MRI COMPOSITIONS AND THEIR USE IN NON-FASTING SUBJECTS - Patent application

Abstract

The present invention relates to an oral magnetic resonance imaging (MRI) composition and its use in the in vivo diagnosis of liver metastases and / or primary liver cancer in subjects consuming a defined diet.

Description

[Technical field]

[0001] The present invention relates to an oral magnetic resonance imaging (MRI) composition and its use in the in vivo diagnosis of liver metastases and / or primary liver cancer in subjects consuming a defined diet. [Background technology]

[0002] Orvigrans is an oral liver imaging agent (i.e., a liver-specific contrast agent) for the detection and visualization of focal liver lesions using magnetic resonance imaging ("MRI") in subjects where the use of the current gold standard gadolinium-based contrast agents ("GBCAs") is medically undesirable or infeasible. MRI is a medical imaging technique used in radiology to produce pictures of the body's anatomical structures and physiological processes. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves to produce images of organs inside the body.

[0003] A study by Leander et al. (Investigative Radology, 45, 2010) showed that administration of an oral manganese-based MRI composition to non-fasting subjects followed by MRI demonstrated very low liver signal enhancement and the subjects were excluded from further efficacy analysis.

[0004] Therefore, fasting before administration of Orvigrans and other contrast agents is a routine procedure to ensure that imaging quality is not affected by interactions with various food components that affect the absorption of the contrast agent and / or by directly affecting the imaging properties of the manganese(II) ion and its complexes. Summary of the Invention

[0005] The inventors confirmed that subjects who consumed a full meal before administering Orvigrance were able to obtain significantly poorer image quality than that observed in fasting subjects. Prolonged fasting (more than 8 hours) is generally undesirable and may limit the willingness to use Orvigrance. In addition, some subjects may experience health risks or significant inconveniences from prolonged fasting. Surprisingly, the inventors demonstrated that consuming a meal with a calorie content of less than or equal to a certain value before administering Orvigrance results in image quality at least comparable to that of fasting subjects. These findings support the diagnostic potential of Orvigrance, especially in subjects for whom fasting is significantly inconvenient or associated with health risks.

[0006] In a first aspect, an MRI composition is provided comprising, separately or together, a physiologically acceptable manganese(II) compound, a proteinogenic amino acid and / or vitamin D, and one or more water-soluble excipients, the MRI composition being used for the in vivo diagnosis of liver metastasis and / or primary liver cancer in a subject, the subject having consumed a meal 0-8 hours prior to or up to about 2 hours after administration of the MRI composition, the meal having a caloric content equal to or less than a predetermined value.

[0007] In a second aspect, an MRI composition is provided comprising, separately or together, a physiologically acceptable manganese(II) compound, a proteinogenic amino acid and / or vitamin D, and one or more water-soluble excipients, the MRI composition being used for the in vivo diagnosis of liver metastasis and / or primary liver cancer in a subject, the subject having consumed a meal 0-8 hours prior to or up to about 2 hours after administration of the MRI composition, the meal having a caloric content of about 500 kcal or less.

[0008] In a third aspect, there is provided a method of magnetic resonance imaging (MRI) of a subject, comprising administering to the subject a composition comprising, separately or together, a physiologically acceptable manganese(II) compound, a proteinogenic amino acid and / or vitamin D, and one or more water soluble excipients, and performing an MRI on the subject, wherein the subject consumes a meal 0-8 hours prior to or up to about 2 hours after administration of the MRI composition, the meal having a caloric content of about 500 kcal or less.

[0009] In a fourth aspect, there is provided a method of reducing or preventing nausea, diarrhea, and / or headache in a subject administered an MRI composition comprising, separately or together, a physiologically acceptable manganese(II) compound, a proteinogenic amino acid, and / or vitamin D, and one or more water-soluble excipients, comprising: i) administering a meal to a subject; and ii) administering to the subject an MRI composition; Methods are provided wherein the meal is administered 0-8 hours prior to administration of the MRI composition or up to about 2 hours after administration of the MRI composition.

[0010] definition As used herein, the term "administration" refers to the act of the MRI composition entering the body of a subject. Thus, calculations of time before or after administration are calculated relative to the time the MRI composition enters the body of a subject.

[0011] The terms "meal," "prescribed meal," "snack," or "light meal," as used interchangeably herein, refer to food having a caloric content below about a pre-determined value, such as about 500 kcal or less. A pre-determined value refers to a caloric content that is significantly below the caloric content of a complete meal, which has a caloric content of about 900 kcal or more.

[0012] The term "water-soluble" is used herein to describe compounds that dissolve in water at room temperature, e.g., about 25° C. The degree of water solubility ranges from infinite solubility (unlimited) (completely miscible), such as ethanol in water, to poor solubility, such as silver chloride in water. The term insoluble is often applied to poorly or very poorly soluble compounds.

[0013] The term "water-insoluble" is used herein to describe a compound that does not dissolve in water at room temperature, e.g., about 25°C.

[0014] A number of other descriptive terms are used to quantify the solubility of a given solute, i.e., the compound of interest, in a solution. [Table 1]

[0015] The aqueous solubility of a given solute is usually temperature dependent. Depending on the nature of the solute, solubility may increase or decrease with temperature. For most solids and liquids, the solubility in water increases with temperature.

[0016] The term "hygroscopic" is used herein to describe a compound that, at 40-60% relative humidity (rH), sorbs water, either by absorption, adsorption, or a combination of the two processes, to any significant extent, e.g., such that the mass and / or volume of said compound increases by about 5% or more within a period of time, such as after about 1 hour.

[0017] The term "non-hygroscopic water-soluble" is used herein to describe a compound that is not hygroscopic as defined herein and at the same time is water-soluble as defined herein.

[0018] The term "absorption enhancer" is used herein synonymously with the term "uptake enhancer" which refers to compounds capable of enhancing manganese transport across the membranes of the gastrointestinal tract. These compounds are well known in the art, for example from WO 96 / 05867, and consist of physiologically acceptable reducing compounds containing an α-hydroxyketone group, physiologically acceptable acids containing α- and / or β-hydroxy or amino groups, or salts thereof, and / or vitamin D. [Brief description of the drawings]

[0019] [Figure 1] Overview of the study design for Example 1, including two periods of fasting and two groups of subjects consuming either a full meal or a snack before administration of Orvigrance. [Diagram 2] The relative change in liver MRI signal intensity (SI%) at 1, 4, 8, and 24 hours after dosing in fasting subjects (black line) is compared with the same subjects after a full meal (dotted line). The SI% obtained from imaging of subjects after a full meal is significantly lower than after a fasting period. The contents of the full meal are further described in Table 1. [Diagram 3] Relative change in liver MRI signal intensity (SI%) in subjects fasting (black line) and after ingestion of a snack (dotted line) at 1, 4, 8, and 24 hours after administration. The SI% obtained from imaging subjects after the snack is surprisingly at least as good as after fasting. The contents of the snack are further described in Table 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] In one embodiment, an MRI composition is provided comprising, separately or together, a physiologically acceptable manganese(II) compound, a proteinogenic amino acid and / or vitamin D, and optionally one or more water-soluble excipients, wherein the MRI composition is used for the in vivo diagnosis of liver metastasis and / or primary liver cancer in a subject, wherein the subject has consumed a meal within 8 hours prior to or up to about 2 hours after administration of the MRI composition, and the caloric content of the meal is about 500 kcal or less.

[0021] In one embodiment, use of the MRI composition reduces or prevents nausea, diarrhea, and / or headaches in a subject compared to a fasted subject who has not consumed food for 3 hours or more prior to administration of the MRI composition, i.e., in one embodiment, the subject experiences reduced nausea, diarrhea, and / or headaches compared to a fasted subject administered the MRI composition.

[0022] In one embodiment, the subject has not fasted for more than 3 hours prior to administration of the MRI composition.

[0023] Subjects who are adversely affected by fasting In addition to being uncomfortable or inconvenient, some subjects may be adversely affected by fasting for health reasons.These subjects are particularly suitable for the MRI composition and its use described herein.Therefore, in one embodiment, the MRI composition is provided for use in subjects who are adversely affected by not eating for 8 hours or more.

[0024] In one embodiment, the subject suffers from a disease that poses a health risk if the subject does not eat for 8 hours or more.Thus, in some embodiments, the present disclosure provides MRI compositions for use in subjects who have not eaten for 8 hours or more prior to administration of the MRI composition.

[0025] In one embodiment, the subject has one or more of the following: a. diabetes, e.g., type I diabetes or type II diabetes, b. Body mass index (BMI) of 20 or less; c. Age 60 years or older; and / or d.Hyperthyroidism.

[0026] timing In one embodiment, the subject consumes a meal about 0-8 hours prior to administration of the MRI composition, e.g., about 0-1 hour, e.g., about 1-2 hours, e.g., about 2-3 hours, e.g., about 3-4 hours, e.g., about 4-5 hours, e.g., about 5-6 hours, e.g., about 6-7 hours, e.g., about 7-8 hours, or up to about 2 hours after administration. In one embodiment, the subject consumes a meal up to about 30 minutes, e.g., up to about 1 hour, e.g., up to about 2 hours after administration of the MRI composition.

[0027] In one embodiment, the subject consumes a meal within about 1 hour prior to administration of the MRI composition, such as within about 45 minutes prior to administration of the MRI composition, such as within about 30 minutes prior to administration of the MRI composition.

[0028] In one embodiment, the subject undergoes an MRI about 30 minutes to about 8 hours, such as 2 hours to 3 hours, such as 3 hours to 4 hours, such as 4 hours to 5 hours, such as 5 hours to 6 hours, such as 6 hours to 7 hours, such as 7 hours to 8 hours, after administration of the MRI composition. In a particular embodiment, the subject undergoes an MRI about 4 hours after administration of the MRI composition.

[0029] In one embodiment, an MRI composition is provided comprising, separately or together, a physiologically acceptable manganese(II) compound, a proteinogenic amino acid and / or vitamin D, and optionally one or more water-soluble excipients, the MRI composition including for use in the in vivo diagnosis of liver metastasis and / or primary liver cancer in a subject, wherein the subject has consumed a meal within 2 hours prior to administration of the MRI composition, the meal having a caloric content of about 500 kcal or less, and the subject undergoes MRI about 30 minutes to 6 hours, e.g., 4 hours, after administration of the MRI composition.

[0030] Meals with less than 500 calories Some diets are too high in calories, such as 500 kcal or more, e.g., 600 kcal or more, e.g., 700 kcal or more, e.g., 800 kcal or more, e.g., 900 kcal or more, and significantly impede signal intensity enhancement during MRI, as shown in Example 1 and FIG. 2. The adverse effects of such foods on diagnostic imaging have been recognized in the art by Leander et al. (Investigative Radiology, 45, 2010). Examples of diets, referred to herein as perfect averages, that significantly impair MRI quality are shown in Table 1. [Table 2]

[0031] In one embodiment, a meal according to the present disclosure having a caloric content of about 500 kcal or less is characterized as a snack or light meal. An exemplary outline of the contents of a meal having a caloric content of about 500 kcal or less is shown in Table 2. [Table 3]

[0032] In the context of this disclosure, "meal" refers to the total caloric intake during a period defined in this disclosure, e.g., from about 0 hours prior to administration of the MRI composition through about 8 hours prior to administration or up to about 2 hours after administration.

[0033] In some embodiments, the meal consists of multiple foods, such as toast with butter and juice. In some embodiments, the subject consumes no more than about 500 kcal from about 0-8 hours prior to or about 2 hours after administration of the MRI composition. In some embodiments, the subject consumes no more than about 400 kcal from about 0-8 hours prior to or about 2 hours after administration of the MRI composition. In some embodiments, the subject consumes no more than about 300 kcal from about 0-8 hours prior to or about 2 hours after administration of the MRI composition.

[0034] In some embodiments, the subject consumes no more than about 500 kcal from a time defined herein before or after administration of the MRI composition to a time defined herein.

[0035] In one embodiment, the meal comprises a predetermined amount of carbohydrates, a predetermined amount of fat, and a predetermined amount of protein.

[0036] In one embodiment, the predetermined amount of carbohydrate in the meal is 20 grams to 50 grams, for example, 20 to 22 grams, for example, 22 to 24 grams, for example, 24 to 26 grams, for example, 26 to 28 grams, for example, 28 to 30 grams, for example, 30 to 32 grams, for example, 32 to 34 grams, for example, 34 to 36 grams, for example, 36 to 38 grams, for example, 38 to 40 grams, for example, 40 to 42 grams, for example, 42 to 44 grams, for example, 44 to 46 grams, for example, 46 to 48 grams, for example, 48 to 50 grams, etc.

[0037] In one embodiment, the predetermined amount of carbohydrate in the meal is about 30 grams or about 31 grams.

[0038] In one embodiment, the specified amount of carbohydrates in a meal is 60 to 200 kcal, for example, 60 to 70 kcal, for example, 70 to 80 kcal, for example, 80 to 90 kcal, for example, 90 to 100 kcal, for example, 100 to 110 kcal, for example, 110 to 120 kcal, for example, 120 to 130 kcal, for example, 130 to 140 kcal, for example, 140 to 150 kcal, for example, 150 to 160 kcal, for example, 160 to 170 kcal, for example, 170 to 180 kcal, for example, 180 to 190 kcal, for example, 190 to 200 kcal.

[0039] In one embodiment, the specified amount of carbohydrates in the meal is 50-70 kcal% of the total calorie content of the meal, such as 50-52 kcal%, for example, 52-54 kcal%, for example, 54-56 kcal%, for example, 56-58 kcal%, for example, 58-60 kcal%, for example, 60-62 kcal%, for example, 62-64 kcal%, for example, 64-66 kcal%, for example, 66-68 kcal%, for example, 68-70 kcal%, etc.

[0040] In one embodiment, the predetermined amount of carbohydrate in the meal is about 59% of the total caloric content of the meal.

[0041] In one embodiment, the predetermined amount of fat in the meal is between 5 grams and 30 grams, such as between 5 and 10 grams, for example, between 10 and 15 grams, for example, between 15 and 20 grams, for example, between 20 and 25 grams, such as between 25 and 30 grams.

[0042] In one embodiment, the predetermined amount of fat in the meal is about 7 grams, about 8 grams, about 9 grams, or about 10 grams.

[0043] In one embodiment, the specified amount of fat in the meal is 30-150 kcal, for example, 30-40 kcal, for example, 40-50 kcal, for example, 50-60 kcal, for example, 60-70 kcal, for example, 70-80 kcal, for example, 80-90 kcal, for example, 90-100 kcal, for example, 100-110 kcal, for example, 110-120 kcal, for example, 120-130 kcal, for example, 130-140 kcal, for example, 140-150 kcal.

[0044] In one embodiment, the specified amount of fat in the meal is 25-45 kcal% of the total calorie content of the meal, such as 25-27 kcal%, for example, 27-29 kcal%, for example, 29-31 kcal%, for example, 31-33 kcal%, for example, 33-35 kcal%, for example, 35-37 kcal%, for example, 37-39 kcal%, for example, 39-41 kcal%, for example, 41-43 kcal%, for example, 43-45 kcal%, etc.

[0045] In one embodiment, the predetermined amount of fat in the meal is about 36% of the total calories in the meal.

[0046] In one embodiment, the predetermined amount of protein in the meal is between 0 grams and 10 grams, such as between 0 and 2 grams, for example, between 2 and 4 grams, for example, between 4 and 6 grams, for example, between 6 and 8 grams, such as between 8 and 10 grams.

[0047] In one embodiment, the predetermined amount of protein in the meal is about 0 grams, about 1 gram, about 2 grams, or about 3 grams.

[0048] In one embodiment, the specified amount of protein in the meal is 0-50 kcal, for example, 0-5 kcal, for example, 5-10 kcal, for example, 10-15 kcal, for example, 15-20 kcal, for example, 20-25 kcal, for example, 25-30 kcal, for example, 30-35 kcal, for example, 35-40 kcal, for example, 40-45 kcal, for example, 45-50 kcal, etc.

[0049] In one embodiment, the specified amount of protein in the meal is 0-10 kcal% of the total calorie content in the meal, such as 0-1 kcal%, for example, 1-2 kcal%, 2-3 kcal%, for example, 3-4 kcal%, for example, 4-5 kcal%, for example, 5-6 kcal%, for example, 6-7 kcal%, for example, 7-8 kcal%, for example, 8-9 kcal%, for example, 9-10 kcal%, etc.

[0050] In one embodiment, the predetermined amount of protein in the meal is about 5% of the total calories in the meal.

[0051] In one embodiment, the meal comprises one or more foods selected from the group consisting of bread, such as toasted bread with butter, and fruit juice, such as sweet lime juice.

[0052] In one embodiment, the diet comprises one or more sugars selected from the list consisting of glucitol, mannitol, glycerol, glycol, α-glucose, α-galactose, α-xylose, β-glucose, β-galactose, β-xylose, β-arabinose and sucrose.

[0053] In one embodiment, the juice is 100 mL to 400 mL, for example, 100 mL to 110 mL, for example, 110 mL to 120 mL, for example, 120 mL to 130 mL, for example, 130 to 140 mL, for example, 140 mL to 150 mL, for example, 150 mL to 160 mL, for example, 160 mL to 170 mL, for example, 170 mL to 180 mL, for example, 180 mL to 190 mL, for example, 190 mL to 200 mL, for example, 200 mL to 210 mL, for example, 210 mL to 220 mL, for example, 220 mL to 230 mL, for example, 230 mL to 240 mL, for example, 240 mL to 250 mL, for example, 260 mL to 270 mL, for example, 270 mL to 280 mL, for example, 280 mL to 290 mL, for example, 290 mL to 300 mL, for example, 300 mL to 310 mL, for example, 310 mL to 320 mL, for example, 320 mL to 330 mL, for example, 330 mL to 340 mL, for example, 340 mL to 350 mL, for example, 350 mL to 360 mL, for example, 360 mL to 370 mL, for example, 370 mL to 380 mL, for example, 380 mL to 390 mL, for example, 390 mL to 400 mL, for example, 400 mL to 410 mL, for example, 420 mL to 430 mL, for example, 430 mL to 440 mL, for example, 440 mL to 450 The liquid is provided in a volume of 300mL to 310mL, for example, 310mL to 320mL, for example, 320mL to 330mL, for example, 330mL to 340mL, for example, 340mL to 350mL, for example, 350mL to 360mL, for example, 360mL to 370mL, for example, 370mL to 380mL, for example, 380mL to 390mL, for example, 390mL to 400mL, etc.

[0054] In one embodiment, the calorie content of the meal is between 100 kcal and 500 kcal, for example, between 100 and 110 kcal, for example, between 110 and 120 kcal, for example, between 120 and 130 kcal, for example, between 130 and 140 kcal, for example, between 140 and 150 kcal, for example, between 150 and 160 kcal, for example, between 160 and 170 kcal, for example, between 170 and 180 kcal, for example, between 180 and 190 kcal. 90kcal, for example, 190kcal to 200kcal, for example, 200kcal to 210kcal, for example, 210kcal to 220kcal, for example, 220kcal to 230kcal, for example, 230kcal to 240kcal, for example, 240kcal to 250kcal, for example, 250kcal to 260kcal, for example, 260kcal to 270kcal, for example, 270kcal to 280kcal, for example, 280kcal to 290kcal, for example, 2 90kcal to 300kcal, for example, 300kcal to 310kcal, for example, 310kcal to 320kcal, for example, 320kcal to 330kcal, for example, 330kcal to 340kcal, for example, 340kcal to 350kcal, for example, 350kcal to 360kcal, for example, 360kcal to 370kcal, for example, 370kcal to 380kcal, for example, 380kcal to 390kcal, for example, 390kcal to 400 kcal, for example, 400 kcal to 410 kcal, for example, 410 kcal to 420 kcal, for example, 420 kcal to 430 kcal, for example, 430 kcal to 440 kcal, for example, 440 kcal to 450 kcal, for example, 450 kcal to 460 kcal, for example, 460 kcal to 470 kcal, for example, 470 kcal to 480 kcal, for example, 480 kcal to 490 kcal, for example, 490 kcal to 500 kcal.

[0055] In certain embodiments, the meal has a caloric content of about 300 kcal or less, and the predetermined amount of carbohydrates in the meal constitutes at least 50% of the caloric content of the meal.

[0056] In some embodiments, the meal employed has a caloric content of about 300 kcal or less, the predetermined amount of carbohydrate in the meal constitutes at least 50% of the caloric content of the meal, and the subject consumes the meal 0-4 hours, such as 0-1 hour, such as 1-2 hours, such as 2-3 hours, such as 3-4 hours, prior to administration of the MRI composition.

[0057] In some embodiments, the diet does not include specific foods, metal ions, or metals as defined herein below.

[0058] In some embodiments, the diet does not include a xanthine or a derivative thereof, such as caffeine, hi some embodiments, the diet does not include one or more foods selected from the group consisting of chocolate, tea, coffee, cola, and tobacco.

[0059] In some embodiments, the diet does not include nutritional supplements, such as vitamin supplements.

[0060] In some embodiments, the diet is free of metal ions, such as metal ions derived from one or more of calcium, chromium, copper, iron, magnesium, manganese, molybdenum, potassium, sodium, and zinc.

[0061] In some embodiments, the diet does not contain iron in an amount greater than or equal to 10 mg, such as greater than or equal to 15 mg.

[0062] In some embodiments, the diet does not contain magnesium in an amount of 100 mg or more, such as 200 mg or more, such as 300 mg or more, such as 400 mg or more.

[0063] In some embodiments, the diet does not contain calcium in an amount greater than or equal to 500 mcg, such as greater than or equal to 1000 mcg.

[0064] In some embodiments, the diet does not contain the amounts of calcium, magnesium and / or iron specified herein.

[0065] In some embodiments, the diet does not include one or more magnesium-containing antacids and one or more laxatives. In some embodiments, the diet does not include grapefruit or grapefruit-derived foods. In some embodiments, the diet does not include ethanol.

[0066] In some embodiments, the diet does not include one or more of the food items, metal ions, or metals in the combinations or amounts specified herein.

[0067] Method and effect In one embodiment, a method of MRI in a subject is provided, comprising administering to the subject an I composition comprising, separately or together, a physiologically acceptable manganese(II) compound, a proteinogenic amino acid and / or vitamin D, and optionally one or more water soluble excipients, and performing MRI on the subject, wherein the subject consumes a meal 0-8 hours prior to or up to 2 hours after administration of the MRI composition, the meal having a caloric content of about 500 kcal or less.

[0068] MRI is typically performed a predetermined period of time after administration of the MRI composition to the subject, as described elsewhere herein.

[0069] In one embodiment, a method for reducing or preventing nausea, diarrhea, and / or headache in a subject to whom an MRI composition is administered, comprising, separately or together, a physiologically acceptable manganese(II) compound, a proteinogenic amino acid, and / or vitamin D, and optionally one or more water soluble excipients; i) administering a meal to the subject; and ii) administering to the subject an MRI composition, Methods are provided wherein the meal is administered 0-8 hours prior to administration of the MRI composition or up to 2 hours after administration of the MRI composition.

[0070] In one embodiment, the meal is administered 0-7 hours, such as 0-1 hour, such as 1-2 hours, such as 2-3 hours, such as 3-4 hours, such as 4-5 hours, such as 5-6 hours, such as 6-7 hours, prior to administration of the MRI composition.

[0071] In one embodiment, imaging quality is unaffected compared to a method in which the MRI composition is administered to a fasting subject, who has not consumed food for more than 8 hours prior to administration of the MRI composition and prior to the MRI. Imaging quality is, in some embodiments, assessed by the enhancement of signal intensity SI (%).

[0072] MRI composition In one embodiment, the MRI composition comprises, separately or together, a physiologically acceptable manganese(II) compound, proteinogenic amino acids and / or vitamin D, and optionally one or more water-soluble excipients.

[0073] Physiologically acceptable manganese(II) compounds In one embodiment, an MRI composition is provided as defined herein, wherein the physiologically acceptable manganese(II) compound is a salt of an inorganic anion or an organic anion. In one embodiment, the inorganic anion is selected from the group consisting of chloride, fluoride, bromide, iodide, sulfate, and phosphate. In one embodiment, the organic anion is selected from the group consisting of ascorbate, succinate, salicylate, and gluconate.

[0074] In one embodiment, an MRI composition is provided as defined herein, wherein the physiologically acceptable manganese(II) compound is selected from the group consisting of manganese(II) sulfate, manganese(II) gluconate, manganese(II) chloride anhydrous, manganese(II) chloride dihydrate, manganese(II) chloride tetrahydrate, and combinations thereof.

[0075] In one embodiment, an MRI composition is provided as defined herein, wherein the physiologically acceptable manganese(II) compound is manganese(II) chloride tetrahydrate or another hydrate of manganese(II) chloride.

[0076] In one embodiment, an MRI composition is provided as defined herein and comprises 0.5 g to 1.2 g of manganese(II) chloride tetrahydrate or an equimolar amount of any corresponding manganese(II) salt.

[0077] In one embodiment, an MRI composition is provided as defined herein and comprises between 0.6g and 1g, such as between 0.65g and 0.95g, for example between 0.70g and 0.90g, such as between 0.75g and 0.85g, for example 0.80g, of manganese(II) chloride tetrahydrate.

[0078] In one embodiment, an MRI composition is provided as defined herein and comprises 0.8 g of manganese(II) chloride tetrahydrate or an equimolar amount of any corresponding manganese(II) salt.

[0079] In one embodiment, an MRI composition provided as defined herein comprises 0.8 g of manganese(II) chloride tetrahydrate or an equimolar amount of the corresponding anhydrate or dihydrate.

[0080] In some embodiments, the MRI composition is Orviglans, which contains 800 mg of manganese(II) chloride tetrahydrate, 500 mg of L-alanine, and 800 IU of vitamin D3. Orviglans was previously known as Mangoral. In some embodiments, the MRI composition further contains one or more water-soluble excipients.

[0081] In some embodiments, the MRI composition comprises manganese(II) chloride tetrahydrate, L-alanine, and vitamin D3. In some embodiments, the MRI composition further comprises one or more water soluble excipients.

[0082] In some embodiments, the MRI composition comprises manganese(II) chloride or a hydrate thereof, L-alanine, vitamin D3, In some embodiments, the MRI composition further comprises one or more water soluble excipients.

[0083] Pharmaceutical Excipients Pharmaceutical excipients are substances that are formulated with an active pharmaceutical ingredient and are included for the purposes of long-term stabilization, increasing the volume of solid dosage forms containing small amounts of a potent active ingredient (hence often referred to as "bulking agents", "fillers", or "diluents"), or enhancing the therapeutic effect of the active ingredient in the final dosage form, such as by facilitating drug absorption, reducing viscosity, or improving solubility. Pharmaceutical excipients are also useful in the manufacturing process to aid in the handling of the active substance, such as by promoting powder flowability and non-stickiness, in addition to aiding in in vitro stability, such as preventing denaturation and aggregation over the expected storage period.

[0084] Those of skill in the art will appreciate that there are excipients that are preferred and excipients that are not preferred for inclusion in the compositions disclosed herein, but that MRI compositions as defined herein (i.e., whether provided together or separately) may be prepared with excipients that are not preferred, provided the relative amounts of the excipients are carefully controlled.

[0085] In one embodiment, an MRI composition is provided as defined herein, wherein the one or more water-soluble excipients are non-hygroscopic water-soluble excipients. In one embodiment, the one or more water-soluble excipients are selected from the group consisting of non-hygroscopic fillers, non-hygroscopic binders, non-hygroscopic disintegrants, and non-hygroscopic lubricants.

[0086] Fillers / Diluents: A "filler" or "diluent" according to the present disclosure is preferably a water-soluble and non-hygroscopic filler, but in some embodiments may also be a hygroscopic filler. In one embodiment, an MRI composition is provided as defined herein, wherein the non-hygroscopic filler is selected from the group consisting of lactose, such as isomalt, spray-dried lactose, alpha-lactose, or beta-lactose, maltitol, maltose, and mannitol.

[0087] Dextrin and lactitol may be used as alternative fillers in small amounts, but typically contain 5% water.

[0088] Dextrin, dextrose, fructose, hypromellose, maltodextrin, sucrose, sorbitol, and xylitol are also water-soluble fillers, but all are hygroscopic. Thus, they may be used in some embodiments where hygroscopicity is not an issue, such as when the MRI composition is formulated in separate compartments. In some embodiments, the MRI composition is provided as defined herein and comprises a hygroscopic filler selected from the group consisting of dextrin, dextrose, fructose, hypromellose, maltodextrin, sucrose, sorbitol, and xylitol.

[0089] In some embodiments, the MRI composition may include a water insoluble filler such as selected from the group consisting of calcium carbonate, calcium phosphate (e.g., basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate), calcium silicate, powdered cellulose, cellulose acetate, magnesium carbonate, magnesium oxide, medium chain triglycerides, microcrystalline cellulose, silicified microcrystalline cellulose, polymethacrylates, starch, calcium sulfate, and pregelatinized starch. In some other embodiments, the MRI composition is provided as defined herein and does not include a water insoluble filler selected from the group consisting of calcium carbonate, calcium phosphate (e.g., basic calcium phosphate, calcium hydrogen phosphate, or dicalcium phosphate), calcium silicate, powdered cellulose, cellulose acetate, magnesium carbonate, magnesium oxide, medium chain triglycerides, microcrystalline cellulose, silicified microcrystalline cellulose, polymethacrylates, starch, calcium sulfate, and pregelatinized starch.

[0090] Binder: The "binder" according to the present disclosure is preferably a water-soluble and non-hygroscopic binder. In one embodiment, the water-soluble and non-hygroscopic binder is selected from the group consisting of hydroxyethylmethylcellulose, maltose, povidone, and dextrin. In one embodiment, the binder is povidone. The binder is particularly important in some embodiments when the contents of the MRI composition as defined herein are formulated together, such as in a tablet.

[0091] Sodium carboxymethylcellulose, dextrin, dextrose, hydroxyethylcellulose, hydroxypropylcellulose, maltodextrin, poloxamer, polydextrose, and sucrose can be used as alternative water-soluble binders in small amounts, but all are hygroscopic.

[0092] In one embodiment, an MRI composition is provided as defined herein, wherein the MRI composition does not contain a poorly water-soluble binder selected from the group consisting of acacia, hypromellose, methylcellulose, sodium alginate, pregelatinized starch, inulin, agar, gelatin, starch, alginic acid, cellulose acetate phthalate, ethylcellulose, hydrogenated vegetable oil, magnesium aluminum silicate, microcrystalline cellulose, and polymethacrylate.

[0093] Disintegrants: It is known in the art that "disintegrants" swell and dissolve when wet, causing a compressed pharmaceutical composition, such as a tablet, to break apart. Disintegrants are therefore particularly important when MRI compositions, as defined herein, are formulated together, such as tablets.

[0094] Povidone is a water soluble disintegrant, but is not a very strong disintegrant. In some embodiments, the MRI composition is provided comprising a non-hygroscopic disintegrant, where the non-hygroscopic disintegrant is povidone.

[0095] Carboxymethylcellulose calcium, croscarmellose sodium, and crospovidone are water insoluble, but very strong disintegrants and can be applied at very low levels, and are preferred. In some embodiments, an MRI composition is provided as defined herein, further comprising a water insoluble disintegrant, such as one selected from the group consisting of carboxymethylcellulose calcium, croscarmellose sodium, and crospovidone.

[0096] Sodium carboxymethylcellulose and hydroxypropylcellulose are examples of hygroscopic water-soluble disintegrants.Therefore, they may be used in some embodiments where hygroscopicity is not an issue, such as when the MRI composition is formulated in separate compartments.In one embodiment, the MRI composition comprises a hygroscopic disintegrant selected from the group consisting of sodium carboxymethylcellulose and hydroxypropylcellulose.

[0097] Lubricant: A "lubricant" prevents ingredients from sticking to and clogging manufacturing machinery, such as filling tubes and tablet punches. For example, in tablet manufacturing, a lubricant keeps friction between the solids and the die walls low, allowing the tablet to form and be ejected.

[0098] Polyethylene glycol 6000 and sodium benzoate are water soluble, non-hygroscopic binders. In one embodiment, an MRI composition is provided as defined herein, wherein the non-hygroscopic lubricant is selected from the group consisting of polyethylene glycol 6000 and sodium benzoate.

[0099] Sodium lauryl sulfate is not preferred due to its bitter taste.

[0100] Poloxamer and polyethylene glycol 4000 are water soluble but hygroscopic lubricants and therefore may be used in some embodiments where hygroscopic issues are not relevant, such as, for example, when the MRI composition is formulated in separate compartments. In some embodiments, an MRI composition as defined herein is provided, wherein the MRI composition comprises a hygroscopic lubricant selected from the group consisting of poloxamer and polyethylene glycol 4000.

[0101] Sodium stearyl fumarate, calcium stearate, colloidal silica, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, medium chain triglycerides, palmitic acid, stearic acid, talc, zinc stearate are all water insoluble. Therefore, it is not preferable to include them in the MRI composition as defined herein. In one embodiment, the MRI composition does not include water insoluble lubricants from the following group: sodium stearyl fumarate, calcium stearate, colloidal silica, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, medium chain triglycerides, palmitic acid, stearic acid, talc, and zinc stearate.

[0102] Absorption enhancers Under physiological conditions, physiologically acceptable manganese(II) compounds are poorly absorbed from the intestine after oral ingestion, but the use of certain absorption enhancers, such as L-alanine and vitamin D3, allows manganese to reach high enough concentrations in the liver to achieve a signal enhancement effect during MRI scans.

[0103] The term "absorption enhancer" is used herein synonymously with the term "uptake enhancer" which refers to compounds capable of enhancing manganese transport across the membranes of the gastrointestinal tract. These compounds are well known in the art, for example from WO 96 / 05867, and consist of physiologically acceptable reducing compounds containing an α-hydroxyketone group, physiologically acceptable acids containing α- and / or β-hydroxy or amino groups, or salts thereof, and / or vitamin D.

[0104] In one embodiment, an MRI composition is provided as defined herein, wherein the one or more absorption enhancers are selected from the group consisting of proteinogenic amino acids and vitamin D.

[0105] In some embodiments, an MRI composition is provided as defined herein, wherein the protein amino acid is selected from the group consisting of alanine, valine, leucine, tryptophan, methionine, isoleucine, proline, phenylalanine, serine, glycine, threonine, cysteine, asparagine, glutamine, tyrosine, aspartic acid, glutamic acid, arginine, lysine and histidine.

[0106] In one embodiment, an MRI composition is provided as defined herein, wherein the protein amino acid is a hydrophobic amino acid selected from the group consisting of alanine, glycine, valine, leucine, isoleucine, proline, phenylalanine, methionine and tryptophan.

[0107] In one embodiment, an MRI composition is provided as defined herein, wherein the proteinogenic amino acid is a neutral amino acid.

[0108] In one embodiment, an MRI composition is provided as defined herein, wherein the proteinogenic amino acid is L-alanine.

[0109] In one embodiment, an MRI composition is provided as defined herein, wherein the vitamin D is vitamin D3.

[0110] In one embodiment, an MRI composition is provided as defined herein and comprises two absorption enhancers, hi one embodiment, the two absorption enhancers are L-alanine and vitamin D3.

[0111] In one embodiment, an MRI composition is provided as defined herein and comprises 0.25g to 0.75g, such as 0.30g to 0.70g, for example 0.35g, for example 0.65g, such as 0.40g to 0.60g, for example 0.45g to 0.55g, for example 0.50g, of a proteinogenic amino acid, such as L-alanine.

[0112] item

[0113] 1. An MRI composition comprising, separately or together, a physiologically acceptable manganese(II) compound, a proteinogenic amino acid and / or vitamin D, and one or more water-soluble excipients, for use in the in vivo diagnosis of liver metastasis and / or primary liver cancer in a subject, wherein the subject has consumed a meal 0-8 hours prior to or up to 2 hours after administration of the MRI composition, the meal having a caloric content of about 500 kcal or less.

[0114] 2. An MRI composition for use according to item 1, wherein the use of the MRI composition reduces or prevents nausea, diarrhea, and / or headache in a subject compared to a fasted subject who has not consumed food for 3 hours or more prior to administration of the MRI composition.

[0115] 3. The MRI composition for use according to any one of the preceding items, wherein the subject has not fasted for more than 3 hours prior to administration of the MRI composition.

[0116] 4. An MRI composition for use according to any one of the preceding items, wherein the subject is adversely affected by fasting for more than 8 hours.

[0117] 5. The MRI composition for use according to any one of the preceding items, wherein the subject suffers from a disease in which fasting for more than 8 hours poses a health risk to the subject.

[0118] 6. The MRI composition for use according to any one of the preceding paragraphs, wherein the subject has one or more of the following: a. diabetes, e.g., type I diabetes or type II diabetes, b. Body mass index (BMI) of 20 or less; c. Age 60 years or older; and / or d.Hyperthyroidism.

[0119] 7. The MRI composition for use according to any one of the preceding items, wherein the subject ingests the meal 0 to 7 hours, such as 0 to 1 hour, for example 1 to 2 hours, such as 2 to 3 hours, for example 3 to 4 hours, such as 4 to 5 hours, for example 5 to 6 hours, for example 6 to 7 hours prior to administration of the MRI composition.

[0120] 8. The MRI composition for use according to any one of the preceding items, wherein the subject consumes the meal within about 1 hour, for example within about 45 minutes, for example within about 30 minutes, prior to administration of the MRI composition.

[0121] 9. The MRI composition for use according to any one of the preceding claims, wherein the meal comprises a predetermined amount of carbohydrates, a predetermined amount of fat, and a predetermined amount of protein.

[0122] 10. The MRI composition for use according to any one of the preceding items, wherein the meal is a snack.

[0123] 11. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of carbohydrate in the meal is from 20 grams to 50 grams, such as from 20 grams to 22 grams, for example, from 22 grams to 24 grams, for example, from 24 grams to 26 grams, for example, from 26 grams to 28 grams, for example, from 28 grams to 30 grams, for example, from 30 grams to 32 grams, for example, from 32 grams to 34 grams, for example, from 34 grams to 36 grams, for example, from 36 grams to 38 grams, for example, from 38 grams to 40 grams, for example, from 40 grams to 42 grams, for example, from 42 grams to 44 grams, for example, from 44 grams to 46 grams, for example, from 46 grams to 48 grams, for example, from 48 grams to 50 grams.

[0124] 12. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of carbohydrate in the meal is about 30 grams or about 31 grams.

[0125] 13. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of carbohydrate in the meal is 60-200 kcal, for example, 60-70 kcal, for example, 70-80 kcal, for example, 80-90 kcal, for example, 90-100 kcal, for example, 100-110 kcal, for example, 110-120 kcal, for example, 120-130 kcal, for example, 130-140 kcal, for example, 140-150 kcal, for example, 150-160 kcal, for example, 160-170 kcal, for example, 170-180 kcal, for example, 180-190 kcal, for example, 190-200 kcal.

[0126] 14. An MRI composition for use according to any one of the preceding items, wherein the predetermined amount of carbohydrate in the meal is 50-70 kcal%, such as 50-52 kcal%, for example 52-54 kcal%, for example 54-56 kcal%, for example 56-58 kcal%, for example 58-60 kcal%, for example 60-62 kcal%, for example 62-64 kcal%, for example 64-66 kcal%, for example 66-68 kcal%, for example 68-70 kcal% of the total caloric content in the meal.

[0127] 15. An MRI composition for use according to any one of the preceding items, wherein the predetermined amount of carbohydrate in the meal is about 59% of the total caloric content of the meal.

[0128] 16. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of fat in the diet is between 5 grams and 30 grams, such as between 5 grams and 10 grams, for example between 10 grams and 15 grams, for example between 15 grams and 20 grams, for example between 20 grams and 25 grams, for example between 25 grams and 30 grams.

[0129] 17. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of fat in the diet is about 7 grams, about 8 grams, about 9 grams, or about 10 grams.

[0130] 18. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of fat in the meal is 30-150 kcal, for example, 30-40 kcal, for example, 40-50 kcal, for example, 50-60 kcal, for example, 60-70 kcal, for example, 70-80 kcal, for example, 80-90 kcal, for example, 90-100 kcal, for example, 100-110 kcal, for example, 110-120 kcal, for example, 120-130 kcal, for example, 130-140 kcal, for example, 140-150 kcal.

[0131] 19. An MRI composition for use according to any one of the preceding items, wherein the predetermined amount of fat in the meal is 25-45 kcal%, such as 25-27 kcal%, for example 27-29 kcal%, for example 29-31 kcal%, for example 31-33 kcal%, such as 33-35 kcal%, for example 35-37 kcal%, for example 37-39 kcal%, for example 39-41 kcal%, for example 41-43 kcal%, for example 43-45 kcal% of the total caloric content of the meal.

[0132] 20. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of fat in the meal is about 36% of the total caloric content of the meal.

[0133] 21. An MRI composition for use according to any one of the preceding items, wherein the predetermined amount of protein in the meal is between 0 grams and 10 grams, such as between 0 grams and 2 grams, for example between 2 grams and 4 grams, for example between 4 grams and 6 grams, for example between 6 grams and 8 grams, for example between 8 grams and 10 grams.

[0134] 22. An MRI composition for use according to any one of the preceding items, wherein the predetermined amount of protein in the meal is about 0 grams, about 1 gram, about 2 grams, or about 3 grams.

[0135] 23. An MRI composition for use according to any one of the preceding items, wherein the predetermined amount of protein in the meal is 0-50 kcal, for example, 0-5 kcal, for example, 5-10 kcal, for example, 10-15 kcal, for example, 15-20 kcal, for example, 20-25 kcal, for example, 25-30 kcal, for example, 30-35 kcal, for example, 35-40 kcal, for example, 40-45 kcal, for example, 45-50 kcal.

[0136] 24. An MRI composition for use according to any one of the preceding items, wherein the predetermined amount of protein in the meal is 0-10 kcal%, such as 0-1 kcal%, for example 1-2 kcal%, for example 2-3 kcal%, such as 3-4 kcal%, for example 4-5 kcal%, for example 5-6 kcal%, such as 6-7 kcal%, for example 7-8 kcal%, for example 8-9 kcal%, for example 9-10 kcal% of the total caloric content in the meal.

[0137] 25. An MRI composition for use according to any one of the preceding items, wherein the predetermined amount of protein in the meal is about 5% of the total caloric content of the meal.

[0138] 26. An MRI composition for use according to any one of the preceding items, wherein the meal comprises one or more foods selected from the group consisting of bread, such as toasted bread, and fruit juice, such as lime juice.

[0139] 27. The juice is 100 mL to 400 mL, for example, 100 mL to 110 mL, for example, 110 mL to 120 mL, for example, 120 mL to 130 mL, for example, 130 mL to 140 mL, for example, 140 mL to 150 mL, for example, 150 mL to 160 mL, for example, 160 mL to 170 mL, for example, 170 mL to 180 mL, for example, 180 mL to 190 mL, for example, 190 mL to 200 mL, for example, 200 mL to 210 mL, for example, 210 mL to 220 mL, for example, 220 mL to 230 mL, for example, 230 mL to 240 mL, for example, 240 mL to 250 mL, for example, 250 mL MRI composition for use according to any one of the preceding items, provided in a volume of from 260 mL to 270 mL, for example, from 270 mL to 280 mL, for example, from 280 mL to 290 mL, for example, from 290 mL to 300 mL, for example, from 300 mL to 310 mL, for example, from 310 mL to 320 mL, for example, from 320 mL to 330 mL, for example, from 330 mL to 340 mL, for example, from 340 mL to 350 mL, for example, from 350 mL to 360 mL, for example, from 360 mL to 370 mL, for example, from 370 mL to 380 mL, for example, from 380 mL to 390 mL, for example, from 390 mL to 400 mL.

[0140] 28. The calorie content of the meal is 100 kcal to 500 kcal, for example, 100 to 110 kcal, for example, 110 kcal to 120 kcal, for example, 120 kcal to 130 kcal, for example, 130 kcal to 140 kcal, for example, 140 kcal to 150 kcal, for example, 150 kcal to 160 kcal, for example, 160 kcal to 170 kcal, for example, 170 kcal to 180 kcal, for example, 180 kcal to 190 kcal, for example, 190 kcal to 200 kcal, for example, 200 kcal to 210 kcal, for example, 210 kcal to 220 kcal, for example, 220 kcal to 230 kcal, for example, 230 kcal to 240 kcal, for example, 240 kcal to 250 kcal, e.g. The MRI composition for use according to any one of the preceding items, for example, 250 kcal to 260 kcal, for example, 260 kcal to 270 kcal, for example, 270 kcal to 280 kcal, for example, 280 kcal to 290 kcal, for example, 290 kcal to 300 kcal, for example, 300 kcal to 310 kcal, for example, 310 kcal to 320 kcal, for example, 320 kcal to 330 kcal, for example, 330 kcal to 340 kcal, for example, 340 kcal to 350 kcal, for example, 350 kcal to 360 kcal, for example, 360 kcal to 370 kcal, for example, 370 kcal to 380 kcal, for example, 380 kcal to 390 kcal, for example, 390 kcal to 400 kcal.

[0141] 29. An MRI composition for use according to any one of the preceding items, wherein the caloric content of the meal is about 300 kcal or less, and the predetermined amount of carbohydrates in the meal constitutes at least 50% of the caloric content of the meal.

[0142] 30. A method for magnetic resonance imaging (MRI) of a subject, comprising administering to the subject an MRI composition comprising, separately or together, a physiologically acceptable manganese(II) compound, a proteinogenic amino acid and / or vitamin D, and one or more water soluble excipients, and performing an MRI on the subject, wherein the subject consumes a meal 0-8 hours prior to or up to about 2 hours after administration of the MRI composition, the meal having a caloric content of about 500 kcal or less.

[0143] 31. A method for reducing or preventing nausea, diarrhea, and / or headache in a subject administered an MRI composition comprising, separately or together, a physiologically acceptable manganese(II) compound, a proteinogenic amino acid, and / or vitamin D, and one or more water soluble excipients, the method comprising: i) administering a meal to the subject; and ii) administering the MRI composition to the subject, wherein the meal is administered 0-8 hours prior to, or up to 2 hours after, administration of the MRI composition.

[0144] 32. The method according to item 31, wherein the meal is administered 0 to 6 hours, such as 0 to 1 hour, such as 1 to 2 hours, such as 2 to 3 hours, such as 3 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours, prior to administration of the MRI composition.

[0145] 33. The method according to any one of items 30 to 32, wherein imaging quality is not affected compared to a method in which the MRI composition is administered to a fasted subject who has been fasting for more than 8 hours. EXAMPLES

[0146] Example 1: Testing the effect of Orvigrans on diet

[0147] material Active drug administration IMP, manganese(II) chloride tetrahydrate (MnCl2·4H2O, working name: Orvigrans) powder for oral administration. A single oral dose of Orvigrans (800 mg manganese(II) chloride tetrahydrate, 500 mg L-alanine, and 800 IU vitamin D3).

[0148] General Pharmacology: Orvigrans is an oral liver imaging agent (i.e., a liver-specific contrast agent) being developed for the detection and visualization of focal liver lesions using magnetic resonance imaging ("MRI") in patients where the use of gadolinium-based contrast agents ("GBCAs") is medically undesirable or cannot be administered.

[0149] Overall objective: To evaluate the effect of food on a single oral dose of Orvigrans in healthy adult subjects.To evaluate the PK and PD of Orvigrans in fasting and fed states (full meal or snack) in healthy subjects.

[0150] method Period-1 was under fasting conditions and Period-2 was under fed conditions (full meal according to Table 1, or snack according to Table 2). A flow chart of the study design is also shown in Figure 1. The rationale for the study design was to allow the evaluation of Orvigrans administered orally under fasted and fed conditions (full meal or snack), respectively, by evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) in healthy adult human subjects (cf). (Figure 1)

[0151] Randomization For each subject, the allocation of receiving the light meal or the full meal during the second period of the study was determined according to a randomization schedule. The randomization schedule was created by a biostatistician using SAS® version 9.4 or higher (SAS Institute Inc., USA). The administration sequence of the treatment drugs to the subjects, i.e., "T1T21" or "T1T22", was determined according to the randomization schedule in Table 3 below, ensuring equal allocation of subjects in each sequence. [Table 4]

[0152] Number of subjects A maximum of 32 subjects were enrolled in the study to obtain data from 24 completers who completed both the fasted and fed (full meal and snack) study periods.

[0153] Detention facilities Subjects were admitted to the clinical site at least 60 hours prior to dose administration and remained at the clinical site for at least 72 hours after administration of study drug throughout the entire period.

[0154] Check-in procedures / activities were conducted according to in-house procedures during each period. Subjects stayed at the facility for 6 consecutive days during each period.

[0155] Liver MRI was performed using imaging parameters 4 hours (within 60 minutes) prior to dose administration and at 1±0.5, 4±0.5, 8±0.5, and 24±0.5 hours post-dose.

[0156] Diet: All subjects abstained from xanthine-containing foods and beverages (e.g., chocolate, tea, coffee, and cola drinks), tobacco, and tobacco-containing products (e.g., bread, pan masala, and gutkha) for 24 hours prior to check-in and throughout their stay at the clinical facility.

[0157] Dietary iron supplementation, including iron-containing multivitamins, was prohibited from 6 hours prior to check-in until the end of the final contrast-enhanced MRI of the study in period -1. Magnesium and / or calcium supplementation was prohibited from 6 hours prior to check-in until the end of the final contrast-enhanced MRI of the study in period -1, as these may decrease manganese absorption.

[0158] Supplementation with vitamin C or vitamin D3, which enhances manganese absorption, was prohibited from 6 hours prior to check-in in period-1 until after the final contrast-enhanced MRI of the study. Magnesium-containing depressants and laxatives were prohibited from 6 hours prior to check-in in period-1 until after the final contrast-enhanced MRI of the study. Quinolone and tetracycline antibiotics were prohibited from 6 hours prior to check-in in period-1 until after the final contrast-enhanced MRI of the study.

[0159] All subjects were to abstain from consuming grapefruit or grapefruit products within 72 hours prior to check-in in Period-1 through the final sample collection of the study. All subjects were to abstain from consuming alcohol or alcohol products and recreational drugs within 48 hours prior to check-in in Period-1 through the final sample collection of the study. Smoking was prohibited and subjects were to abstain from smoking for 6 months prior to check-in in Period-1 through the end of the study.

[0160] Posture Restrictions Orvigrance was administered to subjects in a sitting position. Subjects were in a sitting or ambulatory position for the first 4 hours after dosing in each period. In case of adverse event(s), subjects were appropriately repositioned. Thereafter, subjects avoided strenuous physical activity and engaged in only usual activities. Note: Subjects were in supine position during MRI scans.

[0161] Fasting period and food distribution: For period-1: An overnight fast of at least 4 hours will be performed prior to dosing in Period-1, and lunch will be provided following completion of MRI 4 hours after dosing. For period-2: All subjects were required to fast overnight for at least 6 hours before being offered a full meal according to Table 1 or a snack according to Table 2, which must be consumed completely within 30 minutes of being offered. Lunch was provided 4±1 hours after dose administration in the Post-2 period. A nutritionist / trained study personnel weighed any leftover food and calculated calories for subjects who did not completely consume the full meal or snack. Standard meals were provided at appropriate times during the subjects' stay at the clinical facility. Subjects were given lunch at least 4±1 hours after dosing (4 hours after MRI) (Period-1 and Period-2) and further meals were provided at appropriate intervals thereafter until check-out.

[0162] Subjects were to abstain from drinking water from 1 hour before to 1 hour after each dose during each period, except for 200 mL of water administered during dosing. Water was allowed before and thereafter as needed.

[0163] result The results of the study are shown in the following tables, Table 4 (full vs. fasted), and Table 5 (snack vs. fasted). The optimal SI(%) enhancement is observed in most cases at about 4 hours after dosing. Therefore, the comparison of SI(%) at 4 hours after dosing is important to examine the difference in SI(%) between non-fasted and fasted subjects. [Table 5] [Table 6]

[0164] conclusion This study supports the existing hypothesis that consuming a complete meal according to Table 1 before administering an oral manganese-based MRI agent, such as Orvigrans, significantly reduces the quality of subsequent liver MRI scans. Surprisingly, this study also confirms that subjects who consume a meal (snack) with a caloric content of approximately 500 kcal or less can undergo MRI with Orvigrans with image quality at least as high as that of fasting subjects. These findings strongly support the diagnostic potential of Orvigrans, especially in subjects where fasting may be inconvenient or problematic.

[0165] Item 2

[0166] 1. An MRI composition comprising, separately or together, a physiologically acceptable manganese(II) compound, a proteinogenic amino acid and / or vitamin D, and one or more water-soluble excipients, for use in the in vivo diagnosis of liver metastasis and / or primary liver cancer in a subject, wherein the subject has consumed a meal 0-8 hours prior to or up to about 2 hours after administration of the MRI composition, the meal having a caloric content of about 500 kcal or less.

[0167] 2. An MRI composition for use according to item 1, wherein the use of the MRI composition reduces or prevents nausea, diarrhea, and / or headache in a subject compared to a fasted subject who has not consumed food for 3 hours or more prior to administration of the MRI composition.

[0168] 3. The MRI composition for use according to any one of the preceding items, wherein the subject has not fasted for more than 3 hours prior to administration of the MRI composition.

[0169] 4. An MRI composition for use according to any one of the preceding items, wherein the subject is adversely affected by fasting for more than 8 hours.

[0170] 5. The MRI composition for use according to any one of the preceding items, wherein the subject suffers from a disease in which fasting for more than 8 hours poses a health risk to the subject.

[0171] 6. The MRI composition for use according to any one of the preceding paragraphs, wherein the subject has one or more of the following: a. diabetes, e.g., type I diabetes or type II diabetes, b. Body mass index (BMI) of 20 or less; c. Age 60 years or older; and / or d.Hyperthyroidism.

[0172] 7. The MRI composition for use according to any one of the preceding items, wherein the subject ingests the meal 0 to 7 hours, such as 0 to 1 hour, for example 1 to 2 hours, such as 2 to 3 hours, for example 3 to 4 hours, such as 4 to 5 hours, for example 5 to 6 hours, for example 6 to 7 hours prior to administration of the MRI composition.

[0173] 8. The MRI composition for use according to any one of the preceding items, wherein the meal comprises a predetermined amount of carbohydrates, a predetermined amount of fat, and a predetermined amount of protein.

[0174] 9. The MRI composition for use according to item 8, wherein the predetermined amount of carbohydrate in the meal is 20 grams to 50 grams, for example, 20 grams to 22 grams, for example, 22 grams to 24 grams, for example, 24 grams to 26 grams, for example, 26 grams to 28 grams, for example, 28 grams to 30 grams, for example, 30 grams to 32 grams, for example, 32 grams to 34 grams, for example, 34 grams to 36 grams, for example, 36 grams to 38 grams, for example, 38 grams to 40 grams, for example, 40 grams to 42 grams, for example, 42 grams to 44 grams, for example, 44 grams to 46 grams, for example, 46 grams to 48 grams, for example, 48 grams to 50 grams.

[0175] 10. The MRI composition for use according to any one of items 8 to 9, wherein the predetermined amount of fat in the diet is between 5 grams and 30 grams, such as between 5 grams and 10 grams, for example between 10 grams and 15 grams, for example between 15 grams and 20 grams, for example between 20 grams and 25 grams, for example between 25 grams and 30 grams.

[0176] 11. The MRI composition for use according to any one of items 8 to 10, wherein the predetermined amount of protein in the meal is between 0 grams and 10 grams, such as between 0 grams and 2 grams, for example, between 2 grams and 4 grams, for example, between 4 grams and 6 grams, for example, between 6 grams and 8 grams, for example, between 8 grams and 10 grams.

[0177] 12. An MRI composition for use according to any one of the preceding items, wherein the meal comprises one or more food items, such as bread, such as toasted bread, and / or fruit juice, such as lime juice.

[0178] 13. The calorie content of the meal is 100 kcal to 400 kcal, for example, 100 to 110 kcal, for example, 110 kcal to 120 kcal, for example, 120 kcal to 130 kcal, for example, 130 kcal to 140 kcal, for example, 140 kcal to 150 kcal, for example, 150 kcal to 160 kcal, for example, 160 kcal to 170 kcal, for example, 170 kcal to 180 kcal, for example, 180 kcal to 190 kcal, for example, 190 kcal to 200 kcal, for example, 200 kcal to 210 kcal, for example, 210 kcal to 220 kcal, for example, 220 kcal to 230 kcal, for example, 230 kcal to 240 kcal, for example, 240 kcal to 250 kcal, for example MRI composition for use according to any one of the preceding items, for example, 250 kcal to 260 kcal, for example, 260 kcal to 270 kcal, for example, 270 kcal to 280 kcal, for example, 280 kcal to 290 kcal, for example, 290 kcal to 300 kcal, for example, 300 kcal to 310 kcal, for example, 310 kcal to 320 kcal, for example, 320 kcal to 330 kcal, for example, 330 kcal to 340 kcal, for example, 340 kcal to 350 kcal, for example, 350 kcal to 360 kcal, for example, 360 kcal to 370 kcal, for example, 370 kcal to 380 kcal, for example, 380 kcal to 390 kcal, for example, 390 kcal to 400 kcal.

[0179] 14. The MRI composition for use according to any one of the preceding items, wherein the physiologically acceptable manganese(II) compound is selected from the group consisting of manganese(II) sulfate, manganese(II) gluconate, manganese(II) chloride anhydrous, manganese(II) chloride dihydrate, manganese(II) chloride tetrahydrate, and combinations thereof, preferably the physiologically acceptable manganese(II) compound is manganese(II) chloride tetrahydrate or another hydrate of manganese(II) chloride.

[0180] 15. The MRI composition for use according to any one of the preceding claims, wherein the protein amino acid is a hydrophobic amino acid selected from the group consisting of alanine, glycine, valine, leucine, isoleucine, proline, phenylalanine, methionine and tryptophan.

[0181] 16. An MRI composition for use according to any one of the preceding items, wherein the caloric content of the meal is about 300 kcal or less, and the predetermined amount of carbohydrates in the meal constitutes at least 50% of the caloric content of the meal.

[0182] 17. A method of reducing or preventing nausea, diarrhea, and / or headache in a subject administered an MRI composition comprising, separately or together, a physiologically acceptable manganese(II) compound, a proteinogenic amino acid, and / or vitamin D, and one or more water-soluble excipients, comprising: i) administering a diet to said subject; and ii) administering to said subject said MRI composition; The method, wherein the meal is administered 0-8 hours prior to, or up to about 2 hours after, administration of the MRI composition.

Claims

1. An MRI composition for use in vivo in diagnosis of liver metastases and / or primary liver cancer in a subject, wherein the subject has consumed a meal 0 to 8 hours before administration of the MRI composition or up to 2 hours after administration, the calorie content of the meal is 500 kcal or less, and the MRI composition comprises, separately or together, a physiologically acceptable manganese(II) compound, L-alanine, and vitamin D.

2. The MRI composition according to claim 1, wherein the composition further comprises one or more water-soluble excipients.

3. The MRI composition according to claim 1, wherein the physiologically acceptable manganese(II) compound is manganese(II) chloride tetrahydrate, manganese(II) chloride anhydrous, or manganese(II) chloride dihydrate.

4. The MRI composition according to claim 1, wherein the subject experiences reduced nausea and / or diarrhea and / or headache compared to a fasted subject administered the MRI composition.

5. The MRI composition according to claim 1, wherein the subject has not fasted for 3 hours or more prior to administration of the MRI composition.

6. The MRI composition according to claim 1, wherein the subject suffers from a disease that poses a health risk to the subject if he or she does not eat for more than eight hours.

7. The MRI composition according to claim 1, wherein the subject has one or more of the following: a. Diabetes, for example, type 1 diabetes or type 2 diabetes, b. Body Mass Index (BMI) of 20 or less c. Age 60 or older, and / or d. Hyperthyroidism.

8. The MRI composition according to claim 1, wherein the subject consumes the meal 0 to 7 hours before administration of the MRI composition, for example, within 30 minutes, for example, within 45 minutes, for example, 0 to 1 hour before administration of the MRI composition, for example, 1 to 2 hours before, for example, 2 to 3 hours before, for example, 3 to 4 hours before, for example, 4 to 5 hours before, for example, 5 to 6 hours before, for example, 6 to 7 hours before.

9. The MRI composition according to claim 1, wherein the meal comprises a predetermined amount of carbohydrates, a predetermined amount of fat, and a predetermined amount of protein.

10. The MRI composition according to claim 1 or 9, wherein the predetermined amount of carbohydrates in the meal is 20 to 50 grams, for example, 20 to 22 grams, for example, 22 to 24 grams, for example, 24 to 26 grams, for example, 26 to 28 grams, for example, 28 to 30 grams, for example, 30 to 32 grams, for example, 32 to 34 grams, for example, 34 to 36 grams, for example, 36 to 38 grams, for example, 38 to 40 grams, for example, 40 to 42 grams, for example, 42 to 44 grams, for example, 44 to 46 grams, for example, 46 to 48 grams, for example, 48 to 50 grams.

11. The predetermined amount of carbohydrates in the meal is 60 to 200 kcal, for example, 60 to 70 kcal, for example, 70 to 80 kcal, for example, 80 to 90 kcal, for example, 90 to 100 kcal, for example, 100 to 110 kcal, for example, 110 to 120 kcal, for example, 120 to 130 kcal, for example, 130 to 140 kcal, for example, 140 to 150 kcal, for example, 150 to 160 kcal, for example, 160 to 170 kcal, for example, 170 to 180 kcal, for example, 180 to 190 kcal, for example, 190 to 200 kcal, and / or The MRI composition according to claim 1 or 9, wherein the predetermined amount of carbohydrates in the meal is 50 to 70 kcal% of the total calories in the meal, for example, 50 to 52 kcal%, for example, 52 to 54 kcal%, for example, 54 to 56 kcal%, for example, 56 to 58 kcal%, for example, 58 to 60 kcal%, for example, 60 to 62 kcal%, for example, 62 to 64 kcal%, for example, 64 to 66 kcal%, for example, 66 to 68 kcal%, for example, 68 to 70 kcal%.

12. The MRI composition according to claim 1 or 9, wherein the predetermined amount of fat in the diet is 5 grams to 30 grams, for example, 5 grams to 10 grams, for example, 10 grams to 15 grams, for example, 15 grams to 20 grams, for example, 20 grams to 25 grams, for example, 25 grams to 30 grams.

13. The predetermined amount of fat in the diet is 30 to 150 kcal, for example, 30 to 40 kcal, for example, 40 to 50 kcal, for example, 50 to 60 kcal, for example, 60 to 70 kcal, for example, 70 to 80 kcal, for example, 80 to 90 kcal, for example, 90 to 100 kcal, for example, 100 to 110 kcal, for example, 110 to 120 kcal, for example, 120 to 130 kcal, for example, 130 to 140 kcal, for example, 140 to 150 kcal, and / or The MRI composition according to claim 1, wherein the predetermined amount of fat in the meal is 25 to 45 kcal% of the total calories in the meal, for example, 25 to 27 kcal%, for example, 27 to 29 kcal%, for example, 29 to 31 kcal%, for example, 31 to 33 kcal%, for example, 33 to 35 kcal%, for example, 35 to 37 kcal%, for example, 37 to 39 kcal%, for example, 39 to 41 kcal%, for example, 41 to 43 kcal%, for example, 43 to 45 kcal%.

14. The MRI composition according to claim 1, wherein the predetermined amount of protein in the diet is 0 to 10 grams, for example, 0 to 2 grams, for example, 2 to 4 grams, for example, 4 to 6 grams, for example, 6 to 8 grams, for example, 8 to 10 grams.

15. The predetermined amount of protein in the diet is 0 to 50 kcal, for example, 0 to 5 kcal, for example, 5 to 10 kcal, for example, 10 to 15 kcal, for example, 15 to 20 kcal, for example, 20 to 25 kcal, for example, 25 to 30 kcal, for example, 30 to 35 kcal, for example, 35 to 40 kcal, for example, 40 to 45 kcal, for example, 45 to 50 kcal, and / or The MRI composition according to claim 1, wherein the predetermined amount of protein in the meal is 0 to 10 kcal% of the total calories in the meal, for example, 0 to 1 kcal%, for example, 1 to 2 kcal%, for example, 2 to 3 kcal%, for example, 3 to 4 kcal%, for example, 4 to 5 kcal%, for example, 5 to 6 kcal%, for example, 6 to 7 kcal%, for example, 7 to 8 kcal%, for example, 8 to 9 kcal%, for example, 9 to 10 kcal%.

16. The MRI composition according to claim 1, wherein the calorie content of the meal is 100 kcal to 500 kcal.

17. The MRI composition according to claim 1, wherein the calorie content of the meal is 300 kcal or less, and the predetermined amount of carbohydrates in the meal constitutes at least 50% of the calorie content of the meal.

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