 25-75%. PURs had lower cells viability in comparison to the PURs-M. In the case of undiluted extracts (100%) the cells viability was comparable for both PUR and PUR-M scaffolds. 4. Discussion
Bone tissue engineering is a demanding field of strictly described requirements of biomaterials, which may be used for bone tissue scaffold fabrication. Accordingly of the many biomaterials used in this field PU seems to be the most suitable candidate. This is due to its ease of modification to attain a bioactive material as well as its suitable mechanical property design related to the raw materials selection for its synthesis [14,44-47].
In this paper we described the synthesis of PEEURs carried out with the use of selected raw materials such as aliphatic HDI, polyester (Polios,) and polyether (PEG) polyols, with BDO chain extender to reach the requirements of biocompatible biomaterials for medical applications. The GPCa modifier was selected according to the literature, which describes it as a compound that can improve the bioactivity of the material as well as stimulating bone tissue regeneration. The successful synthesis of PURs was confirmed by FTIR and Raman spectroscopy, which revealed the formation of urethane bonds. Application of GPCa modifier improved hydrogen-bond formation in the PURs-M structure compared to the PURs (see FTIR analysis). Spectroscopic studies and FNCO determination confirmed the fact that GPCa is partially covalently bonded with the PUR chain. This is possible due to the hydroxyl groups present in the GPCa chemical structure. The SEM image of the PUR-M surface was in good agreement with the FTIR analysis due to the fact that it revealed the presence of a homogenous surface (about 80%) of this material, with only little inclusions visible at the top. The presence of these inclusions could be related to the GPCa, which did not react with prepolymer and was partially enclosed in the polyurethane matrix in the form of the filler. This filling effect of GPCa occurring was beneficial in the case of the biocompatibility and calcification study and may be useful as bioactive stimulant to improve bone tissue regeneration. The contact angle was decreased for the PURs-M (57°) in comparison to the PURs (72°). Thus, the addition of GPCa improved in a superior way the hydrophilic characteristic of the obtained materials, which may be beneficial for cell growth. According to Guelcher et al. the contact angle of the polymer surface in the range of 45-76° supports the attachment of mammalian cells, which can have a beneficial influence on the absorption of albumin and a preservative coupler of live tissues [48]. The total surface free energy (59 mN/m for PURs-M and 32 mN/m for PURs respectively) was in good agreement with the contact angle study and is suitable for cell growth only for PURs-M according to the references [11,49,50]. In further studies the total surface free energy can be increased by increased GPCa addition into the materials.
Most researchers have come to the conclusion that rather a surface charge (either positive, or negative) is the most important, not the surface free energy [49]. According to this, a modification of a hydrophilic but not-charged polyurethane surface with bipolar calcium ß-glycerophosphate is a good option for the optimization of cellular adherence at the PU surface. The mechanical properties of the obtained PURs (TSb = 12 MPa, ?b = 390 ± 13%) and PURs-M (TSb = 18 MPa, ?b = 280 ± 15%) were more suitable for bone tissue engineering in the case of PUR-M. The materials used in bone regeneration must have a TSb in the range of 1.5-38 MPa for human cancellous bone regeneration or 35-283 MPa for human cortical bone regeneration [51]. Thus, the obtained PURs and PURs-M may find an application as biomaterials for scaffold fabrication of human cancellous bone. The hardness
was comparable for both PURs and PURs-M (31 ± 3 °ShD for PURs and 35 ± 2 °ShD for PURs-M). The short term interactions study showed that both PURs and PURs-M are sensitive to basic and acidic environment, while in an oxidative one they remain stable. Thus, this is consistent with references [52]. The observed superior mass decrease, in the case of basic (over 50%) and acidic (over 30%) environment, after 15 days of the short-term interactions study may be a sign of the first step of material degradation called defragmentation [53]. This was confirmed by the optical microscopy studies, which showed defragmentation of the obtained PURs and more favorably PURs-M. The SEM Polymers 2017, 9, 329 18 of 21
and EDX verification of the calcification study showed significant improvement in the progress of calcification, the process needed in the case of bone regeneration [11,16,35,54], for PURs-M. Thus, the GPCa modification is a superior factor, which improves calcification, which was indicated by the peaks of Ca present in the EDX spectra. After the calcification study the calcium amount at the materials' surfaces increased over 50% for PURs and 110% on PURs-M. According to the satisfactory physicochemical, mechanical, and biological characteristics of the obtained PURs and PURs-M the fabrication of the scaffolds was performed by using the SC/PL technique combined with TIPS. Obtained PUR scaffolds had pore sizes in the range of 36-100 µm and a porosity of approximately 77%. On the other hand, PUR-M scaffolds had a pore size in the range of 50-100 µm and a porosity of approximately 82%. This morphological characteristic is suitable, according to the references, for using such scaffolds in bone tissue engineering applications. Forthermore, in the case of PURs-M scaffolds particles of GCPa modifier were visible, which were not washed out during the scaffold fabrication process. Thus, according to the results of the MTT assay, it can be concluded that PURsM may be a suitable candidate for bone tisue engineering applications [43].
5. Conclusions
In this paper we reported the synthesis and characteristic of PEEURs, obtained by using raw materials (HDI, Polios, PEG, and BDO), selected to reach high biocompatibility of the materials. Moreover, we successfully modified the PEEUR chains by incorporating into them GPCa modifier, confirmed by various techniques. The stronger hydrogen bonding, lower contact angle, and higher total surface free energy as well as the more suitable mechanical properties and good biocompatibility of PURs-M let to the conclusion that these materials possess satisfactory characteristics of materials dedicated to bone tissue engineering. Further studies of calcification of these materials indicated the superior effect of GPCa on these processes. Moreover, the short term interactions study revealed that the obtained PUR-M materials undergo gradual degradation in selected basic and acidic environment by chain defragmentation and such degradable materials are being widely developed for tissue scaffolds. The obtained porous scaffolds, by using the SC/PL technique combined with TIPS, represented suitable pore sizes (36-100 µm) and porosity (77-82%) to serve as templates for bone tissue regeneration. Moreover, the biocompatibility of PURs-M scaffolds was superior in comparison to PURs. Thus, further studies in this direction will be developed in our team. Acknowledgments: Raman spectroscopy was kindly provided by the Institute of Physics, Polish Academy of Science, Warsaw (Funding No. DEC-2012/07/B/ST5/02080). The authors would like to thank to Michalina Mallach for carrying out the synthesis of the described PEEURs.
Author Contributions: Kucinska-Lipka Justyna provided the idea of this research, designed the experiments to be done and analyzed the results. Gubanska Iga performed and analyzed the short-term interactions study, fabricated the tissue scaffolds and analyzed the results of the MTT test. Korchynskyi Olexandr and Malysheva Khrystyna performed the cytocompatibility studies presented in this work. Kostrzewa Marcin carried out the contact angle measurements. Wlodarczyk Damian performed Raman spectroscopy. Karczewski Jakub carried out the SEM study. Janik Helena analyzed the morphology of the obtained materials.
Conflicts of Interest: The authors declare no conflict of interest.

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