WO2009035847A1

WO2009035847A1 - Apparatus and methods for encapsulation of in vitro diagnostic reagents

Info

Publication number: WO2009035847A1
Application number: PCT/US2008/074359
Authority: WO
Inventors: Gary W. Boys
Original assignee: Siemens Heathcare Diagnostics Inc.
Priority date: 2007-09-14
Filing date: 2008-08-27
Publication date: 2009-03-19

Abstract

Methods, systems and apparatus for containing a reagent for use in an in vitro diagnostic test are provided. A capsule is adapted to retain a reagent. The capsule may be deposited in a test sample and the reagent released to react with the test sample in an in vitro diagnostic test. The results of the test may be automatically analyzed. Numerous other aspects are provided.

Description

APPARATUS AND METHODS FOR ENCAPSULATION OF IN VITRO DIAGNOSTIC REAGENTS

FIELD OF THE INVENTION

[0001] The present invention relates to diagnostic reagents, and more specifically to methods and apparatus for encapsulating in vitro diagnostic reagents.

BACKGROUND

[0002] Different tests may be performed on a sample for diagnostic purposes. In the medical field, the sample may include, for example, blood, urine, DNA, feces, tissue, etc. In other fields, such as bio-terrorism, samples may include, for example, air, water, soil, etc. Frequently, as part of the test, the sample may be mixed with a reagent to produce an outcome. In an in vitro setting, the mixing may take place outside of a patient's body. For example, in a home pregnancy test, a urine sample may be applied to a test strip. The test strip may have a detection substance (reagent) attached to it. The reagent may react with chemicals/hormones in the urine sample to indicate to the tester whether there is a pregnancy or not. In this example, the reagent is in the form of a solid attached to the test strip. However, in other instances, the reagent may be a liquid.

[0003] Liquid reagents may typically be packaged in plastic or glass vials or bottles. However, plastic/glass vials/bottles may result in spillage of the reagent, a lack of uniformity in the amount of reagent used with the sample, excess time used to accurately measure out a precise amount of reagent, etc. Liquid reagents have also been packaged in uniquely designed containers. However, variable amounts of the reagents maybe trapped in corners and/or seams of traditional packages, thus preventing the entire measured reagent from being consistently used in the reaction. Another problem with traditional containers is that it may be difficult to keep reagents in a homogeneous suspension when the container has seams and corners . Accordingly a need exists for an apparatus that allows uniform quantities of reagents to be applied, prevents spillage, reduces time associated with measuring out reagent quantities, and allows reagents to remain in homogenous suspensions.

SUMMARY OF THE INVENTION

[0004] In an aspect of the present invention, a container for encapsulating an in vitro (e.g., in a controlled environment outside a living organism) diagnostic reagent is provided. The container is comprised of a capsule for retaining an in vitro diagnostic reagent, wherein the reagent is reacted with a test sample in an in vitro diagnostic test. [0005] In another aspect of the present invention, a method for applying an encapsulated in vitro diagnostic reagent is provided. The method comprises placing an in vitro diagnostic reagent, contained in a capsule, into a test sample; releasing the reagent into the test sample; reacting the reagent with the test sample; and analyzing the results of the reaction between the reagent and the test sample.

[0006] In yet another aspect of the present invention, a system is provided for administering an in vitro diagnostic reagent. The system comprises a capsule, wherein the capsule contains an in vitro diagnostic reagent for use in an in vitro diagnostic test; a receptacle, adapted to store a test sample to be tested by the reagent, wherein the capsule and test sample are mixed such that a reaction may occur between the reagent and the test sample; and an analyzer, adapted to determine the outcome of the reaction.

[0007] Other features and aspects of the present invention will become more fully apparent from the following detailed description, the appended claims, and the accompanying drawings .

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 is a perspective view of a prior art container storing a reagent.

[0009] FIG. 2A is a perspective view of an example spherical shaped capsule according to some embodiments of the present invention.

[0010] FIG. 2B is a perspective view of an example ellipsoidal (e.g., prolate spheroid) shaped capsule according to some embodiments of the present invention. [0011] FIG. 2C is a perspective view of an example oblate spheroid-shaped capsule according to some embodiments of the present invention.

[0012] FIGs. 3A through 3D are perspective views of an example in vitro diagnostic test system in accordance with some embodiments of the present invention.

[0013] FIG. 4 is a flow chart depicting an example method in accordance with some embodiments of the present invention.

DETAILED DESCRIPTION

[0014] In the manufacture of pharmaceuticals, encapsulation refers to a range of techniques used to enclose medicines in a relatively stable, non-toxic, digestible shell, allowing the medication to be taken orally. Two main types of capsules are hard-shelled capsules, which are normally used for dry, powdered medications, and soft-shelled capsules, primarily used for oil based medicines and vitamins and for medicinal active ingredients that are dissolved or suspended in oil. Both of these classes of capsule are made both from gelatine and from plant-based gelling substances like carrageenans and modified forms of starch and cellulose. These materials selected to be non-toxic, ingestible and to contain medication that is to be delivered in vivo to a patient.

[0015] The present invention provides apparatus and methods for the encapsulation of in vitro reagents. While encapsulation processes have been used for many years to encapsulate medications (oral and suppository in form) , as well as other materials such as bath oils, paint balls and fertilizers, the inventors of the present invention have determined that the use of capsules provides a reliable vehicle to deliver a precise quantity of in vitro reagents that is less susceptible to breakage, may eliminate the risk of cross-contaminating the unused supply of reagent (s) due to the single-use nature of the capsule, facilitates delivery of accurate pre-set amounts of reagent, reduces package waste by, for example, utilizing a neutral material as the encapsulation material that would dissolve within the sample/reagent mix, maximizes auto analyzer reagent handling speed by, for example, incorporating tubes that would propel a capsule from its parental container to the reaction site via pressurized air, and is less costly than traditional containers. In particular, the curved shape and smooth interior of a capsule, as will be described below, also prevents the in vitro diagnostic reagents from becoming trapped in corners or seams of the packaging, as is typical with conventional reagent containers. Additionally, a spherical or capsule shape, versus a container with seams and corners, is better able to keep the reagents comprising a homogeneous mixture of multiple compounds in a homogeneous suspension. This may be the case because it may be difficult, due to the angular design, to get enough energy into these areas retaining the trapped particulates or precipitates from reagents, to guarantee 100% re-suspension or dissolution of the reactive agents. [0016] In some embodiments, the present invention provides for the in vitro reagents to be encapsulated in a material, for example, a gelatin or plastic shell, which may be unreactive or inert relative to both the reagent in the capsule as well as the sample being tested. In other words, the material used to form the shell used to contain the in vitro reagent may be selected so as to have no effect on the diagnostic reaction. Further, the material selected is not required to be ingestible or non-toxic since the reaction is in vitro. In some embodiments, the encapsulation shell may be made from a material that dissolves or otherwise breaks down in the sample being tested. In such embodiments, the quantity and/or concentration of the in vitro reagent and/or the sample may be selected such that the dissolution or break down of the encapsulation material does not alter the outcome of the diagnostic reaction. In some embodiments, the encapsulation material may include or be made from a form of the in vitro reagent or a component of the in vitro reagent and/or the sample solution.

[0017] FIG. 1 is a perspective view depicting an example prior art reagent capsule 100. As described above, capsules or vials may be used to transfer medications and other materials including reagents. The prior art capsule 100 shown herein is generally relatively flat and rectangular or bottle shaped. Reagent particles 102 to be transferred are stored in the capsule 100. At one end of the capsule 100, a twist-off cap 104 is formed such that upon removing the cap 104 an opening 106 is created in the capsule 100 through which the reagent 102 may be dispensed. At the other end of the capsule 100, a plug 108 may be provided that allows the capsule 100 to be filled with reagent 102. Frequently the prior art reagent capsules 100 are formed by stamping a container shape into two sheets of plastic (or other suitable material) that fuses the edges of the shape together to form the sealed enclosure. A spacer (e.g., the plug 108) may be used to create a volume between the sheets for the reagent 102. This process however creates seams at the edges of the capsule 100. [0018] A current problem with the prior art capsule 100 is that a variable amount of the particles of the reagent 102 may be trapped in the corners and seams along the edges of the capsule 100. Even when extra reagent is added to such capsules 100 to compensate for the amount expected to be trapped in the seams, depending upon how hard the capsule 100 is squeezed and kneaded, the quantity of reagent particles 102 that remain in the capsule may prevent a desired amount of reagent (e.g., either too much or too little) from being added to the sample for the diagnostic reaction. The actual variable quantity that is extracted from the prior art capsule 100 may therefore interfere with reactions requiring precise measurements. In some prior art capsules 100 with some types of reagent solutions that include components with differently sized particles, certain sized particles in the reagent may become trapped in the seams of the capsule 100 and this may result in the reagent not remaining a homogenous solution which may further interfere with the intended diagnostic reaction.

[0019] Turning to FIGs. 2A through 2C, perspective views of example embodiments of the present invention are depicted. In the present invention, a sphere-shaped capsule 200A, an ellipsoidal (e.g., prolate spheroid) shaped capsule 200B, and/or an oblate spheroid-shaped capsule 200C may be used to store, transfer and/or deliver an in vitro diagnostic reagent 202. In some embodiments, the outer portion of the capsule 200A, 200B, 200C may be formed in other shapes (e.g., geometric, scalene ellipsoid, etc. ) that have relatively smooth internal surfaces and generally do not have regions that can trap particles. In some embodiments that employ a dissolving encapsulation material, any practicable shape may be used to contain the diagnostic reagent 202. An interior surface 204 of the capsule 200A, 200B, 200C may be in contact with the reagent 202. As such, the capsule interior surface 204 may also be smoothly (e.g., spherically) shaped. Such a smoothly shaped capsule interior surface 204 avoids having corners and seams, thereby preventing reagent particles 202 from being trapped therein, as is often the case with traditional packaging. Such a interior surface 204 also avoids the problem of trapping particular sized particles and interfering with the reagent remaining a homogenous suspension.

[0020] The various shaped capsules 200A, 200B, 200C may be suitable for different applications. For example, the oblate spheroid-shaped capsule 200C may require less force to burst or rupture when mixing the reagent with the sample. The sphere-shaped capsule 200A may be more suitable for use in an automated testing device that dispenses the capsule 200A via an automated tool. In some embodiments, the encapsulation material may have a thickness in the range of approximately 0.005 inches to approximately 0.010 inches. Depending on the application and other factors, the pressure required to rupture the encapsulation material may be, for example, in the range of approximately 3.0 PSI to approximately 10.0 PSI. Other values may be used.

[0021] In some embodiments the capsules 200A, 200B, 200C may include perforations or tear lines 206 that facilitate easily rupturing or bursting the capsules 200A, 200B, 200C to release the reagent 202. Such tear lines 206 may be embodied as one or more lines of thinned encapsulation material that extend along the surface of the capsules 200A, 200B, 200C. Even in embodiments that employ a dissolving encapsulation material, tear lines 206 may be employed to expedite the release of the reagent 202. Thus, by providing an area of the encapsulation material that dissolves relatively quickly since the area is thinned relative to the rest of the encapsulation material, the tear lines 206 may aid in releasing the reagent 202.

[0022] Turning to FIGs. 3A through 3D, an example in vitro diagnostic test system 300 is depicted. A receptacle 302 may contain a test sample 304. The receptacle 302 may be of any practicable shape to hold the test sample 304. In some embodiments for example, a conical flask shaped receptacle 302 may be used to allow the test sample 304 to be mixed vigorously without spillage. The test sample 304 may contain or include, for example, particles of interest 306 (e.g., a particular enzyme, a toxin, etc.) and a medium 308 (e.g., blood, urine, etc. ) within which the particles of interest 306 may be carried. The test samples may be obtained from, for example, bodily fluid or dissolved in the appropriate media if a solid source {i.e., stool). The samples may be, for example, from human or animal sources. To determine whether the test sample 304 contains the particles of interest 306, an in vitro diagnostic test capsule 310 containing diagnostic reagent 312 may be added to the test sample 304 as depicted in FIG. 3B. In some embodiments, the capsule 310 may be added via an automated dispenser 314 of the test system 300. In some embodiments, an automated agitator 316 or transducer may be provided to impart, for example, vibrational or heat energy to rupture or melt the capsule 310. Further, in some embodiments, one or more sensors 318 may be provided to detect and/or determine the outcome of the in vitro diagnostic test reaction in the receptacle 302. In some embodiments, the diagnostic test system 300 may be operated by a controller 320 coupled to the various components of the system 300. For example, the controller 320 may include a processor operative to execute a program adapted to implement various methods of the present invention. In some embodiments, for example, the controller 320 may function as an analyzer which is operative to deposit the capsule 310 in the test sample 304 via the dispenser 314; activate the agitator 316 to rupture the capsule 310; read signals from the sensor (s) 318 to acquire result data; and determine a reaction outcome based on the result data.

[0023] As indicated above, the in vitro diagnostic reagent 312 may be transported and delivered via a capsule 310 having a smoothly shaped interior as described above with respect to FIGs 2A through 2C. As also described above, the spherically shaped interior has no corners or seams to trap reagent particles. Thus, a precise quantity of in vitro reagent 312 may be consistently reacted with the test sample 304. The capsule 310 may be made of a material that dissolves, thereby releasing the reagent 312 into the test sample 304. The dissolvable material may include, for example, gelatin or other materials. Additionally, or alternatively, the capsule may be made from any material that does not react with the reagent 312 or the test sample 304. In some embodiments, the encapsulation material may be reactive with the test sample 304 but in a manner that does not interfere with the reagent 312 and test sample 304 reaction. For example, the encapsulation material may include a chemical that causes a thermal reaction with the test sample 304 and the thermal reaction may server to enhance the reagent 312 and test sample 304 reaction. [0024] As depicted in FIG. 3C, in an additional or alternate embodiment, the reagent 312 may be released from the capsule 310 by applying a force to the capsule 310 via, for example, agitator 316 or by an operator vigorously stirring or mixing the solution. The applied force may act to break open or rupture the capsule 308 to release the reagent 312 into the test sample 304. In such an embodiment, the capsule 310 may be made from plastic or any other non-reactive material. [0025] As depicted in FIG. 3D, after the reagent 312 is released from the capsule 310, the reagent 312 may react with the particles of interest 306, if they are present in the test sample 304. As the reagent 312 diffuses into the test sample 304 and reacts with the particles of interest 306, the reacted particles of interest 322 may become easily detectable (e.g., via solution color change) either manually or automatically. For example, a sensor 318 (e.g., a spectrometer, pH meter, photomultiplier tubes in clinical instruments) may provide a data signal to a controller 320 that is adapted to execute an analyzer program to determine whether the received data indicates the presence of the particles of interest 306. In some embodiments or applications of the present invention, the presence of the particles of interest may be evident as a result of the reaction, without the use of an analyzer. For example, the presence of a hormone in a urine sample may be evidenced by a color, as the hormone reacts with the selected reagent to produce a specific color. [0026] Turning to FIG. 4, a flowchart illustrating an exemplary method 400 of the present invention is depicted. In step SlOO, a test sample 304 is obtained and stored in a receptacle 302. A capsule 310 containing an in vitro diagnostic reagent 312 is added to the receptacle 302 in step S102. A force is applied to the capsule 310 to rupture the capsule 310 in step S104. In step S106, the reagent 312 is released from the capsule 310. The reagent 312 reacts with the test sample 304 in step S108. The reacted test sample 304 and reagent 312 are analyzed in step SIlO. In step S112, a reaction outcome is determined based on the analysis of the reacted test sample 304.

[0027] The foregoing description discloses only exemplary embodiments of the invention. Modifications of the above disclosed apparatus and method which fall within the scope of the invention will be readily apparent to those of ordinary skill in the art.

[0028] Accordingly, while the present invention has been disclosed in connection with exemplary embodiments thereof, it should be understood that other embodiments may fall within the spirit and scope of the invention, as defined by the following claims.

Claims

THE INVENTION CLAIMED IS:

1. A container for encapsulating an in vitro diagnostic reagent comprising: a capsule adapted to contain an in vitro diagnostic reagent, wherein the reagent is adapted to be reacted with a test sample in an in vitro diagnostic test.

2. The container of claim 1, wherein an interior of the capsule is shaped to prevent the reagent from remaining in the interior when the reagent is released from the capsule.

3. The container of claim 2, wherein the interior of the capsule has at least one of a semi-spherical shape and a spherical shape.

4. The container of claim 1, wherein a material used to form the capsule is non-reactive with the reagent.

5. The container of claim 1, wherein a material used to form the capsule is non-reactive with the test sample.

6. The container of claim 1, wherein the reagent is in a homogenous suspension.

7. The container of claim 1, wherein a material used to form the capsule is a gelatin-based substance.

8. The container of claim 1, wherein a material used to form the capsule is plastic.

9. A method for applying an encapsulated in vitro diagnostic reagent comprising: depositing an in vitro diagnostic reagent, contained in a capsule, into a test sample; releasing the reagent into the test sample; reacting the reagent with the test sample; and analyzing the results of the reaction between the reagent and the test sample.

10. The method of claim 9, wherein the reagent is released from the capsule by rupturing the capsule.

11. The method of claim 10, wherein rupturing the capsule includes dissolving the capsule.

12. The method of claim 9, wherein releasing the reagent further includes applying a force to the capsule to release the reagent.

13. The method of claim 9, wherein an interior of the capsule is spherical.

14. The method of claim 13, wherein the interior of the capsule is adapted to release the reagent.

15. The method of claim 9, wherein the capsule is non-reactive with the reagent.

16. The method of claim 9, wherein the capsule is non-reactive with the test sample.

17. A system for administering an in vitro diagnostic reagent comprising: a capsule, wherein the capsule encapsulates an in vitro diagnostic reagent for use in an in vitro diagnostic test; a receptacle, adapted to store a test sample to be tested with the reagent, wherein the capsule and test sample are adapted to be mixed such that a reaction may occur between the reagent and the test sample; and an analyzer, adapted to determine the outcome of the reaction.

18. The system of claim 17, wherein the capsule is non- reactive with the reagent.

19. The system of claim 17, wherein the capsule is non- reactive with the test sample.

20. The system of claim 17, wherein the capsule includes an interior surface that is spherically shaped.

21. The system of claim 17, wherein the capsule is adapted to dissolve to release the reagent into the test sample.

22. The system of claim 17, further including a transducer adapted to apply a force to the capsule to release the reagent into the test sample.