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WO2012039420A1 - Système baroréflexe aortique bionique pour traiter les maladies associées à la dysfonction baroréflexe aortique - Google Patents

Système baroréflexe aortique bionique pour traiter les maladies associées à la dysfonction baroréflexe aortique Download PDF

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Publication number
WO2012039420A1
WO2012039420A1 PCT/JP2011/071470 JP2011071470W WO2012039420A1 WO 2012039420 A1 WO2012039420 A1 WO 2012039420A1 JP 2011071470 W JP2011071470 W JP 2011071470W WO 2012039420 A1 WO2012039420 A1 WO 2012039420A1
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arterial
aortic
bionic
signal
arterial pressure
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English (en)
Japanese (ja)
Inventor
砂川　賢二
公太 船越
細川　和也
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Kyushu University NUC
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Kyushu University NUC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36114—Cardiac control, e.g. by vagal stimulation
    • A61N1/36117—Cardiac control, e.g. by vagal stimulation for treating hypertension
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36135—Control systems using physiological parameters
    • A61N1/36139—Control systems using physiological parameters with automatic adjustment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36146—Control systems specified by the stimulation parameters
    • A61N1/36167—Timing, e.g. stimulation onset
    • A61N1/36171—Frequency
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36146—Control systems specified by the stimulation parameters
    • A61N1/36167—Timing, e.g. stimulation onset
    • A61N1/36175—Pulse width or duty cycle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36146—Control systems specified by the stimulation parameters
    • A61N1/3615—Intensity
    • A61N1/36153—Voltage

Definitions

  • the present invention relates to a system for the treatment of diseases or conditions associated with arterial baroreflex dysfunction.
  • HFpEF heart failure
  • Arterial baroreflex is also called baroreceptor reflex, and is a control system for buffering changes in blood pressure and thereby stabilizing blood pressure.
  • Arterial baroreflex controls arterial pressure (AP) mainly by changing vascular resistance and effective circulating blood volume. That is, the arterial baroreflex disorder is a condition in which control of blood volume has been lost, and a hemodynamic buffering mechanism is lacking for changes in blood volume.
  • Non-patent Document 1 a report that the arterial baroreflex can be artificially mimicked regardless of the treatment of heart failure.
  • HFpEF has a 5-year survival rate of 30% and the prognosis is extremely poor, but treatment has not been established.
  • arterial baroreflex dysfunction induced by arteriosclerosis makes hemodynamics sensitive to changes in blood volume. Therefore, it is considered that pulmonary edema is easily induced in such a state regardless of the presence of left ventricular systolic dysfunction, even with a very small increase in blood volume.
  • the present invention provides a bionic arterial baroreflex system that restores normal capacity tolerance in the absence of physiological arterial baroreflex and is therefore useful for the treatment of HFpEF.
  • the system of the present invention for restoring arterial baroreflex function can be used for the treatment of various diseases that can occur with arterial baroreflex dysfunction.
  • Bio for treating heart failure comprising an arterial pressure sensor, a regulator (bionic brain), and an electrical nerve stimulator that generates a rectangular wave train according to instructions from the regulator and stimulates the aortic decompression nerve Nick arterial baroreflex system.
  • Arterial pressure sensing means for sensing arterial pressure information from a living body and outputting an arterial pressure signal; and inputting an arterial pressure signal sensed by the arterial pressure sensing means to perform clinical
  • a calculation means for calculating a biostimulation signal that is effective and outputting the biostimulation signal; inputting the biostimulation signal calculated by the calculation means;
  • a bionic arterial baroreflex system comprising: biostimulation means (preferably an electrical nerve stimulator for stimulating the aortic decompression nerve) for stimulating a site capable of regulating blood pressure.
  • Arterial pressure sensing means for sensing arterial pressure information from a living body and outputting an arterial pressure signal; and inputting an arterial pressure signal sensed by the arterial pressure sensing means,
  • a calculation means for calculating a biostimulation signal that is effective and outputting the biostimulation signal; inputting the biostimulation signal calculated by the calculation means;
  • a biological stimulation means preferably an electrical nerve stimulating device for stimulating the aortic decompression nerve for stimulating a site where blood pressure can be regulated, and the calculation means receives the input arterial pressure signal.
  • the calculation in the regulator is performed by convolution integration of an impulse response calculated in advance from normal life activity and an arterial pressure signal sensed by the life activity sensing means, or the impulse response is expressed by a delta function.
  • the bionic arterial baroreflex system according to any one of [1] to [3], which is implemented by approximation.
  • the system of the present invention can be used for the treatment of diseases or conditions associated with arterial baroreflex dysfunction. *
  • Arteriosclerosis can cause impairment of arterial baroreflex, but arteriosclerosis-induced arterial baroreflex dysfunction sensitizes hemodynamics to changes in blood volume and therefore increases small blood volume Again, pulmonary edema is easily induced in the absence of left ventricular systolic dysfunction.
  • the bionic arterial baroreflex system of the present invention is a powerful tool in the treatment of heart failure (HFpEF) in which normal capacity tolerance is restored and hence ejection fraction is maintained in the absence of physiological arterial baroreflex.
  • HFpEF heart failure
  • the bionic arterial baroreflex system will also be equally useful in the treatment of heart failure with systolic dysfunction.
  • Orthostatic hypotension is also known as a well-known disease that can be caused by arterial baroreflex dysfunction, but it is considered that orthostatic hypotension can be treated according to the present invention.
  • the critical volume is defined as the injection volume required for the left atrial pressure to reach 20 mmHg. It is the graph which showed the estimated mean blood pressure (mBP) of an arterial baroreflex normal rat and an arterial baroreflex failure rat when a left atrial pressure reached 20 mmHg.
  • mBP mean blood pressure
  • 1 is a schematic diagram of a bionic arterial baroreflex system.
  • FIG. It is a figure regarding the identification of the transfer function of a regulator (bionic brain). It is a graph of a transfer function (left) and an impulse response (right). It is the figure which outlined the experimental system for evaluating the performance of a bionic arterial baroreflex system.
  • CSP carotid sinus pressure
  • AP arterial blood pressure
  • baroreceptors are distributed in the carotid sinus and aortic arch, and when blood pressure rises, impulses are transmitted to the solitary nucleus of the medulla oblong according to the extension of the arterial wall.
  • the solitary nucleus suppresses the sympathetic nerve and stimulates the parasympathetic nerve.
  • the stimulation to the baroreceptor is reduced, the function of the solitary nucleus is attenuated, the parasympathetic nerve is suppressed, and the sympathetic nerve is stimulated.
  • an increase in cardiac contraction force, pulse and contraction of peripheral arteries occur, and blood pressure is maintained.
  • the veins also contract, increasing the amount of blood returned to the heart.
  • the bionic arterial reflex system of the present invention can be used for a patient who cannot maintain normal blood pressure due to some kind of failure in such a blood pressure regulation mechanism.
  • the bionic arterial baroreflex system of the present invention will be described with reference to the drawings.
  • the basic configuration of the bionic arterial baroreflex system is shown in FIG.
  • the bionic arterial baroreflex system of the present invention comprises at least arterial pressure sensing means (2), calculation means (3) and aortic decompression nerve stimulation means (4).
  • Arterial pressure sensing means (2) senses the blood pressure in the artery and outputs the blood pressure.
  • arterial pressure sensing means or “arterial pressure (AP) sensor” means means capable of sensing arterial pressure information from a living body and outputting an arterial pressure signal, unless otherwise specified.
  • the arterial pressure information includes various information correlated with the arterial pressure, and the “arterial pressure sensing means” may include various means as long as it can be continuously detected.
  • the “arterial pressure sensing means” includes means for non-invasive arterial pressure measurement by, for example, oscillometric method, tonometry method, or volume compensation method, in addition to means for invasive blood pressure measurement. .
  • the arterial pressure sensing means (2) is not particularly limited as long as it can sense arterial pressure information from a living body and output an arterial pressure signal.
  • an arterial pressure sensor (narrow sense) is exemplified. Can do.
  • the calculation means (3) receives the arterial pressure signal sensed by the arterial pressure sensing means (2), analyzes and processes the arterial pressure signal, A clinically effective biostimulation signal is calculated and a biostimulation signal is output.
  • the biostimulation signal calculated by the calculation means (3) is output to the biostimulation means (4) described later.
  • an arterial pressure signal sensed by the arterial pressure sensing means is input to calculate a clinically effective biological stimulation signal, Means for outputting a biostimulation signal.
  • the term “clinically effective” as used herein is effective for adjusting the arterial pressure in the same manner as when relying on physiological arterial pressure reflex when stimulating a portion of a living body where the arterial pressure can be adjusted. That means.
  • the arterial pressure signal sensed by the arterial pressure sensing means (2) may be first input to an amplifying device (not shown) and amplified.
  • the amplifying apparatus includes a filter device that can remove a frequency higher than a certain frequency and a frequency lower than a certain frequency to remove a signal derived from a living body and power line noise.
  • the amplified signal may be converted from an analog signal to a digital signal by an A / D conversion device (not shown), and then input to an analysis processing device (not shown).
  • predetermined processing is performed, and a biological stimulus signal is calculated.
  • the calculation means (3) may include an identification means for identifying whether the input arterial pressure signal is due to normal biological activity or abnormal biological activity. When the arterial pressure signal is identified as normal biological activity, the biostimulation signal is not output. When the input biological activity signal is identified as abnormal biological activity, the biostimulation signal is output. You may design as follows.
  • the calculation of the biostimulation signal in the calculation means (3) will be described below, taking as an example the case of controlling the arterial pressure by stimulating the aortic decompression nerve.
  • the blood pressure and the impulse response of the calculation means (3) are convolutionally integrated in order to determine the biological stimulus signal.
  • the impulse response can be calculated by performing a Fourier transform on the arterial pressure signal, obtaining a transfer function based on the Fourier transformed value, and performing an inverse Fourier transform on the transfer function.
  • the transfer function (frequency domain) incorporated in the calculation means (3) was obtained as a graph on the left of FIG. This graph is the impulse response h (t) on the right side of FIG.
  • the history AP (1), AP (2), ..., AP (49) of blood pressure t 1 to 49 observation points is recorded, and the blood pressure just measured is AP
  • the impulse response is approximated by a delta function when calculating the biological stimulus signal.
  • STM AP (0.01) * h (0.01) + AP (0.02) * h (0.02) +... + AP (99.99) * h (99.99 ) + AP (100) * h (100) is calculated every 0.01 seconds (10 6 product-sum operations per second), whereas in the delta function approximation method, one multiplication per 0.01 seconds (1 100 operations per second) is sufficient, and the computational load on the computer can be reduced to 1/10000 or less.
  • the knowledge that the stimulation frequency can be determined by applying a constant value to the blood pressure value is provided for the first time by the present invention.
  • this method has a practically important meaning that the system development becomes easy because the amount of real-time computation can be greatly saved as compared with the convolution integration method.
  • the present inventors have also confirmed that there is no significant difference in control results between the direct convolution and integration method and the simple proportional calculation method.
  • the biological stimulation means (4) inputs the arterial pressure signal calculated by the calculation means (3) described above, and stimulates a part of the living body that can adjust the arterial pressure based on the stimulation signal to Adjust.
  • the term “biological stimulation means” in the present invention includes various means capable of appropriately stimulating a part of a living body where the arterial pressure can be adjusted, unless otherwise specified.
  • the stimulation may be based on electrical stimulation as well as magnetic stimulation, and the stimulation site may be the aortic decompression nerve, the aortic arch itself, the carotid sinus nerve, or the carotid sinus itself. Direct stimulation or electrical field stimulation can be performed.
  • a typical example of the biological stimulation means (4) is an electrical nerve stimulation device that stimulates the aortic decompression nerve. Examples of the site of nerve stimulation include ganglia, the surface of the spinal cord, and a suitable site in the brain, but are not limited thereto as long as the site can be stimulated effectively.
  • the intensity of biostimulation, the width and frequency of the rectangular wave are based on the target species, weight, age, sex, state, stimulation site, target effect, etc. It can be designed as appropriate. Further, it can be designed with reference to an existing treatment device (for example, Rheos® system® (CVRx)) for example for hypertensives.
  • the stimulation voltage can be in the range of 2.0-6.0 Volts for rats (see FIG. 13), and larger voltages, eg, ⁇ 20 when performed on humans. May be Volts.
  • the above-mentioned Rheos® system does not stimulate nerves directly, but adopts a method in which the entire carotid sinus is stimulated by an electric field, but this device can stimulate at a voltage of 7.0 V or less, and can be referred to in the present invention.
  • ⁇ Electric stimulation can also be performed with constant current stimulation in addition to constant voltage stimulation.
  • constant current stimulation for example, 0.01 to 0.2 ⁇ mA for rats and 0.1 to 2.0 ⁇ mA for humans, for example, sufficient stimulation may be possible.
  • the width of the rectangular wave can be 0.5 to 2.0 ms for humans, and the stimulation frequency can be up to 100 Hz for humans. .
  • the bionic arterial baroreflex system is based on blood pressure, and does not use blood pressure as it is as an aortic decompression nerve stimulation signal, but performs an appropriate calculation, and is a therapeutically effective aorta. Since a decompressed nerve stimulation signal is output, stable blood pressure control can be performed in the same manner as a living body.
  • the aortic decompression nerve was cut bilaterally. Normal arterial baroreflex was mimicked by matching CSP to arterial pressure (normal), and arterial baroreflex imperfection was mimicked by maintaining CSP at a steady value regardless of arterial pressure (failure).
  • Dextran was injected stepwise at a rate of 1 to 4 ml / kg / min until the LAP reached 14 to 16 mmHg ( Figure 1).
  • LAP left atrial pressure
  • ⁇ V injection volume
  • Fig. 3 shows typical LAP- ⁇ V and AP- ⁇ V relationships.
  • Arterial baroreflex acts to buffer a critical amount.
  • the critical amount here is ⁇ V required to raise LAP to 20 mmHg.
  • the critical amount was 17.22 ⁇ 1.91 ml / kg under normal conditions, while it significantly decreased to 11.16 ⁇ 1.58 ml / kg under arterial baroreflex failure (p ⁇ 0.01).
  • the difference was 6.05 ml / kg (ie, 25% of the effective circulating blood volume, Ogilivie, Circulation 1992), and the amount corresponding to 420 ml in the 70 kg patient (FIG. 4). Since the carotid sinus is injured by a surgical procedure for experimental convenience, the simulated normal arterial baroreflex function is impaired as compared with the original normal arterial baroreflex function. Therefore, the difference in patients may be even greater than this calculation. Arterial baroreflex failure, on the other hand, increases blood pressure (mBP) at a critical amount ( Figure 5).
  • mBP blood pressure
  • Arterial baroreflex failure makes hemodynamics sensitive to changes in blood volume and makes patients more prone to pulmonary edema regardless of LV function.
  • the HFpEF patient has arteriosclerosis at the base, the patient will be prone to pulmonary edema.
  • Surgical procedure Baroreceptor region was separated from systemic circulation. The carotid sinus pressure was adjusted with a servo-driven piston pump. Bilateral aortic decompression nerve was cut. An electrode pair was attached to the proximal end of any one aortic decompression nerve.
  • Fig. 6 shows a schematic diagram of the bionic arterial baroreflex system.
  • the bionic arterial baroreflex system consists of an arterial pressure (AP) sensor, a regulator (bionic brain) and an electrical nerve stimulator.
  • the stimulator generates a rectangular wave train according to a command from the regulator to stimulate the aortic decompression nerve.
  • the regulator automatically calculates the instantaneous stimulation frequency of the aortic decompression nerve according to the convolution algorithm.
  • the bionic arterial baroreflex system used digitized arterial pressure (BP) at 200 Hz (or higher frequency), averaged over 0.5 seconds (mean blood pressure, mBP), and resampled at 2 Hz.
  • the length of time for averaging blood pressure can vary from the moment (5 ms) to 30 seconds, depending on the purpose of the system.
  • the resampling frequency may be matched to the average time length (Nyquist frequency).
  • the cut-off frequency of the body-specific arterial baroreflex is about 0.1 Hz, and the bionic arterial baroreflex system using a resampling frequency lower than 0.2 Hz cannot reproduce the physiological arterial baroreflex.
  • even such a system can reduce the computational complexity and reproduce the arterial baroreflex in the range below the physiological cutoff frequency.
  • the mBP was converted to the stimulation frequency of the aortic decompression nerve by the controller. Although less accurate, it is possible to make the convolution integration period shorter than 60 seconds (10-60 seconds).
  • the impulse response of the regulator approximated a delta function.
  • the scaling factor is approximated by the time integration of the impulse response.
  • the aortic decompression nerve was stimulated according to the stimulation frequency obtained by the control device.
  • the aortic decompression nerve may be left, right or both.
  • the stimulation frequency was updated with the resampling frequency.
  • the stimulation pulse width could be 0.1-2.0 ms and the stimulation voltage could be in the range of 2.0-6.0 volts.
  • the hypotensive effect of aortic decompression nerve stimulation was saturated above 80 Hz. Therefore, the stimulation frequency was limited to zero to 80 Hz (FIG. 13).
  • Bionic arterial baroreflex system restores normal arterial baroreflex function, which is indistinguishable from physiological arterial baroreflex in the absence of physiological arterial baroreflex.
  • the simplified algorithm of the bionic arterial baroreflex system reduces the computational complexity resulting from real-time convolution and does not degrade performance.
  • Bionic arterial baroreflex system may be a powerful tool in preventing pulmonary edema episodes in heart failure with preserved ejection fraction.

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Abstract

La présente invention concerne un système baroréflexe aortique bionique qui restaure une tolérance de volume normale en l'absence de baroréflexe aortique physiologique et, par conséquent, est utile dans le traitement de l'HFpEF. Plus précisément, l'invention concerne un système baroréflexe aortique bionique comprenant : un moyen de détection de pression aortique (capteur de pression aortique (PA)) pour détecter des données de pression aortique à partir d'un organisme vivant et générer un signal de pression aortique; un moyen de calcul (régulateur) pour entrer le signal de pression aortique, qui est détecté par le moyen de détection de pression aortique, calculer un signal de stimulation du nerf aortique dépresseur cliniquement efficace et générer le signal de stimulation du nerf aortique dépresseur; et un moyen de stimulation du nerf aortique dépresseur (neurostimulateur électrique) pour générer le signal de stimulation du nerf aortique dépresseur, qui est calculé par le moyen de calcul, et stimuler le nerf aortique dépresseur de l'organisme vivant sur ​​la base du signal de stimulation du nerf aortique dépresseur.
PCT/JP2011/071470 2010-09-21 2011-09-21 Système baroréflexe aortique bionique pour traiter les maladies associées à la dysfonction baroréflexe aortique Ceased WO2012039420A1 (fr)

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US10973827B2 (en) 2008-04-03 2021-04-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US11033552B2 (en) 2006-05-04 2021-06-15 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US11084819B2 (en) 2006-05-04 2021-08-10 Boehringer Ingelheim International Gmbh Polymorphs
US11291668B2 (en) 2006-05-04 2022-04-05 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US11911388B2 (en) 2008-10-16 2024-02-27 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug
US11911387B2 (en) 2010-11-15 2024-02-27 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US12312352B2 (en) 2012-05-14 2025-05-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in SIRS and/or sepsis
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JP2007537823A (ja) * 2004-05-17 2007-12-27 シー・アール・バード・インコーポレーテッド 高密度心房細動周期長（ａｆｃｌ）検出およびマッピングシステム
JP2009512505A (ja) * 2005-10-24 2009-03-26 カーディアック ペースメーカーズ インコーポレイテッド 埋め込み型充電式神経刺激装置

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WO2004012814A1 (fr) * 2002-08-05 2004-02-12 Japan As Represented By President Of National Cardiovascular Center Systeme de traitement medical utilisant une alternative de fonction regulatrice biologique, systeme de stimulateur cardiaque fonde sur ce systeme de traitement medical, systeme de regulation de pression sanguine et systeme de traitement de cardiopathie
JP2007537823A (ja) * 2004-05-17 2007-12-27 シー・アール・バード・インコーポレーテッド 高密度心房細動周期長（ａｆｃｌ）検出およびマッピングシステム
JP2009512505A (ja) * 2005-10-24 2009-03-26 カーディアック ペースメーカーズ インコーポレイテッド 埋め込み型充電式神経刺激装置

Cited By (12)

* Cited by examiner, † Cited by third party
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US11033552B2 (en) 2006-05-04 2021-06-15 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US11084819B2 (en) 2006-05-04 2021-08-10 Boehringer Ingelheim International Gmbh Polymorphs
US11291668B2 (en) 2006-05-04 2022-04-05 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US11919903B2 (en) 2006-05-04 2024-03-05 Boehringer Ingelheim International Gmbh Polymorphs
US12171767B2 (en) 2006-05-04 2024-12-24 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US12178819B2 (en) 2006-05-04 2024-12-31 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US10973827B2 (en) 2008-04-03 2021-04-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US11911388B2 (en) 2008-10-16 2024-02-27 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug
US11911387B2 (en) 2010-11-15 2024-02-27 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
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