WEARABLE DEVICE TO SCREEN OPIOID INTOXICATION

A microneedle device comprising a membrane having an adhesive thereon and a microneedle substrate adhered to the membrane via the adhesive. The microneedle substrate may have a plurality of microneedles coupled thereto, or the microneedle substrate can comprise the plurality of microneedles. The microneedle device can be mated with a reagent container and the microneedles aligned with wells on the reagent container said wells configured to hold reagents thus comprising a system for detecting opioids or other drugs. In another embodiment, the device comprises a sweat-absorbent swatch adhered to a membrane. This embodiment can be mated to a screening pad comprising blisters of reagents on the base layer of the screening pad. Upon mating, a needle device can be used to pierce the blisters such that the reagents are released and react with the sweat absorbent swatch to indicate the presence of opioids or other drugs.

BACKGROUND

About two million Americans are addicted to opioid drugs, including prescription pain medicines, heroin and fentanyl or one of its analogues. Many millions more misuse opioids, taking opioid medications longer or in higher doses than prescribed. These statistics are staggering, and the tragic effects of the opioid crisis do not stop there but extend to our entire nation.

The negative impact of these drugs is even greater when used by public first responders, pilots, firefighters, soldiers, and individuals with public responsibilities. Increased overdose and misuse of opioids in the United States (US) makes it more important than ever to have full capability to detect drugs that can impair judgment in subjects responsible for public safety. Between 1999 and 2016, more than 630,000 people died from a drug overdose in the US. The current epidemic of drug overdoses began in the 1990s with overdose deaths involving prescription opioids, driven by dramatic increases in prescribing of opioids for chronic pain. In 2010, rapid increases in overdose deaths involving heroin marked the second wave of opioid overdose deaths. The third wave began in 2013, when overdose deaths involving synthetic opioids, particularly those involving illicitly manufactured fentanyl, began to increase significantly. In addition to deaths, nonfatal overdoses from both prescription and illicit drugs are responsible for increasing emergency department visits and hospital admissions. Roughly 118,000 people died as a result of opioid use disorders in 2015.

Opioids are a drug class that includes heroin, synthetic opioids such as fentanyl (and analogues), and pain relievers such as oxycodone, hydrocodone, codeine, morphine, and others. Side effects of opioids include sedation, nausea, respiratory depression, and euphoria. Fentanyl and analogues have rapid onset of symptoms and vary in duration of action. These drugs are 50-100 times more potent than morphine, which predispose individuals to quantities leading to accidental life-threatening exposure. Because of the risks associated with the low dose required for rapid onset of impairment, there is significant interest in real-time detection of exposure and diagnosis of intoxication at the point-of-need through a wearable medical device.

Sweat Transdermal Patches

Transdermal patches are now widely used as cosmetic, topical, and transdermal delivery systems. These patches are the result of great progress in skin science, technology, and expertise developed through trial and error, clinical observation, and evidence-based studies that date back to the first existing human records. The advantage to using a sweat transdermal patch is the long testing window. Although standard urine-based test strips may be better for immediate results, they only detect drugs that have been metabolized. Sweat patches, however, also detect the parent drug. The longer testing window helps when detecting the most common drugs, such as marijuana, cocaine, methamphetamines, lysergic acid diethylamide (LSD), and heroin, which generally stay in the system of occasional users for about five days.

Urine testing can often miss the detection of drugs as they can only detect the metabolite. Commercially available sweat patches, on the other hand, can detect the parent drug. The variation between individuals in the amount of sweat they excrete has caused difficulty to construct a universal sweat collection device. Earlier attempts to test for the presence of specific substances in sweat have used patches that occlude the skin causing side effects, such as skin irritation, alteration of both the steady-state pH of the skin, and colonization of skin bacteria. Newer, nonocclusive patches use a transparent film that allows oxygen, carbon dioxide, and water vapor to diffuse, while trapping the necessary traces of drug substance excreted in sweat. The newer patch has many benefits including high subject acceptability, low incidence of allergic reactions to the patch adhesive, and ability to monitor drug intake for a period of several weeks with a single patch. Several studies have also found that the patch is resistant to inconspicuous tampering. It has also reported that no special precautions were needed to wear the patch for several days, except to avoid excessive towel rubbing after bathing. Some disadvantages include high inter subject variability, possibility of environmental contamination of the patch before application or after removal, and accidental removal during the monitoring period. In addition, it was reported that the cost of patch testing, based on the panel of drugs tested, was five times that of urine tests. Validation of results from sweat patches, most of which use urine testing as the “gold standard,” have been controversial. It has been reported that good inter-patch reliability and concurrent validity with urine tests when testing for methadone, opiates, and morphine, while tests for cocaine revealed only a moderate level of agreement. In a noted study specifically designed to find possible sources of contamination, it was found that precautionary methods, including cleansing the skin before patch application, are not completely reliable in preventing contamination from the environment. Chawarski et al. evaluated the utility of sweat testing for monitoring of drug use in outpatient clinical settings and compared sweat toxicology with urine toxicology and self-reported drug use during a randomized clinical trial of the efficacy of buprenorphine for treatment of opioid dependence in primary care settings. All study participants were opiate dependent, treatment-seeking volunteers. The findings suggest limited utility of sweat patch testing in outpatient settings. The commercially available transdermal patches need to be transported to a diagnostic laboratory after removal for drug detection.

Interstitial Body Fluid Transdermal Microneedles

Microneedle arrays are minimally invasive devices that can be used to bypass the stratum corneum barrier and thus accessing the skin microcirculation and achieving systemic delivery by the transdermal route for drug delivery. Microneedles (MN) (hundreds of microns in length up to 1000 MNcm−2) with diverse geometries have been produced from silicon, metal, and polymers using various microfabrication techniques. MNs have been prepared using chemical isotropic etching, injection molding, reactive ion etching, surface/bulk micromachining, micro-molding and lithography-electroforming-replication. MNs are applied to the skin surface and pierce the epidermis (devoid of nociceptors) painlessly without skin infection, creating microscopic holes through which drugs diffuse to the dermal microcirculation. MNs can be made long enough to penetrate to the dermis layer but are typically short and narrow enough to avoid stimulation of dermal nerves and puncture dermal blood vessels. MNs are classified as solid, hollow, and polymeric depending on the application. Solid MNs puncture skin prior to application of a drug-loaded patch or are pre-coated with drug prior to insertion. Hollow bore microneedles allow diffusion or pressure-driven flow of drugs through a central lumen. The polymeric MNs are either of dissolved type or hydrogel-forming. The dissolved MNs release their drug payload as they dissolve in the skin layers and are generally a biocompatible polymer. The skin insertion of the array is followed by dissolution of the MNs tips upon contact with skin interstitial fluid. The drug is then released over time. The hydrogel-forming MNs take up interstitial body fluids (IBL) from the tissue, inducing diffusion of the drug located in a patch through the swollen micro-projections. The amount of swelling can be controlled by adding different agents. Hydrogel-forming MNs are removed intact from skin, leaving no measurable polymer residue behind. They cannot be reused since there is a potential of getting softer. MN polymers are drawing increasing attentions because of their excellent biocompatibility, biodegradability, low toxicity and strength/toughness. They are easy to fabricate and cost-effective.

BRIEF SUMMARY

Transdermal Patches

A primary objective of the methods and apparatuses/devices of the present disclosure is to provide new systems and technique to screen opioids more readily and inexpensively than the current systems via transdermal patches. The devices disclosed herein have the following features/benefits: 1) non-invasive, 2) real-time response after removal (Point of Care), 3) passive device which does not need the cooperation of the subject, 4) ability of patch to screen the presence of all opioids of interest at the same time for a desired period of residence time with a single patch, 5) bio-material compatibility, 6) ease of manufacturing, 7) low cost, 8) long shelf life, 9) ease of application/removal, 10) wearable and easy to handle in any application setting, 11) no skin side effects like irritation or allergic reactions to the patch adhesive, 12) screening with very low false negative, 13) resistant to inconspicuous tampering, 14) possibility of oxygen, carbon dioxide, and water vapor to escape while trapping necessary traces of drug use excreted in sweat, and 15) minimum environmental contamination of patch before application or after removal.

It is imperative to know the order of magnitude of the opioids concentration in sweat to search for method(s) capable to achieve the required Level of Detection (LOD) of opioid agents in the patch screening device. The devices of the present disclosure are optimized to screen the drug agents of interest.

Sweat and sebaceous glands are found in the dermis and are distributed throughout the body disproportionately. The highest concentration of sweat glands resides in the hands, while the forehead contains the densest population of sebaceous glands. Both glands deliver byproducts of drugs to the skin's surface through either sweat or sebum. Drugs are thought to enter the sweat by passive diffusion from the blood stream to the sweat gland. Drugs are also dissolved in sweat on skin's surface after they diffuse through stratum corneum. Despite variation between individuals in sweat production, researchers have successfully used sweat to test for cocaine, opiates, benzodiazepines, and others.

The rate of sweating depends on the skin temperature, which is normally 33° C. The rate of sweating increases by a factor of about four when jogging opposed to resting. This relationship holds even if the skin temperature increases to 36° C. The sweating rate increases by a factor of about four when the skin temperature increases to 36° C. from 33° C. An average person sweats between 0.8 to 1.4 liters per hour (L/hr) during exercise, depending on the type of exercise, metabolic rate, skin surface area, and skin temperature. This rate can increase as high as 4 L/hr. The analysis referenced herein is based on 0.2 L/hr, which is the lower limit of sweating at skin temperature of 33° C. at rest. The skin area is about 1.5 to 2.0 square meters for an average adult that results in the sweat amount of about 0.2 ml for an absorbing area of patch of about 2 cm2in 6 to 8 hours. The longer testing window was selected to help detecting the most common drugs, such as marijuana, cocaine, methamphetamines, LSD, and heroin, which generally stay in the system of occasional users for about five days as previously noted herein.

It has been found that free and total peripheral blood morphine concentrations are consistent with fatal heroin intoxications, averaging 0.16 mg/L and 0.35 mg/L, respectively in cases where acetyl fentanyl or fentanyl were not involved. In the heroin cases with fentanyl present, the average fatal free morphine concentration was 0.040 mg/L, the average total morphine concentration was 0.080 mg/L, and the fatal average fentanyl concentration was 0.012 mg/L. In cases involving only acetyl fentanyl (without heroin), the average fatal acetyl fentanyl concentration was 0.47 mg/L and the average fatal acetyl norfentanyl concentration was 0.053 mg/L. These data indicate that the range of agent concentrations in the blood are 10-350 ng/ml. The opioid concentrations in the sweat may be less than what it would be in blood. The total amount of the opioids collected in the absorbing area of the patch of about 2 cm2size is about 0.2 to 7 ng after 6 to 8 hours of patch residence time for an average active subject assuming the concentration of opioid in the sweat is about 10% of concentration of the same opioid found in the blood. This range will be our design requirement for the appropriate patch screening device. This means that we need to have minimum LOD of about 0.2 ng for the opioids of interest.

Interstitial Body Fluid Transdermal Microneedles

A sufficient amount of sweat must be absorbed by the patch to generate the desired concentration of the drugs for color change in a reasonable residence time. Microneedles will be considered to generate the color change if the sweat concentration is too low for screening.

Previous studies have shown that 83% of proteins found in serum are also in Interstitial body fluid (IBF), but 50% of proteins in IBF are not in serum, suggesting that Interstitial body fluid may be a source of unique biomarkers as well as biomarkers found in blood. Skin is the most accessible organ and therefore a source of IBF containing biomarkers. Most of skin's IBF is in dermis, which comprises a network of collagen and elastin fibers surrounded by extracellular matrix that limits IBF flow due to binding and tortuosity. It is estimated that ˜70 wt % of human dermis comprising IBF. There are several mechanisms of IBF collection into MN including diffusion, capillary and osmotic actions.

A primary objective of the present method and apparatus is to provide new systems and technique to screen opioids more readily and inexpensively than the current systems via Interstitial body fluid. The device features will be 1) use of polymer microneedles, 2) minimally invasive, 3) Real time response after removal (Point of Care), 4) Passive device which does not need the cooperation of the subject, 5) Ability of microneedle to screen the presence of all opioids of interest at the same time for a desired period of residence time with a single microneedle, 6) Bio-material compatibility, 7) Ease of manufacturing, 8) Low cost, 9) Long shelf life, 10) Ease of application/removal, 11) No skin side effect like irritation or allergic reactions to the microneedle, 12) Screening with very low false negative, 13) Resistant to inconspicuous tampering, and 14) Minimum environmental contamination of microneedle before application or after removal.

Recent progress indicates the possibility of 1-10 μl of IBF within 20 min though MN. As noted above, the sweat amount is ˜0.2 ml for an absorbing area of patch of about 2 cm2in 6-8 hours which corresponds to 10 μl for 20 min. It is a good assumption that the concentration of opioids in the interstitial body fluid is about the same as in the blood concluded from the remarks noted above and the concentration of opioids in the sweat is at most 10% of the corresponding amount in the blood. Therefore, microneedle patches can increase the opioids detectability by a factor of at least 10 for the same patch residence time. This factor increases for those individuals that usually do not sweat.

The present disclosure includes disclosure of a microneedle device, comprising an adhesive layer, and a microneedle substrate adhered to the adhesive layer, and a) wherein the microneedle substrate has a plurality of microneedles coupled thereto, or b) wherein the microneedle substrate further comprises the plurality of microneedles. The microneedle device can be firmly attached to the skin by adhesive layer. The microneedle device, comprising release liner where release liner covers microneedle device during storage and prior to use, so to avoid potential contamination of microneedle device. Release liner is removed before use.

The present disclosure includes disclosure of a microneedle device, comprising a membrane (which, along with an adhesive, can be considered as an “adhesive layer”). And a microneedle substrate adhered thereto (adhered to the membrane, which, along with the adhesive, can be considered to be the adhesive layer), and a) wherein the microneedle substrate has a plurality of microneedles coupled thereto, or b) wherein the microneedle substrate further comprises the plurality of microneedles

The present disclosure includes disclosure of a microneedle device, forming part of a system, the system further comprising at least one of the following a reagent container having wells defined therein, the wells configured to hold reagents, and/or a detection device.

The present disclosure includes disclosure of a method to use a microneedle device, comprising the steps of placing a microneedle device of the present disclosure upon skin of a wearer so to cause at least part of a plurality of microneedles of the microneedle device to enter a dermis of the skin, and removing the microneedle device from the skin after a period of time elapses, said period of time being enough time to permit interstitial body fluid to at least partially coat the plurality of microneedles.

The present disclosure includes disclosure of a method to use a microneedle device, further comprising the step of positioning the plurality of microneedles of the microneedle device into wells of a reagent container so to potentially cause one or more reactions between the interstitial body fluid at least partially coating the plurality of microneedles and reagents within the wells of the reagent container, said one or more reactions resulting in one or more color changes, the one or more color changes indicative of the presence of one or more opioids and/or chemicals related thereto.

The present disclosure includes disclosure of a method to use a microneedle device, wherein the plurality of microneedles are at least partially coated with reagents prior to the step of placing the microneedle device upon the skin of the wearer; and wherein the method further comprises the step of inspecting the plurality of microneedles in attempt to identify one or more color changes thereon, the one or more color changes indicative of the presence of one or more opioids and/or chemicals related thereto.

The present disclosure includes disclosure of a method to use a microneedle device, wherein the plurality of microneedles have lumens defined therethrough, wherein the step of placing the microneedle device upon the skin of the wearer further includes operating a suction device/mechanism coupled to or formed as part of the microneedle device to cause the interstitial body fluid to flow into the lumens of the plurality of microneedles.

The present disclosure includes disclosure of a method to use a microneedle device, further comprising the step of combining the interstitial body fluid with a plurality of reagents so to potentially cause one or more reactions between the interstitial body fluid and the reagents, said one or more reactions resulting in one or more color changes, the one or more color changes indicative of the presence of one or more opioids and/or chemicals related thereto.

The present disclosure includes disclosure of a system, comprising one or more patches, the one or more patches comprising a membrane, a sweat-absorbent swatch, and an adhesive layer; and one or more screening pads, the one or more screening pads comprising a base layer, one or more blisters positioned upon or formed within the base layer, and one or more reagents positioned within one or more of the one or more blisters.

The present disclosure includes disclosure of a system, wherein the one or more patches have a release liner positioned thereon, configured to cover the sweat-absorbent swatch.

The present disclosure includes disclosure of a method to use a system, comprising the steps of placing a patch of the present disclosure upon skin of a wearer, and removing the patch from the skin after a period of time elapses, said period of time being enough time to permit sweat to transfer from the skin to the patch.

The present disclosure includes disclosure of a method, further comprising the step of positioning a screening pad upon a sweat-absorbent swatch of the patch to potentially cause one or more reactions between the sweat on or within the swatch and reagents within the screening pad, said one or more reactions resulting in one or more color changes, the one or more color changes indicative of the presence of one or more opioids and/or chemicals related thereto.

As such, an overview of the features, functions and/or configurations of the components depicted in the various figures will now be presented. It should be appreciated that not all of the features of the components of the figures are necessarily described and some of these non-discussed features (as well as discussed features) are inherent from the figures themselves. Other non-discussed features may be inherent in component geometry and/or configuration. Furthermore, wherever feasible and convenient, like reference numerals are used in the figures and the description to refer to the same or like parts or steps. The figures are in a simplified form and not to precise scale.

DETAILED DESCRIPTION

Systems50of the present disclosure comprise two parts/portions—a sweat patch100, also referred to herein as a collection part/portion, and a screening pad500, also referred to herein as a screening part/portion or a detection part/portion. Screening pad500is composed of biomarkers, where it will lay on top of the sweat patch after removal. Screening pad500will then be removed from the sweat patch100after several seconds for color determination by either the naked eye or using a detection device such as a spectrometer. Sweat patches100can be slightly heated to evaporate the residual liquid to increase agent concentrations.

An exemplary patch100(also referred to herein as a sweat patch or sweat transdermal patch) of the present disclosure is shown inFIG. 1. As shown therein, sweat patch100comprises a membrane102, a sweat-absorbent swatch104, and an adhesive layer106present upon membrane102(an adhesive being applied to membrane102), whereby adhesive106facilitates adhesion of swatch104to membrane102and adhesion of sweat patch100to a wearer's skin.

As shown inFIG. 2, an exemplary sweat patch100of the present disclosure can comprise a release liner108, where release liner108covers patch100during storage and prior to use, so to avoid potential contamination of swatch104. Release liner108is removed before use, such as shown inFIG. 3, revealing swatch104. Release liners108can have a thickness between 50 to 70 μm, or larger or smaller.

Adhesive layer106, as noted above, is used so that sweat patch100can be firmly attached to the skin of a wearer. Swatch104, as noted above, is positioned at the center of the adhesive layer106.

An exemplary adhesive layer106of the present disclosure can comprise any number of suitable adhesives, such as bioadhesives (Duro-TAK 387-2510/87-2510 from Henkel, for example) or other materials which is/are mixed with sodium carboxymethyl cellulose (NaCMC) or other materials, resulting in a total adhesive layer106thickness of 100 to 150 μm, or thicker or thinner.

Membranes102of the present disclosure essentially exist as a backing film on an opposite side of adhesive layer106used to adhere to swatch104, whereby the configuration of membranes102ensure that gases such as oxygen, carbon dioxide, and water vapor can escape into the surrounding external environment. An exemplary membrane102of the present disclosure could be 3M, Co Tran TM 9701 Backing Polyurethane Monolayer Film with high moisture vapor transmission rate (MVTR) of 709 g/m2/24 hr, or other suitable membrane102materials that permit gas escape as noted herein. The total thickness of the membrane102can be 200 to 300 μm, or thicker or thinner. In such a configuration, sweat400diffuses from the skin402into sweat patch100where it is absorbed by swatch104, such as depicted inFIG. 4.

Manufacture/production of sweat patch100can include three steps, as follows:Step 1: Release liner108and adhesive layer106are put together, and membrane102is added on the outside of the adhesive layer106.Step 2: Swatch104is placed at the center of the adhesive layer106so that swatch104can ultimately and directly contact the skin of a wearer of sweat patch100. In this configuration, the adhesive layer106sticks to the skin all around the absorbing swatch104.Step 3: Cutting edges and corners of sweat patch100to desired dimensions to result in a final sweat patch100.

Other manufacturing/production methods/steps are also contemplated in the present disclosure, such as whereby membrane102is cut to size prior to applying swatch104thereto, such as whereby adhesive layer102before other portions of sweat patch100. The end result of any said method or method steps noted above would be a sweat patch100configured for use as referenced herein.

In use, rapid evaporation of sweat400moisture through membrane102constituting the relative top layer of sweat patch100can reduce the residence time to few hours.

A top view of an exemplary screening pad of the present disclosure is shown inFIG. 5. As shown therein, screening pad500comprises a base layer502and a plurality of blisters504present thereon. Blisters504of the present disclosure are configured to contain/retain one or more reagents506therein. In at least one example, each blister504would contain one reagent506. In other examples, the number of reagents506(one, two, three, or more) can vary within each blister504.

An exemplary screening pad500of the present disclosure has a plurality of blisters504, such as two, three, four, five, six (as shown inFIG. 5), seven, eight, or more blisters504. It is noted that an embodiment of a screening pad500of the present disclosure can have only one blister504with one or more reagents506therein, but such an embodiment would limit the opioid detection to generally one type of opioid. More blisters504having reagent(s)506therein would permit the detection of several opioids at once, as referenced in further detail herein.

FIG. 6shows a side view of an exemplary screening pad500of the present disclosure,FIG. 7shows top view of an exemplary screening pad500positioned upon a swatch104of a patch100of the present disclosure, andFIG. 8shows a side view of an exemplary screening pad500positioned upon a swatch104of a patch100of the present disclosure, whereby a needle device800(namely one or more needles802, including an optional substrate804) is used to pierce blisters504of screening pad500to permit reagents506to transfer from blisters504into swatch104of patch100, so to permit reagents506to react with chemicals within the sweat within swatch104that are indicative of one or more opioids.

An exemplary screening pad500of the present disclosure can contain blisters504that each contain one of the reagents shown in Table 1, provided below.

Table 1 shows a listing of six exemplary reagents for the rapid, real time opioid screening based on the detection grid shown in said table. Eleven exemplary opioids are listed in Table 1 and can be screened by the six reagents. For example, cocaine and hydrocodone can be screened if the reaction of the sweat with cobalt-thiocyanate results in greenish blue color. The raw materials for the reagents are commercially available.

Said reagents506may include, but are not limited to, cobalt-thiocyanate, ferric chloride, Eosin Y, ammonium vanadate, ferric sulphate, and Marquis Reagent. Said reagents, as shown in Table 1, are able to detect one or more opioids, including but not limited to amphetamine, methamphetamine, heroin, cocaine, fentanyl, codeine, oxycodone, morphine, hydrocodone, opium, and hydromorphone.

As shown inFIG. 7andFIG. 8, and after patch100has been placed on the skin of a wearer for a time sufficient to collect chemicals within sweat in swatch104of patch100, screening pad500is positioned upon patch104so that blisters504are positioned relatively above swatch104. A needle device800, such as a needle device800comprising six needles, can puncture blisters504one or more at a time or all at once so to let the reagents506flow on the surface of the collection part (swatch104) to generate different colors depending on the type of the opioid contained within or upon swatch104. Needle devices800of the present disclosure can comprise one or more needles802, such as a plurality of needles802effectively coupled to one another via a substrate804, as shown inFIG. 9.

When reagents506react with an opioid or a chemical indicative of an opioid present upon or within swatch104, a color would appear and indicate a reaction between the reagent506and the opioid or the chemical indicative of an opioid (referred to herein as a reacted indication1050, as shown inFIG. 10).

The reacted indications1050can potentially be identified visually, and should it be impractical to do so, a detection device1000configured to detect reacted indications1050can be used, such as being positioned relative to a patch having potential reacted indications1050thereon or therein. Such a detection device1000could be a portable spectrometer (such as a smartphone spectrometer) or other device, and the detected colors (whether detected visually or via detection device1000) can then be compared with the colors indicted in Table 1, for example, for drug screening purposes.

The qualitative and subjective nature of the screening of the opioids by color change will be overcome by using smartphone spectrometer to read color changes quantitively after screening pad500is removed from the collection patch100. As an example, one commercially available portable spectrometer (an exemplary detection device1000) distributed by Allied Scientific Pro (Lighting Passport) weighs less than 80 grams and can be directly connected to a cell phone to perform color change analysis. Such a detection device1000is suitable for the screening of the agents (reacted indications1050). The wavelength range is 380-780 nm which covers the visible light spectrum with 10 nm resolution is quite adequate for such a screening application. The spectrometer (detection device1000) can be calibrated with known amounts of different agents. Opioid, reagent, and color information, such as that contained within Table 1, can be programmed into the smartphone and/or accessible by the smartphone so that all the screening results can appear on the smartphone without performing any intermediate data analysis.

Schedules I and II opioid substances which include heroin, fentanyl, morphine, oxycodone, and amphetamine from the list of candidate's agents have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression. Screening of these five agents can be most important screening targets. Fentanyl can be abused and is subject to criminal diversion. Fentanyl and its analogues have rapid onset of symptoms and vary in duration of action, as they are 50-100 times more potent than morphine.

Interstitial Body Fluid Transdermal Microneedles

FIG. 11shows an exemplary microneedle device1100of the present disclosure (a type of patch100) incorporating a plurality of microneedles1102. As shown inFIG. 11, microneedle device1100comprises a membrane102with an adhesive106positioned on at least part of the membrane102. Adhesive106, is used so to adhere microneedle device1100to the skin402of a wearer. Adhesive106can also be present between membrane102and a microneedle substrate1106to adhere microneedle substrate1106to membrane102. So to protect and maintain sterility of microneedle device1100, a release layer108can be used to cover the side of microneedle device1100having the plurality of microneedles, such as shown inFIG. 16. When release layer is removed, the plurality of microneedles1102are revealed, such as shown inFIG. 11.

As shown inFIG. 11, microneedles1102can be arranged upon microneedle substrate1106in microneedle groups1104as desired, whereby each microneedle group1104comprises a plurality of microneedles1102. Said groups1104of microneedles1102can be arranged about microneedle substrate1106so to correspond with locations of wells1202defined within a corresponding reagent container1200, whereby reagents506are present within said wells1202of reagent container1200, such as shown inFIG. 12.

Microneedle devices1100of the present disclosure ideally include the fewest number of microneedles1102necessary in order to obtain a suitable sample of interstitial body liquid (IBL) from the skin402of the wearer of microneedle device1100. For example, and as shown in FIG.11, each group1104of microneedles1102contains three microneedles1102, and with six groups1104(an exemplary number of groups containing an exemplary number of biocompatible reagents506), that would be eighteen microneedles1102in total. Other microneedle devices1100may include any desired number of groups1104of microneedles1102, with any desired number of microneedles1102per group1104, such as a) six groups1104of three microneedles1102each (so eighteen total microneedles1102), b) six groups1104of six microneedles1102each (so thirty-six total microneedles1102), c) four groups1104of four microneedles1102each (so sixteen total microneedles1102), d) six groups1104of twelve microneedles1102each (so seventy-two total microneedles1102), etc. As referenced herein, six reagents506can be used to identify eleven different types of opioids, such as shown inFIG. 11, so exemplary and perhaps preferred microneedle device1100embodiments of the present disclosure would comprise six groups1104of microneedles1102, each group1104corresponding ultimately to one reagent506.

In some embodiments of microneedle devices1100of the present disclosure, microneedle devices1100comprises a microneedle substrate1106(which may the same as or similar to substrate804), which is formed as part of an overall unit with microneedles1102, or which is coupled to microneedles1102to help complete an embodiment of the microneedle device1100that can withstand the desired uses as referenced herein. Substrate1106, as referenced herein, can be relatively flexible so to accommodate the irregular topography of the surface of the skin402due to macroscopic curvature of different body regions to prevent breakage of microneedles1102during insertion. As shown inFIG. 12, microneedle substrate1106can be adhered to membrane102on one side and microneedle substrate1106on another, using adhesive106, as may be desired.

FIG. 13shows an exemplary microneedle device used to extract IBL from the skin402so to at least partially coat the microneedles1102with IBL.FIG. 13shows several layers of skin402, including the stratum corneum1300, viable epidermis1302, and dermis1304containing IBL, from the outside moving inward. When microneedle device1100is positioned upon the skin402(first the stratum corneum1300), microneedle device1100can then be pressed in the direction of skin402to cause microneedles1102to puncture the stratum corneum1300, the viable epidermis1302, and the dermis1304, in that order, so that when completely positioned upon the skin402, microneedle device1100contacts the skin402, and the relative tips of microneedles1102are positioned within the dermis1304. This allows IBL to at least partially coat microneedles1102, so that when microneedle device1100is removed from the skin402, IBL remains on said microneedles1102.

Once microneedles1102are at least partially coated with IBL, said microneedles1102can be dipped into wells1202defined within a corresponding reagent container1200, whereby reagents506are present within said wells1202of reagent container1200, such as shown inFIG. 12. IBL present on said microneedles1102can react with reagents506within wells1202of reagent container1200, causing color-changing reactions to occur should opioids or chemicals relating thereto be present upon said microneedles1102. A detection device1000, such as shown inFIG. 10, could be used to detect the colors within wells1202of reagent container1200, or said colors could be detected visually should the colors be intense enough to detect visually.

FIG. 14shows a block diagram of an exemplary system50of the present disclosure, whereby system50comprises two or more of the following: patch100, screening pad500, needle device800, detection device1000, microneedle device1100, and/or reagent container1200.

It is noted that metal and silicone microneedles (MNs)1102are not favored as the tip may break in the skin which will result in irritation. Silicon MNs1102require clean rooms, waste disposal issues, and their FDA approvals can be questionable, although some form of them has been approved. Open MNs1102are also not favored due to potential clogging in the opening of MN1102by tissue, thus preventing the entrance of the IBL; however, a solution to this problem is disclosed herein, as noted in further detail below. The hydrogel forming materials1306, such as shown inFIG. 13, for the opioids screening application can be used, as referenced herein. The needle tips swell in skin to produce conduits. The opioids can diffuse from IBL of the dermal microcirculation using these conduits.

One candidate material1306can be aqueous blends containing 20% w/w Gantrez® AN-139 polymetric microneedles1102. It is robust and not only punctures the stratum corneum1300of human skin in vivo, but also protrudes quite deeply into the underlying viable epidermis1302and upper dermis1304with relatively low insertion force of 0.03 N(newton)/MN. The height of said microneedles1102are or about 600 μm with about 500 μm extended into the skin. The interspacing of MN at the base is about 300 μm with the width at the base of about 300 μm. The MN can fabricated by laser based micro-molding technique. For example, an array of 11×11 needles (forming an exemplary needle device800and/or microneedle device1100) with these dimensions takes about five minutes to be machined at ambient temperature using current technology. The baseplate (substrate804or1204) can ideally possess some degree of flexibility to accommodate the irregular topography of the skin402surface due to macroscopic curvature of different body regions to prevent break of MN1102during insertion.

The following are two exemplary methods for screening opioids. In each option, an eighteen MNs1102array, a set of three MNs1102for each six reagents is utilized. The eighteen MN1102array can be configured in an area of 2 cm2with the dimensions indicated above. Smartphone spectrometer (an exemplary detection device1000) can be used to read three color changes for each reagent and calculate the average. The schematic of the MN array is shown inFIG. 11for the application namely the collection of IBL using a microneedle device1100, and processing said microneedle device1100to identify one or more reacted indications1050.

An array of hydrogel material1306MN1102can be used where the polymer swells when absorbing the body fluid in the dermis layer. The MN1102array resides there for specified residence time. The reagents will be applied to MN1102once it is taken out to screen the opioids, such as by way of applying an exemplary reagent container1200of the present disclosure thereto.

An array of hydrogel material1306MN1102can be used and coat it with the respective reagents before penetrating it to the dermis layer and then take out after specified residence time to detect the color change to screen the opioids. The reagents will have sufficient time to mix with the IBL during the process of hydrogel1306swelling. These reagents need to be biocompatible noting that although they tend to stay in the body for short time.

A microneedle device1100comprising an array (multiple groups1104) of microneedles1102can be used as referenced herein, but also a) using hollow microneedles1102(microneedles1102having a channel or lumen1125defined therein, as best seen in the magnified inset shown inFIG. 15), and b) using a suction source/mechanism. Such a microneedle device1100is shown inFIG. 15, whereby microneedle device1100is coupled to, or is formed along with, a suction source/mechanism1500, such as a syringe, vacuum source, and the like. Procedurally, microneedle device1100with hollow microneedles1102can be positioned upon the skin402as shown inFIG. 13, and while microneedles1102are positioned within the skin402, suction from suction source/mechanism1500can cause IBL to flow within lumens1125of microneedles1102, whereby the IBL from said lumens1125can be tested for opioids or chemicals relating thereto with reagents506as referenced herein.

Other methods, using various embodiments of patches100, screening pads500, needle devices800, detection devices1000, and/or microneedle devices1100of the present disclosure, can also be performed consistent with the present disclosure.

While various embodiments of systems, devices, and methods for using and manufacturing the same have been described in considerable detail herein, the embodiments are merely offered as non-limiting examples of the disclosure described herein. It will therefore be understood that various changes and modifications may be made, and equivalents may be substituted for elements thereof, without departing from the scope of the present disclosure. The present disclosure is not intended to be exhaustive or limiting with respect to the content thereof.

Further, in describing representative embodiments, the present disclosure may have presented a method and/or a process as a particular sequence of steps. However, to the extent that the method or process does not rely on the particular order of steps set forth therein, the method or process should not be limited to the particular sequence of steps described, as other sequences of steps may be possible. Therefore, the particular order of the steps disclosed herein should not be construed as limitations of the present disclosure. In addition, disclosure directed to a method and/or process should not be limited to the performance of their steps in the order written. Such sequences may be varied and still remain within the scope of the present disclosure.

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