WO2024242594A1 - Agent de traitement d'hypertensions pulmonaires - Google Patents

Agent de traitement d'hypertensions pulmonaires Download PDF

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Publication number
WO2024242594A1
WO2024242594A1 PCT/RU2024/050109 RU2024050109W WO2024242594A1 WO 2024242594 A1 WO2024242594 A1 WO 2024242594A1 RU 2024050109 W RU2024050109 W RU 2024050109W WO 2024242594 A1 WO2024242594 A1 WO 2024242594A1
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Prior art keywords
pulmonary
formula
pressure
hypertension
riociguat
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Russian (ru)
Inventor
Сергей Александрович СТАНКЕВИЧ
Владимир Валерьевич БЫКОВ
Валентин Владимирович ЛАРЧЕНКО
Вениамин Абрамович ХАЗАНОВ
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Obschestvo S Ogranichennoi Otvetstvennostju Iphar
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Obschestvo S Ogranichennoi Otvetstvennostju Iphar
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to the field of pharmacology and medicine, in particular to agents that can be used to treat pulmonary hypertension.
  • Pulmonary hypertension is a group of diseases characterized by a progressive increase in pulmonary vascular resistance and pulmonary artery pressure, which leads to the development of right ventricular failure and premature death.
  • the pathogenesis of pulmonary hypertension is based on the narrowing of blood vessels in the lungs, their thrombosis and remodeling (excessive cellular proliferation and fibrosis of the vascular wall), which worsens blood flow, increases pulmonary vascular resistance and pressure in the pulmonary artery.
  • the latter leads to an increase in the load on the right ventricle of the heart and its hypertrophy, but gradually the compensatory mechanisms prove insufficient and right ventricular heart failure occurs [1].
  • PAH pulmonary arterial hypertension
  • CTEPH chronic thromboembolic pulmonary hypertension
  • endothelial dysfunction which is manifested by a decrease in the synthesis of vasodilating factors (nitric oxide (NO), prostacyclin), hyperproduction of vasoconstrictor substances (endothelial-1, thromboxane A2, serotonin), the formation of prothrombotic conditions and the development of inflammatory reactions in the vascular wall, which ultimately leads to hypertension, smooth muscle hypertrophy, thrombosis and vascular remodeling [2].
  • NO-sGC-cGMP nitric oxide - soluble guanylate cyclase - cyclic guanosine monophosphate
  • the main elements of this signaling pathway are the enzymes endothelial NO synthase (eNOS), responsible for the synthesis of nitric oxide (NO), and soluble guanylate cyclase (sGC), responsible for the synthesis of cyclic guanosine monophosphate (cGMP) [3].
  • NO is synthesized by eNOS in the cells of the endothelium of blood vessels and activates sGC, which is present in many cells, including endothelial and smooth muscle cells of blood vessels, platelets, leukocytes, etc.
  • sGC a messenger molecule responsible for relaxation of vascular wall smooth muscle cells (vasodilating or antihypertensive effect).
  • cGMP a messenger molecule responsible for relaxation of vascular wall smooth muscle cells (vasodilating or antihypertensive effect).
  • cGMP also helps reduce inflammation, proliferation, and fibrosis.
  • Many cardiovascular diseases such as arterial hypertension, pulmonary hypertension, heart failure, and others, are associated with disruption of the NO-sGC-cGMP signaling pathway [4, 5].
  • the sGC stimulator BAY 63-2521 (code name) or riociguat (international nonproprietary name) was the first drug in this class approved for the treatment of patients with PAH and CTEPH.
  • Riociguat is methyl H-[4,6-diamino-2-[1-[(2-fluorophenyl)methyl]-1 H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methylcarbamate:
  • riociguat Due to stimulation of sGC, riociguat has a pronounced hypotensive and antihypertensive effect. Thus, in studies on spontaneously hypertensive SHR rats, riociguat, when administered orally once, led to a long-term and dose-dependent decrease in mean arterial pressure [7, Fig. 1]
  • SHR rats are a natural model of progressive arterial hypertension, which develops in them due to dysfunction of the vascular endothelium. Therefore, SHR rats are used as a standard model for studying sGC stimulators or activators, which, due to the mechanism of action, are able to restore the properties of the vascular wall under conditions of endothelial dysfunction.
  • sGC stimulators or activators which, due to the mechanism of action, are able to restore the properties of the vascular wall under conditions of endothelial dysfunction.
  • riociguat improves hemodynamic parameters in animals with a model of pulmonary hypertension and in patients with pulmonary hypertension - it reduces pulmonary vascular resistance, pressure in the pulmonary artery and the right ventricle of the heart.
  • riociguat reduces not only the pressure in the pulmonary artery (i.e., the pressure in the pulmonary circulation), but also the systemic arterial pressure in the systemic circulation.
  • riociguat at doses of 1 and 10 mg/kg dose-dependently reduced both the pressure in the pulmonary artery and the systemic arterial pressure by 5-15% [8, Fig. 2].
  • Riociguat is recommended for use as an antihypertensive agent for the treatment of a number of forms of pulmonary hypertension, such as pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Based on the results of clinical studies and clinical experience, it has been established that the most common and dangerous side effect of riociguat is hypotension (a decrease in systemic blood pressure), which manifests itself as headaches, dizziness, and peripheral edema [9].
  • sGC stimulator vericiguat
  • vericiguat Another sGC stimulator, vericiguat, was approved in 2021 for the treatment of patients with heart failure. It has much in common with riociguat in its chemical structure - it is methyl -[4,6-diamino-2-[5-fluoro-1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]carbamate:
  • vericiguat As well as riociguat, is hypotension, as evidenced by the results of clinical studies of vericiguat in patients with heart failure [10].
  • sGC stimulants including praliciguat, are at various stages of development.
  • praliciguat in doses from 0.3 to 10 mg/kg reduces arterial pressure not only in spontaneously hypertensive SHR rats (by approximately 27% at the maximum dose), but also in normotensive Wistar rats - by 10-12% from the initial level, which reflects the side hypotensive effect of the drug.
  • sGC activators are also known, which differ in the mechanism of binding to the target from sGC stimulators. Activators bind to oxidized, heme-free sGC, formed under the influence of oxidative stress in many cardiovascular diseases, and act independently of the presence of NO. Examples of sGC activators include cinaciguat
  • sGC activators exhibit a powerful vasodilatory effect at nanomolar concentrations.
  • clinical development of cinaciguat and ataciguat was discontinued precisely because of the pronounced side hypotensive effect on systemic arterial pressure [12].
  • sGC stimulators and activators have an antihypertensive effect, useful for the treatment of pulmonary hypertension and a number of other cardiovascular diseases.
  • all of them have a dangerous side hypotensive effect on systemic blood pressure, which greatly limits the use of such drugs.
  • the search for new compounds - sGC stimulators or activators for the treatment of pulmonary hypertension and other cardiovascular diseases capable of eliminating the manifestations of endothelial dysfunction, reducing high pressure in the pulmonary artery and right ventricle of the heart, having an antihypertensive effect at an elevated level of systemic blood pressure, but not having a negative hypotensive effect on systemic blood pressure at its normal level, is of great importance for modern pharmacology.
  • the antithrombotic and antiatherosclerotic agent 2-[2-[5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-ylidene]-2-cyanoethylidene]indolin-3-one of formula I is known which is used as an activator of the enzyme soluble guanylate cyclase, an inhibitor of platelet aggregation with antihypertensive activity to obtain a drug for the treatment of cardiovascular diseases [13].
  • the technical problem to be solved is the elimination of the negative side hypotensive effect on systemic blood pressure in the treatment of pulmonary hypertension.
  • the technical result is the absence of a negative side hypotensive effect on systemic blood pressure while maintaining a positive therapeutic effect in the treatment of pulmonary hypertension, including the elimination of manifestations of endothelial dysfunction and normalization of hemodynamic parameters of the pulmonary circulation (reduction of increased pressure in the pulmonary artery and right ventricle of the heart, reduction of pulmonary vascular resistance, restoration of cardiac output of the right ventricle).
  • 2-[2-[5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-ylidene]-2-cyanoethylidene]indolin-3-one of formula I for the treatment of chronic thromboembolic pulmonary hypertension.
  • 2-[2-[5-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-ylidene]-2-cyanoethylidene]indolin-3-one of formula I is administered orally at a dose of 1.5 to 200 mg.
  • the compound of formula I does not have a hypotensive effect on systemic BP in mammals, including humans, at its initially normal level (see examples 1 and 2).
  • the compound of formula I is at least as good as the known agents in terms of the strength and duration of the antihypertensive effect at an initially elevated BP level - in spontaneously hypertensive SHR rats (example 1).
  • the studies have also shown that the compound of formula I does not reduce systemic BP in animals with a pulmonary hypertension model (example 4).
  • the compound of formula I is as effective as riociguat - normalization of the hemodynamic parameters of the pulmonary circulation in standard models of various forms of pulmonary hypertension: PAH and CTEPH.
  • PAH standard models of various forms of pulmonary hypertension
  • CTEPH CTEPH
  • the compound of formula I does not affect systemic BP in normotensive rats or the BP value in healthy people with initially normal BP (examples 1 and 2).
  • PAH model (example 4) it was found that the compound of formula I even restored (increased to values close to the normal level) the reduced systemic BP in rats with PAH.
  • Riociguat on the contrary, reduced systemic BP even more, which is a dangerous side effect.
  • the antihypertensive action of the compound of formula I is based on its ability to eliminate manifestations of endothelial dysfunction, in particular, the impairment of the vasodilating (vasoconstricting) properties of the endothelium.
  • the compound of formula I is superior to riociguat in its effect on the vasodilating properties of the endothelium, which is manifested in the normalization of the parameters of endothelium-dependent vasodilation (example 4).
  • the compound of formula I unlike riociguat or other known sGC stimulators and activators, does not have a dangerous hypotensive effect on systemic BP at its normal or low value. This allows safe use of drugs based on the compound of formula I as an antihypertensive agent for the treatment of pulmonary hypertension, as well as other cardiovascular diseases.
  • Fig. 1 taken from publication [7], shows the effect of riociguat upon its single oral administration at doses from 0.03 to 3 mg/kg on systemic arterial pressure in spontaneously hypertensive SHR rats.
  • the abscissa axis shows the time after drug administration in hours, the ordinate axis shows the values of mean BP in percent. Shown are the average values for 6-12 animals for each group as a percentage of the initial values (131-142 mmHg).
  • Fig. 2 taken from publication [8], shows the effect of riociguat (BAY 63-2521) administered orally at doses of 1 and 10 mg/kg on pulmonary arterial pressure and systemic arterial pressure in rabbits with a model of pulmonary arterial hypertension.
  • the abscissa axis shows the test compounds: BAY 63-2521, sildenafil and their combination; the ordinate axis shows the values of systemic BP as a percentage of the initial level. Column designations in the figure: > - pulmonary arterial pressure; ⁇ - systemic arterial pressure; the * sign indicates statistically significant differences from the control (p ⁇ 0.05).
  • the presented data show that riociguat (BAY 63-2521) at doses of 1 and 10 mg/kg reduces both pulmonary arterial pressure and systemic arterial pressure to an equal extent in a rabbit model of pulmonary arterial hypertension.
  • Fig. 3 taken from publication [11], shows the effect of praliciguat (IW-1973) administered orally daily for 3 days at doses from 0.3 to 10 mg/kg on systemic arterial pressure in normotensive Wistar rats and spontaneously hypertensive SHR rats.
  • the abscissa axis shows the doses of IW-1973 in mg/kg (0 - vehicle, 0.3, 1, 3 and 10 mg/kg); the ordinate axis shows the values of the decrease in mean arterial pressure on the 3rd day relative to the initial level in mmHg. The number of animals in each group was 6.
  • Fig. 4 shows the results of a study of the effect of a compound of formula I upon its single oral administration at doses of 5, 10 and 20 mg/kg on systemic arterial pressure in normotensive CD rats and spontaneously hypertensive SHR rats.
  • the abscissa axis shows the time after administration of the drug in hours, and the ordinate axis shows the values of mean BP in mm Hg.
  • the data presented show that GRS causes a long-term and dose-dependent decrease in mean BP in spontaneously hypertensive rats, but does not have any effect on systemic BP in normotensive rats.
  • Fig. 5 schematically shows the approach to assessing the parameters of the vasodilatory function of the vascular endothelium based on the area of the triangle above the mean arterial pressure recovery curve, where one leg represents the magnitude of the decrease in mean arterial pressure (AmAP) in response to the introduction of a vasodilator, and the other leg represents the time of mean arterial pressure recovery.
  • AmAP mean arterial pressure
  • the animals were administered the compound of formula I (code name of the compound - GRS) intragastrically at doses of 5, 10 and 20 mg/kg.
  • a 0.5% solution of carboxymethylcellulose was used as a carrier for intragastric administration.
  • Animals of the control groups received only a 0.5% solution of carboxymethylcellulose.
  • Systemic arterial pressure indicators - systolic BP (SBP) and diastolic BP (DBP) were measured before administration and 1, 2, 4, 8 and 24 hours after a single administration of the substances.
  • MAP Mean arterial pressure
  • GRS exerted a pronounced dose-dependent antihypertensive effect in spontaneously hypertensive SHR rats.
  • the most pronounced effect in terms of amplitude and duration was observed with intragastric administration of GRS at doses of 10 and 20 mg/kg - the mean arterial pressure in SHR rats decreased by 45% after 1 hour, reaching the level of normotensive CD rats, the effect lasted for at least 24 hours.
  • the antihypertensive effect of GRS remained unchanged.
  • the arterial pressure of SHR rats returned to the initial level.
  • GRS did not affect the arterial pressure level of animals with normal pressure, which follows from the data shown in Fig. 4 and in Tables 1, 2.
  • the compound of formula I unlike riociguat and other known sGC stimulants and activators, does not have any effect on systemic blood pressure at its normal level, but at the same time has a pronounced antihypertensive effect in animals with elevated blood pressure (SHR rats).
  • the compound of formula I unlike riociguat and other known sGC stimulants and activators, does not have a negative side hypotensive effect on systemic blood pressure at its normal level in a healthy person.
  • Example 3 Effect of the compound of formula 1 on arterial pressure and other hemodynamic parameters in a model of chronic thromboembolic pulmonary hypertension in minipigs
  • CTEPH chronic thromboembolic pulmonary hypertension
  • CTEPH chronic obstructive pulmonary artery .
  • Histological studies in the tissues and vessels of the lungs revealed morphological changes characteristic of developing CTEPH of the precapillary type with the formation of extensive zones of atelectasis (collapse of lung tissue), obliteration of the lumen of small and medium-diameter blood vessels with the formation of intravascular thrombi, hypertrophy of the walls of small blood vessels with collagenization of the wall and the loss of its typical structure.
  • the animals were randomized into 3 groups.
  • the first group received treatment with the compound of formula I (40 mg divided into 20 mg twice daily, orally), the second received riociguat (4 mg divided into 2 mg 2 times a day, orally), the third (control group) of animals was observed without therapy (received the carrier - starch).
  • the duration of the course of therapy was 36 days.
  • a Corodyn catheter (B. Braun, Germany) was inserted into the right ventricle and then into the pulmonary artery through an introducer into the anesthetized animals under fluoroscopy control using a mobile X-ray unit OEC9900 (GE Healthcare, USA), with the help of which the hemodynamic parameters of the pulmonary circulation were measured: average pressure in the pulmonary artery, pulmonary artery wedge pressure and cardiac output.
  • the sign “ # ” indicates statistically significant differences with the indicator in the control group (P ⁇ 0.05).
  • a course of treatment with the compound of formula I has a pronounced therapeutic effect in CTEPH, normalizing the main parameters of hemodynamics of the pulmonary circulation, which are impaired in CTEPH - it reduces the increased mean pressure in the pulmonary artery and pulmonary vascular resistance, and also restores the reduced cardiac output of the right ventricle.
  • Example 4 Effect of compound of formula 1 on hemodynamic parameters and endothelial dysfunction in a model of pulmonary arterial hypertension in rats
  • GRS (10 mg/kg) and riociguat (1 mg/kg) as a suspension in 1% starch mucus were administered intragastrically daily for 2 weeks, starting from the 15th day after monocrotaline administration. Intact animals and control group rats received 1% starch mucus according to the same scheme.
  • the GRS dose used in the study (10 mg/kg) corresponds to the average effective dose at which its antihypertensive effect is manifested.
  • the riociguat dose used in the study (1 mg/kg) is close to the upper limit of the dose range (0.03-3 mg/kg) at which its antihypertensive effect is manifested, i.e. it even exceeds the average effective dose.
  • the maximum (Pmax, mmHg) and minimum (Pmm, mmHg) pressure in the right ventricle, the maximum rate of pressure change during a contraction cycle (dP/dtmax, mmHg/s), and the contractile index (CI, 1/s) were determined from the pressure curve.
  • RVW/BW right ventricular wall weight/body weight
  • RVW/HW right ventricular wall weight/heart weight
  • vascular endothelium To assess the vasodilatory activity of the vascular endothelium, a catheter was implanted into the left carotid artery of rats under inhalation anesthesia (isoflurane). Systemic arterial pressure was recorded using an MP150 high-speed data acquisition and analysis system (BiopacSystems, Inc., USA) with a DA100C general-purpose amplification module and a TSD104A pressure sensor. Data were recorded and processed on a computer using the AcqKnowledge 4.2 for MP 150 program.
  • MAP mean arterial pressure
  • the area of the triangle above the curve of MAP recovery was used, where one leg represented the magnitude of the decrease in MAP (AMAP) in response to the introduction of the vasodilator (mm Hg), and the other ⁇ the time of MAP recovery after the test (Fig. 5).
  • the degree of endothelial dysfunction in experimental animals was assessed by the endothelial dysfunction coefficient (EDC), which is the ratio of the area of the triangle above the curve of MAP recovery after the introduction of NP to the area of the triangle above the curve of MAP recovery after the introduction of ACh [18, 19].
  • the sign “ # ” means reliable differences compared to the values in animals of the control group (p ⁇ 0.05)
  • the control group rats showed a pronounced (2.25-fold) increase in pressure (Pmax) in the right ventricle of the heart, which is typical for PAH, compared to intact animals. Accordingly, the maximum rate of pressure change per contraction cycle (dP/dtmax) increased by 1.8 times.
  • the increase in pressure in the right ventricle in PAH reflects an increase in pressure in the pulmonary circulation (pressure in the pulmonary artery) due to an increase in pulmonary vascular resistance against the background of progressive damage to the vessels and tissues of the lung.
  • the compound of formula I (GRS) and riociguat have a comparable therapeutic effect in animals with a PAH model - they reduce the pressure in the right ventricle of the heart, which is elevated in PAH.
  • the sign “ # ” indicates reliable differences compared to the values in rats of the control group (p ⁇ 0.05).
  • the EDC value increased to 2.36 ⁇ 0.27 compared to 1.80 ⁇ 0.06 in the control, although this decrease did not reach the level of statistical significance.
  • ASmAP value was statistically significantly higher than in the control and did not differ from the value in the intact group
  • recovery time of MAP was statistically significantly higher compared to the value in the intact group and did not differ from the value in the control and the group with riociguat.
  • the ASmAP value was statistically significantly higher compared to the value in the animals of the group receiving riociguat and did not differ from the value in intact animals, and the recovery time of MAP was statistically significantly lower than in the group with riociguat and also did not differ from the values in the control and in intact animals.

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Abstract

L'invention se rapporte au domaine de la pharmacologie et notamment à des agents de traitement d'hypertensions pulmonaires. L'invention concerne du 2-[2-[5-(hydroxyméthyl)-3-méthyl-1,3-oxazolidine-2-ilydène]-2-cyanoéthylidène] indoline-3-one correspondant à la formule I que l'on utilise en qualité d'agent de traitement d'hypertensions pulmonaires sans action d'hypotension indésirable en ce qui concerne la pression artérielle du système. L'agent selon la formule I est utilisé pour normaliser les paramètres de l'hémodynamique de la petite circulation sanguine, comprenant une diminution de la pression accrue dans l'artère pulmonaire et le ventricule droit du cœur, une diminution de la résistance vasculaire pulmonaire, et un rétablissement du refoulement cardiaque du ventricule droit. L'agent selon la formule I est utilisé lors d'une hypertension artérielle pulmonaire ou lors d'une hypertension pulmonaire thrombo-embolique chronique. De manière optimale, l'agent selon la formule I est utilisé pour une administration à des mammifères dans des doses de 1,5 à 200 mg.
PCT/RU2024/050109 2023-05-23 2024-05-23 Agent de traitement d'hypertensions pulmonaires Ceased WO2024242594A1 (fr)

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RU2023113346 2023-05-23
RU2023113346A RU2813890C1 (ru) 2023-05-23 Средство для лечения легочных гипертензий

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2622386C2 (ru) * 2012-01-31 2017-06-15 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Производное ситаксентана
WO2017192553A1 (fr) * 2016-05-02 2017-11-09 The Regents Of The University Of Michigan Compositions et méthodes de traitement de l'hypertension artérielle pulmonaire
EA030938B1 (ru) * 2014-05-14 2018-10-31 Новартис Аг Производные карбоксамида
RU2763525C2 (ru) * 2016-10-27 2021-12-30 Пульмокин, Инк. Комбинированная терапия для лечения легочной гипертензии

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2622386C2 (ru) * 2012-01-31 2017-06-15 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Производное ситаксентана
EA030938B1 (ru) * 2014-05-14 2018-10-31 Новартис Аг Производные карбоксамида
WO2017192553A1 (fr) * 2016-05-02 2017-11-09 The Regents Of The University Of Michigan Compositions et méthodes de traitement de l'hypertension artérielle pulmonaire
RU2763525C2 (ru) * 2016-10-27 2021-12-30 Пульмокин, Инк. Комбинированная терапия для лечения легочной гипертензии

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAHAR KAMRUN ET AL.: "Liposomal Aerosols of Nitric Oxide (NO) Donor as a Long-Acting Substitute for the Ultra-Short- Acting Inhaled NO in the Treatment of PAH", PHARMACEUTICAL RESEARCH, vol. 33, no. 7, 2016, pages 1696 - 1710, XP035927745, DOI: 10.1007/s11095-016-1911-7 *

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