Abstract:
An improved upper capsule portion ( 62 ) of an oral drug delivery capsule ( 60 ) that includes an upper capsule portion ( 62 ) and a lower cup shaped capsule portion ( 64 ), the lower cup shaped capsule portion ( 64 ) containing a medical formulation ( 66 ), the lower capsule portion ( 64 ) being made of a material that disperses in gastrointestinal fluid, the lower capsule portion ( 64 ) having a mouth, the upper capsule portion ( 62 ) dimensioned to engage with the mouth of the lower capsule portion ( 64 ). The improvement is the positioning of a communication device, such as an RFID tag ( 90 ), on or integrally with the upper capsule portion ( 62 ) so that the communication device can communicate that the oral drug delivery capsule has been ingested. An alternate embodiment with an improved lower capsule portion is also disclosed.

Description:
BACKGROUND OF THE INVENTION 
       [0001]    The present invention relates to a method and system for monitoring compliance to an internal dosing regimen and the subsequent analysis of the data generated. More particularly, the present invention relates to the use of an ingested or inserted encapsulated device that delivers a signal to an external data collection device for observation and analysis when a switch sensitive to the ionically conductive environment of the gastrointestinal tract is triggered, thereby indicating that the dose form has been ingested, inserted or otherwise internalized. The data collected in the external data collection device may then be analyzed for management of patient therapy or for clinical study. 
         [0002]    Non-compliance refers to the failure by the patient to take the prescribed dosage at the prescribed time for the prescribed period, resulting in patient under-medication or over-medication. Such non-compliance results in increased cost of medical care, higher complication rates, higher rates of drug-resistance by pathogens, and drug wastage. In a survey of 57 non-compliance studies, failure to comply with the drug regimen ranged from 15% to as high as 95% in all study populations, regardless of medications, patient population characteristics, the drug being delivered, or study methodology. (Greeberg, R. N.: Overview of Patient Compliance with Medication Dosing: A Literature Review, Clin. Therap., 6(5):592-599 [1984].) Reasons for the failure of patients to comply with drug regimens are plentiful and include forgetfulness (30%), other matters taking priority (16%), choosing not to take drug (11%), lack of information (9%) and “emotional factors” (7%). (Osterberg, L., and Blaschke, T.: Compliance to medication, N. Engl. J. Med. 353;5, 490 [2005].) 
         [0003]    Compliance to the instructions given to patients during any clinical trial is usually less than 50% in relatively short-term and less than 40% in longer-term trials using traditional methods (e.g., paper diaries) for making entries to show compliance (Vrijens and Goetghebeur, Statist. Med. 23, 531-544, 2004). A clinical trial on chronic pain patients reported only an 11% compliance with as high as 80% fake entries when paper diaries secretly instrumented to track diary usage were given to patients (Stone et al., Control Clin. Trials. 24, 182-199, 2003) wherein on 32% of study days the paper diary was not opened, yet the compliance entries for those days exceeded 90%. A high incidence of intentional dumping of medications prior to the clinic visit by removing all or most of the medication at one time also occurs in clinical studies (Coutts et al, Arch. Dis. Child. 67, 332-333, 1992; Rand et al, Am. Rev. Respir. Dis. 146, 1559-1564, 1992; Rudd et al, Clin. Pharmacol. Therap. 46, 169-176, 1989; Simmons et al, Chest. 118, 290-295, 2000). Thus, deception among noncompliant patients occurs frequently in clinical trials, and is not often revealed by the traditional monitoring methods. The result is generation of data difficult to interpret and, worse, useless to reliably predict the effectiveness of clinical trials. Better monitoring of the time of actual drug intake will help alleviate many of these issues. For example, blood levels of a drug can be corrected for the time of actual drug intake for better pharmacokinetic/pharmacodynamic interpretations than relying on the time when patient(s) was instructed to take the medication. However, most of the present tracking devices that are utilized in clinical trials only track the initiation of the process of drug intake, i.e., by tracking the time the drug containers are opened or activated. In order to more accurately monitor the compliance of a clinical trial, a more sophisticated method of monitoring the drug intake is needed. 
         [0004]    In the therapeutic setting, accurately measuring and analyzing compliance has a number of important benefits such as enabling the care-giver to warn a patient about the potential for developing a drug resistant infection related to poor compliance to the regimen and enabling the identification of a side effect of a drug related to overdosing. In the clinical drug research stage, accurately measuring and analyzing compliance can lead to a broad range of benefits, including improved statistical reliability of a clinical study, earlier completion of clinical studies, possible identification of side effects, and a determination of the effects of non-compliance as a function of the degree of non-compliance. 
         [0005]    Confirmation of drug compliance by way of direct observation by trained persons is effective but impractical in most settings. Confirmation of drug compliance by blood or urine analysis is also not practical beyond the hospital setting. 
         [0006]    There have been technical efforts made to overcome the impracticality of direct observation and specimen analysis. These technical efforts have been singularly directed to monitoring dosing compliance. Trans-dermal detection devices attached to the skin of a patient have been developed which detect ingested drug components through the skin. Such devices can transmit a signal to a remote receiver at an external site such as a healthcare facility as disclosed in, for example, U.S. Pat. No. 6,663,846 and U.S. Published Patent Application No. 2005/0031536. Electronic sensor systems have also been developed which detect ingested drug components in the breath of a patient, such as set forth in U.S. Published Patent Application No. 2004/0081587. Radio Frequency Identification (“RFID”) tags have been incorporated into pills with each tag capable of identifying the type of medication, its dosage, and its lot number by way of a unique code emitted by the tag when interrogated by a corresponding radio frequency reader, as set forth in U.S. Pat. No. 6,366,206. The RFID of the &#39;206 patent can incorporate a biosensor that switches state, for example, by detecting ionic conductivity, in the gastrointestinal tract detects moisture or change in pH to determine whether the pill has dissolved and exposed the RFID tag to the environment of the gastrointestinal system. 
         [0007]    Statistical models for drug compliance have also been developed. For example, Gerard et al. in Statistics in Medicine (17, 2313-2333 [1998]) describe a Markov mixed effect model for drug compliance data. Vrijens et al., in Statistics in Medicine (23, 531-544 [2004]), describe a data treatment model for reduced bias and improved precision in pharmacokinetic pharmacodynamic population studies. In European Patent Application No. 0526166 a patient compliance monitoring method using a radio transmitter attached to a medicine container to detect medicine consumption is disclosed. A patient compliance monitoring method based on patient entry of data related to medicine consumption is disclosed in U.S Published Patent Application No. 2002/0143577. 
         [0008]    A bar code-based drug dispensing system and database are disclosed in U.S Published Patent Application No. 200310055531. In U.S Published Patent Application No. 2003/0110060, a patient compliance monitoring method that includes interaction with the patient is disclosed. A patient compliance monitoring system which provides the patient with a portable medication dispenser which alerts the patient to take a dose of medication and then gathers compliance data relating to the taking of the medication is set forth in U.S Published Patent Application No. 2004/0133305. 
         [0009]    A patient compliance monitoring method employing a pharmacokinetic model to determine if the prescribed dosing regimen should be adjusted is provided in U.S Published Patent Application No. 2004/01193446. The use of a patient compliance monitoring method for use in clinical trials is disclosed in U.S Published Patent Application No. 2004/0243620. A system and method for tracking drug containers is disclosed in U.S Published Patent Application No. 2004/0008123. Finally, a patient compliance monitoring method employing a capsule or pill containing an RFID tag which is responsive to ingestion by a patient is disclosed in U.S Published Patent Application No. 2005/0131281. 
         [0010]    Each of the above-described patents and publications provides a contribution to the state of the art with respect to monitoring compliance to a dosing regimen. However, as in so many areas of art, there is room for improvement in the monitoring of an internal dosing regimen. 
       SUMMARY OF THE INVENTION 
       [0011]    The instant invention is an improved means of incorporating an RFID tag or other communication device, with a drug delivery capsule. More specifically, the instant invention is an improved upper capsule portion of an oral drug delivery capsule comprised of the upper capsule portion and a lower cup shaped capsule portion, the lower cup shaped capsule portion for containing a medical formulation, the lower capsule portion being made of a material that disperses in gastrointestinal fluid, the lower capsule portion having a mouth, the upper capsule portion dimensioned to engage with the mouth of the lower capsule portion, wherein the improvement comprises: a communication device positioned on or integrally with the upper capsule portion so that the communication device can communicate that the oral drug delivery capsule has been ingested. 
         [0012]    In a related embodiment, the instant invention is an improved lower capsule portion of an oral drug delivery capsule comprised of the upper capsule portion and a lower cup shaped capsule portion, the lower cup shaped capsule portion for containing a medical formulation, the lower capsule portion being made of a material that disperses in gastrointestinal fluid, the lower capsule portion having a mouth, the upper capsule portion dimensioned to engage with the mouth of the lower capsule portion, wherein the improvement comprises: a communication device positioned on or integrally with the lower capsule portion so that the communication device communicates that the oral drug delivery capsule has been ingested. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0013]    For a more complete understanding of this invention, reference should now be made to the embodiments illustrated in greater detail in the accompanying drawings and described below by way of examples of the invention wherein: 
           [0014]      FIG. 1  is an enlarged view, part in cross-section and part in full, of a tamper proof oral drug delivery capsule having an upper capsule portion fitted in the mouth of the lower capsule portion, the upper capsule portion containing an active RFID tag; 
           [0015]      FIG. 2  is an enlarged view, part in cross-section, part broken away and part in full, of an oral drug delivery capsule having an upper capsule portion fitted over the mouth of the lower capsule portion with a passive RFID tag system wrapped on and adhered to the lower capsule portion; 
           [0016]      FIG. 3  is an enlarged view, part in cross-section and part in full, of an oral drug delivery capsule having an upper capsule portion fitted in the mouth of the lower capsule portion, the upper capsule portion containing a magnet; 
           [0017]      FIG. 4  is an enlarged view, part in cross-section and part in full, of a tamper proof oral drug delivery capsule having an upper capsule portion fitted in the mouth of the lower capsule portion, the upper capsule portion containing an infra-red emitting diode; 
           [0018]      FIG. 5  is an enlarged view, part in cross-section and part in full, of an oral drug delivery capsule having an upper capsule portion fitted over the mouth of the lower capsule portion, the upper capsule portion containing a radio frequency transmitter system; 
           [0019]      FIG. 6  is an enlarged view, part in cross-section and part in full, of an oral drug delivery tablet having adhered thereto an RFID tag system; 
           [0020]      FIG. 7  is an enlarged view, part in cross-section and part in full, of a tamper proof oral drug delivery capsule having an upper capsule portion fitted in the mouth of the lower capsule portion, the upper capsule portion containing a fluorescent agent; and 
           [0021]      FIG. 8  is an enlarged view, part in cross-section and part in full, of an oral drug delivery capsule having an upper capsule portion fitted inside the mouth of the lower capsule portion, the upper capsule portion containing an ultrasonic transducer. 
       
    
    
     DETAILED DESCRIPTION 
       [0022]    In the following figures, the same reference numerals will be used to refer to the same components. In the following description, various operating parameters and components are described for one constructed embodiment. These specific parameters and components are included as examples and are not meant to be limiting. 
         [0023]    Referring now to  FIG. 1 , therein is shown a tamper proof oral drug delivery capsule  10  comprising an upper capsule portion made of a molded thermoset plastic core  28  overmolded with gelatin  12  and a lower capsule portion  14  made of gelatin. A drug formulation  16  is positioned in the lower capsule portion  14 . The capsule  10  as illustrated is a capsule, but it is to be understood that other forms of dosing such as tablets and pills may be used as well. The dose form as used herein refers to a dose that includes an active drug ingredient or a may be a placebo. 
         [0024]    An RFID chip  20  is positioned in the core  28 . By way of non-limiting example, the RFID chip  20  may be coded to indicate, among other things, the type of medication, the dose of the medication and the lot and serial numbers of the medication. As set forth below, the capsule  10  emits a signal to indicate that the dose form  10  has, in fact, been ingested, based upon its having a switch activated by exposure to the gastrointestinal tract. The signal may be emitted in a variety of ways, including, as examples, electromagnetic (e.g., visible light, ultraviolet and infrared radiation, or an RFID signal), magnetic, radioactive, chemical (e.g., a tracer detectable on the breath), fluorescent, acoustic (e.g., ultrasonic or gasified candy-type technology), and biological (e.g., using biomarkers, as from the evolving area of tetramer technology). 
         [0025]    The RFID chip  20  may be of any one of several designs and configurations. Accordingly, the RFID chip  20  as shown is for illustrative purposes only and is not intended as being limiting. The signal from the RFID chip  20  can be amplified by a signal amplifier positioned between the RFID chip  20  and a signal-receiving and reading device (neither shown). 
         [0026]    The RFID chip  20  is attached to an antenna  22  and a battery  18 . When the capsule  10  is ingested, the lower capsule portion  14  disperses in gastric fluid and electrodes  24  and  26  are exposed to the gastric fluid. Electrodes  24  and  26  are attached at one end thereof to the RFID chip  20  and comprise a conductivity switch incorporated in RFID chip  20  to turn on the RFID chip  20  when the capsule  10  is ingested thereby exposing the electrodes  24  and  26  to electrically conducting gastric fluid. 
         [0027]    Referring now to  FIG. 2 , therein is shown an oral drug delivery capsule  30  comprising an upper capsule portion  32  made of gelatin and a lower capsule portion  34  made of gelatin. A drug formulation  36  is positioned in the capsule portions  32  and  34 . A passive RFID chip  40  is positioned in a patch  44  wrapped on and adhered to the lower capsule portion  34 . The RFID chip  40  is encoded to identify a drug type, dose, lot number etc. The RFID chip  40  is attached to dipole antennae  38  and  42 . When the capsule  30  is ingested, the capsule portions  32  and  34  disperse in gastric fluid and RFID chip  40  is warmed to body temperature. RFID chip  40  contains a thermal switch to turn on the RFID chip  40  when the capsule  30  is ingested and the RFID chip  40  is warmed to body temperature. 
         [0028]    Referring now to  FIG. 3 , therein is shown an oral drug delivery capsule  50  comprising an upper capsule portion  52  made of a molded thermoplastic and a lower capsule portion  54  made of gelatin. A drug formulation  56  is positioned in the lower capsule portion  54 . A magnet  58  is positioned in the upper capsule portion  52 . When the capsule  50  is ingested, the presence of the magnet  58  is detected by a magnetometer contained in an article that can be placed on or worn by the user, such as a necklace. 
         [0029]    Referring now to  FIG. 4 , therein is shown a tamper proof oral drug delivery capsule  60  comprising an upper capsule portion  62  made of a molded thermoset plastic and a lower capsule portion  64  made of gelatin. A drug formulation  66  is positioned in the lower capsule portion  64 . A microprocessor  70  is positioned in the upper capsule portion  62 . The microprocessor  70  is encoded to identify a drug type, dose, lot number etc. The microprocessor  70  is attached to an infrared diode  76  and a battery  68 . When the capsule  60  is ingested, the lower capsule portion  64  disperses in gastric fluid and electrodes  72  and  74  are exposed to the gastric fluid. Electrodes  72  and  74  are attached at one end thereof to the microprocessor  70  and comprise a conductivity switch incorporated in microprocessor  70  to energize the infrared diode  76  in a modulated encoded manner when the capsule  40  is ingested thereby exposing the electrodes  72  and  74  to electrically conducting gastric fluid. The emitted infrared radiation from the diode  76  is detected by an infrared detector contained in a pouch worn around the abdomen. 
         [0030]    Referring now to  FIG. 5 , therein is shown an oral drug delivery capsule  80  comprising an upper capsule portion made of a molded thermoset plastic core  82  attached to a gelatin skirt  98  and a lower capsule portion  84  made of gelatin. A drug formulation  86  is positioned in the lower capsule portion  84 . A radio frequency generator  90  is positioned in the core  82 . The specific frequency of the radio frequency generator  90  identifies a drug type, dose, lot number etc. The radio frequency generator  90  is attached to an antenna  92  and a battery  88 . When the capsule  80  is ingested, the lower capsule portion  84  disperses in gastric fluid and electrodes  94  and  96  are exposed to the gastric fluid. Electrodes  94  and  96  are attached at one end thereof to radio frequency generator  90  and comprise a conductivity switch incorporated in radio frequency generator  90  to turn on the radio frequency generator  90  when the capsule  80  is ingested thereby exposing the electrodes  94  and  96  to electrically conducting gastric fluid. 
         [0031]    Referring now to  FIG. 6 , therein is shown an oral drug delivery tablet system  100 . An active RFID chip  110  is positioned in a molded thermoplastic body  102  bonded to a drug delivery tablet  106  by a layer of adhesive  104 . The RFID chip  110  is encoded to identify a drug type, dose, lot number etc. The RFID chip  110  is attached to antennae  112 ,  112 ′ and a battery  108 . When the tablet  100  is ingested electrodes  114  and  116  are exposed to the gastric fluid. Electrodes  114  and  116  are attached at one end thereof to the RFID chip  110  and comprise a conductivity switch incorporated in RFID chip  110  to turn on the RFID chip  110  when the tablet  100  is ingested thereby exposing the electrodes  114  and  116  to electrically conducting gastric fluid. 
         [0032]    Referring now to  FIG. 7 , therein is shown a tamper proof oral drug delivery capsule  120  comprising a lower capsule portion  124  made of gelatin and an upper capsule portion  122  also made of gelatin. A drug formulation  126  is positioned in the lower capsule portion  124 . A fluorescing reagent  128  is positioned in the upper capsule portion  122 . When the tamper proof oral drug delivery capsule  120  is ingested, the upper and lower capsule portions disperse in the gastrointestinal system thereby allowing the fluorescing reagent  128  to enter the blood stream to be detected by a fluorescence detector positioned on the skin. 
         [0033]    Referring now to  FIG. 8 , therein is shown an oral drug delivery capsule  130  comprising an upper capsule portion  132  made of a molded thermoset plastic and a lower capsule portion  134  made of gelatin. A drug formulation  136  is positioned in the lower capsule portion  134 . A microprocessor  140  is positioned in the upper capsule portion  132 . The microprocessor  140  is encoded to identify a drug type, dose, lot number etc. The microprocessor  140  is attached to an ultrasonic transducer  138  and one pole of battery  142 . The other pole of battery  142  is connected to first electrical contact  144 . Second electrical contact  146  is connected to microprocessor  140 . Second electrical contact  146  is positioned on pad  148  made of a material that swells upon exposure to gastric fluid. When the capsule  130  is ingested, pad  148  swells upon exposure to gastric fluid and causes second electrical contact  146  to contact first electrical contact  144  thereby turning on ultrasonic transducer  138  in a modulated encoded manner. The emitted ultrasonic radiation from the transducer  138  is detected by an ultrasonic detector contained in a pouch worn around the abdomen. 
         [0034]    The lower capsule portion of the instant invention can be made of any material that disperses in gastrointestinal fluid, such as gelatin, hydroxypropylmethylcellulose and poly-N,N-9-diethylaminoethyl methacrylate. The upper capsule portion can be made of any suitable material, such as molded thermoplastic polymer such as polyethylene, polypropylene, polystyrene and polycarbonate or molded thermoset polymer such as an epoxy resin or a urethane polymer. 
         [0035]    The specific means of detecting the communication device is not critical in the instant invention. The detection system (such as an RFID reader when the communication device is an RFID tag) in communication with the communication device is preferably battery powered and positioned on or near the person, preferably in a watch-like device worn on the wrist, in a necklace-like device worn around the neck, in a device worn on or near the abdomen or in a patch worn on the skin. The detection system is preferably programmed to sense and record the type of drug(s) and times of administration thereof for later downloading or preferably for wireless downloading to, for example, healthcare professionals who could even send a reminder signal to the system to remind the patient of his/her noncompliance. 
         [0036]    When the communication device used in the instant invention is an RFID tag, then it should be understood that any type of RFID tag can be used, including active and passive RFID tags (passive RFID tags are preferred). Although several specific and preferred means of sensing ingestion are described above, it should be understood that any means can be used to sense ingestion including all of the means disclosed in U.S. Ser. No. 11/436,917 filed May 18, 2006, herein fully incorporated by reference. 
         [0037]    Although  FIGS. 1 ,  4  and  7  refer to specific tamper-proof capsule embodiments, it should be understood that any tamper-proof capsule design can be used in the instant invention, including the designs of U.S. Pat. No. 4,893,721, herein fully incorporated by reference. In addition, the oral drug capsule of the present invention can be used with a variety of systems, such as that disclosed in U.S. Ser. No. 11/693,404, filed Mar. 29, 2007, herein fully incorporated by reference. 
       EXAMPLE 
       [0038]    An oral drug delivery capsule like the capsule  10  of  FIG. 1  is assembled. A 433 MHz active RFID tag having a conductivity switch is placed in the upper capsule portion while a simulated drug formulation consisting of food grade lactose is placed in the lower capsule portion. The capsule is placed in a plastic wire screen basket placed in the center of a 50 liter polyethylene tank containing 40 liters of USP Simulated Gastric Fluid at 37 degrees Celsius with agitation. A receiving dipole antenna is positioned at the bottom of the tank. Another receiving dipole antenna is positioned outside the tank. The gelatin capsule disperses in the simulated gastric fluid and the conductivity switch turns on the RFID tag which then transmits its 433 MHz signal. The signal strength received by the antenna in the tank is about 5 nanowatt. The signal strength received by the antenna outside the tank held against the tank is about 0.1 nanowatt. The signal strength received by the antenna outside the tank held 70 centimeters away from the tank is about 0.01 nanowatt. An arm held between the tank and the antenna slightly (2-3 dB) reduces the signal strength received by the antenna. 
         [0039]    The minimum detectable signal strength received by the antenna outside the tank held even further from the tank is estimated to be about 0.0001 nanowatt. The signal strength received by the antenna outside the tank is only slightly dependent (a variation of about 1-5 dB) on the position of the antenna of the RFID tag. 
         [0040]    While the instant invention has been described above according to its preferred embodiments, it can be modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the instant invention using the general principles disclosed herein. Further, the instant application is intended to cover such departures from the present disclosure as come within the known or customary practice in the art to which this invention pertains and which fall within the limits of the following claims.