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WO1990015568A2 - Appareil et methodes pour le controle non-invasif du glucose dans le sang - Google Patents

Appareil et methodes pour le controle non-invasif du glucose dans le sang Download PDF

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Publication number
WO1990015568A2
WO1990015568A2 PCT/US1990/002940 US9002940W WO9015568A2 WO 1990015568 A2 WO1990015568 A2 WO 1990015568A2 US 9002940 W US9002940 W US 9002940W WO 9015568 A2 WO9015568 A2 WO 9015568A2
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WIPO (PCT)
Prior art keywords
glucose
blood glucose
receiving medium
noninvasive blood
glucose monitoring
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PCT/US1990/002940
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English (en)
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WO1990015568A3 (fr
Inventor
Theodore H. Stanley
Charles Dewey Ebert
William I. Higuchi
Jie Zhang
Original Assignee
Stanley Theodore H
Charles Dewey Ebert
Higuchi William I
Jie Zhang
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Stanley Theodore H, Charles Dewey Ebert, Higuchi William I, Jie Zhang filed Critical Stanley Theodore H
Priority to KR1019910700129A priority Critical patent/KR920700014A/ko
Publication of WO1990015568A2 publication Critical patent/WO1990015568A2/fr
Publication of WO1990015568A3 publication Critical patent/WO1990015568A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/14—Devices for taking samples of blood ; Measuring characteristics of blood in vivo, e.g. gas concentration within the blood, pH-value of blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring glucose, e.g. by tissue impedance measurement

Definitions

  • the present invention is directed to methods and apparatus for monitoring blood constituents. More particularly, blood constituents such as glucose, are monitored noninvasively through diffusion across epithelial membranes.
  • the blood is routinely tested for various blood constituents in countless medical procedures. This typically involves drawing an actual blood sample from the patient, followed by blood analysis. Most people can tolerate giving an occasional blood sample, but continually drawing blood for analysis creates additional safety risks for the patient. For those persons suffering from diabetes mellitus (hereinafter referred to as "diabetes”) , blood is often drawn many times a day.
  • Diabetes is a major health problem directly affecting over ten million people in the United States. The prevalence of the disease is increasing rapidly. Most people suffering from diabetes face the probability of major complications and shortened life spans. Diabetes is currently the seventh leading cause of death in the United States, and has been attributed to 35,000 to 50,000 deaths and costs of more than 20 billion dollars per year.
  • Diabetes is a disorder of carbohydrate metabolism characterized by elevated blood sugar (hyperglycemia) , sugar in the urine (glycosuria) , excessive urine production (polyuria) , excessive thirst (polydipsia) , and increase in food intake (polyphagia) .
  • Diabetes is a chronic, incurable disease, but symptoms can be ameliorated and life prolonged by proper therapy. Diabetes results from the inadequate production or utilization of insulin.
  • Insulin is a hormone secreted by the pancreas which is essential for the proper metabolism of blood sugar (glucose) and for the maintenance of the proper blood glucose level. Severe insulin deficiency, or less severe insulin deficiency coupled with other conditions, can cause ketoacidosis which may lead to coma and life-threatening crisis.
  • Chronic diabetes is associated with vascular and neurologic degeneration, and persons with diabetes are at increased risk of heart disease, blindness, renal failure, and inadequate circulation and sensation in peripheral tissues. Women with diabetes also have increased risk of stillbirths and congenital malformations in their children.
  • diabetes makes it a disease that is costly and difficult to manage.
  • complications of diabetes are caused primarily by elevated blood glucose levels, and these complications can be avoided in most cases by monitoring and control of blood glucose levels and close medical supervision with appropriate intervention.
  • blood sugar determinations may need to be made at frequent intervals in order to know if, when, and how much insulin is needed to control blood glucose.
  • noninvasive blood glucose monitoring means determining blood glucose concentration without actually drawing the patient's blood. For example, efforts to monitor blood glucose based upon glucose concentration in a patient's saliva or breath have failed. The reason for these failures is that there is no correlation between glucose in saliva or breath and the actual blood glucose levels. In fact, glucose does not naturally cross body membranes such as the buccal mucosa or membranes of the skin. Because most body membranes are naturally impermeable to glucose, the presence of glucose has historically been used to test whether tissue is intact in transdermal experiments.
  • the present invention is directed to novel methods and apparatus for noninvasive blood glucose monitoring.
  • blood glucose is monitored noninvasively by causing glucose to diffuse across epithelial membranes and then capturing and measuring that glucose for correlation to determine the blood glucose level.
  • epithelium or epithelial membrane refers to a variety of different dermal and mucosal surfaces.
  • glucose diffuses across the buccal mucosal membrane into a glucose receiving medium.
  • the glucose receiving medium includes a permeation enhancer capable of increasing the glucose permeability across the mucosal membrane.
  • the glucose receiving medium is positioned against the mucosal membrane so that the permeation enhancer alters the permeability of the mucosal membrane which it contacts. After sufficient time delay, the glucose receiving medium is removed and analyzed for glucose concentration using conventional analytical techniques.
  • glucose diffuses across the skin into a glucose receiving medium.
  • the glucose receiving medium includes a permeation enhancer capable of increasing the glucose permeability across skin.
  • the glucose receiving medium is positioned against the skin so that the permeation enhancer alters the permeability of the skin which it contacts. After a predetermined time, the glucose receiving medium is removed and analyzed for glucose concentration.
  • the glucose receiving medium is capable of releasing a permeation enhancer and receiving glucose.
  • the driving force behind glucose diffusion from blood into the glucose receiving medium is the glucose concentration gradient.
  • the glucose receiving medium preferably has a relatively low glucose concentration for the entire duration of the measurement, while the interstitial fluid, which is in equilibrium with the capillary blood vessels perfusing the buccal mucosa and dermis, has a substantially higher glucose concentration.
  • the apparatus within the scope of the present invention includes means for supporting the glucose receiving medium.
  • Such means for supporting the glucose receiving medium may include a housing which holds and contains the glucose receiving medium.
  • the means for supporting the glucose receiving medium may also include a hydrogel.
  • the apparatus also includes means for temporarily positioning the glucose receiving medium against the mucosal membrane or skin.
  • means for temporarily positioning the glucose receiving medium against the mucosal membrane or skin For example, if the apparatus includes a housing for supporting the glucose receiving medium, then an adhesive composition is preferably used to temporarily position the glucose receiving medium against the mucosal membrane. If the apparatus includes a hydrogel for supporting the glucose receiving medium, then the hydrogel itself may adhere directly to the mucosal membrane or skin.
  • a rate limiting membrane or medium may be used to temporarily position the glucose receiving medium against the skin.
  • a rate limiting membrane or medium It will be appreciated that the overall rate that glucose diffuses through the epithelial membrane into the glucose receiving medium depends upon the individual glucose permeabilities of the membranes or media that the glucose must pass through to enter the glucose receiving medium. The overall glucose diffusion rate is determined by the net resistance of all diffusional components, the net diffusion being dominated by the single diffusion component with the lowest glucose permeability. Thus, if a rate limiting membrane or medium having a precise and reproducible permeability is used, the overall glucose diffusion rate may be maintained relatively constant despite variations in epithelial membrane permeability from person to person, time to time, and even position to position.
  • Figure 1 is a cross-sectional schematic view of the noninvasive glucose monitoring process of the present invention.
  • Figure 2 is a cross-sectional schematic view of the noninvasive glucose monitoring process of the present invention using a rate regulating membrane.
  • Figure 3 is a cross-sectional view of one possible apparatus within the scope of the present invention.
  • Figure 4 is a graph of glucose permeated ( ⁇ g) verses time for the results of Example 1.
  • Figure 5 is a graph of glucose permeated ( ⁇ g/cm 2 ) verses time for the results of Examples 2 and 3.
  • Figure 6 is a graph of glucose flux ( ⁇ g/min/cm 2 ) verses blood glucose level (mg/dl) .
  • Figure 7 is a graph of glucose permeated ( ⁇ g) verses time for the results of Example 4.
  • Figure 8 is a graph of glucose permeated ( ⁇ g) verses time for the results of Example 5.
  • Figure 9 is a graph of glucose permeated ( ⁇ g) verses time for the results of Example 6.
  • Figure 10 is a graph of glucose permeated ( ⁇ g/cm 2 ) verses blood glucose (mg/dl) for the results of Examples 18 and 19.
  • Figure 11 is a graph of glucose permeated ( ⁇ g/cm 2 ) verses blood glucose (mg/dl) for the results of Example 20.
  • Figure 12 is a graph of glucose permeated ( ⁇ g/cm 2 ) verses blood glucose (mg/dl) for the results of Example 21.
  • Figure 13 is a graph of glucose permeated ( ⁇ g/cm 2 ) verses time for the results of Example 22.
  • Figure 14 is a graph of glucose permeated ( ⁇ g/cm 2 ) verses time for the results of Examples 23 and 24.
  • Figure 15 is a graph of glucose permeated ( ⁇ g/cm 2 ) verses time for the results of Example 26.
  • Figure 16 is a graph of glucose solubility (mg/ml) verses water content for the results of Example 27.
  • Figure 17 is schematic view of a diffusion cell used to perform in vitro skin flux experiments.
  • Figure 18 is a graph of glucose permeated ( ⁇ g/cm 2 ) verses time (hours) for the results of Example 28.
  • Figure 19 is a graph of glucose permeated ( ⁇ g/cm 2 ) verses time (hours) for the results of Example 29.
  • the present invention is directed to novel methods and apparatus for noninvasive blood glucose monitoring. Such noninvasive techniques avoid the inconvenience and risks associated with traditional invasive glucose monitoring techniques because blood does not need to be drawn from a patient.
  • blood glucose is monitored noninvasively by correlation with amount of glucose which permeates an epithelial membrane into a glucose receiving medium over a specified time period.
  • epithelium or epithelial membrane refers to both dermal and mucosal surfaces of the body.
  • Epithelial membranes are generally impermeable to glucose; therefore, a glucose permeation enhancer capable of increasing the glucose permeability across the epithelial membranes is preferably included in the glucose receiving medium in order to enable glucose to back-diffuse from the interstitial fluid into the glucose receiving medium. Alternatively, it may be useful to pretreat the epithelial membrane with a permeation enhancer before applying the glucose receiving medium.
  • glucose diffuses from the interstitial fluid, which is in equilibrium with capillary blood vessels perfusing the epithelial membrane, across the membrane into a glucose receiving medium.
  • the interstitial fluid in equilibrium with the capillary vessels is considered a donor chamber
  • the glucose receiving solution is considered a receiver chamber.
  • the donor chamber and the receiver chamber are separated by the epithelial membrane.
  • C 0 concentration of permeant corresponding to glucose.
  • both Q(t) and flux are proportional to C 0 at any time. Since both Q(t) and flux(t) are at all times proportional to the glucose concentration in the blood, C 0 , they can be used to monitor the blood glucose concentration. However, in practice, precise measurement of Q(t) and the flux can only be made after t(lag) since Q(t) before t(lag) is very low.
  • glucose receiving medium 12 if the permeability coefficient of glucose receiving medium 12 is substantially less than that of epithelial membrane 14, than the quantity of glucose entering the glucose receiving medium is limited by glucose receiving medium 12.
  • one or more additional membranes 26 may be placed between the epithelial membrane and the glucose receiving medium to achieve a rate regulating function.
  • the permeability coefficient of rate regulating membrane 26 is significantly lower than that of epithelial membrane 14 and that of glucose receiving medium 12.
  • the quantity of glucose entering the glucose receiving medium is limited or regulated by the most resistant layer of the glucose diffusion pathway — membrane 26.
  • glucose must diffuse through two membranes to enter the glucose receiving medium: the epithelial membrane and the rate regulating membrane.
  • the effective permeability coefficient of the combined membranes is given by:
  • P ⁇ ", "P M “, and “P R” are the permeability coefficients of the combined membrane, the epithelial membrane, and the rate regulating membrane, respectively.
  • P R can be made precisely and reproducibly by modern techniques, while P H varies from person to person, time to time, and even position to position within the same type of epithelial membrane.
  • a rate regulating medium or membrane is used.
  • the permeability coefficient of the glucose receiving medium is significantly lower than that of the epithelial membrane.
  • the rate regulating membrane one or several membranes are placed between the epithelial membrane and the glucose receiving membrane.
  • C 0 is the concentration of the glucose in the interstitial fluid or capillary blood vessels
  • A is the area of contact
  • t is the time passed from the beginning of contact
  • f is a complicated function of the above variables. This equation is valid at all conditions, even if the "sink condition" is not maintained.
  • the apparatus of the present invention is directed to a glucose receiving medium and to means for supporting the glucose receiving medium against an epithelial membrane.
  • Permeation enhancers added to the glucose receiving medium alter the diffusion coefficient of glucose in the mucosal membrane thereby increasing Q(t) and flux and reducing t(lag). Without a permeation enhancer, the epithelial membrane is effectively impermeable to glucose. It has also been found that increasing the concentration or potency of the permeation enhancer significantly reduces the diffusion lag time. In fact, dramatically increasing the permeation enhancer concentration renders the lag time substantially negligible and enables rapid detection of the blood glucose level noninvasively.
  • Noninvasive glucose monitoring device 10 includes glucose receiving medium 12.
  • Glucose receiving medium 12 is positioned against epithelial membrane 14.
  • Glucose receiving medium 12 includes a permeation enhancer (not shown) for improving the glucose permeability of epithelial membrane 14.
  • Glucose is preferably soluble in the glucose receiving medium.
  • water is one currently preferred glucose receiving medium.
  • Other compositions which dissolve glucose may also be suitably used as glucose receiving media within the scope of the present invention.
  • Suitable glucose receiving media should not unfavorably react with glucose or the permeation enhancer.
  • the glucose receiving medium preferably does not interfere with glucose concentration measurements. It should also be nontoxic to the epithelial membrane and chemically and physically stable (e.g. , does not degrade and nonvolatile) .
  • a glucose receiving medium containing a complexing agent which selectively combines with glucose to form an insoluble product. If such a complexing agent is included in the glucose receiving medium, then the resulting glucose complex is preferably detectable using known analytical techniques. The resulting insoluble glucose product may facilitate quantifying the glucose concentration. Lecithins and other sugar binding materials may be suitably used.
  • Typical permeation enhancers capable of improving the glucose permeability across the epithelial membrane include many natural bile salts such as sodium cholate, sodium glycocholate, sodium glycodeoxycholate, taurodeoxycholate, or sodium deoxycholate.
  • Other permeation enhancers such as sodium lauryl sulfate, salts and other derivatives of saturated and unsaturated fatty acids, surfactants, bile salt analogs, derivatives of bile salts, or such synthetic permeation enhancers as described in United States Patent No. 4,746,508 may also be used.
  • enhancers varies depending on the type of epithelium. For example, some enhancers known to improve skin glucose permeability are not as effective when used to enhance mucosal membrane permeability.
  • the following enhancers are particularly effective when used with the some mucosal membranes (nasal, rectal, gastrointestinal) , but less effective when used with buccal mucosal membranes: IGEPAL 10.5 (octylphenoxy poly(ethoxyethanol) 10.5), EDTA (ethylene-diaminetetraacetic acid) , sodium oleate, and sodium taurocholate (a bile salt) .
  • enhancers may vary depending on the chemical compound to be permeated.
  • the following enhancers effectively alter epithelial permeability with respect to certain drugs, but are not very effective at promoting glucose permeability: ethanol, low chain alcohols, and solvent-type enhancers used transdermally.
  • the following enhancers have been found to be particularly effective at enhancing the transmucosal glucose permeability: sodium cholate, sodium dodecyl sulfate, sodium deoxycholate, and taurodeoxycholate.
  • the following enhancers have been found to be particularly effective at enhancing the dermal glucose permeability individually or in combination: ethanol/water (with or without cell envelope disordering compounds) , dimethyl sulfoxide (DMSO)/water, and isopropyl alcohol with methyl laurate (a cell envelope disordering compound) .
  • the enhancer concentration within the receiving medium may be varied depending on the potency of the enhancer and the desired epithelial membrane. Other criteria for determining the enhancer concentration include the sensitivity of the glucose detection methods, the desired lag time. The upper limit for enhancer concentration is set by toxic effect to or irritation limits of the epithelial membrane. The solubility of the enhancer within the receiving medium may also limit enhancer concentration.
  • the driving force behind glucose diffusion into glucose receiving medium 12 is the glucose concentration gradient between the interstitial fluid 16 and receiving medium 12.
  • the resistance to the permeation is determined by the permeability of epithelial membrane 14, the permeability of glucose receiving medium 12, or some other rate regulating membrane or media.
  • the glucose receiving medium preferably has a relatively low glucose concentration for the entire duration of measurement with respect to that in the interstitial fluid and capillary blood vessels, yet at the end of the measurement, the glucose concentration in the receiving medium is high enough to be measured precisely.
  • a measurable amount of glucose diffuses into the glucose receiving medium.
  • the actual amount of glucose which diffuses into the glucose receiving medium depends upon many factors such as the type of epithelial membrane, the enhancer used, the enhancer concentration, the contact exposure time, the type of glucose receiving medium, the surface area in contact with the glucose receiving medium, intimacy of contact between the glucose receiving medium and the membrane, and the solubility of glucose in the glucose receiving medium. It is within the skill in the art to modify the foregoing factors in order to cause the desired amount of glucose to diffuse into the glucose receiving medium.
  • the amount of glucose which must diffuse into the glucose receiving medium in order to be accurately measured depends upon the sensitivity of the analytical glucose detection methods used. Currently, techniques which detect glucose having a concentration as low as 0.5 ⁇ g/ml provide suitable results for the diagnostic methods within the scope of the present invention.
  • a housing 18 encloses the glucose receiving medium and protects the glucose receiving medium from potential glucose contamination sources such as saliva. Hence, one important function of housing 18 is to isolate the glucose receiving medium from glucose contamination sources. Another important function of housing 18 is to provide support for the glucose receiving medium. Housing 18 is preferably constructed of a material which is nontoxic, chemically stable, nonreactive with glucose and the permeation enhancers used, and inexpensive. Suitable materials include: polyethylene, polyolefins, polyamides, polycarbonates, vinyl polymers, and other similar materials known in the art.
  • Housing 18 may take many different shapes; however, the housing should define a chamber for holding a quantity of glucose receiving medium and provide an opening such that the glucose receiving medium may be placed directly against the epithelial membrane. Housing 18 may also include flanges 20 located about the periphery of the housing for receiving an adhesive so that the housing may be maintained in position against epithelial membrane 14. Housing 18 may also include an access port (not shown) through which glucose receiving medium may be introduced into the housing or through which the glucose receiving medium may be directly tested for glucose or removed for external testing while the housing is maintained in position against the epithelial membrane.
  • a handle 22 may optionally be attached to housing 18 to facilitate placement and removal of the apparatus. Handle 22 is particularly desirable to provide user-control of placement and removal and to maintain housing 18 in contact with the mucosal tissues.
  • the apparatus within the scope of the present invention does not require a housing as illustrated in Figure 3.
  • Other means for supporting and positioning glucose receiving medium 12 against epithelial membrane 14 may be used. For example, it has been found that hydrogels not only provide suitable support for the glucose receiving medium, but also adhere to epithelial membranes, particularly mucosal membranes.
  • the bioadhesive hydrogel itself may be used to temporarily position the glucose receiving medium against the epithelial or mucosal membrane.
  • the glucose receiving medium corresponds to the aqueous portion of the hydrogel, whereas the cellulose frame or other material forming the hydrogel provides the necessary support of the glucose receiving medium.
  • the glucose receiving medium within the scope of the present invention may be supported in a hydrogel.
  • hydrogels are inherently sticky. Such bioadhesive hydrogels adhere directly to mucosal tissues.
  • Cellulose including hydroxypropylcellulose and other cellulose derivatives known in the art, carbopol, gelatin, and other known substance which produce hydrogels may be used within the scope of the present invention.
  • Other support substances which perform substantially the same function as hydrogels may also be used.
  • creams, emulsions, suspensions, and other solid and semisolid media may also provide suitable support for a glucose receiving medium.
  • glucose may not be as soluble in a nonaqueous glucose receiving medium incorporated into such media.
  • a sponge-like embodiment may also provide suitable support for a glucose receiving medium. Whether a hydrogel or other substance is used to support a glucose receiving medium, it is important that the glucose receiving medium be safely supported and maintained in contact with the epithelial tissues for sufficient time to effect glucose diffusion across the epithelial membrane.
  • the hydrogel or other support substance may be preferably covered or sealed from potential contaminants such as saliva.
  • a nonpermeable membrane such as a thin plastic layer, would protect the hydrogel from potential contamination.
  • a housing as described above, would also suitably protect the hydrogel.
  • a housing and optionally a handle
  • the edges may not need to be covered or sealed.
  • lateral edges 24, illustrated in Figures 1 and 2 may not be necessary.
  • the glucose receiving medium is preferably positioned directly against the epithelial membrane so that the permeation enhancer contacts the epithelial membrane and increases the glucose permeability of the membrane.
  • Various epithelial membranes including mucosal and dermal surfaces of the body, may be utilized within the scope of the present invention. Some epithelial membrane surfaces are more preferable than others. For example, post auricular skin is preferable over the palm of the hand.
  • the selection of a suitable epithelial membrane depends upon a number criteria, such as glucose permeability for a given quantity of enhancer, degree of irritation caused by the enhancer, lag time, convenience (e.g.. buccal membrane is more accessible than nasal and rectal membranes) , and the degree of vascularization.
  • the glucose receiving medium is removed and analyzed for the presence of glucose using conventional analytical techniques.
  • Variables affecting sufficient exposure time include: glucose detecting sensitivity, permeability, lag time, enhancer concentration, glucose receiving medium surface contact area to volume ratio, and temperature.
  • the glucose concentration within the glucose receiving medium is proportional to the patient's actual blood glucose level, once the glucose within the glucose receiving medium is determined the actual blood glucose level may be quickly calculated.
  • a color indicator For user convenience, it may be desirable to incorporate a color indicator into the glucose receiving medium. In this way, the glucose concentration may be quickly determined by comparing any color change (not necessarily in the visible light spectrum) of the glucose receiving medium against a standard color chart.
  • Examples of commercially available indicators include a combination of glucose oxidase, 4-aminoantipyrine, and p- hydroxybenzenesulfonate.
  • blood glucose was monitored noninvasively in a laboratory dog.
  • a 0.5 mm - 1.0 BD thick layer of silicone grease was spread on the base of a diffusion cell to provide the adhesiveness and prevent leakage of the glucose receiving solution in the cell.
  • the diffusion cell had an open bottom designed to be placed on the dog's buccal mucosa and an open top through which glucose receiving solution was added and removed. The area of the cell's open bottom was 1.89 cm 2 .
  • the diffusion cell was placed on the dog's buccal mucosa.
  • a glucose receiving solution was pipetted into the cell through the cell's open top.
  • the glucose receiving solution was a 2% by weight solution of sodium cholate in deionized (DI) water.
  • DI deionized
  • One (1) ml of solution was withdrawn from the cell after 3 minutes.
  • the total amount of glucose permeated is given by the following formula:
  • G n C n • V rec ⁇ 1ver + ( ⁇ " C • V. ⁇ ,.
  • the actual blood glucose level was monitored by taking blood samples from the femoral artery about every 10 to 15 minutes for the whole duration of the procedure.
  • the glucose concentration in the blood samples were determined by the combination of Glucostix (Ames 2628C) and Glucometer (type II, model 5625, Ames Division, Miles Labs, Inc., P.O. Box 70, Elkhart, IN 46515) .
  • the standard procedure as described in the user's manual of the Glucometer was followed.
  • Example 2 Blood glucose was monitored noninvasively in a laboratory dog according to the procedure of Example 1, except that the blood glucose was artificially elevated. The elevation of the dog's blood glucose concentration was achieved by intravenous infusion of a glucose solution. The infusion rate was adjusted for the individual dog to achieve the desired blood glucose level. With the particular dog used in this example, 6 grams/hour glucose was needed to increase the blood glucose level from about 97 mg/dl to about 211 mg/dl. It required about 2 hours to establish an elevated steady state blood glucose level. The experimental results of Example 2, along with that of Example 3, are shown graphically in Figure 5.
  • Example 3 Blood glucose was monitored noninvasively in a laboratory dog according to the procedure of Example 1, except that the blood glucose was artificially suppressed.
  • the same laboratory dog used in Example 2 was used in this Example.
  • the suppression of the dog's blood glucose concentration was achieved by intravenous infusion of an insulin solution.
  • the infusion rate was adjusted for the individual dog to achieve the desired blood glucose level.
  • 0.9 U/hour insulin was needed to reduce the blood glucose level from about 97 mg/dl to about 34 mg/dl. It required about 2 hours to establish a suppressed steady state blood glucose level. Additional adjustment of the insulin infusion rate was necessary to maintain the glucose level relatively constant.
  • the experimental results of Example 3, along with that of Example 2 are shown graphically in Figure 5.
  • the results of this example demonstrate that the glucose back diffusion flux, as well as the amount of glucose permeated, do reflect the actual blood glucose level change.
  • the glucose back diffusion flux of Examples 2 and 3 may be determined from the slope of the data plotted in Figure 5.
  • the glucose flux ( ⁇ g/min/cm 2 ) was calculated and plotted in Figure 6.
  • the results of Figure 6 demonstrate that glucose flux is proportional to the blood glucose level. Thus, by determining glucose flux it is possible to determine actual blood glucose levels.
  • Example 4 Blood glucose was monitored noninvasively in a laboratory dog according to the procedure of Examples 1 and 2, except that a glucose receiving solution without a permeation enhancer was tested in addition to the glucose receiving solutions having 2% sodium cholate. The experimental results of Example 4 are shown graphically in Figure 7. These results indicate that no glucose permeated the buccal mucosa without a permeation enhancer.
  • Example 5
  • Blood glucose was monitored noninvasively in a laboratory dog according to the procedure of Example 1, except that the glucose receiving solution was a 2% by weight solution of sodium cholate in 30% ethanol and 70% deionized (DI) water.
  • DI deionized
  • Example 5 The experimental results of Example 5 compared with results using the procedure of Example 1 are shown graphically in Figure 8. These results indicate that the amount of glucose permeated when 30% ethanol is present in the glucose receiving solution is substantially lower than when no ethanol is present. It is currently believed that this result is due to the fact that the solubility of glucose in water is higher than the solubility in ethanol. Consequently, the tendency of glucose to permeate from plasma into the 30% ethanol solution is lower than into a deionized water solution.
  • Example 6 Blood glucose was monitored noninvasively in a laboratory dog according to the procedure of Examples 1 and 3 , except that the normal blood glucose level was about 100.4 mg/dl and that the suppressed blood glucose level was maintained about 32.8 mg/dl.
  • the experimental results of Example 6 comparing the amount of glucose permeated ( ⁇ g) over time when the blood glucose is suppressed and when the blood glucose is normal are shown graphically in Figure 9. This example confirms that the blood glucose level changes may be monitored by the methods of the present invention.
  • Examples 7-17 blood glucose was monitored noninvasively in a laboratory dog according to the procedure of Example 1, except that a variety of different permeation enhancers were examined to determine their respective mucosal glucose permeability enhancement ability.
  • the permeation enhancers tested in this example were sodium cholate, sodium dodecyl sulfate, sodium deoxycholate, taurodeoxycholate, sodium glycocholate, IGEPAL 10.5, EDTA, sodium oleate, and sodium taurocholate.
  • a glucose receiving medium was prepared for each respective permeation enhancer wherein the permeation enhancer concentration was 2% by weight in deionized water, except for EDTA which was tested at a concentration of 0.2% and 1%.
  • hydrogel blood glucose was monitored noninvasively in a laboratory dog using a hydrogel.
  • the hydrogel was prepared by placing 2 g of hydroxypropylcellulose in a glass vial. The glass vial was positioned in a 55°C water bath until temperature equilibrium was reached. Five (5) ml of 55°C deionized water was then introduced into the vial. The mixture was stirred thoroughly and a slurry was formed. Hydroxypropylcellulo ⁇ e is insoluble in water 45°C or warmer. Five (5) ml of room temperature deionized water containing 16% by weight sodium cholate was introduced into the vial. The mixture was stirred gently until a hydrogel was formed. The hydrogel was centrifuged for 45 minutes to remove any air bubbles. The resulting hydrogel had an 83% water content which contained 8% sodium cholate. The hydrogel was transparent and homogeneous.
  • hydrogel slices removed from the dog's buccal mucosa were weighed and placed in separate glass vials.
  • Deionized water was added to the vials such that the combined weight of the hydrogel and the deionized water was
  • each glass vial contained 0.4 g of hydrogel described above and 0.1 g deionized water.
  • One (1) ml of the liquid from each vial was incubated with 2 ml glucose oxidase solution for exactly 18 minutes, and the absorbance at 505 nanometers was measured. The absorbance verses glucose concentration relation was found to be:
  • Blood glucose was monitored noninvasively in a laboratory dog using a hydrogel according to the procedure of Example 18, except that the blood glucose level was about 140 mg/dl.
  • the same laboratory dog used in Example 18 was used in Example 19.
  • the total amount of glucose permeated into the hydrogel is also shown in Figure 10 as a function of blood glucose concentration.
  • Example 20 Blood glucose was monitored noninvasively in a laboratory dog using a hydrogel according to the procedure of Example 18, except that the blood glucose level in the dog was elevated to about 245 mg/dl using the procedure described in Example 2. Blood glucose was also monitored in the same laboratory dog according to the procedure of Example 18, except that the normal blood glucose level was about 120 mg/dl. In both the normal and elevated blood glucose tests, the concentration of sodium cholate in the hydrogel was 4% by weight. In addition, the hydrogel was placed on the buccal mucosa only for a period of 60 minutes. The total amount of glucose permeated into the hydrogel, normalized to ⁇ g/cm 2 , is shown in Figure 11 as a function of blood glucose concentration (mg/dl) .
  • Example 21 Blood glucose was monitored noninvasively in a laboratory dog using a hydrogel according to the procedure of Example 18, except that the blood glucose level in the dog was elevated to about 210 mg/dl using the procedure described in Example 2. Blood glucose was also monitored noninvasively in the same laboratory dog using a hydrogel according to the procedure of Example 18, except that the normal blood glucose level was about 95 mg/dl. The total amount of glucose permeated into the hydrogel, normalized to ⁇ g/cm 2 , for both the elevated and normal blood glucose levels is shown in Figure 12 as a function of blood glucose concentration (mg/dl) .
  • Example 22 blood glucose was monitored noninvasively in a laboratory dog using a hydrogel.
  • the hydrogel was prepared according to the procedure of Example 18, except that the concentration of sodium cholate in the hydrogel was 8%.
  • Six hydrogel slices were placed on the buccal mucosa of a laboratory dog as described in Example 18. Two hydrogel slices were removed after 10, 20, and 30 minutes, respectively, and analyzed according to the procedure of Example 18.
  • the blood glucose level in the dog was about 136.8 mg/dl during the procedure.
  • the total amount of glucose permeated into the hydrogel, normalized to ⁇ g/cm 2 , verses time is shown in Figure 13. The lag time was determined to be 2.7 minutes.
  • Example 23 blood glucose was monitored noninvasively in a laboratory dog using a hydrogel.
  • the hydrogel was prepared according to the procedure of Example 18, except that the concentration of sodium cholate in the hydrogel was 16%. In addition, the hydrogel slices were removed after 9 minutes and 16 minutes, rather than 30 and 60 minutes.
  • the blood glucose level in the dog was about 109.3 mg/dl during the procedure.
  • the total amount of glucose permeated into the hydrogel, normalized to ⁇ g/cm 2 , verses time is shown in Figure 14. The lag time was negligible.
  • Example 24 Blood glucose was monitored noninvasively in a laboratory dog using a hydrogel according to the procedure of Example 23, except that the blood glucose level was elevated according to the procedure described in Example 2. The same laboratory dog used in Example 23 was used in this Example. The blood glucose level in the dog was maintained about 189.5 mg/dl during the procedure. The total amount of glucose permeated into the hydrogel, normalized to ⁇ g/cm 2 , verses time is also shown in Figure 14.
  • Example 25 Blood glucose was monitored noninvasively in a laboratory dog to determine the effect of surface area on glucose flux according to the procedure of Example 1, except that two differently sized diffusion cells were used. Each diffusion cell was placed on one side of the dog's mouth. Diffusion cell “A” had an open bottom area of 1.887 cm 2 , while diffusion cell “B” had an area of 0.866 cm 2 . The glucose flux for diffusion cell “A” was determined to be 4.87 ⁇ g/minute/cm 2 , while the glucose flux for diffusion cell “B” was determined to be 4.80 ⁇ g/minute/cm 2 . The results of Example 25 demonstrate that glucose flux is independent of surface area.
  • Example 26 Blood glucose was monitored noninvasively in a laboratory dog using a diffusion cell and a hydrogel according to the procedures of Examples 1 and 18, respectively, except that the concentration of sodium cholate in both the glucose receiving solution and in the hydrogel was 8%. It was found that the total amount of glucose permeated over time was lower by a factor of about 3 using the hydrogel than with the diffusion cell. This result suggests that glucose permeating into the hydrogel is a rate limiting step when compared to the permeation of glucose across the mucosal membrane. Therefore, the results of Example 26 suggest that use of a hydrogel may provide a substantially uniform glucose permeation rate which is substantially independent of individual variations in mucosal membrane permeability. The hydrogel in Example 26 was acting as a rate regulating medium. The total amount of glucose permeated into the hydrogel, normalized to ⁇ g/cm 2 , verses time is also shown in Figure 15.
  • Example 27 The solubility of glucose in various enhancer systems was determined by adding an excess amount of glucose to 5 ml of the tested enhancer system. After 15 minutes of sonication, the suspension was equilibrated for 3 days with shaking in a 32°C water bath. The suspension was filtered through a Gel an ACRO LC13 filter (pore size, 0.2 ⁇ m) , and the glucose concentration was determined by reverse-phase high pressure liquid chromatography ("HPLC") . The mobile phase was 80/16/2/2 CH 3 CN/H 2 0/NH 4 0H/CHC1 3 . The injection volume was 100 ⁇ l, and the flow rate was 2.0 ml/min at a column pressure of 1200 psi. A Whatman 11 cm x 3.9 mm PartiSphere Polar Amino-Cyano column was used. The run time was from 5-7 minutes with a retention time of 3.4 minutes.
  • HPLC reverse-phase high pressure liquid chromatography
  • glucose solubility is a linear function of H 2 0 content in the enhancer formulations. It ranges from 22 mg/ml to 275 mg/ml in the EtOH/H 2 0 systems and ranges form
  • the enhancers with low glucose solubility will have a
  • Example 28 In order to examine the feasibility of the novel glucose back-diffusion concept toward the design of noninvasive transdermal glucose sensors, the in vitro back- diffusion kinetics of glucose has been measured across the human cadaver skin at 32°C.
  • the in vitro skin flux experiments were carried out using modified Franz diffusion cells such as those illustrated in Figure 17.
  • Human cadaver skin was heat separated at 60°C for 1 minute and the epidermal layer was mounted between the donor and receptor compartments of the cells, the stratum corneum facing the receptor compartment.
  • the diffusion cells were then placed in a heating/stirring module (Pierce Chemical-ReactiTherm ® ) for temperature control and stirring of the donor compartment.
  • the surface temperature of skin was maintained at 32 ⁇ 1°C.
  • PBS saline containing a glucose concentration of 100 mg/ml, which is about 100 times higher than normal blood glucose level (- 100 ml/dl) was introduced to the donor compartment which is the lower portion of the diffusion cell.
  • a selected enhancer system from Table III was introduced to the receptor compartment for 24 hours.
  • the receptor compartment was the upper portion of the diffusion cell illustrated in Figure 17.
  • the enhancer system was then replaced by the same, but fresh, enhancer formulation and the samples were taken afterwards.
  • the back-diffusion of glucose into the enhancer systems were measured at 1, 2, and 24 hours after pretreatment with the enhancer.
  • Glucose was analyzed using reverse phase HPLC.
  • the mobile phase was 80/16/2/2 CH 3 CN/H 2 0/NH 4 0H/CHC1 3 .
  • the injection volume was 100 ⁇ l, and the flow rate was 2.0 l/min at a column pressure of 1200 psi.
  • a Whatman 11 cm x 3.9 mm PartiSphere Polar Amino-Cyano column was used.
  • the run time was from 5-7 minutes with a retention time of 3.4 minutes.
  • This example was designed with the idea that a diabetic patient can apply a transdermal patch containing enhancer formulation to the test site on the body for a certain period of time before the blood glucose is read by another transdermal patch/sensor system.
  • Figure 18 shows the results obtained with four of the enhancer formulations identified in Table III (90/10 DMSO/H 2 0, 90/10 (40/60 ML/IPA)/H 2 0, 70/30 EtOH/H 2 0, and 8 M urea in H z O) .
  • the cumulative amount of glucose back- diffusing across skin was determined with each formulation up to 24 hours after the pretreatment stage in 1 to 3 skin donor samples (each composition evaluated in triplicate per donor skin) .
  • Glucose skin flux determinations were made without pretreating the skin with an enhancer system.
  • the skin was equilibrated with a glucose/PBS saline solution in the donor compartment for 4 hours.
  • the amount of glucose permeating across the skin was measured at 4, 8, 20, 24, and 28 hours.
  • the receptor solutions (3 ml) were removed and glucose concentrations were determined by HPLC.
  • the receptor solutions were replaced with the same, but fresh, enhancer formulations immediately and the caps were closely tightened to prevent the evaporation of enhancer ingredients.
  • T e cumulative amounts of glucose permeating across the skin at time t (Q t , ⁇ g/cm 2 ) were determined using the following equation:
  • C n is the glucose concentration ( ⁇ g/ml) determined by HPLC at time interval "t”
  • V is the receptor volume (ml)
  • S is the surface area (cm 2 ) .
  • the steady-state flux, "J s " ( ⁇ g/cmVhr) was calculated from the linear slope of Q t verses t curve. By extrapolating the steady-state flux curve to the x-axis, the lag time, "t L ", was determined.
  • the in vitro skin flux experiments in this example were conducted under more realistic conditions than in Example 28.
  • the glucose concentration in PBS saline was reduced from 100 mg/ml to 10 mg/ml and 1 mg/ml to mimic the hyperglycemic and normal blood level.
  • the enhancer system was added to the receptor compartment and the samples were taken periodically without pretreating the skin.
  • the purpose of this example was to determine the steady-state flux as well as the lag times required before reaching steady-state permeation.
  • Figure 19 shows the results obtained with the four enhancer systems used in Example 28 (90/10 DMSO/H 2 0, 90/10 (40/60 ML/IPA)/H 2 0, 70/30 EtOH/H 2 0, and 8 M urea in H 2 0) .
  • the glucose concentration was 1 mg/ml in the donor compartments and four enhancer systems were in the receptor compartments.
  • 90/10 DMSO/H 2 a glucose concentration of 10 mg/ml was employed as the donor solution.
  • the steady-state flux rates ranged from 5.8 to 125.8 ⁇ g/cm 2 /hr, with 70/30 EtOH/H 2 0 producing the highest flux.
  • 70/30 EtOH/H 2 0 also generated the longest lag time, 23.2 hours.
  • 90/10 DMS0/H 2 0 produced time lags of approximately 1-2 hours.
  • glucose back- flux was reduced by lowering the donor concentration from 10 mg/ml to 1 mg/ml. However, this flux reduction was substantially less than 10-fold.
  • glucose concentration in the donor side is 1 mg/ml) .
  • the P t value of the enhancer treated skin was close to the epidermis/dermis permeability (i.e. , a P s of around 1 to 5 x 10 "5 cm/sec) indicating that the barrier property of the stratum corneum was essentially abolished in this study.
  • a rate-limiting membrane with a permeability coefficient P H ⁇ 1 x 10 "5 cm/sec the glucose flux may be controlled by the rate-limiting membrane.
  • the present invention permits noninvasive blood glucose monitoring which can be performed nearly as rapidly as conventional monitoring techniques, but without the pain, inconvenience, and risks of current invasive techniques.
  • the present invention provides apparatus and methods for noninvasive blood glucose monitoring which avoids the inconvenience and risks associated with traditional invasive blood glucose monitoring techniques. Additionally the present invention provides apparatus and methods for noninvasive blood glucose monitoring which provide reproducible and accurate correlation with actual blood glucose levels. The present invention also provides apparatus and methods for noninvasive blood glucose monitoring which provide rapid results in sufficient time to administer appropriate medication.

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Abstract

La présente invention décrit de nouvelles méthodes et un nouvel appareil pour le contrôle non invasif du glucose dans le sang. Ce contrôle s'effectue par corrélation avec le taux de glucose qui imprègne une membrane épithéliale (14), peau ou muqueuse, dans un récepteur du glucose (12), sur une période donnée. Le récepteur (12) comprend de préférence un stimulateur d'imprégnation du glucose capable d'augmenter la perméabilité du glucose à travers la membrane épithéliale (14). Le récepteur (12) est placé contre ladite membrane (14), de sorte que le stimulateur d'imprégnation en modifie la perméabilité. Passé un laps de temps suffisant, le récepteur du glucose (12) est enlevé et soumis à analyse pour la recherche de glucose suivant les techniques traditionnelles. L'appareil comprend un dispositif qui sert de support au récepteur du glucose. Ce dispositif peut se composer d'un cadre (18) définissant une chambre réceptrice qui maintient le récepteur (12) et d'une ouverture sur cette chambre. Le dispositif peut aussi inclure un hydrogel. L'appareil comprend aussi de préférence un dispositif (20) servant à positionner temporairement le récepteur du glucose contre la membrane épithéliale.
PCT/US1990/002940 1989-06-02 1990-05-24 Appareil et methodes pour le controle non-invasif du glucose dans le sang WO1990015568A2 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000014535A1 (fr) * 1998-09-09 2000-03-16 Amira Medical Procede et dispositif utilisant les fluides interstitiels pour la determination d'un analysat corporel
US6041253A (en) * 1995-12-18 2000-03-21 Massachusetts Institute Of Technology Effect of electric field and ultrasound for transdermal drug delivery
US6234990B1 (en) 1996-06-28 2001-05-22 Sontra Medical, Inc. Ultrasound enhancement of transdermal transport
US6251083B1 (en) 1999-09-07 2001-06-26 Amira Medical Interstitial fluid methods and devices for determination of an analyte in the body
WO2004006759A1 (fr) * 2002-07-11 2004-01-22 Optical Sensors, Inc. Procede de mesure de plusieurs parametres physiologiques
EP1468109A4 (fr) * 2001-12-17 2005-01-12 Powderject Res Ltd Methodes de surveillance non invasives ou minimalement invasives
WO2023172192A3 (fr) * 2022-03-08 2023-11-02 Agency For Science, Technology And Research Biocapteur épidermique

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7066884B2 (en) 1998-01-08 2006-06-27 Sontra Medical, Inc. System, method, and device for non-invasive body fluid sampling and analysis
US20040171980A1 (en) 1998-12-18 2004-09-02 Sontra Medical, Inc. Method and apparatus for enhancement of transdermal transport
US7432069B2 (en) 2005-12-05 2008-10-07 Sontra Medical Corporation Biocompatible chemically crosslinked hydrogels for glucose sensing
US8386027B2 (en) 2007-04-27 2013-02-26 Echo Therapeutics, Inc. Skin permeation device for analyte sensing or transdermal drug delivery

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2042888B (en) * 1979-03-05 1983-09-28 Teijin Ltd Preparation for administration to the mucosa of the oral or nasal cavity
US4291015A (en) * 1979-08-14 1981-09-22 Key Pharmaceuticals, Inc. Polymeric diffusion matrix containing a vasodilator
US4379454A (en) * 1981-02-17 1983-04-12 Alza Corporation Dosage for coadministering drug and percutaneous absorption enhancer
US4746508A (en) * 1983-06-06 1988-05-24 Beth Israel Hospital Assn. Drug administration
EP0191783A4 (fr) * 1984-07-06 1987-12-09 Avery Internat Corp Pansement pour la liberation entretenue de medicaments.
US4706676A (en) * 1985-02-11 1987-11-17 The United States Of America As Represented By The Secretary Of The Army Dermal substance collection device
ZA885069B (en) * 1987-07-24 1989-03-29 Fujisawa Pharmaceutical Co Sustained-release percutaneous preparations

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6041253A (en) * 1995-12-18 2000-03-21 Massachusetts Institute Of Technology Effect of electric field and ultrasound for transdermal drug delivery
US6234990B1 (en) 1996-06-28 2001-05-22 Sontra Medical, Inc. Ultrasound enhancement of transdermal transport
US6491657B2 (en) 1996-06-28 2002-12-10 Sontra Medical, Inc. Ultrasound enhancement of transdermal transport
WO2000014535A1 (fr) * 1998-09-09 2000-03-16 Amira Medical Procede et dispositif utilisant les fluides interstitiels pour la determination d'un analysat corporel
US6251083B1 (en) 1999-09-07 2001-06-26 Amira Medical Interstitial fluid methods and devices for determination of an analyte in the body
EP1468109A4 (fr) * 2001-12-17 2005-01-12 Powderject Res Ltd Methodes de surveillance non invasives ou minimalement invasives
WO2004006759A1 (fr) * 2002-07-11 2004-01-22 Optical Sensors, Inc. Procede de mesure de plusieurs parametres physiologiques
WO2023172192A3 (fr) * 2022-03-08 2023-11-02 Agency For Science, Technology And Research Biocapteur épidermique

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KR920700014A (ko) 1992-02-19
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