1 / 40

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

jena-sykes
Download Presentation

TD Glucose TM Monitoring System “Technical Review”

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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”

More Related