Design And Evaluation Of Progesterone Hot Melt Pressure Sensitive Adhesive Transdermal Patches

Objective: With the fat soluble medicine progesterone as a model drug,preparation of progesterone hot-melt pressure sensitive adhesive transdermal patch(progesterone HMPSA patch),to test the release properties in vitro and in vivo.Establish the quality standards and test the quality of progesterone patch under the the accelerated stability testing conditions and long-term stability testing conditions.To study the pharmacokinetics of rats in vivo after administration of the drug and distribution in organizations.Caculating relative bioavailability and percutaneous absorption mechanism.Methods: Progesterone solubility and apparent oil-water partition coefficient were determined by high performance liquid chromatography(HPLC)in the preformulation study;selected the receiving solution,compare the influence of promote permeation function of penetrating agent on progesterone,and selecte the best one.Selected SIS hot-melt pressure sensitive adhesive matrix in the preformulation.With evaluating indicator of tack,viscosity,peeling strength and water vapor transmission rate as the indices of compatibility,using orthogonal test to optimize the prescription of patch based on single factor test.With the steady penetration rate as the index for judgement,drug loading and layer thickness were selected,and preparation for progesterone hot-melt pressure sensitive adhesive transdermal patch.On the basis of Chinese Pharmacopoeia and European Pharmacopoeia method,established the quality standard of progesterone patch.The first point is the manufacture process on the investigation of patch related substances of progesterone;second point is test patch changes with time release curve;third point is the pretreatment method of investigation of patch of content and content uniformity.Investigate the stability in accordance with the quality standard.Using 2-mercaptobenzothiazole as positive control medicine,to survey acute toxicity,irritation and hypersensitivity of progesterone transdermal patch on animal skin through skin acute toxicity,skin hypersensitivity in healthy guinea pigs,and skin irritation test in healthy rabbits.To establish a high performance liquid chromatography tandem-mass spectrometry(LC/MS/MS)method to detecte progesterone after administration of progesterone pharmaceutic preparation,calculated the bioavailability of patch and cream.Results: In the preformulation study,progesterone has pH dependence,the apparent oil-water partition is 4.0,chooses the 30% ethanol + saline as receiving solution in vitro transdermal experiment and penetration enhancers for 2% isopropyl myristate(IPM).Choose SIS12 g,C5 hydrogenation petroleum resin 16 g,naphthenic oil 6g,antioxidant 1010 0.2g,drug loading was 4%,the layer thickness of 300?m as final formulation of Progesterone HMPSA transdermal patch.Study of quality standard has shown that temperature of preparation process is the key role in the effect on related substances.In determination of content and content uniformity,the pressure-sensitive adhesive first dissolved in hexane,which is beneficial to extract from the patch of progesterone.The preliminary stability test showed that: the character,identification,examination,content,content uniformity of progesterone patch have not significantly changed in 6 months.Results Show that: with the time prolonged,the patch of progesterone release and cumulative permeation quantity increases gradually,in 30% ethanol medium 24 hours release is 88%,24 hours cumulative permeation quantity is 24%.Results of drug safety test show: patch prepared in accordance with high,low,three dose on skin of guinea pig showed no acute dermal toxicity,allergic reaction,single dose and multiple dose to rabbit skin almost no irritation.On the basic of studies in vitro,rats have been used as animal model,the LC/MS/MS method as the means of analysis,transdermal drug delivery after the study on pharmacokinetics was studied.Progesterone HMPSA transdermal patch and progesterone cream uesd for test preparation,progesterone capsules and progesterone injection as reference preparation,studied the bioavailability of two transdermals.Conclusion:Progesterone HMPSA patch has properties of relatively stable,effect of permeability is good,can be used for hormone replacement therapy.Relative bioavailability of oral preparation is 301.1%,relative bioavailability of muscle injection is 40.9%.A preliminary study on tissue distribution of progesterone.