ADMINISTRATION OF DRUGS TO A PATIENT

Abstract

The invention relates to a method and an electronic pill (20) for administration of at least one drug (3) to a patient, wherein a delivery profile of the at least one drug is determined according to at least one individual parameter of the patient. The at least one individual parameter may particularly relate to a genotype (GEN) or phenotype of the patient and for example comprise a distribution of proteins in the patient's gastrointestinal tract (GIT). Optionally, the individual parameter may be adjusted based on measurements by the electronic pill or external devices during its passage through the patient's gastrointestinal tract.

Claims

1. (canceled)

2. An electronic pill, comprising: a drug reservoir; and a controller configured to control delivery of a drug from the drug reservoir to a patient with a delivery profile that is based on at least one parameter of the patient, wherein the at least one parameter comprises at least one member selected from the group consisting of: pharmacokinetic data based on at least one member selected from the group consisting of blood of the patient, urine of the patient, and pharmacokinetic data based on breath of the patient; a response of the patient to administration of the drug; and a profile of co-administered drugs; and wherein the delivery profile comprises: a composition of the drug to be delivered; an amount of drug to be delivered and/or a rate delivery of the drug to be delivered; and a location in the gastrointestinal tract of the patient where the drug is to be delivered.

3. The electronic pill of claim 2, wherein the at least one parameter relates to an expected response of the patient to administration of the drug.

4. The electronic pill of claim 3, wherein the expected response of the patient to administration of the drug relates to metabolism of the administered drug by the patient.

5. The electronic pill of claim 3, wherein the expected response of the patient to administration of the drug relates to absorption of the administered drug by the patient.

6. The electronic pill of claim 3, wherein the expected response of the patient to administration of the drug relates to efflux of the administered drug by the patient.

7. The electronic pill of claim 3, wherein the expected response of the patient to administration of the drug relates to a genotype that predicts response to a drug.

8. The electronic pill of claim 7, wherein the delivery profile comprises a composition of the drug to be delivered based on the genotype that predicts response to the drug comprises.

9. The electronic pill of claim 8, wherein the composition of the drug comprises a large molecule protein.

10. The electronic pill of claim 2, wherein the pharmacokinetic data comprise expression of a protein in the patient.

11. The electronic pill of claim 10, wherein the expression of the protein in the patient is indicative of the patient's responsiveness to a therapy.

12. The electronic pill of claim 11, wherein the therapy comprises administration of the drug.

13. The electronic pill of claim 12, wherein the protein is present in the gastrointestinal tract of the patient.

14. The electronic pill of claim 12, wherein the protein is present in the blood of the patient.

15. The electronic pill of claim 2, wherein the at least one parameter relates to the a distribution of proteins in the gastrointestinal tract of the patient.

16. The electronic pill of claim 15, wherein the proteins comprise at least one member selected from the group consisting of P-glycoprotein and multidrug resistance protein.

17. The electronic pill of claim 2, wherein the delivery profile comprises a drug dispense rate of the drug versus time.

18. The electronic pill of claim 2, wherein the delivery profile comprises a drug dispense rate for the drug versus location in the gastrointestinal tract.

19. The electronic pill of claim 2, wherein the at least one parameter comprises the pharmacokinetic data, and the electronic pill is configured to sample the pharmacokinetic data during administration of the drug.

20. The electronic pill of claim 2, wherein the at least one parameter comprises the response of the patient to administration of the drug, and the electronic pill is configured to sample the response of the patient to administration of the drug during administration of the drug.

21. The electronic pill of claim 2, wherein the electronic pill is configured to adjust the delivery profile of the drug during administration of the drug.

22. The electronic pill of claim 2, wherein the electronic pill is configured to adjust the delivery profile of the drug after administration of the drug.

23. The electronic pill of claim 2, wherein the electronic pill is configured to determine the delivery profile once and to apply the delivery profile continuously during one or more administrations of the drug by the electronic pill.

24. The electronic pill of claim 2, further comprising a motor configured to move a piston to deliver the drug from the drug reservoir to the patient.

25. The electronic pill of claim 2, further comprising programmable memory.

26. The electronic pill of claim 2, further comprising a sensor configured to gather information relating to a location of the electronic pill in the gastrointestinal tract of the patient.

27. The electronic pill of claim 26, wherein the sensor comprises a member selected from the group consisting of a pH sensor and a sensor for CYP activity.

28. A system, comprising: an electronic pill according to claim 2; a unit configured to wirelessly gather data from the electronic pill.

29. The system of claim 28, further comprising a base station configured to gather data from the unit.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] These and other aspects of the invention will be apparent from and elucidated with reference to the embodiment(s) described hereinafter. These embodiments will be described by way of example with the help of the accompanying drawings in which:

[0019] FIG. 1 shows schematically the components of an electronic pill system;

[0020] FIG. 2 shows a section through an exemplary electronic pill:

[0021] FIG. 3 illustrates the method of drug administration according to the present invention.

[0022] Like reference numbers in the Figures refer to identical or similar components.

DETAILED DESCRIPTION OF EMBODIMENTS

[0023] Problems with limited oral bioavailability are present with a wide variety of drugs. In general the oral route is always preferred when feasible. However if the drug fails to enter systemic circulation after oral administration (poor bioavailability) then it must be delivered by an alternate route. Often this is by injection. Delivery by injection can bring significant additional burdens including need for professional administration, pain and discomfort, sterilization requirements, and injection reactions.

[0024] For various reasons many orally delivered compounds exhibit good uptake in relatively localized regions in the intestines. There are many examples of drugs with site-specific absorption. Factors contributing to the differences include gut composition, mucus thickness, pH, surface area, and enzyme activity. Among the non-peptide drugs known to exhibit regional selective absorption are ciprofloxacin, piretanide, metoprolol, and baclofen (cf. Siccardi D., Adv. Drug Deliv. Rev., 57(2): 219-35 (2005)). Current drug targeting approaches generally rely on enteric coatings to protect a matrix of the drug. After the coating dissolves the drug matrix dissolves thus releasing the drug for absorption through the gut wall. The dissolution process is variable and results are often imperfect.

[0025] Moreover, differences in drug response among patients are common. Therapies are developed to provide benefit to the average patient while minimizing adverse reactions. One known variable is the patient's profile of the cytochrome P-450 enzymes, an important contributor to oxidative metabolism. These enzymes account for almost 50 percent of the overall elimination of commonly used drugs. There are many enzymes in the P-450 family classified by their amino acid similarities. The enzyme activity can be affected by diet, concurrent medications, or inherited variations. The wide range in activity can markedly impact response to a drug and risk for adverse reaction. For example an individual with low activity will slowly metabolize the drug and it can accumulate into toxic concentrations over the course of treatment.

[0026] The liver is the major site of cytochrome P-450 metabolism. However the intestines are also an important site, especially for CYP3A. CYP3A metabolizes a wide array of clinically important drugs and is the most abundant form in the intestines. In a study of twenty human donors, CYP3A represented 63%, 49% and 88% of total small intestinal cytochromes in the duodenum, jejunum, and ileum, respectively (Paine M. F., et. al., J. Pharmacol. Exp. Ther., 283(3): 1552-62 (1997)). There is a progressive decline in CYP3A content from the duodenum to jejunum to ileum. Thus the upper small intestines represent the major site for intestinal CYP-mediated first past metabolism. Results also show significant interindividual variability and this can account for the large differences in oral bioavailability observed in some CYP3A drug substrates. Duodenal and jejunal CYP3A content varied by more than 30-fold among the twenty donors in the study.

[0027] The oral bioavailability of many cytotoxic cancer drugs is low and/or highly variable. Typically they are administered by intravenous injection once every few weeks. In addition to the cost, convenience and compliance advantages that would come from an oral formulation, there is evidence that a more frequent dosing schedule facilitated by oral administration would improve outcomes. In vitro, increasing the duration of taxane exposure above a threshold level is more important than achieving high peak concentrations (Engels F. K., et. al., Br. J. Cancer, 93(2): 173-7 (2005)). Taxanes include placlitaxel and docetaxel, widely used in ovarian, breast, and some lung cancers.

[0028] Factors responsible for the low or variable bioavailability of cytotoxic drugs include high affinity for drug transporters and activity of metabolic enzymes. Many tissues that form a protective barrier, including the epithelial membrane of the intestines, include an excretory function for transporting substances back out of the cell. These drug transporters include P-glycoprotein (P-gp) and multidrug resistance protein (MRP) and are members of the ATP-binding cassette family (ABC). These transporters can also confer multidrug resistance to cancer cells. There is extensive first pass metabolism of taxanes and other cancer drugs by CYP3A. Further an overlap in selectivity and localization of CYP3A and P-gp suggest these two proteins cooperate and constitute an absorption barrier.

[0029] Recognizing that these efflux pumps and CYP metabolism can limit the bioavailability of many drug candidates, strategies have been proposed to inhibit these mechanisms (e.g. U.S. Pat. No. 5,567,592, U.S. Pat. No. 6,803,373, U.S. Pat. No. 7,030,132). In targeting regions in the intestinal tract it is possible to formulate the drug by chemical means using enteric coating, degradable matrices, beads, and the like. Performance of the delivery vehicle is then however based on averages and can vary significantly. Further the range in profiles achievable and the ability to target narrow regions is limited.

[0030] Generally there is a single drug formulation for a given therapy. This formulation will target a given location with a given target release rate. Thus it is a one size fits all approach based on the average best fit while minimizing adverse reactions. As discussed above, the absorption profile can however vary significantly between individuals. The ability to deliver a drug of limited and variable bioavailability may thus be dependent on the ability to tailor the delivery profile to the individual.

[0031] To address the above issues, the present invention proposes to use an electronic pill system in a strategy to deliver a drug to the appropriate areas of the intestinal tract and in concentrations tailored to the individual. In this manner bioavailability is improved and variation between individuals is reduced. This can enable the oral delivery of drugs that must presently be injected due to bioavailability problems.

[0032] An exemplary electronic pill 20 (ePill) is illustrated in FIG. 2. The pill itself is one component of a larger ePill system, as shown in FIG. 1. This system includes the following components:

[0033] a programming station 10, 11 for programming a given drug delivery profile into ePills 20;

[0034] a set of ingestible ePills 20;

[0035] a portable unit 30 for wirelessly gathering data from a pill 20 during its passage through the gastrointestinal tract 2 of a patient 1;

[0036] a home base station 40 to gather data from the portable unit 30;

[0037] a network 50 for transferring the pill data to the computer 60 of an interested party such as the doctor.

[0038] In the embodiment of FIG. 2, the ePill 20 used for drug delivery has the following elements: a battery 21, PICS (power integrated circuits) 22 for microprocessor and receiver, a flex foil 23 with bumped electronic components, a miniature electrical motor 24, a piston 25, a drug reservoir 26, and sensors.

[0039] The invention uses an electronic pill of the kind described above. The delivery profile of the pill may be easily programmed before ingestion by the patient. Further the delivery profile may be tailored to the individual. The drug reservoir may be loaded with the target compound that normally has limited and variable bioavailability. The delivery profile may be determined by the input of one or more data sources. The data sources may be the individual's genetic profile (e.g. determined by the AmpliChip CYP450 microarray of Roche Diagnostics), measurement of expression transport receptors or presence of enzymes in the gut, measurements of the amount of drug delivered into circulation in the individual, or individual response to treatment. The electronic pill may be controlled to release the drug at a specified rate and time. This results in delivery of the drug to target location(s) in the gastrointestinal (GI) tract at a target concentration level(s).

[0040] The drug contained in the reservoir 26 is typically one that suffers from poor and/or highly variable oral bioavailability. The reasons for the poor bioavailability profile can be many. At a minimum the bioavailability of the drug can be improved by delivering to a relatively small region of the GI tract. A first step in the method of delivery is therefore to determine the target location of delivery. This may be known for a given drug by previous experimentation. Next the pill and system are programmed to accurately target that area. The pill is then ingested by the patient and the actions of the pill as controlled by the program will deliver the drug to the area of improved absorption, thus improving bioavailability.

[0041] There are many drugs that show good or improved absorption in only a limited region. For example consider salmon calcitonin. A study of regional absorption in rats determined the location of maximum absorption is in the ileum. The drug reservoir of the pill may be loaded with a formulation of salmon calcitonin and the pill may then be programmed to release drug only in the ileum. Location targeting may be achieved by several strategies. For example, the pill may contain a pH sensor. The pH sensor can reliably determine when the pill exits the stomach by a tell-tale rise in pH. Transit of the pill in the human small bowel is reasonably repeatable. Thus the pill could wait a pre-determined amount of time and begin to release contents over a second time interval. The delay time and release time coincide with norms of GI transit so as to target release in the ileum, for this example.

[0042] Another example of an area where the proposed approach can improve bioavailability is in the delivery of large molecules such as proteins or peptides. Oral delivery of protein and peptides is a topic of extensive research and development. The compounds are degraded by the harsh environment of the stomach, enzymes of the upper GI tract, and are poorly absorbed through the epithelium. This has led to research in a number of strategies for protecting the compound and promoting uptake. Among the many approaches are mucoadhesive systems, receptor mediated transport, location targeting, liposomes, polymer shells, complex formation with a carrier, and temporary opening of tight junctions. The properties of ePill can be quite beneficial to drug delivery strategies in this case. First the compounds are well protected in the drug reservoir from the GI environment until they are dispensed at the target location. Next, ePill can accurately target the location for delivery where the compound is best absorbed. Location targeting and accurate control of the release profile ensures repeatable delivery both in place and concentration. It is probable that the ePill strategy can also make use of drug delivery developments that aim to improve uptake of the compound across the gut wall. That is formulations that make use of carrier or promoter compounds can be made and stably loaded into the drug reservoir or multiple reservoirs if needed.

[0043] In typical embodiments, the drug not only exhibits a regional preference for delivery but also shows potentially large bioavailability variation between individuals. Thus the method should also include an early step to characterize the expected response of the individual. This characterization is used to program the pill and system with a release profile tailored to that person. After programming and administration of the pill, the method may also include a step to evaluate the response of the individual. This response is then used to tailor the release profile of subsequent administration of the pill.

[0044] For example, the drug may be a substrate for cytochrome P-450 metabolism and/or subject to efflux back into the intestinal lumen. The drug may be recognized by P-glycoprotein, BCRP, or other systems responsible for removal of drugs from the intestinal enterocytes and forming a barrier to absorption. In this case bioavailability is improved by the co-administration of a bioenhancer that serves to inhibit CYP metabolism and/or drug efflux. Several examples have been cited where a bioenhancer improves bioavailability thus opening up possibility of oral administration. As a typical example, the delivery of taxane compounds for chemotherapy may be considered. Effective bioenhancement is possible with co-administration of cyclosporine and with second generation enhancers such as elacridar.

[0045] In a preferred method first there is an evaluation of the patient profile. This may include a genetic test to characterize the individual's genotype in regard to cytochrome expression. For example the AmpliChip CYP450 from Roche Diagnostics can be used for this case. Differences in CYP expression can dramatically affect the bioavailability of the drug and also the effectiveness of the bioenhancer intended for CYP inhibition. Results will guide the programming of the ePill system and administration method with regard to dosing levels of both the drug and the bioenhancer. Preferably, but not necessary, there is also a step to characterize the concentration of CYP, P-gp, or BCRP along the intestinal tract. This might be accomplished by means of a diagnostic test including application of a dye-tagged anti-body against for example P-gp. Measurement of fluorescent intensity can then be accomplished by an endoscope procedure, preferably by a capsule endoscope procedure that includes fluorescent imaging capability. Alternatively this could be accomplished by a diagnostic test using a probe drug such as digoxin and midazolam and measuring blood and urine samples (Kirby B., et. al., J. Clin. Pharmacol., 46(11):1313-9 (2006)). Less invasive characterization could be accomplished with a tagged erythromycin breath and urine test (Lemahieu W. P., et. al. Am. J. Physiol. Gastrointest. Liver Physiol., 285(3):G470-82 (2003)).

[0046] Data of the patient's CYP genotype and local concentration of P-gp activity may then be used to program the delivery profile of the ePill. The ePill is loaded with the target formulation and the delivery profile, concentration versus location, is programmed into the pill. The target formulation may for example be paclitaxel. The formulation may include also the presence of the bioenhancer, for example elacridar. Alternatively the bioenhancer may be administered orally in a separate pill taken before or concurrently with the ePill.

[0047] After ingestion of the pill the individual response to the treatment may be measured. For example blood tests may determine the actual amount of target drug, for example paclitaxel, that enters systemic circulation. This can be particularly important when the drug has significant side effects, poorly predictable bioavailability, or a narrow therapeutic window. After measuring the actual bioavailability of the target drug for that person, the release profile for future use of the ePill can be tailored to achieve ideal concentrations. Over the course of treatment the patient response at a disease or other marker level could be measured and again the dosage profile of future pills adapted accordingly.

[0048] In an alternate embodiment the ePill itself may contain a sensor for CYP activity. In this case during the course of pill transit the real time activity level is determined and adjustments in drug delivery rate can be made en-route. The sensor could for example employ a degradable polymer sensitive to the cytochrome enzyme or some surrogate compound.

[0049] In summary the proposed method preferably employs the following steps:

[0050] characterize the expected patient response (metabolism, efflux) to the drug treatment,

[0051] map the expected absorption profile in the patient's intestinal tract for example by concentration of enzymatic activity or expression of relevant receptors,

[0052] create a drug delivery profile of dispense rate versus location,

[0053] administer the ePill,

[0054] gather pharmacokinetic data or monitor response,

[0055] adjust delivery profile, and repeat as necessary from administer the ePill.

[0056] The system and method may be used for oral administration of a therapeutic drug, particularly a drug that suffers from poor or variable bioavailability. They allow to create and maintain a therapeutic concentration of the drug in systemic circulation by measuring some parameter(s) and adjusting the dispense profile for dose and target location. Bioavailability is improved by location targeting the delivery of the drug by use of a programmable electronic pill system. Use of a bioenhancer may also be included. This allows oral administration of drugs that would otherwise require delivery by injection.

[0057] FIG. 3 illustrates in a diagram different aspects of the drug administration method described above. The schematically drawn capsule of an electronic pill 20 comprises inter alia the following components (e.g. as hardware and/or software modules):

[0058] A programmable memory MEM, e.g. realized by a flash memory or RAM embedded in the microprocessor.

[0059] A controller CON, e.g. realized by a microcontroller, which controls (inter alia) the delivery of the drug 3 from the reservoir 26.

[0060] At least one sensor SEN, e.g. for CYP or pH.

[0061] A receiver/transmitter Rx/Tx for a wireless communication with external devices.

[0062] The delivery program of the drug that is executed by the controller CON is based on data stored in the memory MEM, on feedback from the internal sensor SEN, and/or on feedback from external measurements about the patient response RES. The data stored in advance in the memory MEM may be based on various data sources, for example:

[0063] The genotype GEN of the patient.

[0064] The specification of target regions in the gastrointestinal tract GIT of the patient, thus allowing an intestinal targeting.

[0065] Pharmacokinetic data BLD including the response of the patient during previous administrations of the drug.

[0066] Finally it is pointed out that in the present application the term comprising does not exclude other elements or steps, that a or an does not exclude a plurality, and that a single processor or other unit may fulfill the functions of several means. The invention resides in each and every novel characteristic feature and each and every combination of characteristic features. Moreover, reference signs in the claims shall not be construed as limiting their scope.