Patent Publication Number: US-2021169410-A1

Title: Wearable device to screen opioid intoxication

Description:
PRIORITY 
     The present patent application is related to, and claims the priority benefit of, U.S. Provisional Patent Application Ser. No. 62/945,614, filed on Dec. 9, 2019, the contents of which are hereby incorporated by reference in their entirety into this disclosure. 
    
    
     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&#39;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&#39;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 cm 2  in 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 cm 2  size 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&#39;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 cm 2  in 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. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The disclosed embodiments and other features, advantages, and disclosures contained herein, and the matter of attaining them, will become apparent and the present disclosure will be better understood by reference to the following description of various exemplary embodiments of the present disclosure taken in conjunction with the accompanying drawings, wherein: 
         FIG. 1  shows a bottom view of a patch, according to an exemplary embodiment of the present disclosure; 
         FIG. 2  shows a side view of a patch with a release liner positioned thereon, according to an exemplary embodiment of the present disclosure; 
         FIG. 3  shows a side view of a patch with a release liner removed therefrom, according to an exemplary embodiment of the present disclosure; 
         FIG. 4  shows a side view of a patch positioned upon the skin and absorbing sweat therefrom, according to an exemplary embodiment of the present disclosure; 
         FIG. 5  shows a top view of a screening pad, according to an exemplary embodiment of the present disclosure; 
         FIG. 6  shows a side view of a screening pad, according to an exemplary embodiment of the present disclosure; 
         FIG. 7  shows a top view of a screening pad positioned upon a patch, according to an exemplary embodiment of the present disclosure; 
         FIG. 8  shows a side view of a screening pad positioned upon a patch with the blisters of the screening pad using a needle (or microneedle) device, according to an exemplary embodiment of the present disclosure; 
         FIG. 9  shows a perspective view of a needle (or microneedle) device, according to an exemplary embodiment of the present disclosure; 
         FIG. 10  shows a detection device used to detect reacted indications on a patch, according to an exemplary embodiment of the present disclosure; and 
         FIG. 11  shows a schematic of interstitial fluid collection, such as the collection of IBL using a microneedle patch, and processing said microneedle device to identify one or more reacted indications, according to an exemplary embodiment of the present disclosure; 
         FIG. 12  shows a microneedle device positioned relative to a reagent container, according to an exemplary embodiment of the present disclosure; 
         FIG. 13  shows a microneedle device applied to the skin, according to an exemplary embodiment of the present disclosure; 
         FIG. 14  shows a block diagram of various potential components of a system, according to an exemplary embodiment of the present disclosure; and 
         FIG. 15  shows a microneedle device having a plurality of hollow needles, the microneedle device coupled to or formed along with a suction device/mechanism, according to an exemplary embodiment of the present disclosure; and 
         FIG. 16  shows a microneedle device covered by a release liner, according to an exemplary embodiment of the present disclosure. 
     
    
    
     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 
     For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to the embodiments illustrated in the drawings, and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of this disclosure is thereby intended. 
     Systems  50  of the present disclosure comprise two parts/portions—a sweat patch  100 , also referred to herein as a collection part/portion, and a screening pad  500 , also referred to herein as a screening part/portion or a detection part/portion. Screening pad  500  is composed of biomarkers, where it will lay on top of the sweat patch after removal. Screening pad  500  will then be removed from the sweat patch  100  after several seconds for color determination by either the naked eye or using a detection device such as a spectrometer. Sweat patches  100  can be slightly heated to evaporate the residual liquid to increase agent concentrations. 
     An exemplary patch  100  (also referred to herein as a sweat patch or sweat transdermal patch) of the present disclosure is shown in  FIG. 1 . As shown therein, sweat patch  100  comprises a membrane  102 , a sweat-absorbent swatch  104 , and an adhesive layer  106  present upon membrane  102  (an adhesive being applied to membrane  102 ), whereby adhesive  106  facilitates adhesion of swatch  104  to membrane  102  and adhesion of sweat patch  100  to a wearer&#39;s skin. 
     As shown in  FIG. 2 , an exemplary sweat patch  100  of the present disclosure can comprise a release liner  108 , where release liner  108  covers patch  100  during storage and prior to use, so to avoid potential contamination of swatch  104 . Release liner  108  is removed before use, such as shown in  FIG. 3 , revealing swatch  104 . Release liners  108  can have a thickness between 50 to 70 μm, or larger or smaller. 
     Adhesive layer  106 , as noted above, is used so that sweat patch  100  can be firmly attached to the skin of a wearer. Swatch  104 , as noted above, is positioned at the center of the adhesive layer  106 . 
     An exemplary adhesive layer  106  of 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 layer  106  thickness of 100 to 150 μm, or thicker or thinner. 
     Membranes  102  of the present disclosure essentially exist as a backing film on an opposite side of adhesive layer  106  used to adhere to swatch  104 , whereby the configuration of membranes  102  ensure that gases such as oxygen, carbon dioxide, and water vapor can escape into the surrounding external environment. An exemplary membrane  102  of the present disclosure could be 3M, Co Tran TM 9701 Backing Polyurethane Monolayer Film with high moisture vapor transmission rate (MVTR) of 709 g/m 2 /24 hr, or other suitable membrane  102  materials that permit gas escape as noted herein. The total thickness of the membrane  102  can be 200 to 300 μm, or thicker or thinner. In such a configuration, sweat  400  diffuses from the skin  402  into sweat patch  100  where it is absorbed by swatch  104 , such as depicted in  FIG. 4 . 
     Manufacture/production of sweat patch  100  can include three steps, as follows:
         Step 1: Release liner  108  and adhesive layer  106  are put together, and membrane  102  is added on the outside of the adhesive layer  106 .   Step 2: Swatch  104  is placed at the center of the adhesive layer  106  so that swatch  104  can ultimately and directly contact the skin of a wearer of sweat patch  100 . In this configuration, the adhesive layer  106  sticks to the skin all around the absorbing swatch  104 .   Step 3: Cutting edges and corners of sweat patch  100  to desired dimensions to result in a final sweat patch  100 .       

     Other manufacturing/production methods/steps are also contemplated in the present disclosure, such as whereby membrane  102  is cut to size prior to applying swatch  104  thereto, such as whereby adhesive layer  102  before other portions of sweat patch  100 . The end result of any said method or method steps noted above would be a sweat patch  100  configured for use as referenced herein. 
     In use, rapid evaporation of sweat  400  moisture through membrane  102  constituting the relative top layer of sweat patch  100  can reduce the residence time to few hours. 
     A top view of an exemplary screening pad of the present disclosure is shown in  FIG. 5 . As shown therein, screening pad  500  comprises a base layer  502  and a plurality of blisters  504  present thereon. Blisters  504  of the present disclosure are configured to contain/retain one or more reagents  506  therein. In at least one example, each blister  504  would contain one reagent  506 . In other examples, the number of reagents  506  (one, two, three, or more) can vary within each blister  504 . 
     An exemplary screening pad  500  of the present disclosure has a plurality of blisters  504 , such as two, three, four, five, six (as shown in  FIG. 5 ), seven, eight, or more blisters  504 . It is noted that an embodiment of a screening pad  500  of the present disclosure can have only one blister  504  with one or more reagents  506  therein, but such an embodiment would limit the opioid detection to generally one type of opioid. More blisters  504  having reagent(s)  506  therein would permit the detection of several opioids at once, as referenced in further detail herein. 
       FIG. 6  shows a side view of an exemplary screening pad  500  of the present disclosure,  FIG. 7  shows top view of an exemplary screening pad  500  positioned upon a swatch  104  of a patch  100  of the present disclosure, and  FIG. 8  shows a side view of an exemplary screening pad  500  positioned upon a swatch  104  of a patch  100  of the present disclosure, whereby a needle device  800  (namely one or more needles  802 , including an optional substrate  804 ) is used to pierce blisters  504  of screening pad  500  to permit reagents  506  to transfer from blisters  504  into swatch  104  of patch  100 , so to permit reagents  506  to react with chemicals within the sweat within swatch  104  that are indicative of one or more opioids. 
     An exemplary screening pad  500  of the present disclosure can contain blisters  504  that each contain one of the reagents shown in Table 1, provided below. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Screening grid for screening of opioids in human sweat 
               
            
           
           
               
               
            
               
                   
                 COLOR PRODUCING SENSORS (REAGENTS) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Cobalt- 
                 Ferric 
                   
                 Ammonium 
                 Ferric 
                 Marquis 
               
               
                 OPIOID 
                 thiocyanate 1 
                 Chloride 2 
                 Eosin Y 3 
                 Vanadate 4 
                 Sulphate 5 
                 Reagent 6 
               
               
                   
               
               
                 Amphetamine 
                   
                   
                   
                 bluish green 
                   
                   
               
               
                 Meth-amphetamine 
                   
                   
                   
                 dark yellowish green 
               
               
                 Heroin 
                   
                   
                   
                   
                   
                 reddish purple 
               
               
                 Cocaine 
                 greenish blue 
                   
                 pink 
                 orange yellow 
               
               
                 Fentanyl 
                   
                   
                 violet 
                 Dark olive 
               
               
                 Codeine 
                   
                   
                   
                 dark purple 
                   
                 reddish purple 
               
               
                 Oxycodone 
                   
                   
                   
                 greenish yellow 
               
               
                 Morphine 
                   
                 Dark green 
                   
                 dark reddish brown 
                   
                 reddish purple 
               
               
                 Hydrocodone 
                 greenish blue 
               
               
                 Opium 
                   
                   
                   
                 dark brown 
                 brownish purple 
               
               
                 Hydromorphone 
                   
                   
                 pink 
               
               
                   
               
            
           
         
       
     
     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 reagents  506  may 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 in  FIG. 7  and  FIG. 8 , and after patch  100  has been placed on the skin of a wearer for a time sufficient to collect chemicals within sweat in swatch  104  of patch  100 , screening pad  500  is positioned upon patch  104  so that blisters  504  are positioned relatively above swatch  104 . A needle device  800 , such as a needle device  800  comprising six needles, can puncture blisters  504  one or more at a time or all at once so to let the reagents  506  flow on the surface of the collection part (swatch  104 ) to generate different colors depending on the type of the opioid contained within or upon swatch  104 . Needle devices  800  of the present disclosure can comprise one or more needles  802 , such as a plurality of needles  802  effectively coupled to one another via a substrate  804 , as shown in  FIG. 9 . 
     When reagents  506  react with an opioid or a chemical indicative of an opioid present upon or within swatch  104 , a color would appear and indicate a reaction between the reagent  506  and the opioid or the chemical indicative of an opioid (referred to herein as a reacted indication  1050 , as shown in  FIG. 10 ). 
     The reacted indications  1050  can potentially be identified visually, and should it be impractical to do so, a detection device  1000  configured to detect reacted indications  1050  can be used, such as being positioned relative to a patch having potential reacted indications  1050  thereon or therein. Such a detection device  1000  could be a portable spectrometer (such as a smartphone spectrometer) or other device, and the detected colors (whether detected visually or via detection device  1000 ) 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 pad  500  is removed from the collection patch  100 . As an example, one commercially available portable spectrometer (an exemplary detection device  1000 ) 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 device  1000  is suitable for the screening of the agents (reacted indications  1050 ). 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 device  1000 ) 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&#39;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. 11  shows an exemplary microneedle device  1100  of the present disclosure (a type of patch  100 ) incorporating a plurality of microneedles  1102 . As shown in  FIG. 11 , microneedle device  1100  comprises a membrane  102  with an adhesive  106  positioned on at least part of the membrane  102 . Adhesive  106 , is used so to adhere microneedle device  1100  to the skin  402  of a wearer. Adhesive  106  can also be present between membrane  102  and a microneedle substrate  1106  to adhere microneedle substrate  1106  to membrane  102 . So to protect and maintain sterility of microneedle device  1100 , a release layer  108  can be used to cover the side of microneedle device  1100  having the plurality of microneedles, such as shown in  FIG. 16 . When release layer is removed, the plurality of microneedles  1102  are revealed, such as shown in  FIG. 11 . 
     As shown in  FIG. 11 , microneedles  1102  can be arranged upon microneedle substrate  1106  in microneedle groups  1104  as desired, whereby each microneedle group  1104  comprises a plurality of microneedles  1102 . Said groups  1104  of microneedles  1102  can be arranged about microneedle substrate  1106  so to correspond with locations of wells  1202  defined within a corresponding reagent container  1200 , whereby reagents  506  are present within said wells  1202  of reagent container  1200 , such as shown in  FIG. 12 . 
     Microneedle devices  1100  of the present disclosure ideally include the fewest number of microneedles  1102  necessary in order to obtain a suitable sample of interstitial body liquid (IBL) from the skin  402  of the wearer of microneedle device  1100 . For example, and as shown in FIG.  11 , each group  1104  of microneedles  1102  contains three microneedles  1102 , and with six groups  1104  (an exemplary number of groups containing an exemplary number of biocompatible reagents  506 ), that would be eighteen microneedles  1102  in total. Other microneedle devices  1100  may include any desired number of groups  1104  of microneedles  1102 , with any desired number of microneedles  1102  per group  1104 , such as a) six groups  1104  of three microneedles  1102  each (so eighteen total microneedles  1102 ), b) six groups  1104  of six microneedles  1102  each (so thirty-six total microneedles  1102 ), c) four groups  1104  of four microneedles  1102  each (so sixteen total microneedles  1102 ), d) six groups  1104  of twelve microneedles  1102  each (so seventy-two total microneedles  1102 ), etc. As referenced herein, six reagents  506  can be used to identify eleven different types of opioids, such as shown in  FIG. 11 , so exemplary and perhaps preferred microneedle device  1100  embodiments of the present disclosure would comprise six groups  1104  of microneedles  1102 , each group  1104  corresponding ultimately to one reagent  506 . 
     In some embodiments of microneedle devices  1100  of the present disclosure, microneedle devices  1100  comprises a microneedle substrate  1106  (which may the same as or similar to substrate  804 ), which is formed as part of an overall unit with microneedles  1102 , or which is coupled to microneedles  1102  to help complete an embodiment of the microneedle device  1100  that can withstand the desired uses as referenced herein. Substrate  1106 , as referenced herein, can be relatively flexible so to accommodate the irregular topography of the surface of the skin  402  due to macroscopic curvature of different body regions to prevent breakage of microneedles  1102  during insertion. As shown in  FIG. 12 , microneedle substrate  1106  can be adhered to membrane  102  on one side and microneedle substrate  1106  on another, using adhesive  106 , as may be desired. 
       FIG. 13  shows an exemplary microneedle device used to extract IBL from the skin  402  so to at least partially coat the microneedles  1102  with IBL.  FIG. 13  shows several layers of skin  402 , including the stratum corneum  1300 , viable epidermis  1302 , and dermis  1304  containing IBL, from the outside moving inward. When microneedle device  1100  is positioned upon the skin  402  (first the stratum corneum  1300 ), microneedle device  1100  can then be pressed in the direction of skin  402  to cause microneedles  1102  to puncture the stratum corneum  1300 , the viable epidermis  1302 , and the dermis  1304 , in that order, so that when completely positioned upon the skin  402 , microneedle device  1100  contacts the skin  402 , and the relative tips of microneedles  1102  are positioned within the dermis  1304 . This allows IBL to at least partially coat microneedles  1102 , so that when microneedle device  1100  is removed from the skin  402 , IBL remains on said microneedles  1102 . 
     Once microneedles  1102  are at least partially coated with IBL, said microneedles  1102  can be dipped into wells  1202  defined within a corresponding reagent container  1200 , whereby reagents  506  are present within said wells  1202  of reagent container  1200 , such as shown in  FIG. 12 . IBL present on said microneedles  1102  can react with reagents  506  within wells  1202  of reagent container  1200 , causing color-changing reactions to occur should opioids or chemicals relating thereto be present upon said microneedles  1102 . A detection device  1000 , such as shown in  FIG. 10 , could be used to detect the colors within wells  1202  of reagent container  1200 , or said colors could be detected visually should the colors be intense enough to detect visually. 
       FIG. 14  shows a block diagram of an exemplary system  50  of the present disclosure, whereby system  50  comprises two or more of the following: patch  100 , screening pad  500 , needle device  800 , detection device  1000 , microneedle device  1100 , and/or reagent container  1200 . 
     It is noted that metal and silicone microneedles (MNs)  1102  are not favored as the tip may break in the skin which will result in irritation. Silicon MNs  1102  require clean rooms, waste disposal issues, and their FDA approvals can be questionable, although some form of them has been approved. Open MNs  1102  are also not favored due to potential clogging in the opening of MN  1102  by 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 materials  1306 , such as shown in  FIG. 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 material  1306  can be aqueous blends containing 20% w/w Gantrez® AN-139 polymetric microneedles  1102 . It is robust and not only punctures the stratum corneum  1300  of human skin in vivo, but also protrudes quite deeply into the underlying viable epidermis  1302  and upper dermis  1304  with relatively low insertion force of 0.03 N(newton)/MN. The height of said microneedles  1102  are 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 device  800  and/or microneedle device  1100 ) with these dimensions takes about five minutes to be machined at ambient temperature using current technology. The baseplate (substrate  804  or  1204 ) can ideally possess some degree of flexibility to accommodate the irregular topography of the skin  402  surface due to macroscopic curvature of different body regions to prevent break of MN  1102  during insertion. 
     The following are two exemplary methods for screening opioids. In each option, an eighteen MNs  1102  array, a set of three MNs  1102  for each six reagents is utilized. The eighteen MN  1102  array can be configured in an area of 2 cm 2  with the dimensions indicated above. Smartphone spectrometer (an exemplary detection device  1000 ) can be used to read three color changes for each reagent and calculate the average. The schematic of the MN array is shown in  FIG. 11  for the application namely the collection of IBL using a microneedle device  1100 , and processing said microneedle device  1100  to identify one or more reacted indications  1050 . 
     Exemplary Method #1 
     An array of hydrogel material  1306  MN  1102  can be used where the polymer swells when absorbing the body fluid in the dermis layer. The MN  1102  array resides there for specified residence time. The reagents will be applied to MN  1102  once it is taken out to screen the opioids, such as by way of applying an exemplary reagent container  1200  of the present disclosure thereto. 
     Exemplary Method #2 
     An array of hydrogel material  1306  MN  1102  can 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 hydrogel  1306  swelling. These reagents need to be biocompatible noting that although they tend to stay in the body for short time. 
     Exemplary Method #3 
     A microneedle device  1100  comprising an array (multiple groups  1104 ) of microneedles  1102  can be used as referenced herein, but also a) using hollow microneedles  1102  (microneedles  1102  having a channel or lumen  1125  defined therein, as best seen in the magnified inset shown in  FIG. 15 ), and b) using a suction source/mechanism. Such a microneedle device  1100  is shown in  FIG. 15 , whereby microneedle device  1100  is coupled to, or is formed along with, a suction source/mechanism  1500 , such as a syringe, vacuum source, and the like. Procedurally, microneedle device  1100  with hollow microneedles  1102  can be positioned upon the skin  402  as shown in  FIG. 13 , and while microneedles  1102  are positioned within the skin  402 , suction from suction source/mechanism  1500  can cause IBL to flow within lumens  1125  of microneedles  1102 , whereby the IBL from said lumens  1125  can be tested for opioids or chemicals relating thereto with reagents  506  as referenced herein. 
     Other methods, using various embodiments of patches  100 , screening pads  500 , needle devices  800 , detection devices  1000 , and/or microneedle devices  1100  of 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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