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Title: Health-Chem Tech Review


1
TD GlucoseTM Monitoring SystemTechnical
Review
2
Overview
  • Brief introduction to Health-Chems RD
    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
RD PHILOSOPHY
  • 100 Product-Oriented RD focus
  • NO academic research to prove and investigate
    theoretical concepts
  • All RD 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
  • Tomorrows 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 gt
    mg/dL
  • Capillary blood w/Fingerstick (OneTouch) gt
    mg/dL
  • TD-G patch gt 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
    parameterlt1 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 ondermal or transdermalmechanisms
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 (contd)
  • 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 (Ficks 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 cLp?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 Pores diffusive
JD PD?cD
Ficks 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
  • US5,139,023
  • gt 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 ? 150C
  • ? 0.1 mg/cm2hr
  • ? 2 ng/cm2min

31
CONCLUSION / ANSWER
  • Glucose collected in the patch originates from
    skin
  • We dont 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 glucose
    quantities
  • 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
LAG TIME
  • Certain time for the steady state flux to
    develop Lag Time Time interval to establish
    steady state flux
  • Before SS Flux reachedimmediateleachable
    amount
  • Cant 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
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 CANT distinguish
39
SUMMARY
  • The actual glucose skin transport mechanisms all
    the way up to the patch membrane are yet to be
    determined
  • Health-Chems TD-G system is assumed to function
    based on basic reverse transdermal mechanisms.
  • Health-Chems 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 SystemTechnical
Review
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