Patent Grant
10238604
Prescription medications are effective remedies for many patients when taken properly, e.g., according to instructions. However, studies have shown that, on average, about 50% of patients do not comply with prescribed medication regimens. A low rate of compliance with medication regimens results in a large number of hospitalizations and admissions to nursing homes every year. In the United States alone, it has recently been estimated that the cost to the resulting from patient non-compliance is reaching $100 billion annually.
Consequently, various methods and apparatus have been made available to improve patient compliance with prescribed regimens in efforts to improve patient health. To date, many different types of “smart” packaging devices have been developed. In some cases, such devices automatically dispense the appropriate pill. In other cases, there are electronic controls that detect and record when the pill is taken out of the box.
While devices and protocols have been developed for improving patient compliance, there is continued interest in the development of new ways of monitoring patient compliance. It would be an important advancement in clinical medicine if the actual administration and ingestion of a pharmaceutical, such as a pill being dissolved in the stomach, could be monitored in an automatic and accurate manner without dependence on patient or medical staff reporting, where the signal generated by the identifier in the composition is produced upon contact of the composition with a target location.
One system that meets the above needs is the pharma-informatics system described in PCT application serial no. PCT/US2006/016370 filed on Apr. 28, 2006 and published as WO 2006/116718, the disclosure of which is herein incorporated by reference. While the system described in this application provides for many benefits, reliability of signal generation can be an issue under certain situations. For example, depending on how the pharmaceutical composition is ingested, the particular contents of the stomach can have a significant impact on how the identifier in the composition activates. For example, signal generation can be affected by the liquid with which a composition is ingested, e.g., water, juice, etc.
As such, of interest would be the development of an improved pharma-informatics system in which the activation of the identifier was highly controlled, such that the signal generated by the identifier would be independent of the particularly environment, e.g., stomach contents, the target site where activation is desired. The present invention provides, for the first time, such a capability.
The present invention provides for the controlled activation of ingestible identifiers, e.g., as may be incorporated into pharma-informatics enabled pharmaceutical compositions, as may be present in ingestible event markers, etc. Embodiments of the controlled activation identifiers of the invention provide for robust and reliable use despite the presence of variable conditions in the applications in which they are employed, e.g., inadequate degradation of a pharmaceutical carrier, variations in the environment of the target site of interest, etc.
The controlled activation identifiers of the invention are identifiers that are activated upon association with a target site of a body. The controlled activation identifier is one that is activated by the presence of a predetermined specific stimulus at the target site, e.g., liquid (wetting), time, pH, ionic strength, conductivity, presence of biological molecules (e.g., specific proteins or enzymes that are present in the stomach, small intestine, colon), blood, temperature, specific auxiliary agents (foods ingredients such as fat, salt, or sugar, or other pharmaceuticals whose co-presence is clinically relevant), bacteria in the stomach, pressure, light, etc. The predetermined specific stimulus is a known stimulus for which the controlled activation identifier is designed or configured to respond by activation. In certain embodiments, the signal generated by the identifier is independent of the environment of the target site, e.g., the nature of the fluid at the target site.
The controlled activation identifier includes a controlled activation element that may include one or more components, where the one or more components provide for the desired controlled activation in response to the presence of the predetermined specific stimulus at the target site. In certain embodiments, the controlled activation identifier includes a dried conductive medium precursor composition (e.g., a dried salt composition) as the controlled activation element, where this element, upon contact with a fluid (such as stomach fluid), produces a conductive medium resulting in activation of the power source and production of an identifying signal. The presence of the dried conductive medium precursor in the power source provides for a number of advantages, including the ability to obtain reliable activation of the identifier despite variations in the environment of the target site (e.g., variations in terms of stomach content composition), where activation of the identifier is desired. In yet other embodiments, the controlled activation identifier includes a barrier as the controlled activation element, e.g., in the form of a protective film, that is configured to provide for activation of the identifier upon association with the target site of interest. Other types of controlled activation elements include two or more components, such as a dried conductive medium and a barrier, e.g., as described in more detail below.
The broadcasted signal from the identifier may be received by another device, e.g., a receiver, either inside or near the body, which may then record that the identifier, e.g., one that is associated with one or more active agents and pharmaceutical composition, has in fact reached the target site.
The controlled activation identifiers of the invention are identifiers that may be activated upon contact with the target site in response to a specific predetermined stimulus. In certain embodiments, controlled activation is provided despite wide variations in the compositional makeup of the target site. As such, the controlled activation identifier provides for reliable and robust data concerning contact of the composition with the target site in the body, where the provided data is substantially, if not completely, independent of any variations in the environment of the target site. Accordingly, despite wide variations in the composition make up of the target site, e.g., stomach, that may be encountered in using the subject identifiers, the identifiers provide for consistent and reliable signals that are not affected by the composition of the target site environment. The applications of this new information device and system are multi-fold and described in further detail in PCT application Serial No. US20061016370 titled “Pharma-Informatics System,” and published as WO 2006/116718, and U.S. Provisional application Ser. No. 60/949,223 and titled “Ingestible Event Marker”; the disclosure of which applications described therein are incorporated by reference, as well as in the applications reviewed below.
In further describing the invention in greater detail, embodiments of the compositions are reviewed first, followed by a discussion of systems including the subject compositions, methods of using the subject compositions and systems and various illustrative applications in which the compositions and methods find use. Also reviewed in greater detail below are kits that include the subject compositions.
Compositions
Embodiments of the invention include a controlled activation identifier, where the identifier may be associated with a carrier composition, e.g., a pharmaceutically acceptable vehicle, and may or may not be associated with one or more pharmaceutical active agents. In certain embodiments, the compositions are disrupted upon administration to a subject. As such, in certain embodiments, the compositions are physically broken, e.g., dissolved, degraded, eroded, etc., following delivery to a body, e.g., via ingestion, etc. The compositions of these embodiments are distinguished from devices that are configured to be ingested and survive transit through the gastrointestinal tract substantially, if not completely, intact.
As summarized above, the compositions include a controlled activation identifier and an active agent/carrier component. Each of these different components are reviewed separately in greater detail below.
Controlled Activation Identifiers
As summarized above, the compositions of the invention include controlled activation identifiers. The controlled activation identifiers of the present compositions may vary depending on the particular embodiment and intended application of the composition so long as they are activated (i.e., turned on) upon association with or contact with a target physiological location, e.g., stomach, small intestine, large intestine, etc. In certain embodiments, activation occurs in a manner that is substantially, if not completely, environment independent, but for the presence of the predetermined activating stimulus (e.g., fluid, chemical agent, light) that is present at the target site of interest. As such, the identifier may be an identifier that emits a signal when it contacts a target body (i.e., physiological) site, where the nature of the signal is not substantially affected, if affected at all, by the particular makeup of the environment of the target site, apart from the presence of the actual activating stimulus. For example, if the target site is the stomach, the activation of the identifier will be substantially if not completely the same under a variety of different stomach content conditions, e.g., pH variations ranging from about 1 to about 8, etc., where apart from the presence of the fluid stimulus (the activator being activated by wetting) the pH of the fluid does not impact how the identifier is activated. As such, the identifiers are, in certain embodiments, characterized by emitting the same signal in terms of timing and strength following contact with a variety of different fluid compositions having a variety of different pH values. In addition or alternatively, the identifier may be an identifier that emits a signal when interrogated after it has been activated, where activation still occurs in a controlled manner that is independent of target site environment, as reviewed above.
Depending on the needs of a particular application, the signal obtained from the identifier may be a generic signal, e.g., a signal that merely identifies that the composition has contacted the target site, or a unique signal, e.g., a signal which in some way uniquely identifies that a particular composition from a group or plurality of different compositions in a batch has contacted a target physiological site. As such, the identifier may be one that, when employed in a batch of unit dosages, e.g., a batch of tablets, emits a signal which cannot be distinguished from the signal emitted by the identifier of any other unit dosage member of the batch. In yet other embodiments, the identifier emits a signal that uniquely identifies a given unit dosage, even from other identical unit dosages in a given batch. Accordingly, in certain embodiments the identifier emits a unique signal that distinguishes a given type of unit dosage from other types of unit dosages, e.g., a given medication from other types of medications. In certain embodiments, the identifier emits a unique signal that distinguishes a given unit dosage from other unit dosages of a defined population of unit dosages, e.g., a prescription, a batch or a lifetime production run of dosage formulations. In certain embodiments, the identifier emits a signal that is unique, i.e., distinguishable, from a signal emitted by any other dosage formulation ever produced, where such a signal may be viewed as a universally unique signal (e.g., analogous to a human fingerprint which is distinct from any other fingerprint of any other individual and therefore uniquely identifies an individual on a universal level). In one embodiment, the signal may either directly convey information about the composition, or provide an identifying code, which may be used to retrieve information about the composition from a database, i.e., a database linking identifying codes with compositions.
The identifier may be any component or device that is capable of providing a detectable signal following controlled activation, e.g., upon contact with the target site. In certain embodiments, the identifier emits a signal once the composition comes into contact with a physiological target site, e.g., as summarized above. For example, a patient may ingest a pill that, upon contact with the stomach fluids, generates a detectable signal.
Depending on the embodiment, the target physiological site or location may vary, where representative target physiological sites of interest include, but are not limited to: a location in the gastrointestinal tract (such as the mouth, esophagus, stomach, small intestine, large intestine, etc.); another location inside the body, such as a parental location, vascular location, etc.; or a topical location; etc. In certain embodiments, the identifier is configured to be activated upon contact with fluid in the target site, regardless of the particular composition of the target site.
In certain embodiments, the identifier is dimensioned to be orally ingestible, e.g., either by itself or upon combination with a physiologically acceptable carrier component of the composition so as to produce a composition that can be readily administered to a subject in need thereof. As such, in certain embodiments, the identifier element is dimensioned to have a width ranging from about 0.05 to about 2 or more mm, e.g., from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm; a length ranging from about 0.05 to about 2 or more mm, e.g., from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm and a height ranging from about 0.05 to about 2 or more mm, e.g., from about 0.1 mm to about 1 mm, such as from about 0.05 mm to about 0.3 mm, including from about 0.1 mm to about 0.2 mm. In certain embodiments the identifier is 1 mm3 or smaller, such as 0.1 mm3 or smaller, including 0.2 mm3 or smaller. The identifier element may take a variety of different configurations, such as but not limited to: a chip configuration, a cylinder configuration, a spherical configuration, a disc configuration, etc, where a particular configuration may be selected based on intended application, method of manufacture, etc.
The identifier may generate a variety of different types of signals, including but not limited to: RF signals, magnetic signals, conductive (near field) signals, acoustic signals, etc. Of interest in certain embodiments are the specific signals described in PCT application serial no. PCT/US2006/16370 titled “Pharma-Informatics System” and filed on Apr. 28, 2006 and published as WO 2006/116718; the disclosures of various types of signals in these applications being specifically incorporated herein by reference.
The transmission time of the identifier may vary, where in certain embodiments the transmission time may range from about 0.1 μsec to about 48 hours or longer, e.g., from about 0.1 μsec to about 24 hours or longer, such as from about 0.1 μsec to about 4 hours or longer, such as from about 1 sec to about 4 hours. Depending on the given embodiment, the identifier may transmit a signal once or transmit a signal two or more times, such that the signal may be viewed as a redundant signal.
In certain embodiments, the identifier may be one that is programmable following manufacture, in the sense that the signal generated by the identifier may be determined after the identifier is produced, where the identifier may be field programmable, mass programmable, fuse programmable, and even reprogrammable. Such embodiments are of interest where uncoded identifiers are first produced and following incorporation into a composition are then coded to emit an identifying signal for that composition. Any convenient programming technology may be employed. In certain embodiments, the programming technology employed is RFID technology. RFID smart tag technology of interest that may be employed in the subject identifiers includes, but is not limited to: that described in U.S. Pat. Nos. 7,035,877; 7,035,818; 7,032,822; 7,031,946, as well as published application no. 20050131281, and the like, the disclosures of which are herein incorporated by reference. With RFID or other smart tag technology, a manufacturer/vendor may associate a unique ID code with a given identifier, even after the identifier has been incorporated into the composition. In certain embodiments, each individual or entity involved in the handling of the composition prior to use may introduce information into the identifier, e.g., in the form of programming with respect to the signal emitted by the identifier, e.g., as described in U.S. Pat. No. 7,031,946 the disclosure of which is herein incorporated by reference.
The identifier of certain embodiments includes a memory element, where the memory element may vary with respect to its capacity. In certain embodiments, the memory element has a capacity ranging from about 1 bit to 1 gigabyte or more, such as 1 bit to 1 megabyte, including from about 1 bit to about 128 bit. The particular capacity employed may vary depending on the application, e.g., whether the signal is a generic signal or coded signal, and where the signal may or may not be annotated with some additional information, e.g., name of active agent, etc.
Controlled activation identifier components of embodiments of the invention have: (a) a controlled activation element made up of one or more components; and (b) a signal generation component, where the signal generation component is activated by the controlled activation component to produce an identifying signal, e.g., as described above.
Controlled Activation Component
The controlled activation component is a component that activates the signal generation element of the identifier to provide a signal, e.g., by emission or upon interrogation, following contact of the composition with a target physiological site of interest, such as the stomach. The controlled activation component is configured to be activated in a manner that is substantially, if not completely, independent of the particularly compositional makeup of the target site, such that activation is independent of the compositional makeup of the target site.
As reviewed in PCT application serial no. PCT/US2006/16370 titled “Pharma-Informatics System” and filed on Apr. 28, 2006 and published as WO 2006/116718, activation of the identifier may be achieved in a number of different ways, where such approaches include, but are not limited to: battery completion, battery connection, etc. The different activation approaches disclosed in this co-pending application may be readily adapted to provide controlled activation, as described herein, and as such are herein incorporated by reference in their entirety.
For example, controlled activation elements based on battery completion formats may employ a battery that includes, when completed, a cathode, an anode, and an electrolyte. When the composition is administered, e.g., ingested, and travels through the esophagus, it proceeds to enter the stomach. The cathode and anode provided within the composition do not constitute a full battery. However, as the composition dissolves to expose the cathode and anode, the stomach fluid (either by itself or when combined with a dried conductive precursor medium component of the identifier) acts as the electrolyte component of the battery. The added component of the stomach fluid thus completes the battery. Therefore, as the composition contacts the target site, e.g., by entering the stomach and dissolving to the point of cathode and anode exposure, a power source is provided which activates the identifier, e.g., in chip configuration. The data signal is then transmitted.
In certain embodiments, the battery that is employed is one that comprises two dissimilar electrochemical materials which constitute the two electrodes (e.g., anode and cathode) of the battery. When the electrode materials are exposed and come in contact with the body fluid, such as stomach acid or other types of fluid (either alone or in combination with a dried conductive medium precursor, as reviewed below), a potential difference, that is, a voltage, is generated between the electrodes as a result of the respective oxidation and reduction reactions incurred to the two electrode materials. A voltaic cell, or battery, can thereby be produced. Accordingly, in embodiments of the invention, such batteries are configured such that when the two dissimilar materials are exposed to the target site, e.g., the stomach, the digestive tract, etc., during the physical and chemical erosion of the composition in which the signal generation element is present, a voltage is generated. The two dissimilar materials in an electrolyte are at different potentials, similar to the physics model of a ‘potato battery’. As an example, copper and zinc when put into a cell have different potentials. Similarly, gold and magnesium have different potentials. As a result, a potential difference between the two dissimilar materials is generated.
In certain of these embodiments, the battery power source may be viewed as a power source that exploits electrochemical reaction in an ionic solution such as gastric fluid, blood, or other bodily fluids and some tissues.
Electrodes 32 and 33 can be implemented in various ways; for instance, areas on opposing surfaces of an integrated circuit chip can be coated with two different metals, and the entire chip can be placed in the ionic solution. Alternatively, electrodes 32 and 33 may extend away from element 40 as shown. Other arrangements may also be used.
Electrodes 32 and 33 can be made of any two materials appropriate to the environment in which the identifier 30 will be operating. The active materials are any pair of materials with different electrochemical potentials. For instance, in some embodiments where ionic solution 39 comprises stomach acids, electrodes 32 and 33 may be made of a noble metal (e.g., gold, silver, platinum, palladium or the like) so that they do not corrode prematurely. Alternatively, the electrodes can be fabricated of aluminum or any other conductive material whose survival time in the applicable ionic solution is long enough to allow identifier 30 to perform its intended function. Suitable materials are not restricted to metals, and in certain embodiments the paired materials are chosen from metals and non-metals, e.g., a pair made up of a metal (such as Mg) and a salt (such as CuI). With respect to the active electrode materials, any pairing of substances—metals, salts, or intercalation compounds—with suitably different electrochemical potentials (voltage) and low interfacial resistance are suitable.
A variety of different materials may be employed as the battery electrodes. In certain embodiments, electrode materials are chosen to provide for a voltage upon contact with the target physiological site, e.g., the stomach, sufficient to drive the signal generation element of the identifier. In certain embodiments, the voltage provided by the electrode materials upon contact of the metals of the power source with the target physiological site is 0.001 V or higher, including 0.01 V or higher, such as 0.1 V or higher, e.g., 0.3 V or higher, including 0.5 volts or higher, and including 1.0 volts or higher, where in certain embodiments, the voltage ranges from about 0.001 to about 10 volts, such as from about 0.01 to about 10 V.
Materials and pairings of interest include, but are not limited to those reported in Table 1 below.
In certain embodiments, one or both of the metals may be doped with a non-metal, e.g., to enhance the voltage output of the battery. Non-metals that may be used as doping agents in certain embodiments include, but are not limited to: sulfur, iodine and the like.
In certain embodiments, the electrode materials are cuprous iodine (CuI) or cuprous chloride as the anode and magnesium (Mg) metal or magnesium alloy as the cathode. Embodiments of the present invention use electrode materials that are not harmful to the human body.
Additional battery configurations of interest include, but are not limited to, those described in: U.S. Provisional Application Ser. No. 60/889,868 titled “Pharma Informatics System Power Source,” and filed on Feb. 14, 2007; U.S. Provisional Application Ser. No. 60/889,870 titled “Pharma Informatics System Power Source Having High Surface Area Cathodes,” and filed on Feb. 14, 2007; and U.S. Provisional Application Ser. No. 60/889,871 titled “Pharma Informatics System Having Short Resistant Series Battery”; the disclosures of which applications are herein incorporated by reference.
The controlled activation element of the identifier that provides for controlled activation may be responsive to a variety of different types of stimuli. Stimuli of interest for which the controlled activation element can be configured to be responsive to include but are not limited to: liquid (wetting), time, pH, ionic strength, conductivity, biological molecules (e.g. specific proteins or enzymes that are present in the stomach, small intestine, colon), blood, temperature, specific auxiliary agents (foods ingredients such as fat, salt, or sugar, or other pharmaceuticals whose co-presence is clinically relevant), bacteria in the stomach, pressure, and light.
The controlled activation element is made up of one or more components that provides for the desired controlled activation functionality, such that the controlled activation element is responsive to the stimulus of interest. The nature of the component or components that make up the controlled activation element may vary. For example, where the stimulus of interest is temperature, the controlled activation element may be a barrier of a material, such as a film (e.g., a polymeric film) whose solubility is a function of temperature, specifically one that becomes soluble at or near body temperature. Such a film may be insoluble/impermeable to water at room temperature but soluble/permeable at 37° C. Materials of interest that may be used for such films include, but are not limited to the polymeric materials listed below. In those embodiments where pressure is the stimuli of interest, the controlled activation element may be a pressure sensitive material, e.g., a capsule or shell (for example, made of a cellulosic material), that has a specific mechanical strength such that at a pressure threshold above the threshold the element will be crushed and allow the identifier to be activated and transmit a signal. In other embodiments of interest, the stimulus may be light. For example, the stimulus may be a fluorescent label which has been attached to a tumor. As the identifier passes by the tumor, the controlled activation element may include a component that provides light at a stimulating wavelength for the label and also a component that detects emitted light from the label. Any convenient light source and detector may be employed. When the detector component detects the emitted light, it will activate the identifier in a controlled activation manner.
In certain embodiments, the one or more controlled activation components of the invention provide for controlled activation, i.e., activation in a manner that is substantially, if not completely, independent of target site environment, as reviewed above. In one embodiment of interest, the controlled activation component includes a dried conductive medium that, upon combination with target site fluid, produces an ionic medium in the presence of the first and second dissimilar materials to activate the battery, e.g., as reviewed above. A representative configuration of such activation component that includes a dried conductive medium precursor component is provided in
When present, the dried conductive medium precursor may be any of a variety of different types of compositions. Compositions of interest include, but are not limited to: salts of physiologically acceptable electrolytes, such as but not limited to: sodium ion, chloride ion, potassium ion and calcium ion, magnesium ion, etc. Specific physiologically compatible salts of interest include, but are not limited to: KCl, NaCl, MgCl2, and the like. Aspects of the invention include the presence of a dried conductive medium precursor. When the precursor is a salt, e.g., as described above, the dried salt may be provided in any convenient format, such as a lyophilized salt composition.
A variation of the embodiment shown in
Instead of a semi-permeable membrane, a solid barrier that includes one or more fluid flow paths may be present. For example, in
In certain embodiments, the surface of the flow path may be modified to provide for desired fluid flow properties. For example, the surface energy of one or more surfaces of the flow path may be modified to provide for enhanced fluid flow through the capillary. For example, the surface energy of one or more surfaces of the flow path may be increased, such that the surface becomes more hydrophilic. A variety of different surface energy modification protocols may be employed, where the particular protocol chosen may depend on the particular composition of the barrier and the desired surface energy properties. For example, if one wishes to increase the surface energy of a given surface, the surface may be subjected to plasma treatment, contacted with a surface energy modification such as surface modifying polymer solutions described in, e.g., U.S. Pat. Nos. 5,948,227 and 6,042,710, each of which is incorporated herein in its entirety for all purposes.
In certain embodiments, the barrier may be one that disrupts upon contact with a fluid having sufficient conductivity to activate the identifier in a predetermined manner, either alone or in combination with dried conductive medium precursor that may be present on the support. For example,
While
A variation of the embodiment shown in
It is noted that with the time-delay configuration as exemplified by the embodiment of
The above discussion, in combination with
In one embodiment, several layers of film are present on the identifier, so that the first layer protects the identifier during processing/storage, the second layer dissolves when a target pH is reached, and the third layer releases a salt to finally activate the device and transmit a signal. Advantages of this type of approach include additional protection and margin against accidental or premature activation. The device can only activate once all the activation events have occurred. Another use of a multilayered film is as an anti-tempering mechanism, because the identifier will activate only after the specific sequence of conditions have been encountered, which makes it difficult or impossible to incorrectly active the device by dipping it into a single fluid or holding it in the mouth without swallowing.
Another example is multiple patches of activating films that are deposited on different parts of the activating surface of the identifier, e.g., the electrodes. For example, the battery on the identifier may be micropatterned or covered by several micropatterned patches of film that activate in different parts of the GI tract, so that a signal is transmitted by an identifier once it reaches the stomach, then transmitted again when the identifier reaches the intestine, and again when it reaches the colon, etc. This configuration allows the same identifier to detect multiple events, such as passage through different parts of the GI tract.
Another use of combined activation is for the identifier to detect a combined event, e.g., to detect when a patient has ingested an identifier along with a certain type of food, drink, or other medication. This allows detection of interactions or of patients ingesting things they are not supposed to with their medication.
Another use in certain embodiments is to transmit a different signal depending on different conditions in the GI tract. An identifier may be built with two separate transmitting elements that are activated via different mechanisms, so that in addition to activation of the identifier information can be obtained about the GI tract's condition. For example, one element is activated by a low pH condition and the other, in a high pH condition.
Identifiers of the invention may be associated with carrier compositions that can potentially interfere with the functionality of the identifier if the carrier does not degrade properly upon ingestion. For example, a typical gel capsule (e.g., made by Capsugel, Peapack, N.J.) dissolves in aqueous solutions in a manner that is strongly dependent on physical (e.g., temperature) and chemical environment of the device. Under certain combinations of conditions, the gel residue may only dissolve partially, leaving an undissolved or congealed layer or residue on the surface of an identifier associated with the capsule. Such remaining residue can completely prevent activation of the device or reduce signal strength. Where the identifier is configured to be associated with a gel capsule formulation or analogous carrier structure, in certain embodiments the controlled activation element is one which is designed to ensure that when the intended activation time or chemical/physical environment is reached, the device is not hindered by residue from a carrier such as a gel capsule. One configuration designed to present remaining residue from interfering with function of the device includes a soluble film deposited on the device surface such that the partially dissolved gel residue adheres to this film. Upon ingestion, the film then dissolves away in a timed or chemically-sensitive manner, leaving the device surface free of gel. In another approach, an absorbent substance (e.g. powder or granular form) is added to the gel capsule such that the partially dissolved gel residue adheres to the powder or granules. The powder then falls away from the device. Examples may include any edible powder or granules, such as starch, sugar, salt, or proteins. In another configuration, a substance added to the gel capsule that swells significantly upon wetting, resulting in the bursting of the gel capsules and release of the device. Examples include swelling polymer matrices such as pharmaceutical excipients that are disintegrating agents (the so-called superdisintengrants) and dissolution aids. Examples are Ac-Di-Sol (made by FMC) and carboxymethyl cellulose and related compounds. In yet another embodiments, a substance is added to the gel capsule that generates heat upon dissolution. Gel capsule dissolution is very sensitive to heat. Certain salts undergo exothermic dissolution reaction in water. Such salts can be added to the capsule or deposited on the surface of the device so that upon wetting, sufficient heat is generated to raise the local temperature by a few ° C. (e.g., 0.1 to 20° C., such as 1 to 10° C., including 1 to 5° C.). Examples of these salts are: ZnC2, BaCl2, MgCl2. In yet another embodiment (e.g., as shown in
In controlled activation elements that include a film or layer, e.g., as described above, the film or layer can be on only one surface of the device or a portion thereof (e.g., it may cover only an active surface of the device or electrode elements present thereon) or it may cover all surfaces of the device, such that the device is encased or encapsulated in the film or layer. In certain embodiments, the identifier device is encapsulated entirely in a polymeric pellet that dissolves in response to chemical/physical environment and/or time. The resultant pellet is placed inside a gel cap or compressed into a tablet, where it also protects the identifier from damage caused by the large compression forces used to make a tablet.
Film barriers have been described in the above discussion in terms of their functionality in providing controlled activation for the identifier. In addition or alternatively to this function, a film barrier may be present that is configured to prevent mechanical damage to the identifier (e.g., damage to IC or battery layers) during processing, handling, bottling, or storage. For example, the device includes in certain embodiments a film that prevents activation or degradation of the device performance or lifetime during processing steps (e.g., when the battery may get wet) or storage (e.g., via moisture absorption from the atmosphere). For example, a film that is soluble only in low pH solution is employed in certain instances to protect the device during processing in high pH aqueous environments. In certain embodiments, a film is present that prevents device-to-device contact (e.g., when multiple devices are placed in the same gel capsule or in a bottle).
Another type of controlled activation identifier is one that is configured so that it is activated only upon elimination of the identifier from the body. For example, the identifier may be covered (partially or wholly) in a barrier layer that is impervious and remains intact while the identifier passes through the GI tract. Upon elimination of the identifier from the GI tract, the barrier may dissolve when it comes in contact with water present in a waste elimination device, e.g., toilet. For example, the barrier may be sensitive to chemicals present in the water of the toilet. When the barrier is disrupted, the water activates the identifier to emit a signal, where the signal may be picked up by a sensor, e.g., associated with the toilet. To prevent tampering, a second controlled activation element that is disrupted by the GI tract may be included, such that activation only occurs when this second element is disrupted by the GI tract and the first barrier is disrupted by the toilet water.
The identifiers may be fabricated using any convenient processing technology, for example, planar processing technology, e.g., as employed in MEMS fabrication, may be employed, coupled with deposition technologies, such as precipitation, for providing the dried conductive medium precursor.
The subject controlled activation batteries may be fabricated in a number of different ways. In certain embodiments, fabrication protocols which may be categorized as “planar” processing protocols are employed, as developed in greater detail below.
After the battery is activated, further activation configurations can be employed to activate the signal generation component. For example, the signal generation component can be activated through the activation of the gate of a metal oxide semiconductor (MOS) circuit, such as a CMOS switch. Activation of the gate of the MOS circuit can be based on one or more parameters, which include but are not limited to: gate current, gate charge, and gate capacitance. The gate current, for activation purposes, can be a function of the conductivity of surrounding body fluids or tissues. Such conductivity can further be a function of one or more parameters, which include but are not limited to: solution concentration, solution pH value, ionic content of solution, enzymatic content of solution, temperature, and carrier mobility. Carrier mobility can also be a function of temperature. Similarly, the gate charge can be a function of one or more parameters, which include but are not limited to: solution composition, crystal potential, electrical potential, gravitational potential, gate capacitance, and carrier concentration. The carrier concentration can also be a function of temperature. The gate capacitance can be a function of the capacitive geometry of the gate, which can further be a function of pressure, a resonant input, or the characteristics of a dielectric material coupled to the gate. The characteristics of the dielectric material can vary with one or more parameters, which include but are not limited to: chemical contents of a digestive tract, chemical character of a physiological location, and amount of dissolution of the dielectric material in body fluids.
Signal Generation Component
The signal generation component of the identifier element is a structure that, upon activation by the controlled activation component, emits a detectable signal, e.g., that can be received by a receiver, e.g., as described in greater detail below. The signal generation component of certain embodiments can be any convenient device that is capable of producing a detectable signal and/or modulating transduced broadcast power, upon activation by the activation component. Detectable signals of interest include, but are not limited to: conductive signals, acoustic signals, etc. As reviewed above, the signals emitted by the signal generator may be generic or unique signals, where representative types of signals of interest include, but are not limited to: frequency shift coded signals; amplitude modulation signals; frequency modulation signals; etc.
In certain embodiments, the signal generation element includes circuitry, as developed in more detail below, which produces or generates the signal. The type of circuitry chosen may depend, at least in part, on the driving power that is supplied by the power source of the identifier. For example, where the driving power is 1.2 volts or above, standard CMOS circuitry may be employed. In other embodiments where the driving power ranges from about 0.7 to about 1.2 V, sub-threshold circuit designs may be employed. For driving powers of about 0.7 V or less, zero-threshold transistor designs may be employed.
In certain embodiments, the signal generation component includes a voltage-controlled oscillator (VCO) that can generate a digital clock signal in response to activation by the activation component. The VCO can be controlled by a digital circuit, which is assigned an address and which can control the VCO with a control voltage. This digital control circuit can be embedded onto a chip that includes the activation component and oscillator. Using amplitude modulation or phase shift keying to encode the address, an identifying signal is transmitted.
The signal generation component may include a distinct transmitter component that serves to transmit the generated signal to a remote receiver, which may be internal or external to the patient, as reviewed in greater detail below. The transmitter component, when present, may take a number of different configurations, e.g., depending on the type of signal that is generated and is to be emitted. In certain embodiments, the transmitter component is made up of one or more electrodes. In certain embodiments, the transmitter component is made up of one or more wires, e.g., in the form of antenna(e). In certain embodiments, the transmitter component is made up of one or more coils. As such, the signal transmitter may include a variety of different transmitters, e.g., electrodes, antennas (e.g., in the form of wires) coils, etc. In certain embodiments, the signal is transmitted either by one or two electrodes or by one or two wires. A two-electrode transmitter is a dipole; a one electrode transmitter forms a monopole. In certain embodiments, the transmitter only requires one diode drop of power. In some embodiments, the transmitter unit uses an electric dipole or electric monopole antenna to transmit signals.
The present invention also allows the possibility that, where appropriate, each pharmaceutical batch can be provided with a batch specific address. This allows identification of where the pill was made, when the pill was made, and in what batch it was made. In some cases, each pill will have a unique identifier. This would be particularly useful when drugs are more likely to be subsequently stolen or used illicitly, and thus should be tracked, or where questions of contamination may arise.
According to one embodiment, mux 65 produces a control voltage, which encodes the address serially and is used to vary the output frequency of oscillator 61. By example, when the control voltage is low, that is, when the serial address bit is at a 0, a 1 megahertz signal is generated by the oscillator. When the control voltage is high, that is, when the address bit is a 1, a 2 megahertz signal is generated the oscillator. Alternately, this can be 10 megahertz and 20 megahertz, or a phase shift keying approach where the device is limited to modulating the phase. The purpose of mux 65 is to control the frequency of the oscillator or an AC alternative embodiment of the amplified signal of oscillation.
The outputs of mux 65 are coupled to electrode drive 66 which can drive the electrodes to impose a differential potential to the solution, drive an oscillating current through a coil to generate a magnetic signal, or drive a single electrode to push or pull charge to or from the solution.
In this manner, the device broadcasts the sequence of 0's and 1's which constitute the address stored in mux 65. That address would be broadcast repeatedly, and would continue broadcasting until the first metal or the second metal (32 and 33) is consumed and dissolved in the solution, when the battery no longer operates.
In a further embodiment, the device can avoid the use of separate transmission electrodes by using the battery electrodes for transmission.
Other configurations for the signal generation component are of course possible. Other configurations of interest include, but are not limited to: those described in copending PCT application serial no. PCT/US2006/016370; the disclosure of which is herein incorporated by reference.
Additional Components
Depending on the particular embodiment, the identifier may include a number of different additional components. Some components of interest include, but are not limited, those reviewed below.
Deactivation Component
Where desired, the identifier may also include a deactivation mechanism that disables the identifier if the identifier is not employed as intended, e.g., the composition with which it is associated is not ingested. In certain embodiments, the identifier includes a deactivation mechanism that deactivates the identifier so that it if someone tries to turn it on in a way other than ingesting it, the identifier is deactivated and no signal can be transmitted. Deactivation mechanisms of interest may include one or more of the following components: inclusion of a light-sensitive film that destroys a component of the identifier, e.g., memory, upon exposure to light, a light sensitive battery material, e.g., that is disrupted or destroyed if exposed to light, an identifier that includes components which are sensitive to and inactivated in response to exposure to oxygen, air, moisture, etc. Inactivation of the identifier may include opening a trace, shorting a trace, reducing battery voltage, etc.
Power Enhancers
Where the activator is a power source that is turned on upon contact with a target physiological site, in certain embodiments, circuits for enhancing or boosting voltage output of the power source, e.g., battery, are provided, e.g., charge pumping circuits, charge doublers, etc. Such voltage enhancing elements may enhance the voltage output by at about 2-fold or more, such as by about 5-fold or more.
Power Storage
In certain embodiments, the activation component includes a power storage element. For example, a duty cycle configuration may be employed, e.g., where slow energy production from a battery is stored in a power storage element, e.g., in a capacitor, which then provides a burst of power that is deployed to the signal generation component. In certain embodiments, the activation component includes a timing element which modulates, e.g., delays, delivery of power to the signal generation element, e.g., so signals from different compositions, e.g., pills, that are administered at substantially the same time are produced at different times and are therefore distinguishable.
Additional Features
In certain embodiments, the compositions are characterized by having one or more of the following features. In certain embodiments, the compositions include an identifier which employs a conductive near-field mode of communication in which the body itself is employed as a conductive medium. In such embodiments, the compositions include circuitry that, when freed from the composition upon disruption of the composition (e.g., as described above) the circuitry comes into direct contact with the body and does not remain encapsulated or protected in some manner. In these embodiments, the signal is not a magnetic signal or high frequency (RF) signal. In certain embodiments, the systems are ones that include a receiver which is stably associated with the body, e.g., implanted or topically applied to an external location, such that the systems are distinguished from those in which an external device that is not stably associated with the body is employed to collect data. In certain embodiments, the compositions do not include an imaging system, e.g., camera or other visualization or imaging element, or components thereof, e.g., CCD element, illumination element, etc. In certain embodiments, the compositions do not include a sensing element, e.g., for sensing a physiological parameter, beyond the activator which detects contact with the targeted physiological site. In certain embodiments, the compositions do not include a propulsion element. In certain embodiments, the compositions do not include a sampling element, such as a fluid retrieval element. In certain embodiments, the compositions do not include an actuatable active agent delivery element, such as an element that retains an active agent with the composition until a signal is received that causes the delivery element to release the active agent.
Active Agent Component
Certain embodiments of the subject compositions include an active agent component. “Active agent” includes any compound or mixture of compounds which produces a physiological result, e.g., a beneficial or useful result, upon contact with a living organism, e.g., a mammal, such as a human. Active agents are distinguishable from such components as vehicles, carriers, diluents, lubricants, binders and other formulating aids, and encapsulating or otherwise protective components. The active agent may be any molecule, as well as binding portion or fragment thereof, that is capable of modulating a biological process in a living subject. In certain embodiments, the active agent may be a substance used in the diagnosis, treatment, or prevention of a disease or as a component of a medication. In certain embodiments, the active agent may be a chemical substance, such as a narcotic or hallucinogen, which affects the central nervous system and causes changes in behavior. Active agents of interest include those listed in PCT application serial no. PCT/US2006/016370; the disclosure of which list is herein incorporated by reference. Broad categories of active agents of interest include, but are not limited to: cardiovascular agents; pain-relief agents, e.g., analgesics, anesthetics, anti-inflammatory agents, etc.; nerve-acting agents; chemotherapeutic (e.g., anti-neoplastic) agents; etc. The active agent of the compositions are typically present in a pharmaceutically acceptable vehicle or carrier, e.g., as described below. In certain embodiments, the active agent is present in an amount of from about 0.1% to about 90% by weight, e.g., from about 1% to about 30% by weight of the active compound.
Pharmaceutically Acceptable Carrier
Where desired, the compositions of the invention may include a pharmaceutically acceptable vehicle (i.e., carrier). Common carriers and excipients, such as corn starch or gelatin, lactose, dextrose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid are of interest. Disintegrators commonly used in the formulations of the invention include croscarmellose, microcrystalline cellulose, corn starch, sodium starch glycolate and alginic acid.
A liquid composition may comprise a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s), for example, ethanol, glycerine, sorbitol, non-aqueous solvent such as polyethylene glycol, oils or water, with a suspending agent, preservative, surfactant, wetting agent, flavoring or coloring agent. Alternatively, a liquid formulation can be prepared from a reconstitutable powder. For example, a powder containing active compound, suspending agent, sucrose and a sweetener can be reconstituted with water to form a suspension; and a syrup can be prepared from a powder containing active ingredient, sucrose and a sweetener.
A composition in the form of a tablet or pill can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid compositions. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, microcrystalline cellulose and binders, for example, polyvinylpyrrolidone. The tablet can also be provided with a color film coating, or color included as part of the carrier(s). In addition, active compound can be formulated in a controlled release dosage form as a tablet comprising a hydrophilic or hydrophobic matrix.
“Controlled release”, “sustained release”, and similar terms are used to denote a mode of active agent delivery that occurs when the active agent is released from the delivery vehicle at an ascertainable and controllable rate over a period of time, rather than dispersed immediately upon application or injection. Controlled or sustained release may extend for hours, days or months, and may vary as a function of numerous factors. For the pharmaceutical composition of the present invention, the rate of release will depend on the type of the excipient selected and the concentration of the excipient in the composition. Another determinant of the rate of release is the rate of hydrolysis of the linkages between and within the units of the polyorthoester. The rate of hydrolysis in turn may be controlled by the composition of the polyorthoester and the number of hydrolysable bonds in the polyorthoester. Other factors determining the rate of release of an active agent from the present pharmaceutical composition include particle size, acidity of the medium (either internal or external to the matrix) and physical and chemical properties of the active agent in the matrix.
As such, an active pharmaceutical agent can be placed within any controlled-release structure (e.g. a gastroretentive formulation, enteric formulations, timed-release formulations, colonic formulation). Thus the identifier becomes active at the same time that the active ingredient is released. Further, more than one identifier can be incorporated into a controlled release structure, e.g. two identifiers, one of which activates at the start of the controlled release and the second in the middle or at the end.
A composition in the form of a capsule can be prepared using routine encapsulation procedures, for example, by incorporation of active compound and excipients into a hard gelatin capsule. Alternatively, a semi-solid matrix of active compound and high molecular weight polyethylene glycol can be prepared and filled into a hard gelatin capsule; or a solution of active compound in polyethylene glycol or a suspension in edible oil, for example, liquid paraffin or fractionated coconut oil can be prepared and filled into a soft gelatin capsule.
Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropyl methyl-cellulose, sucrose, starch and ethylcellulose. Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.
Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used. Additionally, it may be desirable to add a coloring agent to make the dosage form more attractive in appearance or to help identify the product.
Other components suitable for use in the formulations of the present invention can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, Pa., 17th ed. (1985).
Identifier Fabrication
In certain embodiments of interest, the identifier element includes a semiconductor support component. Any of a variety of different protocols may be employed in manufacturing the identifier structures and components thereof. For example, molding, deposition and material removal, e.g., planar processing techniques, such as Micro-Electro-Mechanical Systems (MEMS) fabrication techniques, including surface micromachining and bulk micromachining techniques, may be employed. Deposition techniques that may be employed in certain embodiments of fabricating the structures include, but are not limited to: electroplating, cathodic arc deposition, plasma spray, sputtering, e-beam evaporation, physical vapor deposition, chemical vapor deposition, plasma enhanced chemical vapor deposition, etc. Material removal techniques included, but are not limited to: reactive ion etching, anisotropic chemical etching, isotropic chemical etching, planarization, e.g., via chemical mechanical polishing, laser ablation, electronic discharge machining (EDM), etc. Also of interest are lithographic protocols. Of interest in certain embodiments is the use of planar processing protocols, in which structures are built up and/or removed from a surface or surfaces of an initially planar substrate using a variety of different material removal and deposition protocols applied to the substrate in a sequential manner. Illustrative fabrication methods of interest are described in greater detail in PCT application serial no. PCT/US2006/16370 titled “Pharma-Informatics System” and filed on Apr. 28, 2006 and published as WO 2006/116718; the disclosure of which is herein incorporated by reference.
Methods of Making Compositions
A variety of manufacturing protocols may be employed to produce compositions according to the invention. In manufacturing the subject compositions, a signal generation element is stably associated with a carrier composition, e.g., pharmaceutical dosage composition, in some manner. By stably associated is meant that the signal generation element and the dosage form are not separate from each other, at least until administered to the subject in need thereof, e.g., by ingestion. The signal generation element may be stably associated with the pharmaceutical carrier/active agent component of the composition in a number of different ways. In certain embodiments, where the carrier/active agent component is a solid structure, e.g., such as a tablet or pill, the carrier/active agent component is produced in a manner that provides a cavity for the signal generation element. The signal generation element is then placed into the cavity and the cavity sealed, e.g., with a biocompatible material, to produce the final composition. For example, in certain embodiments a tablet is produced with a die that includes a feature which produces a cavity in the resultant compressed tablet. The signal generation element is placed into the cavity and the cavity sealed to produce the final tablet. In a variation of this embodiment, the tablet is compressed with a removable element, e.g., in the shape of a rod or other convenient shape. The removable element is then removed to produce a cavity in the tablet. The signal generation element is placed into the cavity and the cavity sealed to produce the final tablet. In another variation of this embodiment, a tablet without any cavity is first produced and then a cavity is produced in the tablet, e.g., by laser drilling. The signal generation element is placed into the cavity and the cavity sealed to produce the final tablet. In yet other tablet embodiments, an open face pharmaceutical carrier/active agent tablet configuration (e.g., as shown in
Systems
Also provided are systems that include the subject compositions. Systems of the subject invention include, in certain embodiments, one or more controlled activation identifiers, e.g., as reviewed above, as well as a signal detection component, e.g., in the form of a receiver. The signal detection component may vary significantly depending on the nature of the signal that is generated by the signal generation element of the composition, e.g., as reviewed above.
In certain embodiments, the signal detection component is an implantable component. By implantable component is meant that the signal detection component is designed, i.e., configured, for implantation into a subject, e.g., on a semi-permanent or permanent basis. In these embodiments, the signal detection component is in vivo during use. In yet other embodiments, the signal detection component is ex vivo, by which is meant that the detection component is present outside of the body during use. In certain of these embodiments, as developed in greater detail below, either separate from or integrated with the ex vivo detection component may be a dosage dispenser element, e.g., for dispensing dosages of the compositions based on signal detected from the signal generation element of the detector. Such features may also be present in implantable detection components, e.g., to provide a closed loop administration system that administers a subsequent dosage based on input about ingestion of a previous dosage.
As reviewed above, in certain embodiments the signal generation element of the composition is activated upon contact with a target body site. In certain of these embodiments, the signal detection component is activated upon detection of a signal from the signal generation element. In certain of these embodiments, the composition generates an intermittent signal. In certain of these embodiments, the detection element is capable of simultaneously detecting multiple compositions.
Signal receivers for use in the invention are further described in PCT application serial no. PCT/US2006/16370 titled “Pharma-Informatics System” and filed on Apr. 28, 2006 and published as WO 2006/116718, as well as provisional application Ser. Nos.: 60/887,780 titled “Signal Receivers for Pharma-Informatics Systems,” and filed on Feb. 1, 2007; 60/949,223 titled “Ingestible Even Marker,” and filed on Jul. 11, 2007 and 60/956,694 titled “Personal Health Signal Receivers,” and filed on Aug. 18, 2007; the disclosures of which are herein incorporated by reference.
In certain embodiments, the signal detection component includes a cardiac monitoring element, such as shown in the system of
Methods
Controlled activation identifiers of the invention find use in a variety of different applications, including delivery of pharmaceutical agents, in diagnostic and monitoring applications, etc. In methods where the identifiers are employed in compositions that include one or more pharmaceutically active agents, an effective amount of a composition of the invention is administered to a subject in need of the active agent present in the composition, where “effective amount” means a dosage sufficient to produce the desired result, e.g., an improvement in a disease condition or the symptoms associated therewith, the accomplishment of a desired physiological change, etc. The amount that is administered may also be viewed as a therapeutically effective amount. A “therapeutically effective amount” means the amount that, when administered to a subject for treating a disease, is sufficient to effect treatment for that disease.
The composition may be administered to the subject using any convenient means capable of producing the desired result, where the administration route depends, at least in part, on the particular format of the composition, e.g., as reviewed above. As reviewed above, the compositions can be formatted into a variety of formulations for therapeutic administration, including but not limited to solid, semi solid or liquid, such as tablets, capsules, powders, granules, ointments, solutions, suppositories and injections. As such, administration of the compositions can be achieved in various ways, including, but not limited to: oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intracheal, etc., administration. In pharmaceutical dosage forms, a given composition may be administered alone or in combination with other pharmaceutically active compounds, e.g., which may also be compositions having signal generation elements stably associated therewith.
The subject methods find use in the treatment of a variety of different conditions, including disease conditions. The specific disease conditions treatable by with the subject compositions are as varied as the types of active agents that can be present in the subject compositions. Thus, disease conditions include, but are not limited to: cardiovascular diseases, cellular proliferative diseases, such as neoplastic diseases, autoimmune diseases, hormonal abnormality diseases, infectious diseases, pain management, and the like.
By treatment is meant at least an amelioration of the symptoms associated with the disease condition afflicting the subject, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g. symptom, associated with the pathological condition being treated. As such, treatment also includes situations where the pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g. prevented from happening, or stopped, e.g. terminated, such that the subject no longer suffers from the pathological condition, or at least the symptoms that characterize the pathological condition. Accordingly, “treating” or “treatment” of a disease includes preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side-effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease). For the purposes of this invention, a “disease” includes pain.
A variety of subjects are treatable according to the present methods. Generally such subjects are “mammals” or “mammalian,” where these terms are used broadly to describe organisms which are within the class mammalia, including the orders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees, and monkeys). In representative embodiments, the subjects will be humans.
In certain embodiments, the subject methods, as described above, are methods of managing a disease condition, e.g., over an extended period of time, such as 1 week or longer, 1 month or longer, 6 months or longer, 1 year or longer, 2 years or longer, 5 years or longer, etc. The subject methods may be employed in conjunction with one or more additional disease management protocols, e.g., electrostimulation based protocols in cardiovascular disease management, such as pacing protocols, cardiac resynchronization protocols, etc; lifestyle, such a diet and/or exercise regimens for a variety of different disease conditions; etc.
In certain embodiments, the methods include modulating a therapeutic regimen based data obtained from the compositions. For example, data may be obtained which includes information about patient compliance with a prescribed therapeutic regimen. This data, with or without additional physiological data, e.g., obtained using one or more sensors, such as the sensor devices described above, may be employed, e.g., with appropriate decision tools as desired, to make determinations of whether a given treatment regimen should be maintained or modified in some way, e.g., by modification of a medication regimen and/or implant activity regimen. As such, methods of invention include methods in which a therapeutic regimen is modified based on signals obtained from the composition(s).
In certain embodiments, also provided are methods of determining the history of a composition of the invention, where the composition includes an active agent, an identifier element and a pharmaceutically acceptable carrier. In certain embodiments where the identifier emits a signal in response to an interrogation, the identifier is interrogate, e.g., by a wand or other suitable interrogation device, to obtain a signal. The obtained signal is then employed to determine historical information about the composition, e.g., source, chain of custody, etc.
In yet other embodiments where the identifier is one that survives digestion, the methods generally include obtaining the signal generation element of the composition, e.g., by retrieving it from a subject that has ingested the composition, and then determining the history of the composition from obtained signal generation element. For example, where the signal generation element includes an engraved identifier, e.g., barcode or other type of identifier, the engraved identifier may be retrieved from a subject that has ingested the composition and then read to identify at least some aspect of the history of the composition, such as last known purchaser, additional purchasers in the chain of custody of the composition, manufacturer, handling history, etc. In certain embodiments, this determining step may include accessing a database or analogous compilation of stored history for the composition.
The present invention provides the clinician an important new tool in their therapeutic armamentarium: automatic detection and identification of pharmaceutical agents actually delivered into the body. The applications of this new information device and system are multi-fold. Applications include, but are not limited to: (1) monitoring patient compliance with prescribed therapeutic regimens; (2) tailoring therapeutic regimens based on patient compliance; (3) monitoring patient compliance in clinical trials; (4) monitoring usage of controlled substances; and the like. Each of these different illustrative applications is reviewed in greater detail below in PCT/US2006/16370 titled “Pharma-Informatics System” and filed on Apr. 28, 2006 and published as WO 2006/116718; the disclosure of which is herein incorporated by reference.
Also of interest are methods in which the identifier is ingested apart from any pharmaceutical agent. Such methods include those in which the identifier is employed as an ingestible event marker. In such methods, the identifier is ingested without a pharmaceutically active agent. The identifier may be ingested in a pharmaceutically acceptable vehicle, e.g., as described above. Specific applications in which the identifier is employed as an ingestible event marker include, but are not limited to, those described in U.S. Provisional Application Ser. No. 60/949,223 titled “Ingestible Event Marker,” and filed on Jul. 11, 2007; the disclosures of which are herein incorporated by reference.
One example of a specific application in which the controlled activation identifier is not administered with an active agent and is instead employed as an ingestible event marker is the application of monitoring GI tract motility. In such applications, a controlled activation device that activates only at high pH is employed to determine the transit time from ingestion to the small intestine. In a variation of this embodiment, multiple devices that activate in different parts of the GI tract are employed, where this embodiment may be used for mapping the residence time of the device in various parts of the GI tract. For example, in one instance three controlled activation identifiers (which may be present in the same pill or separate pills) are employed. The first identifier is configured to activate immediately upon ingestion (e.g., which it reaches the stomach). The second controlled activation identifier includes a low pH-insoluble, high-pH soluble coating (e.g., Eudragit) that delays activation until the identifier reaches the small intestine. The third identifier includes a controlled activation element a coating (e.g., amylase+ethyl cellulose) that is only soluble in the colon. From the activation time of the various identifiers one can determine or measure the transition time to the stomach, small intestine, and colon, and thereby gain a detailed data collection of the subject's gastrointestinal motility.
Kits
Also provided are kits for practicing the subject methods. Kits may include one or more compositions of the invention, as described above. The dosage amount of the one or more pharmacological agents provided in a kit may be sufficient for a single application or for multiple applications. Accordingly, in certain embodiments of the subject kits a single dosage amount of a pharmacological agent is present and in certain other embodiments multiple dosage amounts of a pharmacological agent may be present in a kit. In those embodiments having multiple dosage amounts of pharmacological agent, such may be packaged in a single container, e.g., a single tube, bottle, vial, and the like, or one or more dosage amounts may be individually packaged such that certain kits may have more than one container of a pharmacological agent. Suitable means for delivering one or more pharmacological agents to a subject may also be provided in a subject kit. In certain embodiments the kits may also include a signal receiving element, as reviewed above. In certain embodiments, the kits may also include an external monitor device, e.g., as described above, which may provide for communication with a remote location, e.g., a doctor's office, a central facility etc., which obtains and processes data obtained about the usage of the composition.
The subject kits may also include instructions for how to practice the subject methods using the components of the kit. The instructions may be recorded on a suitable recording medium or substrate. For example, the instructions may be printed on a substrate, such as paper or plastic, etc. As such, the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or sub-packaging) etc. In other embodiments, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g. CD-ROM, diskette, etc. In yet other embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this embodiment is a kit that includes a web address where the instructions can be viewed and/or from which the instructions can be downloaded. As with the instructions, this means for obtaining the instructions is recorded on a suitable substrate.
Some or all components of the subject kits may be packaged in suitable packaging to maintain sterility. In many embodiments of the subject kits, the components of the kit are packaged in a kit containment element to make a single, easily handled unit, where the kit containment element, e.g., box or analogous structure, may or may not be an airtight container, e.g., to further preserve the sterility of some or all of the components of the kit.
It is to be understood that this invention is not limited to particular embodiments described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are now described.
All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
It is noted that, as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.
As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.
Accordingly, the preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims.
This application is a continuation of U.S. patent application Ser. No. 12/447,172, filed on Apr. 24, 2009, now U.S. Pat. No. 8,945,005, which is a U.S. national stage application of International Application No. PCT/US2007/082563, filed on Oct. 25, 2007, which pursuant to 35 U.S.C. § 119 (e), claims priority to the filing date of: U.S. Provisional Patent Application Ser. No. 60/862,925 filed Oct. 25, 2006 the disclosures of each application are herein incorporated by reference.
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| Number | Date | Country | |
|---|---|---|---|
| 20150182463 A1 | Jul 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60862925 | Oct 2006 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12447172 | US | |
| Child | 14570673 | US |
