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TD Glucose TM Monitoring System “Technical Review”

TD Glucose TM Monitoring System “Technical Review”. Overview. Brief introduction to Health-Chem’s R&D Philosophy Product oriented approach Show videos Update on current clinical results Show representative clinical examples Review general & basic understanding

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TD Glucose TM Monitoring System “Technical Review”

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  1. TD GlucoseTM Monitoring System“Technical Review”

  2. Overview • Brief introduction to Health-Chem’s R&D Philosophy • Product oriented approach • Show videos • Update on current clinical results • Show representative clinical examples • Review general & basic understanding • Transdermal Drug Delivery (TDD) • Relate basic TDD facts • TD Glucose Monitoring System (TD-G) information • Hypothesize on underlying product mechanisms • Q & A

  3. R&D PHILOSOPHY • 100% Product-Oriented R&D focus • NO academic research to prove and investigate theoretical concepts • All R&D efforts are focused solely on product development • Assure that product works and introduce into market fast • After product introduction, theoretical concepts will be investigated and researched by academia or other organizations • Health-Chem supports these efforts, but will not take on a leading role

  4. ASSURE PRODUCT FUNCTIONALITY • Mainly Lab Work … • Produce product and demonstrate that it achieves desired goal and objective • Generate all pertinent information required for FDA approval • … supported by Theoretical Review • Assure that theoretical mechanisms and available scientific background information can explain or support the feasibility of the new product

  5. VIDEOS • BBC - Weekly Science and Technology Program • “Tomorrow’s World” (6/2/99) 1 • CBS Ch4 - St. Louis Station KMOV-TV • On local News Segment (8/5/99) 2 • CBS - Nationwide “The Early Show” • “HealthWatch” Segment (11/17/99) 3

  6. UPDATE – CLINICAL DATA • WashU Study Objective • Confirm patch performance in hypo & hyperglycemic range • Triggered by Barcelona, Spain, Presentation 9/98 (Dr.’s Office) • Basic Study Design • Enrolled 13 patients (3 Type I & 10 Type II) • Hospitalized, under constant medical supervision • Infusion lines for glucose and insulin delivery • Catheter for venous blood sampling • Glucose Measurements • Venous blood glucose was analyzed w/ YSI ==> mg/dL • Capillary blood w/Fingerstick (OneTouch) ==> mg/dL • TD-G patch ==> mV • Develop correlation model, evaluate best fit parameters

  7. MATHEMATICAL CORRELATION • Fit TDG Data to corresponding REFERENCE data • Simple 2-parameter Model: • TDG = (INT- mV)*MPL • Choose correlation model parameters (INT & MPL) GOAL: Correlation curve on centerline in Clarke ERROR Grid Slope = 1, Intercept = 0 • Evaluate feasibility of UNIVERSAL Correlation

  8. PATCH METER SYSTEM • Patch • Proprietary detection membrane • All patch materials • can be easily mass produced • very cost efficient • GMP • track record with FDA (cosmetic or medical use) • Patch assembly still manual • Meter • Dual optics • Operator Error correcting software not implemented, yet!

  9. PATIENT GF-WU4R Glucose Profile (YSI, Fingerstick & Patch) Model Parameters: 810 - 3.4

  10. PATIENT RF-WU5 Glucose Profile (YSI, Fingerstick & Patch) Model Parameters: 798 - 4.8

  11. PATIENT CM-WU9 Glucose Profile (YSI, Fingerstick & Patch) Model Parameters: 796 - 5.3

  12. PATIENT RL-WU14 Glucose Profile (YSI, Fingerstick & Patch) Model Parameters: 809 - 4.8

  13. SUMMARY – “INDIVIDUAL” Each patient individually fitted 600 B A E C 550 WU4 - 16 500 A y = 1.00x + 0.27 R 2 = 0.93 450 400 B 350 TDG (mg/dL) 300 250 200 150 D D 100 50 E C 0 0 100 200 300 400 500 600 YSI Reference Blood Glucose - (mg/dL) outliers

  14. MODEL PARAMETER ANALYSIS • Found excellent prediction/correlation • Both parameters vary from patient-to-patient • INT parameter varies less then MPL parameter;<1% compared to 17% • Reasons for variations? • Variety of causes • electronics related issues • physiological differences (skin) • else! • Overall, small fluctuation • Universal Calibration? INT MPL Wu4 812 3.3 Wu5 798 4.8 Wu6 789 5.2 Wu7 793 5 Wu8 802 4.4 Wu9 796 5.3 5 Wu10 808 Wu11 793 5.6 Wu12 798 5 Wu13 794 6.7 Wu14 809 4.8 5.4 Wu15 809 Wu16 802 6.7 800 5.2 7 0.9 0.9% 17.1%

  15. Summary – “UNIVERSAL” Every patient fitted with AVG Model parameters 600 B A E C 550 WU4 - 16 y = 1.01x - 0.52 500 A R 2 = 0.84 450 400 B 350 TDG (mg/dL) 300 250 200 D D 150 Universal Parameters: 100 800/5.2 50 E C 0 0 100 200 300 400 500 600 YSI Reference Blood Glucose - (mg/dL)

  16. DISCUSSION • Scatter probably related to non-optimized product • Worst case scenario • Hand-made patches compared to fully automated MFG • Meter software not fully implemented (correction algorithms) slide • Individual calibration resulted in excellent correlation between TDG and YSI or Fingerstick • NEXT STEP: Compare to Cygnus • UNIVERSAL calibration? • Acceptable for FDA approval? Likely, need more data!

  17. CONCLUSION – CLINICAL DATA • TD Glucose System is successful in predicting hypo & hyperglycemic range • Accuracy of prediction is similar to YSI and Fingerstick • Recent data suggest that UNIVERSAL patient calibration may be achievable

  18. THEORY SECTION Where is the Glucose- collected in the patch -coming from?

  19. ASSUMPTION TD-G based ondermalortransdermalmechanisms

  20. THEORETICAL CONCEPT • Glucose partitions into / exchanges between compartments • Blood, ISF & Skin Tissues

  21. GLUCOSE AND SKIN • Non-invasive blood glucose monitoring systems under development using skin as “portal” • Electro transport • Infrared technique • Light absorption • “reverse” transdermal • Conventional • Health-Chem • Rationale: Prevent lancing the skin to draw blood • Inconvenient and distressful (daily basis, several times a day) • Allow for more frequent daily monitoring

  22. GLUCOSE AND SKIN (cont’d) • TD-G based on the facts that: • Glucose levels equilibrate between blood and interstitial fluids(Lonnroth et. al., Am. J. of Physiology, 253: E228-31, 1987) • Skin glucose varies in synchrony with blood glucose levels during tolerance testing(Fusaro et. al., J. Invest. Dermatol., 42: 359, 1964) • Skin tissue when immersed into glucose solutions equilibrates linearly with external glucose concentration(Halprin et. al., J. Invest. Dermatol., 49(6): 561, 1967) • Available information supports concept of a dermal or transdermal type mechanism

  23. Transdermal Drug Delivery • Typically focus on enhancer formulations to facilitate • partitioning into and diffusion through skin layer (Fick’s Law) • in particular SC and epidermis

  24. Schematic Transport Routes & Equations Compartments TD-G Patch Gel SC ISF/(Epi)Dermis Blood JP JD Glucose exchanges between compartments Total Transport = Sum of transports through “dense” and “porous” sections DENSE membrane: JD = PD·cD POROUS membrane: JP = PP·cP + c·(1-) Jv [Jv = Lp(p-g)]

  25. “Porous Membrane” Concept JP = PP·cP + c·(1-) Jv JP = PP·cP JP = c·Lpp (at steady state) Patch Reservoir SC ISF/(Epi)Dermis Blood SUCTION JP,c JP,d Permeability PP is proportional to number of pores Permeability LP is proportional to porosity, tortuosity, etc.

  26. SKIN HYDRATION • Sweating may have impact on glucose transport to the skin surface • Pores, sweat ducts, hair follicle shafts, etc. • Transcellular route (swollen keratinocytes) • Intracellular route via water section of the lipid bilayer • Clinical data supports this thinking • Patients under hypoglycemic stress experience profuse sweating • Measurements at this extreme condition typically show stronger meter responses suggesting more glucose was transported to skin surface via transpiration • Needs continued research to develop appropriate counter measures

  27. “Dense Membrane” Concept(JP = 0) Skin Area with “NO” Poresdiffusive JD = PD·cD Fick’s Law (Steady State) JD Permeability PD can be modified by skin permeation enhancers

  28. WHAT IS THE ACTUAL TRANSPORT PROCESS? • At the time not absolutely defined • Safe to speculate that glucose partitions into the adjoining tissues How it gets there is with high probability a mix of • “Regular” intracellular and extra-cellular diffusive transport • Shunt transport through • Hair follicles • Sweat ducts • Other? Hydration, ionic convection (see Cygnus), etc. • References for glucose skin flux

  29. GLUCOSE SKIN FLUX Examples: • US#5,139,023 > 4 g/cm2min flux = f(c) • Cygnus*  6 ng/cm2min * Private conversation

  30. THEORETICAL ESTIMATION • Melting Point Theory • Baker, R., Kochinke, F., 1988. "Transdermal Drug Delivery Systems", Controlled Release of Drugs: Polymers and Aggregate Systems. VCH, 277-305 • mp 150°C  0.1 mg/cm2hr  2 ng/cm2min

  31. CONCLUSION / ANSWER • Glucose collected in the patch originates from skin • We don’t know the exact pathways and related transport parameters • Glucose travels along regular transdermal routes • Experimentally and theoretically determined glucose skin flux values are very different • Qualitatively, data suggest glucose is crossing the skin Quantitatively?

  32. ADD DATA TO THEORY What and How Much is the Patch measuring?

  33. QUALITY CONTROL TESTING • Patches are charged with defined glucosequantities • 40 ml gel with increasing “finite” amounts of glucose • 3 patches per STD • STD span the complete range of in vivo elicited responses 1 850 2 INT(?) 3 Patch Average (STD = 0.8%) linear (Patch Average) 750 In Vivo Meter Reading (mV) “finite” Glucose amount from Skin 650 y = -0.2705x + 789.26 2 R = 0.9962 550 0 100 200 300 400 500 Standards (ng/40ml)

  34. CALCULATED GLUCOSE FLUX • STD Calibration Testing (less than 5 minutes): • 20 to 300 ng per 0.5 cm2 40 to 600 ng/cm2 • Corresponding flux value ~ 8 – 120 ng/cm2min Hypothesis: Membrane response can be elicited by • a “STEADY” glucose skin flux or • the glucose already partitioned into and available to the patch from the “outermost” skin layers

  35. STEADY FLUX ? • Membrane reaction has an “Endpoint” • “Endpoint” suggests a limited or “finite” amount of glucose is detected by the membrane • Reaction is “concentration-dependent” • STEADY Skin Flux would NOT allow “Endpoint” • Constant supply of glucose, reaction would continue • In addition, lag time does not allow STEADY flux in the initial time interval

  36. Steady State Flux Region Immediately Leachable Amount LAG TIME • Certain time for the steady state flux to develop: Lag Time “Time interval to establish steady state flux” • Before SS Flux reachedimmediate“leachable” amount • Can’t measure reliably(poor assay sensitivity) • Health-Chem membrane can! • Within 3 minutes: • 0.34 mg through 1.89 cm2 180 ng/cm2 • Comparable amount to Health-Chem findings compare

  37. Activity c/cs Concentration Steady State SC ISF/Dermis Blood PARTITIONING • Glucose equilibrates between compartments • Leachable amount increases with rising blood level

  38. “REVERSE TRANSDERMAL” MECHANISMS • “Conventional” • Measure in steady state region • e.g. Cygnus • Health-Chem • Very sensitive device • Capable to measure immediate leachable amount Conventional methods CAN distinguish Conventional methods CAN’T distinguish

  39. SUMMARY • The actual glucose skin transport mechanisms all the way up to the patch membrane are yet to be determined • Health-Chem’s TD-G system is assumed to function based on basic “reverse transdermal” mechanisms. • Health-Chem’s glucose reaction membrane is extremely sensitive (only small and “finite” glucose amounts are required to generate enzymatic color change) • Measures outside of “conventional” understanding of transdermal transport modality (steady state flux vs. within lag time interval) • Requires “New” Thinking Approach

  40. TD GlucoseTM Monitoring System“Technical Review”

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