Research Of Hydrophobic Drugs-loaded Dissolving Microneedles

Transdermal drug delivery is hampered by the skin’s stratum corneum barrier and low drug loading capacity,limiting the scope of drug and disease applications.Dissolving microneedle,as a new transdermal drug delivery agent,can directly break the stratum corneum barrier and release drugs rapidly.Compared to oral and injectable drug delivery,dissolving microneedles have the advantages of painless,efficient,easy administration,and avoiding the first-pass effect of liver.In the current study,dissolving microneedles mainly deliver water-soluble drugs.For hydrophobic drugs,only nanoparticles,inclusion compounds or solid dispersions can be used to obtain water-soluble or highly dispersed intermediates before preparation into microneedles,which is a complicated preparation process and has a low drug loading capacity.At the same time,it is found that the drug loading capacity and mechanical strength of microneedles are contradictory,increasing the drug loading capacity,the mechanical strength of microneedles decreases;while increasing the mechanical strength,it is inevitable to reduce the drug loading capacity.Therefore,the preparation of dissolving microneedles with high drug loading and mechanical strength is a major challenge.In this paper,two typical hydrophobic drugs,armodafinil and estriol,were selected to prepare their dissolving microneedles,and their physicochemical properties and therapeutic effects were systematically evaluated.The dissolving microneedles designed in this study are easy to prepare and have universal applicability,which is the basis for the application of dissolving microneedles to hydrophobic drugs.(1)Study of estriol dissolving microneedlesEstriol is a sex hormone that is used clinically for age-related vaginitis.It has been found to elevate peripheral blood leukocytes and is used in the treatment of acute radiation sickness.However,estriol injections are painful to administer intramuscularly and inconvenient to administer.In this study,we prepared an estriol dissolving microneedle with efficient protection against hematopoietic system.Polyvinyl pyrrolidone(PVP)K90was used as the microneedle matrix after optimization to prepare the needle tip layer by dissolving in an organic alcohol solution using a micro-mold casting method.N-Vinyl-pyrrolidone(NVP)was synthesized to PVP under UV as the backing layer.The drug loading of estriol-dissolving microneedles was determined to be 1.2 mg/cm~2 by enzyme-linked immunoassay,and the mechanical strength was demonstrated to be high by a universal pressure tester and COMSOL simulation software,which met the expected design purpose.Differential scanning calorimetric analysis,and X-ray diffraction were used to demonstrate that drugs exist in the microneedle in an amorphous molecular state.Scanning electron microscopy showed that estriol microneedles were morphologically intact and released rapidly in vitro,with a cumulative transdermal penetration of 169μg.Pharmacokineticts demonstrated that estriol microneedles released rapidly,reached the peak at 1 h and again at 12 h,respectively,with a longer protection time than intramuscular injection.After contacting with skin,the drug rapidly released after the needle tip dissolves,and the drug in the backing layer dissolved and slowly penetrated along the original orifice for continuous drug release.Pharmacodynamic experiments demonstrated that microneedle administration could increase peripheral blood leukocytes and protect bone marrow hematopoietic function after irradiation,which significantly improved the survival rate of mice.Therefore,estriol dissolving microneedles can effectively protect the bone marrow hematopoietic system in irradiated mice,providing a new idea for the prevention and treatment of acute radiation diseases.(2)Study of armodafinil dissolving microneedlesArmodafinil is used clinically to treat episodic sleeping sickness,also as a wake-promoting drug to effectively counteract sleep deprivation and maintain wakefulness.However,the high dose and frequency of administration make its practical application very inconvenient.In this study,we prepared an armodafinil dissolving microneedle patch to explore a new route of drug delivery for a new dosage form.The micro-mold casting method was used to prepare the microneedle tip layer by using PVP K90 as the base material,and after dissolving the drug in solution to prepare the microneedle tip layer,UV curing NVP to form the backing layer.The drug loading of the prepared armodafinil microneedle patch was 4.44 mg/cm~2,and the universal pressure tester proved that it had sufficient strength to puncture the skin stratum corneum.The microneedle penetration depth of was up to 200μm observed by H.E.pathology section,which proved that it had good mechanical strength.Armodafinil microneedles were observed with sharp tips and intact morphology by microscopy and scanning electron microscopy.The drug was released rapidly in vitro and completely within 3 h.The cumulative transdermal penetration in vitro was 1695μg.A 72-h acute sleep deprivation mouse model was established by using a sleep deprivation apparatus,and its efficacy was evaluated by behavioral evaluation after microneedle transdermal administration,including morris water maze,open field test,and elevated plus maze,which demonstrated that armodafinil microneedle could improve the cognitive level and enhance the exploratory spirit in sleep deprived mice.In this study,a dissolving microneedle drug delivery system based on PVP suitable for carrying hydrophobic drugs was designed on the analysis of characteristics of hydrophobic drugs,practical needs and characteristics of microneedle formulations.The use of PVP K90 as a microneedle matrix does not require the addition of sugar and other excipients,and can be air-dried to obtain greater strength.The combination with organic alcohol solution can increase the drug loading capacity of hydrophobic drugs,meeting the needs of both drug loading capacity and mechanical strength,and achieving the desired design purpose.The simple preparation process greatly reduces the production cost of hydrophobic drug formulations.This microneedle is easy to use,which not only improves patient compliance but also reduces the frequency of administration.The novel drug delivery system can make up for the shortage of traditional formulation technology and products,and can meet both rapid-acting and long-acting drug delivery,which provide a new option for transdermal delivery of hydrophobic drugs with promising applications.