| In order to improve bioavailability of drugs and drug efficacy, drug-loaded hydrogels were directed into diseased tissue to form drug repositories by in-situ cross-linking in pathological tissue to maintain drug concentration in affected area for a longer period of time. Injected hydrogel to medicine preparations for malignant tumor treatment and prevention of postoperative prevention has broad application prospects. Although the formulation has many advantages, but there are a few limitations. One of the fundamental problems needed to be solved is how to uniformly and stably disperse insoluble drugs in hydrogel during hydrogel medicine preparation. In recent years, high gravity anti-solvent precipitation has been used for the preparation of micro-powder, showing wide application prospects, especially in the preparation of micro-drugs. Uniform particle size, good dispersibility, high dissolution and high bioavailability of drug nanoparticles can be achieved by using molecules with fast and efficient mixing characteristics in the high gravity environment and the use of assistive dispersing agent. This paper aims at developing a new type of load antitumor drugs DOX injection hydrogel medicine preparation. By aqueous dispersion of NanoDOX by HGAP particle size can be controlled, in-situ injection and storage of drugs is achieved, and combined with HA-AC hydrogel material and Michael addition reaction long-term release is possible. The main contents are as follows:1. In this paper, the preparation of DOX nanoparticles by HGAP and the effect of process parameters are discussed. First, the influence of Poloxamer188 on drug particle dispersion and particle size by anti-solvent precipitation is considered. Results demonstrate that the preparation of NanoDOX had small particle size and better dispersion when the mass ratio of DOX and Poloxamerl 88 was 1:1. Preparation of NanoDOX using HGAP showed that the greater the machine rotor speed and the flow rate ratio of solvent and anti-solvent, the smaller the size of the drug particle. The average particle size was about 168nm of NanoDOX by HGAP when the rotor speed was 2300 rpm and solvent and anti-solvent flow ratio was 1:15. The in vitro dissolution rate of DOX showed that the accumulative dissolution of NanoDOX by anti-solvent precipitation, NanoDOX by HGAP and DOX particles by raw DOX after removal of HCL was 28%,58% and 92%, respectively. Cell toxicity test by MTT method showed that the preparation of NanoDOX has an inhibition effect on the MCF 7 cells, and the smaller the particle size, the greater the cytotoxicity. FACS and CLSM results showed that the smaller the particle sizes the greater the drug intake by the nucleus.2. In this paper, HA-ADH with amino was prepared by condensation reaction of HA and ADH, and then HA-AC was synthesized by reaction of amino and N-Acryloxysuccinimide. The preparation enhances certain mechanical and structural properties of the space mesh hydrogels by Michael addition reaction of PEG (crosslinking agent) and HA-AC. The study of gelation time showed that the solid content of the HA-AC hydrogel has great influence on gel time, and the time was 5 minutes when solid content was 20%. A study of the swelling properties of the hydrogel showed that the swelling ratio was 2.785 after 2 hours, and the volume increased by more than three times. A large water channel was formed inside of hydrogel after swelling which could be used as a drug diffusion channel.3. Based on the above research, loaded-NanoDOX HA-AC hydrogel preparation can be achieved with NanoDOX by HGAP and HA-AC hydrogel. In vitro dissolution experiment of loaded-NanoDOX HA-AC hydrogel showed continuous drug release for 120 days and accumulation reached 80%. This demonstrated that the hydrogel preparation can attain long-term drug release. The experimental testing by MTT and Calsein dyeing method to determine the cell survival rate showed that the loaded-DOX hydrogel have cell inhibiting or killing effect, but the hydrogel has no effect on cell growth. |
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