| Herpes is broadly defined as the disease caused by the family of herpes viruses.Currently there are eight kinds of viruses are known to cause human disease in this Section, this type of virus is collectively known as human herpes virus. The common herpes are simplex virus, varicella zoster virus, which can cause a variety of violations of human multiple organ diseases such as cold sores,keratitis,shingles,genital herpes and encephalitis.Acyclic nucleoside phosphate ester derivatives of Cidofovir is a broad-spectrum anti-DNA virus drugs, which also has good antiviral activity for herpes virus.Cidofovir can inhibit viral replication by inhibiting viral DNA polymerase, exert antiviral activity. In addition to the cytomegalovirus(CMV), there are successful reports for Cidofovir curing infections caused by herpes simplex virus(HSV),varicellazoster virus, EB virus, human herpes virus-8(HHV-8), and other herpes virus.Topical Drug Administration can be directly applied to the skin surface with better effect and low toxicity.In Topical Drug Administration, gel is easy to apply, and clear of staining clothes,this paper aims to develop a safe, effective, stable and controllable Cidofovir gel,which can be used in combination with oral, intravenous drugs to achieve more ways of treatment for the herpes virus infections.In this study, orthogonal design was used to screen cidofovir gel formulation, and the preparation process was optimized and validated, while quality and stability evaluation research was carried. The study includes four parts: research before cidofovir gel formulation screening and process optimization cidofovir gel, cidofovir gel quality research and cidofovir gel stability research.(1) Researches before prescribing cidofovir gelCidofovir is an acyclic nucleoside phosphate ester derivative, white or almost white crystalline powder, insoluble in methanol or acetonitrile, soluble in water, considered of the p H of the skin, select p H5.8 phosphate buffer as a media of release.UV-visible spectrophotometry method were studied which is constructedfor detecting cidofovir release. By scanning, 274 nm was determined to be the6 wavelength of release detectionfor cidofovir gel; Experimental results showed a goodlinear relationship in the range of 2.01~40.10 μg/ml. The linear regression equation is:A =0.0291C-0.0028(r = 0.9999), direct assay and filtration was used, membrane adsorption study results showed that discard 2 ml filtrate continued determination almost no absorption on cidofovir; good precision of the method, RSD was 0.89%;stability of test solution samples found that it has good stability at room temperature within 12 hours.(2)Cidofovir gel formulation screening and process optimizationThe gel formulation and process were studied mainly from the following four parts in this chapter.1.Select common gel materials, such as carbomer, hydroxyethyl cellulose,polyethylene glycol, polysorbate-80, etc., measuring the absorbance at 274 nm, results show that the selected materials has no interference with cidofovir.2. Uses appearance, viscosity, ductility, high temperature, low temperature,centrifuged and freeze-thaw stability as index for the gel matrix screening and comprehensive evaluation, finally, select hydroxyethyl cellulose as gel matrix.3.Orthogonal design was used to optimization by using appearance, viscosity, p H,stability and release as a comprehensive index, hydroxyethyl cellulose, glycerin,polyethylene glycol 400 dosage as three main factors and three levels, results show that cellulose, glycerin, polyethylene glycol 400 three dosage best ratio is 2%: 10%:10%.4.Test the influence on stability of gel p H, the p H value of 7-8 is the best.5.Order of addition of materials was screened for the preparation process optimization. Through transparency and scalability study,determined the order and preparation process of adding accessories. And three batches of cidofovir gel were prepared in accordance with the prescription and preparation process identified.(3) Research on the quality of cidofovir gelThe quality of the three batches of cidofovir gel was studied; the main results are as follows:1. Appearance: translucent solid;2.Load difference: in line with Pharmacopoeia;3.Identification: Identification of the ultraviolet spectrum and Highly performance liquid chromatography;4.p H: p H of 3 batches of cidofovir gel are 7.0 ~8.0;5.Viscosity: the viscosity of 3 batches of cidofovir gel is 25~35 Pa?s;6.Stability(centrifugal, high temperature, low temperature): 3 batches of cidofovir gel were stable in high temperature, low temperature and centrifugal tests,hierarchical deterioration phenomenon was not found;7.Release: The release of 3 batches cidofovir gel is approximately 40%, 85% and100% at 1 h, 4 h, 8 h.8.Related substances: AHPLC method was established for the determination of related substances of cidofovir gel, the related substances of 3 batches of cidofovir gel measured according to the method is 0.35%,0.36% and 0.35%;9.Content: A HPLC method for the determination of cidofovir gel content was validated through linear relationship, the method precision, precision instruments,stability and recovery. The content of 3 batches of cidofovir gel measured according to the method is 102.84%,102.32% and 101.60%.(4) Stability of cidofovir gelStudy the stability of Cidofovir gel, including influencing factor test(high temperature test, light experiments, low temperature test, freeze-thaw test),accelerated rest and long-term test.Influencing factor test results show that cidofovir gel is not sensitive to light, after10 days under light conditions, There is no significant changes in appearance,viscosity, and p H, related substances, content and release showed no significant change comparing with 0 days. Temperature has more influence to cidofovir gel, after10 days under high temperature conditions, the appearance, viscosity, and p H of cidofovir gel has no significant changes, content and release also has no clear changes comparing with 0 days, but related substances increased significantly.After six months of the accelerated test, cidofovir gel has no significant changes in appearance, viscosity and p H, content and release has no significant changes comparing with 0 days, but a slight increase in related substances.After nine months of long-term test, cidofovir gel has no significant changes in appearance, viscosity and p H, related substances, content and release has no significant changes comparing with 0 days.Results of the stability study show that temperature has a greater effect on cidofovir gel, the gel should be preserved in low temperature.Refer to these findings, formulation and preparation of cidofovir gel is reasonable,stable, and the quality is stable and controllable. |
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