Coated Microneedles: A novel approach to Transdermal drug delivery

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Presented by S. ANURAG B.Pharmacy IV Year PRIYADARSHINI COLLEGE OF PHARMACEUTICAL SCIENCES Coated Microneedles: A Novel Approach to Transdermal Drug Delivery

PRESENTATION OVERVIEW:

PRESENTATION OVERVIEW INTRODUCTION SKIN ANATOMY MECHANISM OF DRUG PERMEATION COATED MICRONEEDLES History Mechanism Models for drug delivery Fabrication Coating rows of microneedles Micro needle patch assembly CONCLUSION ACKNOWLEDGEMENTS REFRENCES

INTRODUCTION THE NEED FOR DEVELOPMENT OF TRANSDERMAL DELIVERY SYSTEM:

INTRODUCTION THE NEED FOR DEVELOPMENT OF TRANSDERMAL DELIVERY SYSTEM POOR BIOAVAILABILITY FIRST PASS EFFECT RAPID BLOOD SPIKES (HIGH or LOW) LIMITATIONS Drugs with high blood levels cannot be administered (< 500 Daltons) May cause irritation or sensitization of skin. May not be suitable for all types of skin and may cause uncomfortable to wear. Even high cost of the product is also a major drawback. Drug should be highly lipophillic.

ADVANTAGES DISADVANTAGES :

ADVANTAGES DISADVANTAGES Avoidance of absorption and shortened metabolism of GIT. Cause no Pain No pitfalls of Enzymes & p H Reduce dosing. Constant dosing. Multi-day therapy Capacity to terminate drug effects Drugs that require high blood levels cannot be administered. Is not a means to achieve rapid bolus type drug input. Adequate solubility of the drug in both lipophillic and a aqueous environments, to reach and gain access to the systemic circulation. The molecular size of the drug should be small. Difficulty of permeation of the drug through human skin

SKIN ANATOMY :

SKIN ANATOMY

MECHANISM OF DRUG PERMEATION THROUGH SKIN:

MECHANISM OF DRUG PERMEATION THROUGH SKIN A molecule traversing must partition into and diffuse through the keratinocyte, but in order to move to the next keratinocyte, the molecule must partition into and diffuses through the lipid lamellae between each keratinocyte.

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The skin is multilayered organ complex in both structure and function. Consists of three distinct layers EPIDERMIS:

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The stratum corneum consists of 10-15 layers of corneocytes and varies in thickness from approx 10-15 μm in the dry state to 40 μm when hydrated . It comprises a multi-layered “brick and mortar” like structure of keratin-rich corneocytes(bricks) in an intercellular matrix (mortar). It also Composed primarily of long chain ceramides, free fatty acids, triglycerides, cholesterol, cholesterol sulfate and sterol/wax esters . In the initial layers of the stratum corneum material rearranges to form broad intercellular lipid lamellae which then associate into lipid bilayers ,with the hydrocarbon chains aligned and polar head groups dissolved in an aqueous layer .

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As a result of the lipid composition, the lipid phase behavior is different from that of other membranes. The hydrocarbon chains are arranged into regions of crystalline, lamellar gel and lamellar liquid crystal phases creating various domains within the lipid bilayers . The presence of intrinsic & extrinsic proteins, may also affect the lamellar structure of the corneum. Also consists of Viable epidermis (150µm thick) Papillary layer of dermis (100-200)µm thick) It is supplied by blood to convey nutrients, remove waste & regulate body temperature and drug is well absorbed by this rout e DERMIS:

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SUBCUTANEOUS TISSUE: This is a sheet of the fat containing areolar tissue known as the superficial fascia, attaching the dermis to the underlying structures. SKIN APPENDAGES: Sweat glands produces sweat of pH 4-6.8 & absorbs drugs, secretes proteins, lipids and antibodies, Its function is to control heat. HAIR FOLLICLES: They have sebaceous glands which produces sebum and includes glycerides, cholesterol and squalene.

CLASSIFICATION OF SKIN PENETRATION ENHANCEMENT:

CLASSIFICATION OF SKIN PENETRATION ENHANCEMENT

INTRODUCTION TO MICRONEEDLES:

INTRODUCTION TO MICRONEEDLES They are one micron in diameter and range from 1-100 microns in length. Microneedles have been fabricated with various materials such as: metals, silicon, silicon dioxide, polymers, glass . Smaller the hypodermic needle, Various types of needles have been fabricated ex: solid (straight, bent filtered, hollow) The hollow needle designs include tapered and beveled tips, and could be used to deliver micro liter quantities of drugs to very specific locations.

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Parenteral delivery - decreased patient compliance due to needle phobia . Coated micro needles are a mongrel

MAJOR DIFFERENCE :

MAJOR DIFFERENCE TRANSDERMAL PATCH TRANSDERMAL MICRONEEDLES

HISTORY OF MICRONEEDLES:

HISTORY OF MICRONEEDLES Microneedles have been in development since the 80s. Current microneedle designs look like miniaturized beds of nails fabricated from stainless steel, titanium, and plastic. Last fall Zosano Pharma presented results of a Phase II trial of microneedle delivery of parathyroid hormone (PTH) for osteoporosis. The Zosano product, the ZP-PTH patch, is a band-aid type patch containing a bed of microneedles coated with PTH, significantly more convenient compared with the daily conventional injections required by Zosano’s competitor,Forteo.

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Other clinical trials involving microneedle delivery include three studies (proof of concept, pre-phase I by NanoPass technologies using their Micron jet microneedle technology for flu ,vaccines, anesthesia and diabetes. Similar to the Zosano patch, the Micron Jet is an array of microneedles, but instead of being in band-aid form, the Micron Jet connects to a conventional syringe presumably enabling delivery of larger fluid volumes. Finally, Emory University is also conducting a Phase II/III clinical trial for insulin delivery in Type 1 diabetes.

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MECHANISM Is not based on diffusion as it is in other transdermal drug delivery products. Instead, it is based on the temporary mechanical disruption of the skin and the placement of the drug within the epidermis, where it can more readily reach its site of action.

MODELS OF DELIVERY :

MODELS OF DELIVERY Piercing microneedle + application of drug patches Coated microneedle Encapsulated biodegradable microneedle Injecting drug through hollow microneedles

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Essential characters of coating process Uniform coating Limit deposition onto microneedle Avoid high temperature High drug loading Good adhesion of coating solution Aqueous coating solution Rapid or controlled – dissolution kinetics Coating processes dip coating – micron scale-used roll coating not used spray coating

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MICRONEEDLE FABRICATION Laser cutting : Stainless steel sheets using Infrared laser, shapes were obtained from AUTOCAD software and three phases are required. cutting speed of 2mm/s ,air purge at 140KPa. Prepared either by individual rows (‘in-plane’) or two dimensional array into plane and bent at 90 degrees (‘out of -plane’). Cleaning and Bending microneedles: Manually cleaned with detergents (Alconox, White plains) to de-grease the surface an remove slag and oxides and rinsed with running water (out of –plane) were pushed out manually by using forceps or Hypodermic needle and then bent at 90 degrees with aid of a single –edged razor blade .

Electro polishing : In a solution of Glycerin, ortho-phosporic acid(85%) and water (6:3:1),in a 300ml glass beaker at 700 at a stirring rate 150 rpm. A copper plate was used as cathode ,microneedles as anode and vibrated at 10Hz to remove bubbles with a current density of 1.8mA/mm2 and then cleaned in de-ionized water and 25% nitric acid for 30s each then again in hot running water and a final wash in running de-ionized water by this thickness recedes to 50micro meter ,then dried and stored. :

Electro polishing : In a solution of Glycerin, ortho-phosporic acid(85%) and water (6:3:1),in a 300ml glass beaker at 70 0 at a stirring rate 150 rpm. A copper plate was used as cathode ,microneedles as anode and vibrated at 10Hz to remove bubbles with a current density of 1.8mA/mm 2 and then cleaned in de-ionized water and 25% nitric acid for 30s each then again in hot running water and a final wash in running de-ionized water by this thickness recedes to 50micro meter ,then dried and stored. Micro-dip coating : Coating solution : composed of 1% carboxy-methylcellulose sodium salt+0.5%(w/v) Lutrol F-68 NF + mode l drug Model drugs used are 0.01% sulforhodamine calcein ,0.05% luciferase plasmid DNA ,1% bovine serum ,10% barium sulfate , 1.2% 10-um latex beads ,8.5% 20um latez beads. DNA and viruses are made fluorescent by incubating with YOYO-1 at a dye:basepair/virus ratio 1:5 for 1 h r at room temperature in dark .

COATING ROWS OF MICRONEEDLES:

COATING ROWS OF MICRONEEDLES COATIN SOLUTION RESERVIOR. (A) Made of PMMA Dip holes act as reservoir Both plates adhere with methylene chloride Contains 50-60 dip holes (each 1mm deep *0.5mm wide) MICROPOSTIONING DIP COATER . (B) To enable 3-D X=control the in plane position needles Y-Z= Micropositioner (A) is stationary while microneedle-row-holder slides up and down.

MICRONEEDLE PATCH ASSEMBLY: Coated Microneedles array are assembled into transdermal patch containing pressure sensitive adhesive to adhere to the skin. They are fabricated in plane rows or individual arrays of out-of-plane microneedles.:

MICRONEEDLE PATCH ASSEMBLY: Coated Microneedles array are assembled into transdermal patch containing pressure sensitive adhesive to adhere to the skin. They are fabricated in plane rows or individual arrays of out-of-plane microneedles.

MICRONEEDLE PATCH ASSEMBLY: :

MICRONEEDLE PATCH ASSEMBLY: Multiple In-plane rows of microneedles. Multiple out-of-plane rows of microneedle. A patch of 50 microneedles are taken . 1 st ten slits each 75um wide &7. 7mm long were laser cut into a 1.6mm thick, single-sided polyethylene medical foam tape using a co 2 l aser and then manually inserted into each slit from the non-adhesive side of the foam tape and glued to the foam tape using a medical grade adhesive. A polyethylene medical foam tape (0.8 mm thick) was then cut into a disc of 16 mm diameter and affixed onto the dried glue area to provide a cushioned backing to facilitate pressing the patch during insertion. A circular disc of 20mmdiameter was first cut from a 0.8-mm thick, single-sided medical foam tape using the CO2 laser. In the middle of this disc, a rectangular piece of the adhesive release liner equal in dimensions to the periphery of the array (12 ×12mm) was cut out using the CO2 laser and peeled off. The stainless steel microneedle array was then attached to this exposed adhesive. A double-sided, poly-ethylene-phthalate carrier tape is attached. The tape is then slipped over the microneedles .

MICRONEEDLE ARRAY PATCHES:

MICRONEEDLE ARRAY PATCHES The adhesive layer was periodically disrupted via small holes or slits to allow the microneedles to stick out for penetration. The adhesive served to hold microneedles firmly against the skin by compensating for the mechanical mismatch between the flexible skin tissue and the rigid microneedle substrate, especially in the case of out-of-plane microneedle arrays. Microneedle arrays prepared on the basis of this design are shown for patches of in-plane microneedles (Fig. 4B) out-of-plane microneedles (Fig. 4D).

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Poor and good microneedle coatings via bright field micrographs of vitamin B coated microneedles. Poor, non-uniform coatings with base-substrate contamination on: a single microneedle and ( B ) a 50- microneedle out-of-plane array. Improved coating uniformity and elimination of base-substrate contamination after addition of coating-solution excipients and use of a micro-dip-coating device for ( C ) a single microneedle, ( D ) a 50-microneedle out-of-plane array. (E) an in-plane microneedle row. (E1) uncoated,(E2) 25% coated, (E3) 50% coated ,(E4) 75% coated ,(E5) 100% coated. MICRO-DIP-COATING OF MICRONEEDLES:

COATING A LARGE RANGE OF COMPOUNDS:

COATING A LARGE RANGE OF COMPOUNDS Breadth of molecules and micro particles coated onto microneedles. Fluorescent or bright field micrographs of single microneedles coated with: Calcein Vitamin B, Bovine serum albumin conjugated (BSA) With Texas Red. (D) plasmid DNA conjugated with YOYO1, (E) modified vaccinia virus — Ankara conjugated with YOYO-1. (F) 1- μ m diameter barium sulfate Particles. (G) 10-μm diameter latex particles.

Delivery from coated microneedles:

Delivery from coated microneedles No residue on skin surface Increased bioavailability Vaccine delivery – potent immune response Storage - antigen stability Eliminate cold-chain storage.

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Successful delivery was achieved from microneedles when surface was coated. A novel micro-dip-coating apparatus was designed to control surface tension-driven wicking of coating solution up micro needle shafts and onto the base substrate. A coating formulation was also developed to achieve uniform coating-solution deposition on micro needles by using low concentrations of carboxymethyl cellulose and Lutrol F-68 NF as excipients to increase viscosity and decrease surface tension, Using this approach, single microneedles, in-plane rows and out-of-plane arrays of microneedles were coated without contaminating the base and with micron-scale control over the length of the microneedle shaft to be coated. CONCLUSION

ACKNOWLEDGEMENT:

ACKNOWLEDGEMENT I would like to thank our Respected principal Dr.Mahalaxmi Mohan Garu and all the other college faculty members for giving me this opportunity to give the seminar, I would like to thank Mr. Ashok Mateti sir for providing me the useful information about the topic, helping at each and every time constantly, thank you sir for your support and would also like to thank Mukunda Nageshwar sir for his reluctant support in organizing this seminar and helping me doing my best in all ways . Thank you All

REFRENCES:

REFRENCES H. S. Gill, Mark R. Prausnitz . Coated microneedles for transdermal delivery. Journal of Controlled Release 117 (2007) 227–237. G. Walsh, Biopharmaceuticals: recent approvals and likely directions, Trends Biotechnol. 23 (11) (2005) 553–558. Y. Nir, A. Paz, E. Sabo, I. Potasman, Fear of injections in young adults: prevalence and associations, Am. J. Trop. Med. Hyg. 68 (3) (2003) 341–344. L. Simonsen, A. Kane, J. Lloyd, M. Zaffran, M. Kane, Unsafe injections in the developing world and transmission of blood borne pathogens: a review, Bull. World Health Organ. 77 (10) (1999) 789–800. G. Orive, R.M. Hernandez, A. Rodriguez Gascon, A. DLang J. Ocular drug delivery: conventional ocular formulations.Adv Drug Deliv Rev. 1995;16:39–43 Tasman W. Duane’s Foundations of Clinical Ophthalmology. Philadelphia, PA: Lippincott-Raven; 1995. Maurice D. Review: practical issues in intravitreal drug delivery. JOcul Pharmacology Ther. 2001;17:393–401. Prausnitz MR. Microneedles for transdermal drug delivery. Adv Drug Deliv Rev. 2004;56:581–587. . 14 (6) (2003) 659–664. W. Martanto, S.P. Davis, N.R. Holiday, J.Wang, H.S. Gill, M.R. Prausnitz, Transdermal delivery of insulin using microneedles in vivo, Pharm. Res.21 (6) (2004) 947–952.

THANK YOU :

THANK YOU