Studies On Preparation And Transdermal Permeability Of Thermosensitive Hydrogel Of Xylometazoline Hydrochloride

Objective: As a new drug delivery system, nasal delivery system plays its role in prevention and treatment though intranasal administration and absorption though the nasal mucosa. Nasal administration is generally used to treat a variety of diseases of nasal rhinitis, colds and other departments. Meanwhile, it can replace some of the drugs for injectable route of administration because it can pitch the brain through the blood.Xylometazoline hydrochloride imidazoline derivatives, is an effective topical nasal vasoconstrictor, which can be directly applied to the nasal mucosa ?- adrenergic receptors, resulting in vasoconstriction and reducing blood flow and nasal congestion, with its advantages of quick, ventilation fast, lasting-effect and less side effects, etc. The ordinary Nasal can be easily removed by cilia and the liquid can hardly retain in the nasal mucosa which resulting in poor efficacy. Nasal inevitably flow to the throat, to stimulate the pharyngeal mucosa and cause dry mouth, throat, sore throat and other symptoms following subsequent reuse thus patients with medication compliance decreases. Therefore, it is necessary to study a novel nasal formulation to overcome deficiencies common nasal drops to a certain extent.Nasal thermosensitive in situ gel(Nasal in-situ gel) refers to the case of a solution at a low temperature state, as for the body later, in the nasal cavity at a temperature(32 ~ 34?) phase transition, a semi-solid the gel state which can be a long time adhered to mucous membranes, prolonged residence time of the drug, and is conducive to full absorption of drugs. It can achieve long-term release and improve the bioavailability of drugs with slow release characteristics.In this study, we prepare thermosensitive hydrogel with a suitable phase transition temperature using xylometazoline hydrochloride as model drug. To improve the permeation characteristics, we initially screened the solvent with good promoting effect, transdermal enhancers and gel matrix by transdermal experiments. By orthogonal design, using the gelation temperature as an index, the prescription of thermosensitive hydrogel is optimal screened. Lastly the HPLC method for determination of xylometazoline hydrochloride was established to verify the stability and perform the transdermal absorption experiments.Methods: To Establish the determination method of xylometazoline hydrochloride in transdermal absorption liquid. By wavelength scanning, the maximum absorption peak at 265 nm wavelength is determined as detection wavelength. The UV spectrophotometry is used to determine the content.The vitro penetration experiments were performed on Franz diffusion cell. The transdermal effect of different solvents, different transdermal enhancers and different gel matrix is investigated with corresponding concentration, transdermal diffusion rate constant and enhancement Ratio as the index and then obtain a gel formulation with good penetration enhancement effect preliminarily.In this paper, we prepare the thermosensitive hydrogel respectively for xylometazoline hydrochloride of 1% and blank bases by cold method and evaluate the effect of factors of P407, P188 and glycerin in the prescription. We initially identify the concentration range of several factors that affect greatly on the gelation temperature and the best prescription is obtained by using the orthogonal experimental design. Then 3 batches of gel are prepared according to the optimal prescription for verification and the HPLC method for determination of xylometazoline hydrochloride was established.To get the best transdermal enhancers, the prepared gel was respectively added volatile oil and inclusion of volatile oil and then perform the transdermal absorption test as well as examining the impact of temperature, light and storage conditions and other factors on the stability of the gel.Results: The UV method for determination of xylometazoline hydrochloride in percutaneous receptor fluid was established. The standard curve is A=0.9973C+0.009(r2=0.9997, n=3) which has a good linear relationship in the concentration range of 0.25~0.8 mg·mL-1. The established UV method is specific, simple, rapid and accurate.The vitro studies indicate that different concentrations of nitrogen ketone, peppermint oil, volatile oil and inclusion of Angelica oil have a certain permeation enhancing effect. The 1% volatile oil and its inclusion have the best effect which 24 h accumulative penetration amount is 10486.3?g·cm-2 and 8916.3?g·cm-2 and the permeation rate is 433.95?g·cm-2·h-1 and 366.2?g·cm-2·h-1. However the enhancement ratio of xylometazoline hydrochloride without transdermal enhancers is 3.33 and 2.81, respectively.The optimized prescription form of single-factor test and orthogonal test is 18% P407, 6% P188, 2.5% glycerin. The average content of which is 9.54 mg·mL-1 and it's RSD is 1.15%. The average gelling temperature is 32.9 ?and RSD of the three gels results is 1.8%. The transdermal absorption experiment was carried out on the preparation of thermosensitive hydrogel and the 1% volatile oil of inclusion has a good promoting effect. And then, the determination was carried out three times for the xylometazoline hydrochloride thermosensitive hydrogel with the volatile oil of angelica sinensis.The stability test indicates that the appearance and content of gels did not change significantly under the conditions of normal temperature.Conclusion: The established UV method of xylometazoline hydrochloride in percutaneous receptor fluid is specific and simple. The study of the transdermal characteristics suggest that xylometazoline hydrochloride permeated across the skin by passive way and has a concentration dependence. The 1% volatile oil and its inclusion have the best promoting effect in three kinds of penetration enhancers of azone, peppermint oil and angelica naphtha. The thermosensitive hydrogel of xylometazoline hydrochloride by using the orthogonal experimental design can gell into semi-solid gel state in the nasal cavity temperature(32~34?). The further transdermal experiments of the gel suggest that the volatile oil of inclusion has a good promoting effect and does not affect the preparation of gelation temperature. The content determination and stability experiment suggest that the xylometazoline hydrochloride thermosensitive hydrogel preparation developed by our experiment has a clear appearance and a stable quality. The study on thermosensitive hydrogel provides a novel nasal dosage forms for xylometazoline hydrochloride.