EP2198299A2 - Dispositif diagnostic pour identifier la rupture de la membrane pendant la grossesse - Google Patents

Dispositif diagnostic pour identifier la rupture de la membrane pendant la grossesse

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Publication number
EP2198299A2
EP2198299A2 EP08838980A EP08838980A EP2198299A2 EP 2198299 A2 EP2198299 A2 EP 2198299A2 EP 08838980 A EP08838980 A EP 08838980A EP 08838980 A EP08838980 A EP 08838980A EP 2198299 A2 EP2198299 A2 EP 2198299A2
Authority
EP
European Patent Office
Prior art keywords
dry
diagnostic device
reagent
reagents
carrier matrices
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08838980A
Other languages
German (de)
English (en)
Other versions
EP2198299A4 (fr
Inventor
Jacob Mullerad
Hagit Frenkel-Mullerad
Ronen Nahary
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MOMTEC LIFE LTD.
Original Assignee
Jacob Mullerad
Hagit Frenkel-Mullerad
Ronen Nahary
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jacob Mullerad, Hagit Frenkel-Mullerad, Ronen Nahary filed Critical Jacob Mullerad
Publication of EP2198299A2 publication Critical patent/EP2198299A2/fr
Publication of EP2198299A4 publication Critical patent/EP2198299A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/558—Immunoassay; Biospecific binding assay; Materials therefor using diffusion or migration of antigen or antibody
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/70—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving creatine or creatinine
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/36—Gynecology or obstetrics

Definitions

  • the present invention relates to diagnostic methods and devices. More particularly, the present invention relates to diagnostic test and devices for identification of membrane rupture during pregnancy.
  • the baby's head may act as a cork at the opening of the uterus and so, instead of gushing out, the amniotic fluid will only be slowly released. Moreover, amniotic fluid may leak out drop by drop from a tiny opening of the uterus, and the pregnant woman may not feel the first contractions until hours later.
  • women often have difficulty controlling their urination. Because of this, a gradual flow of amniotic fluid from the vagina will not be noticed when the woman is accustomed to having small amounts of urine escape involuntarily from time to time.
  • a dipstick is an assay strip that is made up of chemical reagents bonded to a reagent carrier matrix (pad) on a strip.
  • the strip itself is formed from polymeric materials such as polyethylene, polycarbonate or polystyrene.
  • Each carrier matrix has a different reagent in it.
  • This dipstick is dipped into a urine sample and removed. Upon contact between the reagents imbedded in the matrices and the urine sample, color reactions occur.
  • a dipstick can be designed either as a single pad test strip (for the assay of one analyte) or as a multiple pad test strip (for the assay of several different analytes all together). Dipstick can be used manually or with the appropriate chemistry analyzer. Multiple profile reagent strip for simultaneously or sequentially performing multiple analyses of analyte is disclosed in U.S. Pat. Nos. 4,595,439, 4,526,753, 4,160,008 3,123,443, 3,212,855, 3,814,668, 4,038,485, 3,531 ,254.
  • test devices are available in the market. The following is a partial list of dipstick trademarks CLINISTIX, MULTISTIX, KETOSTIX, N- MULTISTIX, DIASTIX, DEXTROSTIX, AUTION STICKS, CHEMSTRIP.
  • the reagent carrier matrix is usually an absorbent material which allows the liquid sample to move through the matrix. This movement of liquid sample is in response to capillary forces formed in the matrix. During the movement of the liquid through the matrix, it contacts the chemical reagent composition impregnate in the matrix. Thereafter, detectable and measurable color transition occurs. If the dipstick can measure several analytes simultaneously, the color change in each reagent carrier matrix can be correlated to the amount of different analyte in the liquid sample. Manual analysis of the results requires comparison of the color development of the test on the dipstick to a color chart.
  • the reagent carrier matrix material can be of any substance that can incorporate the chemical reagents necessary to carry out the assay of interest.
  • the preferable matrix should be inert with respect to the chemical reagents and should not alter the sample or the test results.
  • Reagent carrier matrices can be made of many materials, some of these materials are: fiber- containing papers such as filter papers, woven and nonwoven fabrics, synthetic or modified natural polymers, sponge materials, cellulose, glass fiber, microporous membranes, and wood.
  • the reagent matrix can also differ in regards to roughness and smoothness together with softness and hardness. The following list of patents describe the use of different matrices: U.S. Pat. Nos. 3,846,247, 3,552,928, 3,802,842, 3,418,083.
  • Sewell DL, et al. discusses, among other things, the cost of using the dipstick as a screening method for urinalysis in a scientific paper published in the American Journal of Clinical Pathology Vol. 83 (6) pages 740-743, 1985. The authors state that using a dipstick procedure "cost approximately $0.76 for reagents".
  • Various devices are described in the literature for the determination of particular urinary analytes with the use of reagent carrier matrices (filter paper, microcapsules, dipstick, etc.). The following list of assay devices utilizing prior art includes dry tablets, dipsticks, or other techniques for the analysis urinary constituents.
  • U.S. patent no. 4,147,514 describe the detection of ketone bodies; U.S. Pat. no.
  • 3,146,070 discloses chemical compositions in dry form on a carrier (dipstick) impregnated with a pH indicator for the determination of pH.
  • Methods, composition, and test device for determining the ionic strength or specific gravity of a test sample such as urine are disclosed in the following U.S. patents: 4,318,709, 5,403,744.
  • Jaffe method is a widely known method for the determination of creatinine. This method involves formation of orange-red color with an alkaline picrate solution.
  • U.S. pat. no. 6,001 ,656 discloses a device for the assay of creatinine in fluid test samples. The improvement in this patent involves the inclusion of one or more selected quinolines in the reagent formulation.
  • Suitable materials for the detection of creatinine include picric acid, 3,5-dinitrobenzoic acid, 3,4- dinitrobenzoic acid, 2,4-dinitrobenzene sulfonic acid, (3,5-dinitrobenz)yl alcohol, (3,5-dinitrobenzo)-nitrile, (3,5-dinitrobenz)amide and N,N-diethyl-(3,5- dinitrobenz)amide.
  • picric acid 3,5-dinitrobenzoic acid, 3,4- dinitrobenzoic acid, 2,4-dinitrobenzene sulfonic acid, (3,5-dinitrobenz)yl alcohol, (3,5-dinitrobenzo)-nitrile, (3,5-dinitrobenz)amide and N,N-diethyl-(3,5- dinitrobenz)amide.
  • Different methods for protein determination in fluid have been reported.
  • protein interacts with substances, principally with dyes such as coomassie brilliant blue, bromphenol blue (tetrabromophenol blue), and eosine as well as metal ions such as copper (II), lead (II) zinc (ll)and silver (I).
  • dyes such as coomassie brilliant blue, bromphenol blue (tetrabromophenol blue), and eosine as well as metal ions such as copper (II), lead (II) zinc (ll)and silver (I).
  • dyes such as coomassie brilliant blue, bromphenol blue (tetrabromophenol blue), and eosine as well as metal ions such as copper (II), lead (II) zinc (ll)and silver (I).
  • metal ions such as copper (II), lead (II) zinc (ll)and silver (I).
  • More protein indicators include those described as well as the merocyanine and nitro or nitroso substituted polyhalogenated phenolsulfonephthaleins disclosed
  • Various dipsticks used for urine testing contain tests for urobilinogen.
  • CHEMSTRIP of Roch diagnostics, and MULTISTIX of Bayer diagnostics are typical examples of such products which include tests for urobilinogen.
  • the classical urobilinogen test developed by Paul Ehrlich in 1901 , employs paradimethylaminobenzaldehyde as a test for which in strongly acid medium produces a brown-orange-red color with Ehrlich's reagent. More background on urobilinogen, Ehrlich reaction and urobilinogen testing is described in, Tietz, Textbook of Clinical Chemistry, W. B. Saunders Company. Examples of U.S.
  • alkaline phosphatase test was introduced by Kay in 1930. Later, a popular assay method for the determination of alkaline phosphatase using p-nitrophenyl phosphate introduced in 1946 by Bessey, Lowry and Brock. This method relays on the fact that after exposure to fluids containing alkaline phosphatase, the colorless p-nitrophenyl phosphate is catalytically hydrolyzed into a yellow colored product p-nitrophenol (and phosphate). Thus, the concentration of the enzyme is determined by following the increased intensity of the yellow color of the reaction's product. Alkaline phosphatase activity is naturally present in raw milk, whereas after pasteurization, the enzyme is denatured.
  • alkaline phosphatase activity is used as an indicator for proper milk pasteurization.
  • One such dry test of alkaline phosphatase activity in milk is PHOSPHATESMO Ml, manufactured by MACHEREY-NAGEL GmbH & Co.
  • hemoglobinuria The presence of hemoglobin in urine is called hemoglobinuria, such a condition can occur as a result of lysis of red blood cells (RBS) in the urinary tract.
  • RBS red blood cells
  • hematuria is used when intact RBS are present in the urine. This condition can occur in bleeding in the renal or genitourinary systems.
  • the most widely used tests for the detection of blood in urine or feces depend on the fact that the heme proteins can act as peroxidases. This reaction requires a hydrogen donor molecule. Typical examples of products that include tests for blood detection are MULTISTIX 10SG, HEMOCCULT II, and AUTION STICKS.
  • United States Patent 4,357,945 issued on Nov. 9, 1982 to Janco for DEVICE FOR TESTING AND RUPTURING AMNIOTIC MEMBRANE, describes a finger-engaging device provided with a pH indicator. Upon exposure to fluids, the indicator changes color if the amniotic membrane has ruptured.
  • United States Patent 5,425,377 issued on Jun. 20, 1995 to Caillouette for PH MEASUREMENT OF BODY FLUID, describes a swabbing structure on a stick, provided with a pH indicator for the measurement of vaginal fluid pH.
  • United States Patent 5,554,504 issued on Sep. 10, 1996 to Rutanen for DIAGNOSTIC METHOD FOR DETECTING THE RUPTURE OF FETAL MEMBRANES describes the detection of insulin-like growth factor binding protein 1 in a vaginal secretion sample.
  • United States Patent 5,281 ,522 issued on Jan. 25, 1994 to Senyei et al. for REAGENTS AND KITS FOR DETERMINATION OF FETAL FIBRONECTIN IN A VAGINAL SAMPLE, describes kits for detection of rupture of membranes by sampling from the vaginal cavity and exposing it to antibodies such as anti-fetal fibronectin antibody and an anti-fibronectin antibody.
  • United States Patent 5,096,830 issued on Mar.
  • United States Patent 5,217,444 issued to Schoenfeld for ABSORBENT TAMPON demonstrates an absorbent material containing a pH indicator material indicating by a color change the acidity or alkalinity of a liquid coming into contact with it. It should be mentioned that tests that measure only the pH of the vaginal secretion for the differentiation of amniotic fluid from urine are not accurate due to the following: 1) The pH of urine may vary from 4.5 to 8 depending on the kidneys homeostatic activity and water intake, and 2) The pH of amniotic fluid ranges from 6.9 to 7.15 in late pregnancy. This overlapping range of pH can lead to false diagnosis that may cause medical complications.
  • a woman or a medical caretaker will be able to observe immediately after the first drop of leaking liquid meets the device, whether it contains amniotic fluid or urine.
  • another object of the present invention is the point of care practice of rapid chemical analysis of biological fluids such as urine, saliva, sweat, cerebrospinal fluid (CSF), milk or fluids from other sources.
  • CSF cerebrospinal fluid
  • a dry diagnostic device for distinguishing between amniotic fluid and urine in female secretion, the dry diagnostic device comprising: a base layer; at least two inert carrier matrices provided on said base layer; dry reagents provided on said at least two inert carrier matrices wherein said dry reagents are capable of forming a chemical reaction with substances in the female secretion so as to visually distinguishing between the amniotic fluid and urine wherein said dry reagents in each of said at least two carrier matrices is capable of reacting with different substance of said substances.
  • said at least two carrier matrices are made of absorbent material selected from a group of materials such as fiber-containing papers, woven and non-woven fabrics, synthetic or modified natural polymers, sponge materials, celiulose, glass fiber, micro-porous membranes, wood, micro porous polymer materials such as styrene based copolymer, latex based, cellulose based or cotton based matrices.
  • said dry reagents are capable of reacting with substances present in the amniotic fluid or in the urine, wherein the substances have concentration markedly higher in one of the amniotic fluid or urine than their concentration in the former.
  • said substances include substances such as creatinine, alkaline phosphatase, total protein, urea, urobilinogen and blood.
  • one of the dry reagents in one of said at least two carrier matrices is capable of reacting with creatinine.
  • said one of the carrier matrices comprises two reagent layers; one of which contains creatinine sensitive dye fixed with a dye fixing agent and a second one containing a buffer capable of keeping said one of the test zones in a relatively high pH value. Furthermore and in accordance with yet another preferred embodiment of the present invention, said one of the carrier matrices comprises a unique layer containing a creatinine sensitive dye, buffer, and dye fixing agent.
  • said creatinine sensitive dye is selected from a group of dinitro derivatives such as 3'5'-dinitrobenzoic acid, 2'4'-dinitrobenzoic acid,
  • said dye fixing agent selected from polymerized quaternary ammonium cations (quats) such as polydiallyldimethylammoniumchloride, polymonoallyltrimethylammoniumchloride, polytrimethylaminoethylmethacrylatechloride, polyvinylbenzyltrimethylammoniumchlohde, polyvinylm ⁇ thylpyridine- chloride.
  • quats polymerized quaternary ammonium cations
  • said creatinine sensitive dye and said dye fixing agent are buffered so as to keep a stable pH in a range of about 9 to 13.5.
  • a buffer is selected from a group of sodium metasilicate, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydroxide-potassium chloride, potassium carbonate, glycine - sodium hydroxide, and sodium borate.
  • one of the dry reagents in one of the carrier matrices is capable of reacting with total protein.
  • said one of the dry reagents is a dye selected from a group of 3',3",5',5"-Tetrabromophenolsulfonephthalein, coomassie brilliant blue, Fast Green, Light Green, Pyrogallolsulfonephthalein (pyrogallol red),
  • the device further comprising a buffer such as potassium citrate, potassium chloride, potassium sulfate, potassium iodate or potassium phosphate.
  • a buffer such as potassium citrate, potassium chloride, potassium sulfate, potassium iodate or potassium phosphate.
  • the device further comprising metal ion selected from Copper, lead, Zink, Silver.
  • metal ion selected from Copper, lead, Zink, Silver.
  • one of the dry reagents in one of the carrier matrices is capable of reacting with alkaline phosphatase.
  • said one of the dry reagents Alkaline phosphates' substrate selected from p-nitrophenyl phosphate, indoxyl phosphate, 4- methylumbelliferyl phosphate and alpha-naphthyl-phosphate
  • one of said dry reagents is a pH sensitive reagent.
  • said dry reagents cannot exit the carrier matrices.
  • said at least two carrier matrices are covered by a protective layer.
  • said protective layer is transparent.
  • said protective layer can be made of a thin "one-way structure" membrane permeable to liquids flowing to said at least two carrier matrices and prevents flow of reagents outwardly from the device.
  • a sticky backing layer is provided beneath said base layer.
  • said sticky backing layer is adjacently provided with an outer protective layer.
  • said at least two carrier reagent matrices are organized in substantially parallel lines.
  • said at least two reagent carrier matrices are organized in concentric lines.
  • said at least two reagent carrier matrices are surrounded by adhesive material so as to allow adhering the diagnostic device when said at least two test zones are opposite a vaginal canal of a female animal.
  • Figure 1 illustrates a cross sectional view of the diagnostic device in accordance with a preferred embodiment of the present invention.
  • FIGS 2-5 illustrate diagnostic devices for adhering onto women panties in accordance with preferred embodiments of the present invention.
  • FIGS 6a-d illustrate diagnostic pads in accordance with preferred embodiments of the present invention.
  • Figure 7 illustrates a veterinary diagnostic pad in accordance with another preferred embodiment of the present invention.
  • compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • the present invention provides unique and novel devices to distinguish amniotic fluids from urine in a simple and fast manner so as to allow a pregnant woman to know her pregnancy condition.
  • a device that resembles an 'adhesive plaster' which is a disposable strip containing sensitive chemical indicators, is used during last months of pregnancy.
  • the strip is relatively small in its dimensions and comprises at least two layers; an adhesive backing and an absorbing material containing the indicators.
  • the woman using the device simply adheres it to her panties with the test zones facing up towards the body. In case the woman uses panty liner, she can place the strip on top of it.
  • the rapid chemical reactions in the test zones of the device cause a distinct color change in the case of amniotic fluid leakage and a clearly different color change when urine has contacted the test zones.
  • the device of the present invention acts as a diagnostic tool to allow the customer to detect whether the secretion contains amniotic fluid or only urine, according to a known color index supplied with the device.
  • a device resembling a pad containing sensitive indicators is used independently of contacting the woman body.
  • This device can be used by pressing it against wet underwear or a wet panty liner after leakage of fluids has been noticed. This will cause the reagents in the reagent carrier matrices to come in contact with the body fluids and almost immediately after the leaking liquid meets the diagnostic device, chemical reactions occur in the reagent carrier matrices and cause a color change. Again, the woman (or caregiver) using this device will be able to see whether the liquid contains amniotic fluid or only urine, according to a known color index supplied with the device.
  • a device that resembles a panty-liner is containing the sensitive indicators that allow the distinction between amniotic fluid and urine.
  • the pregnant woman will attach this product to her underwear and will get on with her day.
  • the indicator reagent areas should be positioned directly opposite the vagina. This way, the sensitive panty-liner will be in a close contact with the woman body fluids.
  • the sample can be transferred to a suitable container for storage.
  • immediate processing of the sample can be performed. If used, the sample is placed directly on the reagent carrier matrices of the device and testing is performed within minutes of sample collection.
  • a veterinary device is provided.
  • the device containing the sensitive reagents will be directly attached to a non-human female vagina opening. This may be achieved simply by a bandage design in which the adhesive zone is around or on the sides of the reagent carrier matrices test zone. Thus, a close contact with the animal body fluids will be achieved.
  • Using a device without direct contact with the animal body can also be achieved by obtaining a fluid sample with a swab having a fibrous tip or by suction or lavage device, and applying it to the indicators areas on the device.
  • the determination whether amniotic fluid or urine is present in the woman's secretion relies upon several non-enzymatic and non-immunological separated reactions that can be determined as associated with either urine or amniotic fluid by their distinguished color. In most of the tests available today for the identification of the cause of wetness during pregnancy, concentration difference of only one analyte in urine or amniotic fluid is measured. In the present invention, the existence of at least two of the following substances: protein, creatinine, urea, urobilinogen, blood, and alkaline phosphatase are identified as well as pH.
  • diagnostic device that comprises reagent carrier matrices provided with chemical indicators according to the present invention is capable of detecting at least two of the following substances: protein, creatinine, urobilinogen, urea, blood, and alkaline phosphatase as well as pH value.
  • the method of the present invention is based on the following facts 1)
  • the concentration of total protein in amniotic fluid is normally substantially 15 times higher than its concentration in urine
  • the concentration of creatinine and urobilinogen in urine is normally about 10 times more than their concentration in amniotic fluid
  • the concentration of urea in urine is normally more than 2 times its concentration in amniotic fluid
  • the concentration of alkaline phosphatase in amniotic fluid is normally more than 7 times higher than the concentration in urine
  • 5) During rupture of the fetal membranes, the amniotic fluid coming out may contain blood, which is in contrast to urine of healthy woman.
  • the pad allows the diagnostic of fetal membrane rupture with an extremely high accuracy. Other substances with similar concentration differences may also be detected.
  • the present invention is further illustrated by the following examples of devices provided with sensitive indicators for the detection and distinction of urine or amniotic fluid leakage.
  • Figure 1 illustrating a diagnostic device in accordance with a preferred embodiment of the present invention, in an upper view and cross sectional view, respectively.
  • a device 10 has at least two, and preferably several reagent carrier matrices 12.
  • Figure 1 illustrates a device that is adapted to be attached to the woman's body and therefore covered with a first layer 14 of soft and comfortable material that does not irritate skin upon contact so it can be worn in a woman panty.
  • First layer 14 prevents direct contact between reagents that are provided in within device 10 and the adjacent skin.
  • first layer 14 may be transparent so as to allow easy visual distinction of the colors formed in layers beneath it.
  • Device 10 is further comprises with a supportive base layer 16 that can support reagent carrier matrices 12 capable of carrying out the assays of interest.
  • Reagent carrier matrices 12 are preferably an absorbent material that allows the liquid sample to move through the matrix.
  • Reagent carrier matrices 12 should be inert with respect to the chemical reagents and should not alter the sample or the test results.
  • reagent carrier matrices 12 can be made of many materials, for example: fiber-containing papers such as filter papers, woven and nonwoven fabrics, synthetic or modified natural polymers, sponge materials, cellulose, glass fiber, micro-porous membranes, and wood. Additional materials can be micro porous polymer materials such as styrene based copolymer, latex based, cellulose based or cotton based matrices.
  • the reagent carrier matrices can also be different in characteristics such as roughness, smoothness, softness, and hardness. It should be noted that in the manufacturing process, the reagent carrier matrices can be made from several layers, some of which carry different reagents in different areas of the test zone. Any combination of the supportive base layer and additional matrices carrying the indicators are covered by the scope of the present invention and by no means limit the scope of the present invention.
  • Reagent carrier matrices 12 are organized preferably in groups wherein each group is provided with indicators capable of indicating one of the substances that were listed herein before. Following are examples of chemical reagents and methods of preparing the test zone for each:
  • Creatinine concentration in urine is normally about 10 times higher than its concentration in amniotic fluid. Creatinine dry test is made in two optional ways:
  • Two reagent layers system that contains fixed creatinine sensitive dye that is placed on one matrix and a buffer that keeps the system in a relatively high pH value is placed on a second matrix.
  • the creatinine sensitive dye can be one of dinitro derivatives such as: 3'5'-dinitrobenzoic acid, 2'4'-dinitrobenzoic acid, 3'5'- dinitrobenzotrifluoride, 3'5'-dinitrobenzamide, 3'5'-dinitrobenzoyl- phenyl glycine, S. ⁇ -dinitrohydroxyphenylpropionic acid.
  • the sensitive dye fixing agent preferably includes polymerized quaternary ammonium cations (quats) such as: polydiallyldimethylammoniumchloride (Poly DADMAC), polymonoallyltrimethylammoniumchloride, polytrimethylaminoethylmethacrylatechloride, polyvinylbenzyltrimethylammoniumchloride, polyvinylm ⁇ thylpyridine- chloride.
  • quats polymerized quaternary ammonium cations
  • the buffer should be a strong base capable of keeping a stable pH in a range of about 9 to 13.5.
  • examples for such buffers are sodium metasilicate, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydroxide-potassium chloride, potassium carbonate, glycine - sodium hydroxide, and sodium borate.
  • non volatile solid reagents are added to the sensitive dye in order to improve the reaction.
  • Creatinine test indicator consisting of two reagent carrier matrices was mounted on the diagnostic device base layer.
  • the first matrix can be Whatman filter paper or napkin paper
  • the first matrix was impregnated with creatinine sensitive dye, 3'5'-dinitrobenzoic acid (dBA), and poly DADMAC (optional) as a fixing agent that were dissolved in water.
  • the dBA stock solution was mixed in sodium carbonate buffer.
  • a second reagent matrix was impregnated with Sodium Metasilicate buffer. After both reagent matrices were dry, the first reagent matrix was laid on the second reagent matrix that was impregnated with Sodium Metasilicate buffer. Both dry reagent matrices were tightened on the base layer of the device.
  • Two reagent absorbent matrices were impregnated each in one solution, dried and were tightened on a base layer of the device.
  • the first reagent matrix was impregnated with solution 1 that consist of dBA (stock solution was dissolved in Sodium Hydroxide) as a creatinine sensitive dye, non volatile solid reagent and Poly DADMAC (optional) as a fixing agent.
  • the second reagent matrix was impregnated with solution 2 that include Sodium Hydroxide. Both reagent matrices were dried. Dry reagent matrix with solution 1 was placed above dry reagent matrix with solution 2 and both of them were tighten on the base layer of the device.
  • one reagent layers system has the same rational as the “two reagent layers system” but contains all the chemicals on one reagent carrier matrix. In both cases, the goal is differentiation between urine and amniotic fluid using creatinine concentration.
  • Creatinine test device was prepared from the same absorbent and support carriers as in the two reagent layers system.
  • the reagent carrier matrix consists of a creatinine sensitive dye, non volatile solid reagent, a fixing agent (optional) and a buffer that was dried and mounted on the carrier matrix.
  • the reagents were dried all together and were ready for urine or amniotic fluid sample test.
  • Styrene Acrylic acid Sodium Metasilicate and a non volatile solid reagent was prepared.
  • a thin layer of the emulsion was spread on a latex based matrix, and dried. Dry matrices were tightening on the support base layer polymer of the device.
  • the concentration of total protein in amniotic fluid is normally about 15 times more than its concentration in urine.
  • a group of dyes and metal ions such as: 3',3",5',5"- Tetrabromophenolsulfonephthalein, coomassie brilliant blue, Fast Green, Light Green, Pyrogallolsulfonephthalein (pyrogallol red),
  • Pyrocatecholsulfonphthalein (Pyrocatechol Violet), 3',3"-Dibromo-5',5"- dichlorophenolsulfonephthalein, Fuchsin acid, 2,4-Dinitro-1-naphthol (martius yellow), Copper, lead, Zink, Silver, phloxine B, congo red, ethyl orange and methyl orange can be used.
  • the reagent carrier matrix of the total protein test device is an absorbent carrier that can be one of the matrices already mentioned, for example micro porous polymer material such as styrene based copolymer, latex based, cellulose based or cotton based matrices.
  • the reagent carrier matrix can be polymerized urethane-based compound (as described in U.S. Patent no. 5,124,266) incorporating an indicator reagent compound capable of interacting with proteins to produce a visually detectable response.
  • the test solution may include a low pH potassium salt based buffer such as potassium citrate, potassium chloride, potassium sulfate, potassium iodate or potassium phosphate.
  • the total protein solution test comprises a combination of two solutions: the dye reagent solution and the buffer.
  • the dye solution 3',3",5',S" Tetrabromophenolsulfonephthalein was used and was dissolved in a weak organic acid such as citric acid.
  • the buffer potassium citrate, was tittered with the same weak organic acid to a low pH value of around 3.5.
  • the dye solution was then diluted with the buffer solution in a wide ratio scale. After the dilution, a very thin layer of the resulting solution was spread on a reagent carrier matrix and dried. While a urine and amniotic fluid comes in contact with the reagents imbedded in the device, a distinct color reaction can differentiate between them.
  • pH test zone preparation As mentioned herein before, the preparation is placed on an absorbent reagent carrier matrix of any type.
  • the reagent matrix is impregnated with a pH indicator for the measurement of fluid pH.
  • the urine pH may vary from 4.5 to 8 while the amniotic fluid pH ranges from 6.9 to 7.15 in late pregnancy. This pH range can be check with one indicator or two different pH indicators; a low pH indicator and a middle pH indicator.
  • Methyl yellow, Methyl orange, Methyl red, Bromofhenol Blue, Tetrabromphenol blue or Bromcresol green can be used.
  • Cresol Red, Nitrizine, Bromthymol blue, Neutral red, Rosolic acid, ⁇ -Naphtholphthalein or phenol red can be used.
  • Cresol Red was dissolved in water and was impregnated on 3M paper (blotting paper ra- reeve angel ® ). After the material is fully impregnated, the matrix is dried.
  • Alkaline phosphatase activity in amniotic fluid is much higher then in normal urine. Therefore, this activity can be used to differentiate and identify amniotic fluid from urine in vaginal secretion by using a dry test by which direct contact with such secretions is resulted by a distinct and different color formation for the secretions. When drop of vaginal secretion meets the dry matrix reaction zone, a distinct color change will identify the secretion content and indicate whether it contains amniotic fluid or urine.
  • Alkaline phosphatase contained dry buffered solution of Alkaline phosphates' substrate such as p-nitrophenyl phosphate, indoxyl phosphate, 4- methylumbeHiferyl phosphate and alpha-naphthyl-phosphate and may also contain sensitive indicators such as bromocresol green.
  • Figures 2 - 5 illustrating diagnostic device for adhering onto women panties in accordance with preferred embodiments of the present invention.
  • All diagnostic devices shown in Figures 2-5 comprises a base layer 22 that includes layers similar to the layers that are shown in Figure 1 that allows the device to be used in the panty of a women, adhered directly to the woman's panty or adhered onto a panty shield while the layer with the test zone, which will be explained herein after, is directly positioned beneath the vaginal canal of the woman.
  • the protective layer is removed from the drawings.
  • Figure 2 illustrates a diagnostic device 20 having test zones that are divided into five reagent carrier matrices
  • each of the reagent carrier matrices is provided with diagnostic indicator that is capable of identifying a specific substance as elaborated herein before - e.g. creatinine test, protein test, alkaline phospatase test ect.
  • Figure 3 illustrates a diagnostic device 40 having three distinct test zones 12. Each zone is divided into five different reagent carrier matrices wherein each one is provided with different indicator capable of distinguishing between urine and amniotic fluid.
  • Figure 4 illustrates a diagnostic device 50 similar to device 20 wherein different indicators are in 4 reagent carrier matrices 54-58.
  • Figure 5 illustrates a diagnostic device 60 having test zones 12, each having a reagent carrier matrices 62-68 provided with different indicators so as to distinguish between urine and amniotic fluid.
  • the device may contain two or more reagent carrier matrices in lines, circles or any other formation so at least two indicators are changed in their color so as to be able to clearly distinguish between the urine and the amniotic fluid.
  • Figures 6a-d illustrating diagnostic pads in accordance with preferred embodiments of the present invention.
  • a pad can be used in a way that it is pressed against a regular wet panty shield or wet panties, as an example, so as to prevent contact between the skin and the pad.
  • the pad is built similarly to the adhered one, however, there is no adherence layer on the pad.
  • Figure 6a illustrates a pad 70 having a base layer 72 onto which different reagent carrier matrices 74-79 provided with different indicators. Each reagent carrier matrices is capable of identifying a certain substance as explained herein before.
  • Figure 6b illustrates a pad with base layer 82 onto which reagent carrier matrices 94-98 or 104-106 are arranged in different arrangement.
  • Figures 6c and 6d illustrate additional embodiments of pads 90 and 100 provided with less reagent carrier matrices zones, respectively.
  • Veterinary device 120 is basically similar to the diagnostic device used for humans however, the figure shows an upper view of pad 120 in which the adhesive zone 122 is around the test zones 124.

Abstract

L'invention concerne un dispositif de diagnostic destiné à distinguer le liquide amniotique et l'urine dans la sécrétion féminine. Le dispositif peut être utilisé en tant que serviette hygiénique ou peut être collé à une serviette hygiénique ou peut être utilisé simplement sous la forme d'un tampon qui est appuyé contre un substrat imprégné de sécrétion féminine.
EP08838980A 2007-10-18 2008-10-22 Dispositif diagnostic pour identifier la rupture de la membrane pendant la grossesse Withdrawn EP2198299A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US99932707P 2007-10-18 2007-10-18
PCT/IL2008/001371 WO2009050711A2 (fr) 2007-10-18 2008-10-22 Dispositif diagnostic pour identifier la rupture de la membrane pendant la grossesse

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EP2198299A2 true EP2198299A2 (fr) 2010-06-23
EP2198299A4 EP2198299A4 (fr) 2010-09-29

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EP (1) EP2198299A4 (fr)
JP (1) JP2011501810A (fr)
KR (1) KR20100098606A (fr)
AU (1) AU2008313294A1 (fr)
BR (1) BRPI0818779A2 (fr)
CA (1) CA2703254A1 (fr)
MX (1) MX2010004156A (fr)
WO (1) WO2009050711A2 (fr)

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IL214096A (en) * 2011-07-14 2016-02-29 Gideon Mor A system for detecting meconium in amniotic fluid
JP5542888B2 (ja) * 2011-10-17 2014-07-09 アークレイ株式会社 蛋白質濃度評価方法、分析用具、及び分析装置
JP6697394B2 (ja) * 2014-04-10 2020-05-20 イェール ユニバーシティーＹａｌｅ Ｕｎｉｖｅｒｓｉｔｙ 異常折り畳みタンパク質を検出するための方法および組成物
CN109613177B (zh) 2014-07-01 2021-08-20 科蒙森斯公司 用于鉴定羊水的诊断组合物
CN108542596A (zh) * 2018-04-03 2018-09-18 顾勍 胎膜早破检测护垫

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US20050131287A1 (en) * 2003-12-16 2005-06-16 Kimberly-Clark Worldwide, Inc. Detection of premature rupture of the amniotic membrane

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Also Published As

Publication number Publication date
EP2198299A4 (fr) 2010-09-29
JP2011501810A (ja) 2011-01-13
CA2703254A1 (fr) 2009-04-23
WO2009050711A2 (fr) 2009-04-23
BRPI0818779A2 (pt) 2015-04-14
MX2010004156A (es) 2011-04-13
WO2009050711A3 (fr) 2010-03-11
AU2008313294A1 (en) 2009-04-23
KR20100098606A (ko) 2010-09-08

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