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Publication Number
US-11793757-B2
Publication Date
2023-10-24
Expiration Date
Abstract
A porous silica particles according to an embodiment of the present disclosure includes a plurality of pores with a diameter of 5 nm to 100 nm. The porous silica particles have particular physical properties, can deliver all various drugs by a supported amount in a sustained manner, and can be parenterally administered.
Core Innovation
The invention relates to a physiologically active substance carrier based on biodegradable porous silica particles having a plurality of pores with a diameter of 5 nm to 100 nm. The carrier supports diverse drugs and bioactive substances and enables sustained release after parenteral administration. The particles are characterized by a degradation/dissolution behavior quantified by an absorbance ratio At/A0 measured using Equation 1 with UV-vis at 640 nm.
A core characterization parameter t is defined as the time at which the ratio of absorbance At/A0 becomes 1/2. In the specified measurement setup, A0 denotes an absorbance measured after preparing a suspension of the porous silica particle, and At denotes the absorbance measured t hours after A0. The method uses a cylindrical permeable membrane with pores with a diameter of 50 kDa, with the inner and outer portions of the membrane horizontally agitated at 37°C and 60 rpm, and the suspension having pH 7.4.
The particles are further described as having t of not less than 24 hours, and t can be tuned by particle and pore dimensions and surface substituents/charge. The disclosed characterization is used to provide sustained release profiles, and the degradation behavior is documented in simulated body fluid, including a measured time t where At/A0 equals 1/2 at about 48 hours. The invention also describes loading of bioactive substances including hydrophobic, charged, nucleic acids, proteins, doxorubicin, irinotecan, sorafenib, retinoic acid, and siRNA.
Claims Coverage
The independent claim covers porous silica particles defined by pore diameter (5 nm to 100 nm) and a degradation characterization parameter t such that the absorbance ratio At/A0 becomes 1/2 at a time t of not less than 24 hours, using a specified membrane-and-agitation measurement setup. The dependent claims refine the inventive concept by adding quantitative ranges for t and specific At/A0 targets, constraining pore diameter and physical surface properties, and introducing hydrophilic/hydrophobic and charge-related surface/pore characteristics.
Porous silica particle with 5 nm to 100 nm pore diameter and t for At/A0=1/2 measurement
A porous silica particle having a plurality of pores with a diameter of 5 nm to 100 nm, and having t of not less than 24 hours, at which a ratio of absorbance measured by Equation 1 is 1/2, where A0 and At are defined by absorbance measurements in a cylindrical permeable membrane (50 kDa) with horizontally agitated inner and outer portions at 37°C and 60 rpm and suspension pH 7.4.
Time parameter refinement for t of 24 to 120 hours
The porous silica particle is characterized by a parameter t ranging from 24 to 120 hours.
Specific At/A0 target with t of 70 to 120 hours
The porous silica particle has a value of t from 70 to 120 hours, where the absorbance ratio (Equation 1) is 1/5.
Pore diameter constraint of 7 nm to 30 nm
The porous silica particle has a pore diameter ranging from 7 nm to 30 nm.
Hydrophilic or hydrophobic substituent on outer surface or inside the pore
A porous silica particle is defined as having a hydrophilic substituent or hydrophobic substituent on its outer surface or inside the pore.
BET surface area constraint of 200 m2/g to 700 m2/g
A porous silica particle is defined by having a BET surface area between 200 m2/g and 700 m2/g.
Across the independent and dependent claims, the inventive concept is the definition of biodegradable porous silica particles (with 5 nm to 100 nm pores, and t≥24 hours) using a membrane-and-agitation absorbance-ratio characterization (At/A0=1/2). Dependent claims further narrow the behavior through specific t and At/A0 targets, constrain pore diameter and BET surface area, and add hydrophilic/hydrophobic substituent characteristics on the outer surface or inside the pores.
Stated Advantages
Sustained release after parenteral administration.
Biodegradability as documented in simulated body fluid.
Documented Applications
Loading and sustained release profiles for drugs and biomolecules including doxorubicin, irinotecan, sorafenib, retinoic acid, siRNA, proteins, and nucleic acids, with examples indicating prolonged release and in vivo retention.
Physiologically active substance carrier use after parenteral administration.
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