Patent Application: US-201113583768-A

Abstract:
the present invention relates to a cement based on magnesium sodium phosphate with clinical applications in bone surgery and odontology . this cement has an intrinsic antimicrobial effect as its main property . it also has a fast setting time , along with a high short - term compressive strength . another property inherent to these cements is their adhesive character . use of the cement is indicated for bone and dental applications , as well as filling bone defects or sealing dental cavities . the cement is especially indicated in cases in which an antimicrobial effect and / or adhesive properties are necessary .

Description:
this invention presents an inorganic cement for bone and / or dental applications , comprising a mixture of a solid phase formed by magnesium oxide ( mgo ) and a sodium phosphate , and a liquid phase formed by water or an aqueous solution . the cement in question has several specific properties making it of special interest . for the purpose of enhancing said properties , the preparation conditions of the material have been optimised as detailed below . a first aspect of this invention is that the cement has an intrinsic antimicrobial effect . this effect is due to the composition of the cement . on one hand , the ph increase occurring in the medium surrounding the cement [ 12 - 14 ] and , on the other hand , the active oxygen which is released in the medium due to the presence of an excess of magnesium oxide [ 15 ] are the mechanisms through which said effect takes place . due to the reasons explained , among others which will be explained below , magnesium oxide is added at a molar amount greater than that of phosphate salt , such that the antimicrobial properties of the cement are enhanced . said antimicrobial properties are of special interest since they make the cement a very suitable candidate for some treatments in orthopaedic surgery and in endodontic surgery , among other possible applications . a second aspect of this invention is that said cement sets fast , with a high short - term compressive strength . there are several parameters affecting the mechanical properties and setting time , such as the ratio of the oxide with respect to the compound containing phosphates , the reactivity of the oxide , the reagents used , the liquid / powder ratio for preparing the cement and the amount of retarder added . a third aspect of this invention , essential so that this material can be used in clinical applications , is that it is biocompatible . to that end it is necessary that : i ) during the setting reaction the cement does not reach temperatures greater thane 40 - 45 ° c ., representing a threshold above which the protein denaturation and surrounding tissue necrosis can start , and ii ) toxic by - products are not released . both conditions can be controlled , respectively , by means of i ) controlling the setting reaction kinetics , for example , decreasing the reactivity of the reagents , increasing the particle size thereof and / or adding a retarder to the reaction ; ii ) selecting reagents not containing chemical elements or compounds susceptible to having harmful effects , such as ammonium phosphate present in magnesium ammonium phosphate cements [ 6 - 9 ]. a fourth aspect of this invention is the formation of an amorphous reaction product , unlike the crystalline product obtained in cements based on magnesium oxide and ammonium phosphate , in which struvite [ 16 ] is formed . a fifth aspect of this invention is the high adhesion which the cement has to living materials or objects . the method of preparing the proposed cement requires two components . on one hand , a magnesium oxide favouring a high basicity of the final material and , on the other hand a compound containing phosphates which is slightly acidic . a retarder can also be added , which makes the setting reaction slower and thus allows reducing the exothermic nature of the process caused by the reaction between the basic component and the acid . given that the heat released during setting could be detrimental to the surrounding tissue , reducing the exothermic nature of the reaction is a key aspect of this invention . in addition to adding a retarder , the exothermic nature can also be reduced by decreasing the reactivity of the reagents , increasing the particle size thereof and / or increasing the liquid / powder ratio of the cement . the more retarder is added to the cement powder , the greater the setting time is and the lower the temperature which the cement reaches when setting is . the recommended reagents for preparing magnesium sodium phosphate cements are indicated below . the basic compound provides the magnesium , and the preferred option is magnesium oxide ( mgo ). the use of sodium phosphate salt is proposed as a phosphate source , sodium dihydrogen phosphate ( nah 2 po 4 ) being the preferred reagent . sodium dihydrogen phosphate can also be combined with another phosphate such as nh 4 h 2 po 4 , in different molar ratios . the possible compounds which can be used as retarders are sodium fluorosilicate , sodium polyphosphate , sodium borate , boric acid , boric acid ester , and mixtures derived therefrom . among those mentioned , sodium borate decahydrate or borax ( na 2 b 4 o 7 · 10 h 2 o ) is preferred . the retarder can be added to the cement powder in the solid phase or be dissolved in the liquid phase of the cement . to favour the formation of the reaction product [ 17 ], as well as for enhancing a greater antimicrobial effect , it is recommended that magnesium oxide is at a greater molar amount than sodium phosphate . the recommended magnesium oxide to sodium phosphate molar ratio is in the 1 & lt ; mgo : nah2po4 & lt ; 6 range , the 3 & lt ; mgo : nah2po4 & lt ; 5 range being preferred . the amount of retarder added regulates the setting time , as well as the short - term mechanical properties and the exothermic nature of the reaction . the amount of retarder to be added can range between 0 . 05 - 10 % by weight . preferably , an amount of retarder between 2 - 6 % by weight is used . for the purpose of achieving suitable setting of the cement , as well as a moderate exothermic nature , controlling the reagent particle size is necessary . in the case of mgo , reducing its reactivity to control the exothermic nature is also necessary . the reactivity of mgo can be reduced by means of calcining thereof , which can be performed at a temperature greater than 1400 ° c . for 0 . 5 - 15 h . mgo particle size can range between 0 . 1 - 100 μm . if necessary , mgo can be ground to reduce its particle size . phosphate reagents require a particle size between 50 - 500 μm to assure a good mixture with the alkaline compound , but without causing a reaction which is too exothermic . if necessary , the phosphate reagent can be ground . for better retarder efficiency , it is convenient that the retarder also has a particle size between 50 - 500 μm to assure a good mixture with the majority reagents . if necessary , the retarder can be ground . in reference to the first aspect of the invention , the antimicrobial effect of the magnesium sodium phosphate cement has been demonstrated in the present patent due to two complementary effects . in other studies it has been shown that when the ph of the surrounding medium has a value greater than 9 . 5 , this is toxic for most microbes [ 12 ]. the effect of the ph can also be enhanced by means of changes in the ratios of the reagents used , as well as in their particle size distribution and reactivity . for example , the increase in mgo reactivity by means of calcination at a lower temperature , or the increase of the sodium phosphate particle size by means of a less vigorous grinding , are two methods for increasing the ph produced by the cement and thus increasing the antimicrobial effect . finally , it has been reported that mgo can release active oxygen , a component which also has a toxic effect for microbes [ 15 ]. magnesium sodium phosphate cement is of interest for bone and dental applications , especially in situations where a microbial infection is to be fought . said cement can be used in endodontic therapies . it can be applied for directly or indirectly covering pulp , for example , in the case of deep caries . it can also be used for sealing dentinal tubules and in treating pulpal or periapical inflammations , and in apexification therapies , consisted of filling the pulp with a material inducing the development of the root or the closure of the end thereof . the cement could also be used to fill the root canal in endodontic therapy . the antimicrobial properties of the cement reduce the risk of pulpal and root area re - infection . the powder for preparing the magnesium phosphate cement is obtained by homogenising the powders of the compounds indicated in the recommended ratios . the preparation of the cement paste requires adding an aqueous liquid , preferably water . this liquid can be added at a liquid / powder ratio of 0 . 05 - 0 . 30 ml / g , preferably 0 . 10 - 0 . 20 ml / g obtaining a paste with a good consistency requires constantly stirring the powder with the liquid for a time between 45 s and 2 min . when this time has passed , a paste with a workable consistency which is ready for being introduced into a dental or bone cavity is obtained . it is important to take into account that to use the cement in vivo , the powder and liquid must have been sterilised beforehand . furthermore , a clean and , if possible , sterile working area is required to prevent contaminating the reagents at the time of preparing and introducing the paste . the examples included below are described for the purpose of illustrating the specific compositions described therein and the method of preparing the mixture of ingredients in a practical and non - limiting manner . magnesium phosphate cement prepared based on magnesium oxide , sodium hydrogen phosphate and borax 50 g of mgo calcined at 1475 ° c . for 6 h were ground in an agate jar by means of using 4 agate balls , a planetary mill and grinding conditions of 150 rpm for 15 min . the same process was performed separately for nah 2 po 4 and borax . 25 g of mgo were mixed with 19 . 584 g of nah 2 po 4 and 1 . 379 g of borax in a homogeniser for 20 min . the preparation of the paste consisted of mixing 1 . 5 g of powder with 195 μl of water , and it was homogenised for 1 min to yield a paste with good consistency . the initial and final setting time were measured by means of the gillmore needle test [ 18 ], according to which the initial setting time is defined as the time taken from the moment the powder contacts the liquid until a pressure of 0 . 3 mpa leaves no mark on the surface of the cement ; and the final setting time as the time elapsed from the moment the powder contacts the liquid until a pressure of 5 mpa leaves no mark on the surface of the cement . the test was performed by introducing the cement paste into plastic cylindrical moulds 10 mm in height . the initial setting time of the cement was 8 min , and the final time was 9 min . the exothermic nature of the cement was evaluated by inserting the tip of a thermocouple into the recently prepared paste . the temperature of the cement was monitored until it reached its maximum value . the maximum temperature reached during the setting of the cement was 41 . 3 ° c . test specimens of the cement 12 mm in height and 6 mm in diameter were prepared in teflon moulds to measure compressive strength . said moulds were introduced in a 0 . 9 % wt nacl solution ( ringer solution ) and were maintained at 37 ° c . for different time periods . compressive strength was measured using a universal mechanical testing machine with a 10 kn load cell and clamp displacement speed of 1 min / min . compressive strength of the cements at different setting times is depicted in fig1 . fig2 depicts the x - ray diffraction diagram of the set cement for 7 days . the diffraction maximums observed correspond to magnesium oxide , which is the reagent present in excess in the formulation . this indicates that an amorphous compound is formed during the setting of the cement . evolution of the ph produced by a magnesium sodium phosphate powder . calcined mgo powder with a particle size between 0 . 1 and 40 μm and a specific surface area of 0 . 63 m 2 / g , and nah 2 po 4 powder with a particle size between 100 and 500 μm and a specific surface area of 0 . 07 m 2 / g were mixed with a mgo : nah 2 po 4 molar ratio of 3 . 8 : 1 . a saturated solution of the cement was prepared by mixing the powder mentioned in the preceding paragraph with water at a liquid / powder ratio of 10 ml / g , and the evolution of ph over time was measured . said process was reported by serraj [ 12 ] as an indirect method for evaluating the antimicrobial effect of a cement due to the basicity produced in its environment . fig3 shows how a saturated solution of magnesium sodium phosphate powder makes ph rapidly increase , giving ph close to 9 . 5 in only 20 min and reaching ph greater than 10 . 5 in 90 min . it is known that microbes are sensitive to ph values higher than 9 . 5 , accordingly this ph is sufficient for having an antimicrobial effect . magnesium phosphate cement prepared based on magnesium oxide , sodium hydrogen phosphate , ammonium hydrogen phosphate and borax 50 g of mgo calcined at 1475 ° c . for 6 h were ground in an agate jar by means of using 4 agate balls , a planetary mill and grinding conditions of 150 rpm for 15 min . the same process was performed separately for nh 4 h 2 po 4 , nah 2 po 4 and borax . 25 g of mgo were mixed with 9 . 388 g of nh 4 h 2 po 4 , 9 . 792 g of nah 2 po 4 and 1 . 484 g of borax in a homogeniser for 20 min . the preparation of the paste consisted of mixing 1 . 5 g of powder with 195 μl of water , and it was homogenised for 1 min to yield a paste with good consistency . the initial and final setting time was measured by the gillmore needle test as described in example 1 . the test was performed by introducing the cement paste into plastic cylindrical moulds 10 mm in height . the initial setting time of the cement was 11 . 5 min , and the final time was 13 min . the exothermic nature of the cement was evaluated by inserting the tip of a thermocouple into the paste . the temperature of the cement was monitored until it reached its maximum value . the maximum temperature reached during the setting of the cement was 44 ° c . test specimens of the cement 12 mm in height and 6 mm in diameter were prepared in teflon moulds to measure compressive strength . said moulds were introduced in a 0 . 9 % wt nacl solution ( ringer solution ) and were maintained at 37 ° c . for different time periods . compressive strength was measured using a universal mechanical testing machine with a 10 kn load cell and clamp displacement speed of 1 mm / min . compressive strength of the cements at different setting times is depicted in fig4 . fig1 shows the compressive strength of magnesium sodium phosphate cement at different setting times ( 1 h = 1 hour ; 2 h = 2 hours ; 1 d = 1 day ; 7 d = 7 days ). fig2 shows x - ray diffraction of the reaction product of set magnesium sodium phosphate cement in ringer &# 39 ; s solution for 7 days . fig3 shows a saturated solution of the magnesium sodium phosphate powder in water with a liquid / powder ratio of 10 . fig4 shows the compressive strength of magnesium sodium and ammonium phosphate cement at different setting times ( 1 h = 1 hour ; 2 h = 2 hours ; 1 d = 1 day ; 7 d = 7 days ). the magnesium sodium phosphate cement which has been described has several applications in the clinical field , especially in the fields of orthopaedic surgery , endodontics , the prosthodontics and periodontics . this invention can be easily applied at an industrial scale . preparing the powder of the cement is very simple since all the reagents are commercial reagents and it only requires optimising reactivity for being able to control the properties listed below , which increase the value of said cement in the field of biomaterials : ( a ) increase of the ph of the medium surrounding the cement , giving it an antimicrobial effect ; preparing the cement is also simple . the use of the cement in biomedical applications requires sterilisation of the reagents as well as an adequate use thereof ; likewise , the cement must be introduced into the bone or dental defect in a short time period , limited by its hardening . 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