Patent Application
20050171436
The technical field of this invention is Raman spectroscopy and, in particular, the use of Raman scattering to monitor in situ drug-eluting medical devices, for example, drug-eluting stents used for vascular repair.
Coronary heart disease is a major cause of death and disability, accounting for substantial health costs. Underlying most cases is development of atherosclerotic lesions in coronary arteries, or at least, coronary artery narrowing generally due to plaque. Initially, balloon angioplasty was used to enlarge narrowing arteries in a preventative strike against heart disease. Such procedures successfully opened narrowed arteries in most patients and relieved symptoms such as chest pain. Over months, however, recurrent chest pain developed in many patients as restenosis, or a “re-narrowing” of the arteries, occurred at the treatment site.
Coronary stents offered improvements when used in conjunction with balloon angioplasty, but also had drawbacks due to scar tissue formation at the treatment site. Stents are generally metallic mesh devices placed at the treatment site in the artery to provide support to the artery wall, and in general, can result in a larger flow channel. Although stents significantly decrease restenosis, unfortunately, scar formation can form at the treatment site. For example, in approximately 20% to 30% of patients, scar tissue grows through openings of the stent, narrowing the flow channel therethrough and causing, in many ways, the same issues associated with restenosis.
Drug-eluting coronary stents, however, can reduce scar tissue formation thus improving treatment outcome. Scar tissue formation can be reduced or eliminated by various antiproliferate drugs, such as Sirolimus (Rapamune™ American Home Products Corp.). The drug is combined with a polymer that is applied to an outer aspect of the stent as a thin coating. The stent is inserted into a vessel, and the coating activated to begin release of the drug and consequently, drug absorption by vessel walls in proximity to the stent. Various studies show drug-eluting stents dramatically decrease chances of detrimental scar tissue growth. For example, positive results are described in M. Morice et al., N. Engl. J. Med., 346, 1773 (2002); P. W. Serruys et al., Circulation, 106 798 (2002); and F. Listro et al., Circulation 105, 1883 (2002).
Unfortunately, performance of a drug-eluting stent can only be determined by repeated patient evaluations over time in an attempt to identify signs of restenosis or other detrimental changes in a subject patient. Generally, it is unknown if the drug-polymer coating is correctly eluting a drug in sufficient amounts for substantially full therapeutic benefits. The amount of drug eluted can be different than expected because of, for example, “pre-elution” of the drug occurring while the device is in its packaging during shipping and/or storage, elution occurring after removal of the device from its packaging but before insertion into a lumen, and insertion and activation of the polymer coating in a lumen of the subject.
Thus, there is a need for monitoring of drug-eluting medical devices.
The present invention is directed to low-resolution Raman spectroscopic systems for monitoring of drug-eluting medical devices before and/or after insertion and activation in a lumen of a subject. The system can include a light source such as a multi-mode laser, a light collector and/or a light dispersion element, and a detector to measure spectral patterns that indicate the presence of the drug released from the medical device. Based on a spectral response of a target (e.g., the lumen wall), the presence, or absence, of the drug can be determined, and an amount of drug that will be eluted in a lumen of a subject can be predicted.
In one aspect of the invention, an optical sensor system is employed in making Raman spectroscopic measurements of a drug-eluting device, its packaging container, and or the device after insertion and activation in a lumen of a subject to determine the presence or absence of a drug. Systems according to the invention can also allow in situ Raman spectroscopic measurements of a lumen wall adjacent or in close proximity to an inserted and activated drug-eluting device.
Accordingly, in one aspect, the present invention provides a system for detecting the presence or absence of a drug using low-resolution Raman spectroscopy in a target region and can allow for a prediction of an amount of drug that will be eluted in the lumen of the subject over a time period. The target region can be a device, its packaging container and/or the device in a lumen of a subject. The system can include a catheter comprising an excitation fiber through which multi-mode radiation can propagate to irradiate the target region. A multi-mode laser, such as a GaAs laser diode, can produce the multi-mode radiation. A low-resolution dispersion element can receive scattered radiation, e.g., that light scattered by the target, and separate the received radiation into different wavelength components. A detection array optically coupled to the dispersion element or other light collecting element can detect least some of those wavelength components. A processor receives data from the detection array and processes that data to determine the presence or absence of the drug, and can lead to a prediction of drug-release curves of the device corresponding a time period.
In use, the multi-mode laser irradiates the target to produce a Raman spectrum composed of scattered electromagnetic radiation characterized by a particular distribution of wavelengths. The Raman spectrum results from scattering of the laser radiation as it interacts with the target.
A collector element collects and communicates the scattered radiation from the target to the dispersion element. Thus, the collector element can be an optical fiber with a first end positioned for collecting scattered radiation, and a second end positioned in proximity to the dispersion element. One or more filters can be employed, e.g., notch filters, to reduce or attenuate optical noise, for example, excitation source background noise.
The dispersion element distributes (e.g., separates) the scattered radiation into different wavelength components. This can be accomplished by a diffraction grating, for example. At least a portion of the wavelength components are detected by the detection array which can be a charged-coupled diode (CCD) array. The resolving power of the dispersion element determines the position of specific wavelengths in the detection array in such way that a signal from a particular diode in the array will generally correspond to the same or similar narrow range of wavelengths.
The processor receives and processes the signals and/or other data from the detection array. For example, the processor can store data corresponding to background noise of the medical device in an unactivated state prior to insertion into the subject. After insertion and activation of that (or a similar) device in the subject, the processor can receive data from the detection array corresponding to measurements taken in the lumen of the subject, and separate the background noise attributable to the medical devices itself. The remaining Raman spectrum then corresponds to an amount of drug released from the medical device. In another feature of the invention, the processor can predict a drug-release curve for a time period longer that the actual in situ Raman sampling time interval. Thus, based on a relatively short time interval, a drug-release curve can be extrapolated or otherwise predicted for a significantly longer time period.
In another aspect, the invention provides methods for detecting the presence or absence of a drug released from a drug-eluting medical device inserted and activated in a lumen of a subject. The method includes providing a catheter generally paralleling one as described herein. Background Raman features of the medical device before installation and activation are known or can be determined via, for example, Raman spectral analysis. After installation and activation of the device, Raman features, taken in situ, can be used to verify and measure the rate of drug elution from the medical device by monitoring the appearance and intensity of the Raman signals from the drug as it is released. The background features can be differentiated from the in situ features, thus enabling a determination of the amount of drug released and/or elution rates.
Systems according to the present invention can be suitable for measuring drug levels in the sub-milligram range. In a further related aspect, systems such as those described herein can predict drug release curves for extended periods, e.g., 90-days, based on an amount of drug released from the medical device over a relatively shorter period, e.g., during the stenting procedure.
The invention will be more fully understood from the following detailed description taken in conjunction with the accompanying drawings, in which:
The invention is directed to in situ monitoring of drug-eluting medical devices such as stents inserted into a lumen of a subject (e.g., a blood vessel), using low-resolution Raman spectroscopy to monitor the extent and/or rate of a drug released prior to, during, and/or after stenting of an atherosclerotic lesion, for example. Thus, evaluation of a packaged and/or an inserted and activated stent is performed to determine drug-release characteristics that can be expected from that stent, and to verify adequate release of the drug at a time when the stent can be easily replaced. Although the invention is described in terms of stents, it will be obvious to one skilled in the art that the invention can be used with other drug-eluting devices, and in other fields, such as for detection of other blood-borne drugs and/or components within a vessel or body cavity, or detection of other drugs absorbed by a lumen wall such as a wall of a blood vessel.
General background information on Raman spectral analysis can be found in U.S. Pat. No. 5,139,334, issued to Clarke and incorporated herein by reference, which teaches a low resolution Raman analysis system for determining certain properties related to hydrocarbon content of fluids. The system utilizes a Raman spectroscopic measurement of the hydrocarbon bands and relates specific band patterns to the property of interest. See also, U.S. Pat. No. 6,208,887 also issued to Clarke and incorporated herein by reference, which teaches a low-resolution Raman spectral analysis system for determining properties related to in vivo detection of samples based on a change in the Raman scattered radiation produced in the presence or absence of a lesion in a lumen of a subject.
The present invention provides a Raman system for monitoring drug-eluting devices before insertion into a patient or after the device has been inserted and activated in a lumen of a subject based on the difference in the Raman spectrum patterns associated with components of the eluted drug. In one application, the present invention can be used, specifically, as a quality control measure to test packaged devices.
The excitation fiber 3 is connected at a first end to the multi-mode laser 2 and has a second end adjacent to the light directing element 6. Multi-mode laser radiation 4 is carried through the excitation fiber 3, exiting at the second end towards the light directing element 6 which directs the radiation in a sideways direction. Preferably, at least a second portion of the excitation fiber is disposed within a catheter 13 sized to be slidably received by a vessel or other lumen in proximity to the inserted stent 14 or other drug-eluting device. The directed radiation 7 exits the catheter 13 through an opening 20 and irritates a portion of a target such as the inserted stent 14 or lumen wall in proximity to the stent. The opening 20 can be a radial opening having a lens or radiation-transparent covering around the catheter 13, or an orifice either with or without a lens, for example. The light directing element 6 can be for example, conical or flat in shape depending on the size and shape of the opening 20 in the catheter. The light directing element 6 can be a material that is reflective, refractive or diffusive. Where the stent 14 is of a mesh design, the directed radiation 7 can be focused through the mesh of the stent. Raman scattered radiation from the target is collected by the collection bundle 8, which may optionally have a notched filter 21 to remove noise components. The scattered radiation is dispersed into various components by the dispersion element 9 and detected to the detection array 10, which is preferably, a charged-coupled device (CCD) array using diodes.
The resolving power of the dispersion element 9 determines the position of specific wavelength components in the detection array 10 in such a way that the signal from a particular diode in the array will typically correspond to the same (or a similar) narrow range of wavelengths. A low-resolution dispersion element can provide greater transmission of scattered radiation to the detector array. For example, a low-resolution diffraction grating with wider slits than a typical diffraction grating can be used, providing greater transmission of incident scattered radiation to the detector array. Thus, the combination of a low cost, high energy multi-mode laser and a low loss dispersion element provides an inexpensive low-resolution Raman spectroscopy system that can provide a high intensity signal.
The processor 11 selects a particular diode (or diodes) of the array 10 according to the property, e.g., the drug components, to be measured and receives signals corresponding to the diodes illuminated by wavelength components from the dispersion element 9. Signals received from multiple diodes relating to multiple wavelength components can be arithmetically divided to form intensity ratios. The processor 11 can compare these ratios with known values or a correlating function to obtain an estimate of the chemical constituent or property of interest. In a preferred embodiment, the processor can correct received signals for background scatter caused by devices or other characteristics in the target area. For example, background scatter caused by the drug-eluting device can be compensated for to determine a Raman spectrum for the drug eluted from the device absent that background scatter.
By way of background, it will be understood that multi-mode laser radiation energy encountering a target region can be distributed in several distinct modes: absorption, reflection and scattering. Scattering can occur either where the distributed radiation wavelength is unchanged from the incoming wavelength (e.g., Raleigh Scattering), or alternatively, where the distributed wavelengths are altered from that of the incoming wavelengths (e.g., Raman Scattering). Scattering will occur when a target is irradiated with a beam of monochromatic light of frequency w; preferably selected so that it is not strongly absorbed by the target. The resulting electromagnetic field induces a polarizability change in target molecules, and this interaction results in a transfer of energy between the molecules in the target and an electromagnetic wave, as described in Ferraro et al., Introductory Raman Spectroscopy, Academic Press, San Diego, 1994.
A time variance of the electric field, E0 cos wt, of the radiation passing a molecule will distort its electronic structure and produce an induced dipole in the direction of the electric field. If the polarizability, α, is introduced as the proportionality constant between the electric field and the induced dipole moment, then the induced dipole can be expressed as:
μind=αE0 cos wt. [1]
For a vibrating molecule that is not spherically symmetric, the polarizability along a direction can vary about an average value expressed according to the relationship:
α=αav+Δα cos wvibt. [2]
The induced dipole will vary with time according to the relationship:
μind=[αav+Δα cos wvibt][E0 cos wt]. [3]
Thus, using the trigonometric relation:
2 cos m cos n=cos(m+n) [4]
Eq. 3 is equivalent to:
μind=αavE0 cos wt+(Δα)E0[cos(w+wvib)t+cos(w−wvib)t]. [5]
The first term of Eq. 5 corresponds to radiation that is scattered without any change in the frequency, w, of the light, and is identified as Raleigh scattering. The second term of Eq. 5 describes an energy-exchange interaction that depends on the non-spherical, or anisotropic, part of the polarizability and involves frequencies shifted from that of the incident radiation by an amount that depends on the vibrational frequency of the molecules in the target. Thus, the second term is Raman scattering, with the frequency of the light, w, changed by an amount±wvib, equal to a molecular vibration. The vibrational frequencies observed are specific to a given molecular structure, and the chemical makeup of the sample can be determined by the characteristic vibrational frequencies observed.
It is through use of those so-called “fingerprint” vibrational frequencies, unique to each particular species in the target, that allow monitoring of the released drug components against a background of other chemical signature vibrations that constitute the stented site within the artery wall.
Thus, since a Raman measurement is the difference in wavelength between the returned scattered light and the laser radiation excitation line, an excitation line that has a larger spectral full width at half-maximum causes a proportional loss of resolution in the resulting Raman measurement. However, this reduction of resolution is generally offset by the advantages of lower cost and increased signal intensity. The increased signal intensity is a result of a higher energy laser source and wider slits in the diffraction grating allowing more light into the detector array. Since the spectrometer system resolution has been reduced by the use of a multi-mode laser, for example, the width of the slits can be increased with negligible effect on the overall resolution. Additionally, a charged-coupled device detector array can be matched to the lower resolution laser source and the wider dispersion element by reducing the number of elements (e.g., diodes) in the array. For example, instead of a 4,096 element diode array, a system can implement a 2,048 element diode array without significantly affecting the overall resolution of the system.
Advances in the field of solid-state lasers have introduced several important laser sources into Raman analysis. For high-resolution Raman systems, the laser linewidth must be severely controlled, often adding to the cost of the excitation source and the system as a whole. For low-resolution Raman spectroscopy, however, the strategy of relinquishing resolution details in favor of emphasizing essential identifying spectral features, allows the use of a low cost, light energy multi-mode laser which can be used with a low-resolution system, according to a preferred embodiment of the present invention, is available in higher power ranges (e.g., between 50 milliwatts (mw) and 1,500 mw) than is available with a traditional single mode laser (generally less than 150 mw). The higher power of a multi-mode laser increases the amount of scattered radiation available to the spectrometer system. The sensitivity of the low-resolution system increases at least linearly with the laser power.
Raman spectra can be obtained at around typical room temperatures using, for example, a R-2001™ fiberoptic-based spectrometer system, commercially available from Raman Systems, Inc., although systems can also be used. In particular, however, the system preferably uses a laser source with a wavelength of between approximately 300 nm and approximately 1,500 nm, and more preferably with a wavelength of between approximately 600 nm and 1,000 nm, and even more preferably at approximately 785 nm at a power level of between approximately 50 milliwatts and 300 milliwatts, more preferably approximately 150 milliwatts measured at the target. A 785 nm laser (or one having a wavelength of approximately 785 nm) source can reduce fluorescence interference while collecting Raman spectra from targets and minimize target heating. The laser preferably generates a light having a line width of between about between 1 nm and about 10 nm, and preferably having a line width of at least about 2 nm. Low-resolution spectra can be taken over a range of approximately 100 cm−1 to approximately 5,000 cm−1, and preferably over a range of approximately 400 cm−1 to approximately 3,000 cm−1, at a resolution of approximately 1 cm−1 to 40 cm−1, more preferably on the order of approximately 10 cm−1 to 30 cm−1, and still more preferably of approximately 15 cm−1, thus providing a wide vibrational range suitable for many drug-eluting device monitoring applications. It will be appreciated that the wavelength, power and range of the Raman system can vary depending on the characteristics of the drug-eluting device, as well as the characteristics of the drug to be detected.
Typically, a drug-eluting medical device can release a drug over a period exceeding hours, days, and weeks or even months. The device can begin eluting the drug shortly after manufacture and packaging, for example, and continue eluting while in storage. It is possible, therefore, that insufficient drug amounts remain in the stent coating to effect an optimal therapeutic benefit to a patient. Thus, in a preferred embodiment, Raman spectrums are acquired from the device and/or package to determine an amount of drug previously eluted prior to inserting the stent into a lumen of a subject. Alternatively, or in addition, the drug-eluting stent can again be irradiated using Raman spectroscopy just prior to insertion into a lumen of a subject. This can ensure adequate drug reserves in the drug-containing coating before beginning the insertion procedure.
It will be appreciated that a drug-eluting medical device, when either packaged and stored, or when inserted and activated, can cause background noise when low-resolution Raman scattering takes place, and it is advantageous to differentiate or otherwise remove from a Raman scattering any wavelength components attributable to any un-released drug components held by the medical device. Thus, a preferred method comprises determining a background scattering of a drug-eluting stent before insertion and activation in a patient to determine a Raman scattering attributable to the device. The background scattering can then be differentiated or otherwise removed from in situ Raman scattering resulting in a determination of the drug released from the medical device.
During insertion of the drug-eluting device in a lumen, the drug-containing coating can be activated to release the drug in therapeutic quantities via, for example, applying UV radiation to the coating. To validate proper activation, and sufficient drug elution, Raman spectroscopy can again be utilized to detect the presence or absence of the drug. In a preferred embodiment, the stent or a wall of the lumen in proximity to the stent is irradiated and resulting Raman spectrums are analyzed to determine the quantity of drug released, if any.
It will be appreciated, however, that continuous monitoring of the stent over the entire drug-eluting period (e.g., 9-months) is difficult or even impossible. Thus, in a preferred embodiment, a drug-eluting stent is monitored for a period shorter than its entire drug-eluting life span, and the results from that shorter period are used to predict, via extrapolation for example, the drug-eluting characteristics expected for the longer drug-eluting life span. For example, Raman spectrums can be obtained shortly after insertion and again multiple times thereafter for a time period, e.g., minutes and/or hours. These Raman spectrums can be analyzed to predict drug-release curves predicting an amount of drug that will be released over a longer time period, e.g., hours and/or months.
This provides in situ analysis of an inserted and activated stent at a time when correction of an improperly activated or otherwise defective stent is possible without waiting for a subject's recurrent symptoms.
Thus, methods for monitoring a drug-eluting medical device according to a preferred embodiment of the invention include providing for a low-resolution Raman spectroscopy device such as one described herein for directing laser radiation at a target region to determine the presence or absence of a drug. For example, the amount of drug present in a drug-eluting device can be measured using low-resolution Raman spectroscopy before and after insertion in a lumen of a subject. The returned Raman spectrums can be analyzed to predict the amount of drug that will be eluted by the device over a time period. Multiple spectroscopy samples can be taken over a time period of seconds or minutes, for example, to determine a rate of release of a drug. These samples are processed to remove background scattering noise attributable to, among other things, the medical stent and drug-containing polymer coating, and can be processed, for example via a partial least-squares analysis, to predict an expected drug-release curve for the device over its drug-eluting life-span.
In a preferred embodiment, a drug-eluting device in situ is irradiated with radiation suitable for inducing Raman scattering as noted above. Scattered radiation is collected from a target region, generally proximal to the drug-eluting device. A Raman spectrum is determined using the collected radiation, which is then analyzed to determine the presence or absence of at least one drug in the target region. A drug-release curve can be predicted using a rate of drug-release, and such can be accomplished by taking several Raman spectrum measurement over time. This may be done in situ either in the original device packaging or at the time of the procedure.
As a demonstration that the approach described above is suitable achieving the objectives of the invention, a low-resolution Raman spectrum of the CYPHER™ Sirolimus (Rapamune™)—Eluting Coronary Stent manufactured by Cordis Corporation was obtained to determine that the drug can be detected via low-resolution Raman spectroscopy. A Raman spectrum of a 1-milligram (mg) Sirolimus tablet was taken in a 10 second scan using an RSL-1 model portable fiberoptic-based low-resolution Raman system.
With knowledge that Raman spectroscopy can identify the drug Sirolimus, measurement of the background Raman features of the drug-coated stent itself is necessary. As noted above, the stent is coated with a drug-containing polymer that can be, e.g., UV activated and covalently bonded to a surface of the metal stent. Encapsulated in the polymeric coating is the drug agent at a total concentration generally on the order of micrograms, which is released slowly by diffusion from its polymeric matrix over time. To properly evaluate the release of the drug agent, detection of the drug at the microgram level is preferably, and differentiation of the released drug spectral features from background sources of low-resolution Raman scattering signals, such as those arising from the stent itself as well as the organic polymer coating, is also preferable.
The initial Raman spectra of a drug-eluting stent surface generally reveals how much of the signature bands from Sirolimus within the polymer matrix are detectable at the microgram levels when presented against the polymeric background peaks over the same spectral region as had been observed in the preliminary results shown in
With use of the background spectral features of the combined drug stent surface, release of the active Sirolimus agent from the inserted and activated stent is possible. In a preferred operation, the drug is released from the stent surface to the artery wall over a period of approximately 90 days, although maintaining uniform release over that period is difficult. Even so, Raman monitoring is possible prior to, and during the stenting procedure, with a full time-dependent curve of drug release obtained by measuring an initial growth of the Raman peaks from the releasing drug over a short initial monitoring period, e.g., several minutes, and using extrapolated results from that initial monitoring data.
One skilled in the art will appreciate further features and advantages of the invention based on the above described embodiments. Accordingly, the invention is not to be limited by what has been particularly shown and described, except as indicated by the appended claims. All publication and references cited herein are expressly incorporated herein by reference in their entirety.
