MRI compositions and their use in non-fasting subjects

Abstract

The present invention relates to an oral magnetic resonance imaging (MRI) composition and its use in the in vivo diagnosis of liver metastasis and / or primary liver cancer in a subject eating a predetermined meal.

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 metastasis and / or primary liver cancer in a subject consuming a predetermined meal. Background Art

[0002] Orviglance is an oral liver imaging drug (i.e., a liver-specific contrast agent) for detecting and visualizing focal lesions of the liver using magnetic resonance imaging ("MRI") in subjects where the use of current gold standard gadolinium-based contrast agents ("GBCAs") may not be medically advisable or can not be administered. MRI is a medical imaging technique used in radiology to form pictures of the body's anatomy and physiological processes. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves to generate images of organs in the body.

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

[0004] Therefore, fasting is routine procedure prior to administration of Orvigran and other contrast agents to ensure that imaging quality is not affected by interactions with various food components that affect contrast agent absorption and / or directly affect the imaging properties of manganese (II) ions or their complexes. Summary of the invention

[0005] The inventors have demonstrated that the consumption of a meal by a subject prior to the administration of Orvigran results in image quality significantly lower than that observed for fasting subjects. Fasting for long periods of time (>8h) is generally undesirable and may limit the willingness to use Orvigran, and for some subjects, fasting for very long periods of time may present health risks or significant inconveniences. Surprisingly, the inventors have now demonstrated that a meal having a caloric content of a predetermined value or less may be consumed prior to the administration of Orvigran to obtain an imaging quality at least as high as that obtained for fasting subjects. These findings support the diagnostic potential of Orvigran, particularly for subjects in whom fasting is significantly inconvenient or presents a health risk.

[0006] In a first aspect, an MRI composition is provided, comprising, alone or together, a physiologically acceptable manganese (II) compound, proteinogenic amino acids and / or vitamin D and one or more water-soluble excipients; wherein the MRI composition is for use in the in vivo diagnosis of liver metastasis and / or primary liver cancer in a subject; wherein the subject consumes a meal 0 to 8 hours before or up to about 2 hours after administration of the MRI composition and wherein the calorie content of the meal is about a predetermined value or lower.

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

[0008] In a third aspect, a method for magnetic resonance imaging (MRI) of a subject is provided, the method comprising administering to the subject a composition comprising, alone or together, a physiologically acceptable manganese (II) compound, proteinogenic amino acids and / or vitamin D, and one or more water-soluble excipients; and performing MRI on the subject; wherein the subject consumes a meal 0 to 8 hours before or up to about 2 hours after administration of the MRI composition, and wherein the caloric content of the meal is 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 receiving an MRI composition comprising, alone or together, a physiologically acceptable manganese (II) compound, proteinogenic amino acids and / or vitamin D and one or more water-soluble excipients; the method comprising:

[0010] i) administering a meal to the subject; and

[0011] ii) administering the MRI composition to the subject;

[0012] wherein the meal is administered 0 to 8 hours before administration of the MRI composition or up to about 2 hours after administration of the MRI composition.

[0013] definition

[0014] As used herein, the term "administering" refers to the act of entering the body of a subject with an MRI composition. Thus, the time before or after administration is calculated relative to the time point at which the MRI composition enters the body of a subject.

[0015] The terms "meal", "predetermined meal", "snack" or "light meal" as used interchangeably herein refer to a serving of food having a calorie content of about a predetermined value or less (e.g., about 500 kcal or less). The predetermined value refers to a calorie content significantly lower than a regular meal having a calorie content of about 900 kcal or more.

[0016] 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 widely, from infinitely soluble (unrestricted) (completely miscible) (e.g., ethanol in water) to poorly soluble (e.g., silver chloride in water). The term "insoluble" is generally applied to compounds that are poorly soluble or very poorly soluble.

[0017] The term "water-insoluble" is used herein to describe compounds that are insoluble in water at room temperature (eg, about 25°C).

[0018] Many other descriptive terms are also used to quantify the degree of solubility of a given solute (i.e., a compound that undergoes a dissolution process):

[0019] the term The mass of water required to dissolve 1 mass of solute Very soluble ＜1 Soluble 1 to 10 Soluble >10 to 30 Poorly soluble >30 to 100 Slightly soluble >100 to 1000 Very slightly soluble >1000 to 10,000 Almost insoluble or insoluble ≥10,000

[0020] The water solubility of a given solute is typically temperature dependent. Depending on the nature of the solute, the solubility may increase or decrease with temperature. For most solids and liquids, their solubility in water increases with temperature.

[0021] The term "hygroscopic" is used herein to describe a compound that absorbs water by absorption, adsorption, or a combination of these two processes to any significant extent at a relative humidity (rH) between 40% and 60%, such as to an extent where the mass and / or volume of the compound increases by about 5% or more over a period of time (e.g., after about 1 hour).

[0022] The term "non-hygroscopic water-soluble" is used herein to describe compounds that are not hygroscopic as defined herein and at the same time are water-soluble as defined herein.

[0023] The term "absorption enhancer" is used interchangeably herein with the term "uptake enhancer" and refers to a compound capable of enhancing the transport of manganese across the gastrointestinal membrane. These compounds are well known in the art, for example from WO 96 / 05867, and include physiologically tolerated reducing compounds containing an α-hydroxy ketone group, physiologically tolerated acids or salts thereof containing an α- and / or β-hydroxy or amino group, and / or vitamin D. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 : Overview of the study design from Example 1, where two time periods were fasting and two groups of subjects received a meal or snack prior to dosing with Orvigran.

[0025] Figure 2 : Relative change in MRI signal intensity (SI%) from liver imaging at 1, 4, 8 and 24 hours after dosing in fasting subjects (black line) compared to the same subjects after receiving a meal (dashed line). The SI% obtained from imaging of subjects after a meal was significantly lower than after a fasting period. The contents of the meal are further described in Table 1.

[0026] Figure 3 : Relative change in MRI signal intensity (SI%) from liver imaging at 1, 4, 8 and 24 hours after dosing in fasting subjects (black line) compared to the same subjects after receiving a meal (dashed line). Surprisingly, the SI% obtained from imaging of subjects after a meal was at least as good as after fasting. The contents of the meal are further described in Table 2. DETAILED DESCRIPTION

[0027] In one embodiment, an MRI composition is provided, comprising, alone or together, a physiologically acceptable manganese (II) compound, proteinogenic amino acids and / or vitamin D, and optionally one or more water-soluble excipients; wherein the MRI composition is for use in the in vivo diagnosis of liver metastasis and / or primary liver cancer in a subject; wherein the subject consumes a meal within 8 hours before or up to about 2 hours after administration of the MRI composition and wherein the caloric content of the meal is about 500 kcal or less.

[0028] In one embodiment, the use of the MRI composition reduces or prevents nausea, diarrhea and / or headache in a subject compared to a fasting subject who has not consumed food for 3 hours or more prior to administration of the MRI composition. That is, in one embodiment, the subject has reduced nausea and / or diarrhea and / or headache compared to a fasting subject to which the MRI composition is administered.

[0029] In one embodiment, the subject has not fasted for 3 hours or more prior to administration of the MRI composition.

[0030] Subjects negatively affected by fasting

[0031] In addition to fasting being unpleasant or inconvenient, some subjects may be negatively affected by fasting for health reasons. For these subjects, the MRI compositions described herein and their uses are particularly suitable. Therefore, in one embodiment, an MRI composition for use by such a subject is provided, and the subject is negatively affected by not eating for more than 8 hours.

[0032] In one embodiment, the subject suffers from a disease that causes health risks to the subject if the subject does not eat for more than 8 hours. Thus, in some embodiments, the present disclosure provides an MRI composition for use by such a subject, wherein the subject has not eaten for more than 8 hours prior to administration of the MRI composition.

[0033] In one embodiment, the subject suffers from / has one or more of the following:

[0034] a. Diabetes mellitus, such as type 1 diabetes mellitus or type 2 diabetes mellitus;

[0035] b. Body mass index (BMI) of 20 or less;

[0036] c. 60 years of age or above; and / or

[0037] d. Hyperthyroidism.

[0038] time

[0039] In one embodiment, the subject eats a meal about 0 to 8 hours before or about 2 hours after the administration of the MRI composition, such as about 0 to 1 hour, such as about 1 to 2 hours, such as about 2 to 3 hours, such as about 3 to 4 hours, such as about 4 to 5 hours, such as about 5 to 6 hours, such as about 6 to 7 hours, such as about 7 to 8 hours before the administration of the MRI composition. In one embodiment, the subject eats a meal at most about 30 minutes, such as at most about 1 hour, such as at most about 2 hours after the administration of the MRI composition.

[0040] 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, such as within about 30 minutes prior to administration of the MRI composition.

[0041] In one embodiment, the subject undergoes MRI about 30 minutes to about 8 hours after administration of the MRI composition, 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 specific embodiment, the subject undergoes MRI about 4 hours after administration of the MRI composition.

[0042] In one embodiment, an MRI composition is provided, comprising, alone or together, a physiologically acceptable manganese (II) compound, proteinogenic amino acids and / or vitamin D, and optionally one or more water-soluble excipients; wherein the MRI composition is for use in the in vivo diagnosis of liver metastasis and / or primary liver cancer in a subject; wherein the subject consumes a meal within 2 hours prior to administration of the MRI composition and wherein the caloric content of the meal is about 500 kcal or less, and wherein the subject undergoes MRI about 30 minutes to 6 hours (e.g., 4 hours) after administration of the MRI composition.

[0043] Meals with a calorie content of about 500 kcal or less

[0044] Some meals contain too many calories (e.g., more than 500 kcal, such as more than 600 kcal, such as more than 700 kcal, such as more than 800 kcal, such as more than 900 kcal) and significantly interfere with the signal intensity enhancement during MRI, as demonstrated in Example 1 and as Figure 2 Such negative food effects on imaging are also recognized in the art by Leander et al. (Investigative Radiology, 45, 2010). Examples of meals (referred to herein as meals) that significantly and negatively affect MRI quality are shown in Table 1.

[0045]

[0046] Table 1: Contents of the main meal.

[0047] In one embodiment, a meal according to the present disclosure having a calorie content of about 500 kcal or less is characterized as a snack or light meal. An exemplary summary of the contents of a meal having a calorie content of about 500 kcal or less is provided in Table 2.

[0048]

[0049] Table 2: Contents of snacks.

[0050] In the context of this disclosure, "meal" refers to total caloric intake during a time period specified in this disclosure, such as total caloric intake from about 0 to 8 hours before administration of the MRI composition or up to about 2 hours after administration of the MRI composition.

[0051] In some embodiments, the meal consists of a variety of food items (such as buttered toast and juice). In some embodiments, about 0 to 8 hours before the administration of the MRI composition or up to about 2 hours after the administration of the MRI composition, the subject eats no more than about 500kcal. In some embodiments, about 0 to 8 hours before the administration of the MRI composition or up to about 2 hours after the administration of the MRI composition, the subject eats no more than about 400kcal. In some embodiments, about 0 to 8 hours before the administration of the MRI composition or up to about 2 hours after the administration of the MRI composition, the subject eats no more than about 300kcal.

[0052] In some embodiments, the subject consumes no more than about 500 kcal at a time specified herein prior to administration of the MRI composition or up to a time specified herein after administration of the MRI composition.

[0053] In one embodiment, the meal comprises a predetermined amount of carbohydrates, a predetermined amount of fat, and a predetermined amount of protein.

[0054] In one embodiment, the predetermined amount of carbohydrates in the meal is 20 to 50 grams, such as 20 to 22 grams, such as 22 to 24 grams, such as 24 to 26 grams, such as 26 to 28 grams, such as 28 to 30 grams, such as 30 to 32 grams, such as 32 to 34 grams, such as 34 to 36 grams, such as 36 to 38 grams, such as 38 to 40 grams, such as 40 to 42 grams, such as 42 to 44 grams, such as 44 to 46 grams, such as 46 to 48 grams, such as 48 to 50 grams.

[0055] In one embodiment, the predetermined amount of carbohydrate in the meal is about 30 grams or about 31 grams.

[0056] In one embodiment, the predetermined amount of carbohydrate in the meal is 60 to 200 kcal, such as 60 to 70 kcal, such as 70 to 80 kcal, such as 80 to 90 kcal, such as 90 to 100 kcal, such as 100 to 110 kcal, such as 110 to 120 kcal, such as 120 to 130 kcal, such as 130 to 140 kcal, such as 140 to 150 kcal, such as 150 to 160 kcal, such as 160 to 170 kcal, such as 170 to 180 kcal, such as 180 to 190 kcal, such as 190 to 200 kcal.

[0057] In one embodiment, the predetermined amount of carbohydrates in the meal is 50 kcal% to 70 kcal%, such as 50 kcal% to 52 kcal%, such as 52 kcal% to 54 kcal%, such as 54 kcal% to 56 kcal%, such as 56 kcal% to 58 kcal%, such as 58 kcal% to 60 kcal%, such as 60 kcal% to 62 kcal%, such as 62 kcal% to 64 kcal%, such as 64 kcal% to 66 kcal%, such as 66 kcal% to 68 kcal%, such as 68 kcal% to 70 kcal%.

[0058] In one embodiment, the predetermined amount of carbohydrates in the meal is about 59% of the total calories in the meal.

[0059] In one embodiment, the predetermined amount of fat in the meal is 5 to 30 grams, such as 5 to 10 grams, such as 10 to 15 grams, such as 15 to 20 grams, such as 20 to 25 grams, such as 25 to 30 grams.

[0060] 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.

[0061] In one embodiment, the predetermined amount of fat in the meal is 30 to 150 kcal, such as 30 to 40 kcal, such as 40 to 50 kcal, such as 50 to 60 kcal, such as 60 to 70 kcal, such as 70 to 80 kcal, such as 80 to 90 kcal, such as 90 to 100 kcal, such as 100 to 110 kcal, such as 110 to 120 kcal, such as 120 to 130 kcal, such as 130 to 140 kcal, such as 140 to 150 kcal.

[0062] In one embodiment, the predetermined amount of fat in the meal is 25 kcal% to 45 kcal%, such as 25 kcal% to 27 kcal%, such as 27 kcal% to 29 kcal%, such as 29 kcal% to 31 kcal%, such as 31 kcal% to 33 kcal%, such as 33 kcal% to 35 kcal%, such as 35 kcal% to 37 kcal%, such as 37 kcal% to 39 kcal%, such as 39 kcal% to 41 kcal%, such as 41 kcal% to 43 kcal%, such as 43 kcal% to 45 kcal%.

[0063] In one embodiment, the predetermined amount of fat in the meal is about 36% of the total calories in the meal.

[0064] In one embodiment, the predetermined amount of protein in the meal is 0 to 10 grams, such as 0 to 2 grams, such as 2 to 4 grams, such as 4 to 6 grams, such as 6 to 8 grams, such as 8 to 10 grams.

[0065] 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.

[0066] In one embodiment, the predetermined amount of protein in the meal is 0 to 50 kcal, such as 0 to 5 kcal, such as 5 to 10 kcal, such as 10 to 15 kcal, such as 15 to 20 kcal, such as 20 to 25 kcal, such as 25 to 30 kcal, such as 30 to 35 kcal, such as 35 to 40 kcal, such as 40 to 45 kcal, such as 45 to 50 kcal.

[0067] In one embodiment, the predetermined amount of protein in the meal is 0 kcal% to 10 kcal% of the total calories in the meal, such as 0 kcal% to 1 kcal%, such as 1 kcal% to 2 kcal%, such as 2 kcal% to 3 kcal%, such as 3 kcal% to 4 kcal%, such as 4 kcal% to 5 kcal%, such as 5 kcal% to 6 kcal%, such as 6 kcal% to 7 kcal%, such as 7 kcal% to 8 kcal%, such as 8 kcal% to 9 kcal%, such as 9 kcal% to 10 kcal%.

[0068] In one embodiment, the predetermined amount of protein in the meal is about 5% of the total calories in the meal.

[0069] In one embodiment, the meal comprises one or more food items selected from the group consisting of: bread (eg, toast with butter) and juice (eg, orange juice).

[0070] In one embodiment, the meal comprises one or more sugars selected from the group consisting of glucitol, mannitol, glycerol, ethylene glycol, α-glucose, α-galactose, α-xylose, β-glucose, β-galactose, β-xylose, β-arabinose, and sucrose.

[0071] In one embodiment, the juice is provided in a volume of 100 mL to 400 mL, such as 100 mL to 110 mL, such as 110 mL to 120 mL, such as 120 mL to 130 mL, such as 130 mL to 140 mL, such as 140 mL to 150 mL, such as 150 mL to 160 mL, such as 160 mL to 170 mL, such as 170 mL to 180 mL, such as 180 mL to 190 mL, such as 190 mL to 200 mL, such as 200 mL to 210 mL, such as 210 mL to 220 mL, such as 220 mL to 230 mL, such as 230 mL to 240 mL. mL, such as 240mL to 250mL, such as 250mL to 260mL, such as 260mL to 270mL, such as 270mL to 280mL, such as 280mL to 290mL, such as 290mL to 300mL, such as 300mL to 310mL, such as 310mL to 320mL, such as 320mL to 330mL, such as 330mL to 340mL, such as 340mL to 350mL, such as 350mL to 360mL, such as 360mL to 370mL, such as 370mL to 380mL, such as 380mL to 390mL, such as 390mL to 400mL.

[0072] In one embodiment, the calorie content of the meal is 100 kcal to 500 kcal, such as 100 to 110 kcal, such as 110 kcal to 120 kcal, such as 120 kcal to 130 kcal, such as 130 kcal to 140 kcal, such as 140 kcal to 150 kcal, such as 150 kcal to 160 kcal, such as 160 kcal to 170 kcal, such as 170 kcal to 180 kcal, such as 180 kcal to 190 kcal. 0kcal, such as 190kcal to 200kcal, such as 200kcal to 210kcal, such as 210kcal to 220kcal, such as 220kcal to 230kcal, such as 230kcal to 240kcal, such as 240kcal to 250kcal, such as 250kcal to 260kcal, such as 260kcal to 270kcal, such as 270kcal to 280kcal, such as 280kcal to 290kcal, such as 2 90kcal to 300kcal, such as 300kcal to 310kcal, such as 310kcal to 320kcal, such as 320kcal to 330kcal, such as 330kcal to 340kcal, such as 340kcal to 350kcal, such as 350kcal to 360kcal, such as 360kcal to 370kcal, such as 370kcal to 380kcal, such as 380kcal to 390kcal, such as 390kcal to 400kcal, such as 400kcal to 410kcal, such as 410kcal to 420kcal, such as 420kcal to 430kcal, such as 430kcal to 440kcal, such as 440kcal to 450kcal, such as 450kcal to 460kcal, such as 460kcal to 470kcal, such as 470kcal to 480kcal, such as 480kcal to 490kcal, such as 490kcal to 500kcal.

[0073] 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.

[0074] In some embodiments, the meal used 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, and the subject consumes the meal 0 to 4 hours before administration of the MRI composition, such as 0 to 1 hour, such as 1 to 2 hours, such as 2 to 3 hours, such as 3 to 4 hours before administration of the MRI composition.

[0075] In some embodiments, the meal does not include certain food items, metal ions, or metals as specified below.

[0076] In some embodiments, the meal does not contain xanthine or a derivative thereof, such as caffeine. In some embodiments, the meal does not contain one or more food items selected from the group consisting of: chocolate, tea, coffee, cola, and tobacco.

[0077] In some embodiments, the meal does not include dietary supplements, such as vitamin supplements.

[0078] In some embodiments, the meal does not contain metal ions, such as metal ions derived from one or more of the following: calcium, chromium, copper, iron, magnesium, manganese, molybdenum, potassium, sodium, and zinc.

[0079] In some embodiments, the meal does not contain iron in an amount of 10 mg or more (such as 15 mg or more).

[0080] In some embodiments, the meal does not comprise magnesium in an amount of 100 mg or more (eg, 200 mg or more, such as 300 mg or more, such as 400 mg or more).

[0081] In some embodiments, the meal does not contain calcium in an amount of 500 meg or more (eg, 1000 meg or more).

[0082] In some embodiments, the meal does not contain calcium, magnesium, and / or iron in the amounts specified herein.

[0083] In some embodiments, the meal does not include one or more magnesium-containing antacids and one or more laxatives. In some embodiments, the meal does not include grapefruit or food products derived from grapefruit. In some embodiments, the meal does not include ethanol.

[0084] In some embodiments, the meal does not contain one or more of the food items, metal ions, or metals in any combination or amount specified herein.

[0085] Methods and effects

[0086] In one embodiment, a method for MRI of a subject is provided, the method comprising administering to the subject a composition comprising, alone or together, a physiologically acceptable manganese (II) compound, proteinogenic amino acids 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 to 8 hours before or up to 2 hours after administration of the MRI composition, and wherein the caloric content of the meal is about 500 kcal or less.

[0087] The MRI is typically performed after a defined period of time following administration of the MRI composition to the subject as described elsewhere herein.

[0088] In one embodiment, a method of reducing or preventing nausea, diarrhea and / or headache in a subject receiving an MRI composition comprising, alone or together, a physiologically acceptable manganese (II) compound, proteinogenic amino acids and / or vitamin D and optionally one or more water-soluble excipients is provided; the method comprising:

[0089] i) administering a meal to the subject; and

[0090] ii) administering the MRI composition to the subject;

[0091] wherein the meal is administered 0 to 8 hours before administration of the MRI composition or up to 2 hours after administration of the MRI composition.

[0092] In one embodiment, the meal is administered 0 to 7 hours prior to administration of the MRI composition, 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, such as 6 to 7 hours prior to administration of the MRI composition.

[0093] In one embodiment, image quality is not affected compared to a method in which the MRI composition is administered to a fasting subject, wherein the fasting subject has not eaten for more than 8 hours prior to administration of the MRI composition and prior to MRI. In some embodiments, imaging quality is assessed as signal intensity SI (%) enhancement.

[0094] MRI composition

[0095] In one embodiment, the MRI composition comprises a physiologically acceptable manganese (II) compound, proteinogenic amino acids and / or vitamin D, alone or together, and optionally one or more water-soluble excipients.

[0096] Physiologically acceptable manganese(II) compounds

[0097] In one embodiment, there is provided an MRI composition 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 chloride, fluoride, bromide, iodide, sulfate and phosphate. In one embodiment, the organic anion is selected from ascorbate, kojate, salicylate and gluconate.

[0098] In one embodiment, there is provided an MRI composition as defined herein, wherein the physiologically acceptable manganese (II) compound is selected from: manganese (II) sulfate, manganese (II) gluconate, anhydrous manganese (II) chloride, manganese (II) chloride dihydrate, manganese (II) chloride tetrahydrate and combinations thereof.

[0099] In one embodiment, there is provided an MRI composition as defined herein, wherein the physiologically acceptable manganese (II) compound is manganese (II) chloride tetrahydrate or another hydrate of manganese (II) chloride.

[0100] In one embodiment there is provided an MRI composition as defined herein, wherein the MRI composition comprises between 0.5 g and 1.2 g of manganese(II) chloride tetrahydrate or an equimolar amount of any corresponding manganese(II) salt.

[0101] In one embodiment, there is provided an MRI composition as defined herein, wherein the MRI composition comprises between 0.6g and 1g of manganese(II) chloride tetrahydrate, such as between 0.65g and 0.95g, such as between 0.70g and 0.90g, such as between 0.75g and 0.85g, such as 0.80g of manganese(II) chloride tetrahydrate.

[0102] In one embodiment, there is provided an MRI composition as defined herein, wherein the MRI composition comprises 0.8 g manganese(II) chloride tetrahydrate or an equimolar amount of any corresponding manganese(II) salt.

[0103] In one embodiment, there is provided an MRI composition as defined herein, wherein the MRI composition comprises 0.8 g of manganese (II) chloride tetrahydrate or an equimolar amount of the corresponding anhydrate or dihydrate.

[0104] In some embodiments, the MRI composition is Ovigra, which comprises: 800 mg manganese (II) chloride tetrahydrate, 500 mg L-alanine and 800 IU vitamin D3. Ovigra was previously known as Mangoral. In some embodiments, the MRI composition further comprises one or more water-soluble excipients.

[0105] 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.

[0106] In some embodiments, the MRI composition comprises: manganese (II) chloride or any hydrate thereof, L-alanine and vitamin D3. In some embodiments, the MRI composition further comprises one or more water-soluble excipients.

[0107] Pharmaceutical excipients

[0108] Pharmaceutical excipients are substances formulated with the active ingredients of a pharmaceutical formulation that are included for the following purposes: long-term stabilization, bulking up solid formulations containing small amounts of effective active ingredients (thus often referred to as "bulking agents," "fillers," or "diluents"), or to impart therapeutic enhancements to the active ingredient in the final dosage form, such as, but not limited to, promoting drug absorption, reducing viscosity, or enhancing solubility. Pharmaceutical excipients may also be used during the manufacturing process to aid in the handling of the active substance involved (e.g., by promoting powder flow or non-sticking properties), in addition to aiding in vitro stability (e.g., preventing denaturation or aggregation during the expected shelf life).

[0109] It will be understood by those skilled in the art that, while some excipients are preferred for inclusion and some are not preferred in the compositions as disclosed herein, it is possible to produce an MRI composition as defined herein comprising the excipient (i.e., provided simultaneously or separately) if the relative amounts of the non-preferred excipients are carefully controlled.

[0110] In one embodiment, there is provided an MRI composition 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: non-hygroscopic fillers, non-hygroscopic binders, non-hygroscopic disintegrants and non-hygroscopic lubricants.

[0111] Filler / Diluent : 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 as defined herein is provided, wherein the non-hygroscopic filler is selected from: isomalt; lactose, such as spray-dried lactose, α-lactose or β-lactose; maltitol; maltose; and mannitol.

[0112] Dextrin and lactitol can be used as alternative bulking agents in small amounts, but typically contain 5% moisture.

[0113] Dextrose mixture (dextrate), dextrose, fructose, hypromellose, maltodextrin, sucrose, sorbitol and xylitol are also water-soluble fillers, but are all hygroscopic. Therefore, these can be used in some embodiments where hygroscopicity is not a relevant problem (such as when the MRI composition is formulated in a separate compartment). In some embodiments, an MRI composition as defined herein is provided, wherein the MRI composition comprises a hygroscopic filler selected from the group consisting of dextrose mixture, dextrose, fructose, hypromellose, maltodextrin, sucrose, sorbitol and xylitol.

[0114] In some embodiments, the MRI composition may include a water-insoluble filler such as selected from the following: 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, polymethacrylate, starch, calcium sulfate, and pregelatinized starch. In other embodiments, an MRI composition as defined herein is provided, wherein the MRI composition does not include a water-insoluble filler selected from the following: calcium carbonate; calcium phosphate, such as basic calcium phosphate, calcium hydrogen phosphate, or dicalcium phosphate; calcium silicate; cellulose powder; cellulose acetate; magnesium carbonate; magnesium oxide; medium chain triglycerides; microcrystalline cellulose; silicified microcrystalline cellulose; polymethacrylate; starch; calcium sulfate; and pregelatinized starch.

[0115] Adhesives : A "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: hydroxyethyl methylcellulose, maltose, povidone and dextrin. In one embodiment, the binder is povidone. The binder is particularly relevant when the contents of the MRI composition as defined herein are formulated together (e.g., in a tablet) in some embodiments.

[0116] Sodium carboxymethylcellulose, dextrose blends, dextrose, hydroxyethylcellulose, hydroxypropylcellulose, maltodextrin, poloxamers, polydextrose, and sucrose may be used in low amounts as alternative water-soluble binders, but they are all hygroscopic.

[0117] In one embodiment, there is provided an MRI composition as defined herein, wherein the MRI composition does not comprise a poorly water-soluble binder selected from the group consisting of gum arabic, hypromellose, methylcellulose, sodium alginate, pregelatinized starch, inulin, agar, gelatin, starch, alginic acid, cellulose acetate phthalate, ethyl cellulose, hydrogenated vegetable oil, magnesium aluminum silicate, microcrystalline cellulose and polymethacrylate.

[0118] Disintegrants : "Disintegrants" are known in the art to swell and dissolve when wetted, causing compressed pharmaceutical compositions (such as tablets) to break apart. Therefore, disintegrants are particularly relevant when formulating MRI compositions as defined herein (such as in tablets).

[0119] Povidone is a water soluble disintegrant, but not a very strong disintegrant.In some embodiments, an MRI composition comprising a non-hygroscopic disintegrant is provided, wherein the non-hygroscopic disintegrant is povidone.

[0120] Carboxymethylcellulose calcium, croscarmellose sodium and crospovidone are insoluble in water but are very strong disintegrants and can be used at very low levels and are preferred. In some embodiments, there is provided an MRI composition as defined herein, further comprising a water-insoluble disintegrant, such as a water-insoluble disintegrant selected from the group consisting of carboxymethylcellulose calcium; croscarmellose sodium; and crospovidone.

[0121] Sodium carboxymethylcellulose and hydroxypropylcellulose are examples of hygroscopic water-soluble disintegrants. Therefore, these can be used in some embodiments where hygroscopicity is not a relevant issue (such as when the MRI composition is formulated in separate compartments). In one embodiment, the MRI composition comprises a hygroscopic disintegrant selected from sodium carboxymethylcellulose and hydroxypropylcellulose.

[0122] Lubricants : "Lubricants" prevent ingredients from sticking and clogging production machinery (such as filling tubes and tablet punches). For example, in the tablet production process, lubricants also ensure that tablet forming and demolding can be carried out with low friction between the solid and the die wall.

[0123] Polyethylene glycol 6000 and sodium benzoate are water soluble and non-hygroscopic binders. In one embodiment, there is provided an MRI composition as defined herein, wherein the non-hygroscopic lubricant is selected from the group consisting of: polyethylene glycol 6000 and sodium benzoate.

[0124] Sodium lauryl sulfate imparts a bitter taste and is therefore not preferred.

[0125] Poloxamers and polyethylene glycol 4000 are water-soluble but hygroscopic lubricants and can therefore be used in some embodiments where hygroscopicity is not a relevant issue (such as 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 poloxamers and polyethylene glycol 4000.

[0126] Sodium stearyl fumarate, calcium stearate, colloidal silicon dioxide, glyceryl 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 and are therefore not preferably included in the MRI composition as defined herein. In one embodiment, the MRI composition does not contain a water-insoluble lubricant selected from the following: sodium stearyl fumarate, calcium stearate, colloidal silicon dioxide, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, medium chain triglycerides, palmitic acid, stearic acid, talc and zinc stearate.

[0127] Absorption enhancers

[0128] Under physiological conditions, manganese in physiologically acceptable manganese(II) compounds is poorly absorbed from the intestine after oral ingestion, but by using specific absorption enhancers (such as L-alanine and vitamin D3), sufficiently high concentrations can be achieved in the liver to achieve significant signal enhancement during MRI.

[0129] The term "absorption enhancer" is used interchangeably herein with the term "uptake enhancer" and refers to a compound capable of enhancing the transport of manganese across the gastrointestinal membrane. These compounds are well known in the art, for example from WO 96 / 05867, and include physiologically tolerated reducing compounds containing an α-hydroxy ketone group, physiologically tolerated acids or salts thereof containing an α- and / or β-hydroxy or amino group, and / or vitamin D.

[0130] In one embodiment, there is provided an MRI composition as defined herein, wherein the one or more absorption enhancers are selected from: proteinogenic amino acids and vitamin D.

[0131] In one embodiment, there is provided an MRI composition as defined herein, wherein the proteinogenic 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.

[0132] In one embodiment there is provided an MRI composition as defined herein, wherein the proteinogenic amino acid is a hydrophobic amino acid selected from the group consisting of alanine, glycine, valine, leucine, isoleucine, proline, phenylalanine, methionine and tryptophan.

[0133] In one embodiment there is provided an MRI composition as defined herein, wherein the proteinogenic amino acid is a neutral amino acid.

[0134] In one embodiment there is provided an MRI composition as defined herein, wherein the proteinogenic amino acid is L-alanine.

[0135] In one embodiment, there is provided an MRI composition as defined herein, wherein the vitamin D is vitamin D3.

[0136] In one embodiment, there is provided an MRI composition as defined herein, comprising two absorption enhancers. In one embodiment, the two absorption enhancers are L-alanine and vitamin D3.

[0137] In one embodiment, an MRI composition as defined herein is provided, wherein the MRI composition comprises between 0.25g and 0.75g of a proteinogenic amino acid (such as L-alanine), such as between 0.30g and 0.70g, such as between 0.35g and 0.65g, such as between 0.40g and 0.60g, such as between 0.45g and 0.55g, such as 0.50g of a proteinogenic amino acid (such as L-alanine).

[0138] project

[0139] 1. An MRI composition comprising, alone or together, a physiologically acceptable manganese (II) compound, proteinogenic amino acids and / or vitamin D and one or more water-soluble excipients; wherein the MRI composition is for use in the in vivo diagnosis of liver metastases and / or primary liver cancer in a subject; wherein the subject consumes a meal 0 to 8 hours before or up to 2 hours after administration of the MRI composition and wherein the caloric content of the meal is about 500 kcal or less.

[0140] 2. An MRI composition for use according to claim 1, wherein the use reduces or prevents nausea, diarrhea and / or headache in the subject compared to a fasting subject who has not consumed food for 3 hours or more prior to administration of the MRI composition.

[0141] 3. The MRI composition for use according to any one of the preceding items, wherein the subject has not fasted for 3 hours or more prior to administration of the MRI composition.

[0142] 4. The MRI composition for use according to any one of the preceding items, wherein the subject is negatively affected by not eating for more than 8 hours.

[0143] 5. The MRI composition for use according to any one of the preceding items, wherein the subject suffers from a disease that causes health risks to the subject if the subject does not eat for more than 8 hours.

[0144] 6. The MRI composition for use according to any one of the preceding items, wherein the subject suffers from / has one or more of the following:

[0145] a. Diabetes mellitus, such as type 1 diabetes mellitus or type 2 diabetes mellitus;

[0146] b. Body mass index (BMI) of 20 or less;

[0147] c. 60 years of age or above; and / or

[0148] d. Hyperthyroidism.

[0149] 7. The MRI composition for use according to any one of the preceding items, wherein the subject consumes the meal 0 to 7 hours before administration of the MRI composition, 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, such as 6 to 7 hours before administration of the MRI composition.

[0150] 8. The MRI composition for use according to any of the preceding items, wherein the subject consumes the meal within about 1 hour prior to administration of the MRI composition, such as within about 45 minutes, such as within about 30 minutes prior to administration of the MRI composition.

[0151] 9. 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.

[0152] 10. The MRI composition for use according to any one of the preceding items, wherein the meal is a snack.

[0153] 11. The MRI composition for use according to any of the preceding items, wherein the predetermined amount of carbohydrates in the meal is 20 to 50 grams, such as 20 to 22 grams, such as 22 to 24 grams, such as 24 to 26 grams, such as 26 to 28 grams, such as 28 to 30 grams, such as 30 to 32 grams, such as 32 to 34 grams, such as 34 to 36 grams, such as 36 to 38 grams, such as 38 to 40 grams, such as 40 to 42 grams, such as 42 to 44 grams, such as 44 to 46 grams, such as 46 to 48 grams, such as 48 to 50 grams.

[0154] 12. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of carbohydrates in the meal is about 30 grams or about 31 grams.

[0155] 13. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of carbohydrates in the meal is 60 to 200 kcal, such as 60 to 70 kcal, such as 70 to 80 kcal, such as 80 to 90 kcal, such as 90 to 100 kcal, such as 100 to 110 kcal, such as 110 to 120 kcal, such as 120 to 130 kcal, such as 130 to 140 kcal, such as 140 to 150 kcal, such as 150 to 160 kcal, such as 160 to 170 kcal, such as 170 to 180 kcal, such as 180 to 190 kcal, such as 190 to 200 kcal.

[0156] 14. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of carbohydrates in the meal is 50 kcal% to 70 kcal%, such as 50 kcal% to 52 kcal%, such as 52 kcal% to 54 kcal%, such as 54 kcal% to 56 kcal%, such as 56 kcal% to 58 kcal%, such as 58 kcal% to 60 kcal%, such as 60 kcal% to 62 kcal%, such as 62 kcal% to 64 kcal%, such as 64 kcal% to 66 kcal%, such as 66 kcal% to 68 kcal%, such as 68 kcal% to 70 kcal%.

[0157] 15. The MRI composition for use according to any one of the preceding clauses, wherein the predetermined amount of carbohydrates in the meal is about 59% of the total amount of calories in the meal.

[0158] 16. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of fat in the meal is 5 to 30 grams, such as 5 to 10 grams, such as 10 to 15 grams, such as 15 to 20 grams, such as 20 to 25 grams, such as 25 to 30 grams.

[0159] 17. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of fat in the meal is about 7 grams, about 8 grams, about 9 grams or about 10 grams.

[0160] 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 to 150 kcal, such as 30 to 40 kcal, such as 40 to 50 kcal, such as 50 to 60 kcal, such as 60 to 70 kcal, such as 70 to 80 kcal, such as 80 to 90 kcal, such as 90 to 100 kcal, such as 100 to 110 kcal, such as 110 to 120 kcal, such as 120 to 130 kcal, such as 130 to 140 kcal, such as 140 to 150 kcal.

[0161] 19. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of fat in the meal is 25 kcal% to 45 kcal%, such as 25 kcal% to 27 kcal%, such as 27 kcal% to 29 kcal%, such as 29 kcal% to 31 kcal%, such as 31 kcal% to 33 kcal%, such as 33 kcal% to 35 kcal%, such as 35 kcal% to 37 kcal%, such as 37 kcal% to 39 kcal%, such as 39 kcal% to 41 kcal%, such as 41 kcal% to 43 kcal%, such as 43 kcal% to 45 kcal%.

[0162] 20. The MRI composition for use according to any one of the preceding clauses, wherein the predetermined amount of fat in the meal is about 36% of the total amount of calories in the meal.

[0163] 21. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of protein in the meal is 0 to 10 grams, such as 0 to 2 grams, such as 2 to 4 grams, such as 4 to 6 grams, such as 6 to 8 grams, such as 8 to 10 grams.

[0164] 22. The 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.

[0165] 23. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of protein in the meal is 0 to 50 kcal, such as 0 to 5 kcal, such as 5 to 10 kcal, such as 10 to 15 kcal, such as 15 to 20 kcal, such as 20 to 25 kcal, such as 25 to 30 kcal, such as 30 to 35 kcal, such as 35 to 40 kcal, such as 40 to 45 kcal, such as 45 to 50 kcal.

[0166] 24. The MRI composition for use according to any one of the preceding items, wherein the predetermined amount of protein in the meal is 0 kcal% to 10 kcal%, such as 0 kcal% to 1 kcal%, such as 1 kcal% to 2 kcal%, such as 2 kcal% to 3 kcal%, such as 3 kcal% to 4 kcal%, such as 4 kcal% to 5 kcal%, such as 5 kcal% to 6 kcal%, such as 6 kcal% to 7 kcal%, such as 7 kcal% to 8 kcal%, such as 8 kcal% to 9 kcal%, such as 9 kcal% to 10 kcal%.

[0167] 25. The MRI composition for use according to any one of the preceding clauses, wherein the predetermined amount of protein in the meal is about 5% of the total amount of calories in the meal.

[0168] 26. The MRI composition for use according to any one of the preceding items, wherein the meal comprises one or more food items selected from the group consisting of bread, such as toast, and fruit juice, such as lime juice.

[0169] 27. The MRI composition for use according to any of the preceding items, wherein the juice is provided in a volume of 100 mL to 400 mL, such as 100 mL to 110 mL, such as 110 mL to 120 mL, such as 120 mL to 130 mL, such as 130 mL to 140 mL, such as 140 mL to 150 mL, such as 150 mL to 160 mL, such as 160 mL to 170 mL, such as 170 mL to 180 mL, such as 180 mL to 190 mL, such as 190 mL to 200 mL, such as 200 mL to 210 mL, such as 210 mL to 220 mL, such as 220 mL to 230 mL L, such as 230mL to 240mL, such as 240mL to 250mL, such as 250mL to 260mL, such as 260mL to 270mL, such as 270mL to 280mL, such as 280mL to 290mL, such as 290mL to 300mL, such as 300mL to 310mL, such as 310mL to 320mL, such as 320mL to 330mL, such as 330mL to 340mL, such as 340mL to 350mL, such as 350mL to 360mL, such as 360mL to 370mL, such as 370mL to 380mL, such as 380mL to 390mL, such as 390mL to 400mL.

[0170] 28. The MRI composition for use according to any one of the preceding items, wherein the calorie content of the meal is 100 kcal to 500 kcal, such as 100 to 110 kcal, such as 110 kcal to 120 kcal, such as 120 kcal to 130 kcal, such as 130 kcal to 140 kcal, such as 140 kcal to 150 kcal, such as 150 kcal to 160 kcal, such as 160 kcal to 170 kcal, such as 170 kcal to 180 kcal, such as 180 kcal to 190 kcal, such as 190 kcal to 200 kcal, such as 200 kcal to 210 kcal, such as 210 kcal to 220 kcal, such as 220 kcal to 230 kcal, such as 230 kcal kcal, such as 240 kcal to 250 kcal, such as 250 kcal to 260 kcal, such as 260 kcal to 270 kcal, such as 270 kcal to 280 kcal, such as 280 kcal to 290 kcal, such as 290 kcal to 300 kcal, such as 300 kcal to 310 kcal, such as 310 kcal to 320 kcal, such as 320 kcal to 330 kcal, such as 330 kcal to 340 kcal, such as 340 kcal to 350 kcal, such as 350 kcal to 360 kcal, such as 360 kcal to 370 kcal, such as 370 kcal to 380 kcal, such as 380 kcal to 390 kcal, such as 390 kcal to 400 kcal.

[0171] 29. The 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 wherein the predetermined amount of carbohydrates in the meal constitutes at least 50% of the caloric content of the meal.

[0172] 30. A method for magnetic resonance imaging (MRI) of a subject, the method comprising administering to the subject a composition comprising, alone or together, a physiologically acceptable manganese (II) compound, proteinogenic amino acids and / or vitamin D, and one or more water-soluble excipients; and performing MRI on the subject; wherein the subject consumes a meal 0 to 8 hours before or up to 2 hours after administration of the MRI composition, and wherein the caloric content of the meal is about 500 kcal or less.

[0173] 31. A method of reducing or preventing nausea, diarrhea and / or headache in a subject receiving an MRI composition comprising, alone or together, a physiologically acceptable manganese (II) compound, proteinogenic amino acids and / or vitamin D and one or more water-soluble excipients; the method comprising:

[0174] i) administering a meal to the subject; and

[0175] ii) administering the MRI composition to the subject;

[0176] wherein the meal is administered 0 to 8 hours before administration of the MRI composition or up to 2 hours after administration of the MRI composition.

[0177] 32. A method according to claim 31, wherein the meal is administered 0 to 6 hours before the administration of the MRI composition, 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 before the administration of the MRI composition.

[0178] 33. A method according to any one of items 30 to 32, wherein the imaging quality is not affected compared to a method in which the MRI composition is administered to a fasting subject who has not eaten for more than 8 hours.

[0179] Example

[0180] Example 1: Study of the Ovigran Food Effect

[0181] Material

[0182] Active agent treatment

[0183] IMP: Manganese(II) chloride tetrahydrate (MnCl2·4H2O; working name: Orvigran) powder for oral administration. A single oral dose of Orvigran (800 mg manganese(II) chloride tetrahydrate, 500 mg L-alanine and 800 IU vitamin D3).

[0184] General Pharmacology :

[0185] Oviglan is an oral liver imaging drug (i.e., a liver-specific contrast agent) being developed for the detection and visualization of focal lesions of the liver using magnetic resonance imaging ("MRI") in patients where the use of gadolinium-based contrast agents ("GBCAs") may not be medically advisable or cannot be administered.

[0186] Overall goal :

[0187] Evaluation of the Effect of Food on Orvigran Following a Single Oral Administration in Adult Healthy Subjects The PK and PD of Orvigran were evaluated in healthy human subjects under fasting and fed (meal or snack) conditions.

[0188] method

[0189] Time period 1 was under fasting conditions and time period 2 was under fed conditions (main meal according to Table 1, or snack according to Table 2). A flow chart of the study design is also depicted in Figure 1 The rationale for the study design was to allow evaluation of the pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered ovagellan in healthy adult subjects under fasting and fed conditions (with or without meals), respectively. Figure 1 .

[0190] Randomization

[0191] The randomization schedule determined the allocation of snacks and meals to each subject during the second period of the study. The randomization schedule was generated using SAS version 9.4 or higher (SAS Institute Inc., USA). The order of treatment administration to the subjects was determined according to the randomization schedule as shown in Table 3, i.e., “T1T2”. 21 or T1T 22 ”. Ensure equal distribution of subjects in each sequence.

[0192]

[0193] Table 3: Summary of the randomization schedule for Example 1.

[0194] Number of subjects

[0195] A maximum of 32 subjects were enrolled in the study to obtain data for 24 completers who completed both the fasting and feeding (meals and snacks) study periods.

[0196] Housing Supply

[0197] Subjects were housed in the clinical facility at least 60 hours prior to administration of the dose and continued to remain in the clinical facility for at least 72 hours after administration of the study drug in all time periods.

[0198] During each time period, the check-in process / check-in activities were conducted according to internal procedures. Subjects stayed in the facility for six consecutive nights during each time period.

[0199] Using imaging parameters, MRI of the liver was performed 4 hours prior to administration of the dose (within 60 minutes) and at 1±0.5, 4±0.5, 8±0.5, and 24±0.5 hours post-dose.

[0200] diet

[0201] All subjects abstained from xanthine-containing foods or beverages (eg, chocolate, tea, coffee, or cola drinks), tobacco, and tobacco-containing products (eg, pan, pan masala, gutkha) 24 hours prior to enrollment until their overnight stay in the clinical facility.

[0202] Dietary iron supplements (including multivitamins containing iron) were prohibited from 6 hours before enrollment in Period 1 until after the last contrast-enhanced MRI on study. Magnesium and / or calcium supplements may reduce manganese absorption and were prohibited from 6 hours before enrollment in Period 1 until after the last contrast-enhanced MRI on study.

[0203] Supplementation with vitamin C or vitamin D3 (which promotes manganese absorption) was prohibited from 6 hours prior to enrollment in Period 1 until after the last contrast-enhanced MRI on study. Magnesium-containing antacids and laxatives were prohibited from 6 hours prior to enrollment in Period 1 until after the last contrast-enhanced MRI on study. Quinolone and tetracycline antibiotics were prohibited from 6 hours prior to enrollment in Period 1 until after the last contrast-enhanced MRI on study.

[0204] All subjects abstained from grapefruit or its products within 72 hours prior to enrollment in Period 1 until the last sample collection of the study. All subjects abstained from alcohol or alcohol products, recreational drugs within 48 hours prior to enrollment in Period 1 until the last sample collection of the study. Smoking was prohibited and subjects were to quit smoking 6 months prior to enrollment in Period 1 until the completion of the study.

[0205] Posture restrictions

[0206] Orvigran was administered to subjects in a sitting position. For the first 4 hours after dosing in each period, subjects were in a sitting or ambulatory position. In the event of one or more adverse events, the subject's position was changed appropriately. Thereafter, subjects were allowed to participate only in normal activities while avoiding any strenuous physical activity. Note: Subjects were in the supine position during MRI.

[0207] Fasting duration and meal distribution:

[0208] For time period 1 :

[0209] In Period 1, overnight fasting will be at least 4 hours prior to dosing and lunch will be provided after completion of MRI 4 h post-dose.

[0210] For time period 2 :

[0211] All subjects will be required to fast overnight for at least 6 hours before providing a full meal according to Table 1 or a snack according to Table 2, requiring them to be completely eaten within 30 minutes of providing the full meal or snack. Lunch will be provided in time period 2 after 4 ± 1 hours after dosage administration. Nutritionists / trained researchers weigh the remaining food and calculate the calories of any subject who does not fully consume a full meal or snack. Standardized meals are provided to them at the appropriate time during the subject's stay in the clinical facility. Subjects receive lunch at least 4 ± 1 hours (after 4 hours MRI) (for time period 1 and time period 2) after administration, and from then on, other meals are provided at appropriate intervals until registration and departure.

[0212] In addition to the administration of 200 mL of water during dosing, in each time period, the subjects refrained from drinking water from 1 hour before each dosing until 1 hour after each dosing. Before and after this, water could be drunk as needed.

[0213] result

[0214] The results of the study are shown in the following tables: Table 4 (comparison of meal and fasting); and Table 5 (comparison of meal and fasting). The best SI (%) increase is most common at about 4 hours after dosing; therefore, comparison of SI (%) at 4 hours after dosing is important to examine the difference in SI (%) between non-fasting subjects and fasting subjects.

[0215]

[0216] Table 4. MRI signal intensity (SI%) from liver imaging and relative change in signal intensity at 1, 4, 8 and 24 hours post-dose in fasted subjects (T1) compared to the same subjects after receiving a meal (T21). The SI% obtained from imaging of subjects after a meal was significantly lower than after the fasting period.

[0217]

[0218]

[0219] Table 5. MRI signal intensity (SI%) from liver imaging and relative change in signal intensity at 1, 4, 8 and 24 hours post-dose in fasted subjects (T1) compared to the same subjects after receiving a meal (T22). Surprisingly, the SI% obtained from imaging of fed subjects was at least as good as that after fasting.

[0220] in conclusion

[0221] This study supports the existing hypothesis that consumption of a meal according to Table 1 prior to administration of an oral manganese-based MRI agent such as Orvigran significantly reduces the image quality of subsequent liver MRI. Surprisingly, this study also supports that subjects who have consumed a meal with a caloric content of about 500 kcal or less (snack) are still able to undergo MRI using Orvigran and the image quality is at least as high as that of fasting subjects. These findings significantly support the diagnostic potential of Orvigran, especially for subjects for whom fasting may be inconvenient or problematic.

[0222] Project 2

[0223] 1. An MRI composition comprising, alone or together, a physiologically acceptable manganese (II) compound, proteinogenic amino acids and / or vitamin D and one or more water-soluble excipients; wherein the MRI composition is for use in the in vivo diagnosis of liver metastases and / or primary liver cancer in a subject; wherein the subject consumes a meal 0 to 8 hours before or up to about 2 hours after administration of the MRI composition and wherein the caloric content of the meal is about 500 kcal or less.

[0224] 2. An MRI composition for use according to claim 1, wherein the use reduces or prevents nausea, diarrhea and / or headache in the subject compared to a fasting subject who has not consumed food for 3 hours or more prior to administration of the MRI composition.

[0225] 3. The MRI composition for use according to any one of the preceding items, wherein the subject has not fasted for 3 hours or more prior to administration of the MRI composition.

[0226] 4. The MRI composition for use according to any one of the preceding items, wherein the subject is negatively affected by not eating for more than 8 hours.

[0227] 5. The MRI composition for use according to any one of the preceding items, wherein the subject suffers from a disease that causes health risks to the subject if the subject does not eat for more than 8 hours.

[0228] 6. The MRI composition for use according to any one of the preceding items, wherein the subject suffers from / has one or more of the following:

[0229] a. Diabetes mellitus, such as type 1 diabetes mellitus or type 2 diabetes mellitus;

[0230] b. Body mass index (BMI) of 20 or less;

[0231] c. 60 years of age or above; and / or

[0232] d. Hyperthyroidism.

[0233] 7. The MRI composition for use according to any one of the preceding items, wherein the subject consumes the meal 0 to 7 hours before administration of the MRI composition, 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, such as 6 to 7 hours before administration of the MRI composition.

[0234] 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.

[0235] 9. The MRI composition for use according to claim 8, wherein the predetermined amount of carbohydrates in the meal is 20 to 50 grams, such as 20 to 22 grams, such as 22 to 24 grams, such as 24 to 26 grams, such as 26 to 28 grams, such as 28 to 30 grams, such as 30 to 32 grams, such as 32 to 34 grams, such as 34 to 36 grams, such as 36 to 38 grams, such as 38 to 40 grams, such as 40 to 42 grams, such as 42 to 44 grams, such as 44 to 46 grams, such as 46 to 48 grams, such as 48 to 50 grams.

[0236] 10. The MRI composition for use according to any one of items 8 to 9, wherein the predetermined amount of fat in the meal is 5 to 30 grams, such as 5 to 10 grams, such as 10 to 15 grams, such as 15 to 20 grams, such as 20 to 25 grams, such as 25 to 30 grams.

[0237] 11. An MRI composition for use according to any one of items 8 to 10, wherein the predetermined amount of protein in the meal is 0 to 10 grams, such as 0 to 2 grams, such as 2 to 4 grams, such as 4 to 6 grams, such as 6 to 8 grams, such as 8 to 10 grams.

[0238] 12. The 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 toast, and / or juice, such as lime juice.

[0239] 13. The MRI composition for use according to any one of the preceding items, wherein the calorie content of the meal is 100 kcal to 400 kcal, such as 100 to 110 kcal, such as 110 kcal to 120 kcal, such as 120 kcal to 130 kcal, such as 130 kcal to 140 kcal, such as 140 kcal to 150 kcal, such as 150 kcal to 160 kcal, such as 160 kcal to 170 kcal, such as 170 kcal to 180 kcal, such as 180 kcal to 190 kcal, such as 190 kcal to 200 kcal, such as 200 kcal to 210 kcal, such as 210 kcal to 220 kcal, such as 220 kcal to 230 kcal, such as 230 kcal kcal, such as 240 kcal to 250 kcal, such as 250 kcal to 260 kcal, such as 260 kcal to 270 kcal, such as 270 kcal to 280 kcal, such as 280 kcal to 290 kcal, such as 290 kcal to 300 kcal, such as 300 kcal to 310 kcal, such as 310 kcal to 320 kcal, such as 320 kcal to 330 kcal, such as 330 kcal to 340 kcal, such as 340 kcal to 350 kcal, such as 350 kcal to 360 kcal, such as 360 kcal to 370 kcal, such as 370 kcal to 380 kcal, such as 380 kcal to 390 kcal, such as 390 kcal to 400 kcal.

[0240] 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, anhydrous manganese (II) chloride, manganese (II) chloride dihydrate, manganese (II) chloride tetrahydrate and combinations thereof, wherein the physiologically acceptable manganese (II) compound is preferably manganese (II) chloride tetrahydrate or another hydrate of manganese (II) chloride.

[0241] 15. The MRI composition for use according to any one of the preceding items, wherein the proteinogenic amino acid is a hydrophobic amino acid selected from the group consisting of alanine, glycine, valine, leucine, isoleucine, proline, phenylalanine, methionine and tryptophan.

[0242] 16. The MRI composition for use according to any one of the preceding clauses, wherein the caloric content of the meal is about 300 kcal or less, and wherein the predetermined amount of carbohydrates in the meal constitutes at least 50% of the caloric content of the meal.

[0243] 17. A method of reducing or preventing nausea, diarrhea and / or headache in a subject receiving an MRI composition comprising, alone or together, a physiologically acceptable manganese (II) compound, proteinogenic amino acids and / or vitamin D and one or more water-soluble excipients; the method comprising:

[0244] i) administering a meal to the subject; and

[0245] ii) administering the MRI composition to the subject;

[0246] wherein the meal is administered 0 to 8 hours before administration of the MRI composition or up to about 2 hours after administration of the MRI composition.

Claims

1. An MRI composition comprising, alone or together, manganese (II) chloride tetrahydrate, L-alanine and vitamin D; wherein the MRI composition is for use in the in vivo diagnosis of liver metastasis and / or primary liver cancer in a subject; wherein the subject consumes a meal 0 to 8 hours before or up to 2 hours after administration of the MRI composition and wherein the calorie content of the meal is about 500 kcal or less.

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

3. The MRI composition for use according to any one of the preceding claims, wherein the subject has reduced nausea, diarrhea and / or headache compared to a fasting subject to which the MRI composition is administered.

4. The MRI composition for use according to claim 3, wherein the subject has reduced nausea and / or diarrhea compared to a fasting subject to which the MRI composition is administered.

5. The MRI composition for use according to any one of the preceding claims, wherein the subject has not fasted for 3 hours or more prior to administration of the MRI composition.

6. The MRI composition for use according to any one of the preceding claims, wherein the subject is classified as a subject negatively affected by not eating for more than 8 hours.

7. The MRI composition for use according to any one of the preceding claims, wherein the subject suffers from a disease that causes health risks to the subject if the subject does not eat for more than 8 hours.

8. The MRI composition for use according to any one of the preceding claims, wherein the subject suffers from / has one or more of the following: a. Diabetes mellitus, such as type 1 diabetes mellitus or type 2 diabetes mellitus; b. Body mass index (BMI) of 20 or less; c. 60 years of age or above; and / or d. Hyperthyroidism.

9. The MRI composition for use according to any one of the preceding claims, wherein the subject consumes the meal 0 to 7 hours prior to administration of the MRI composition, 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, such as 6 to 7 hours prior to administration of the MRI composition.

10. The MRI composition for use according to any one of the preceding claims, wherein the subject consumes the meal within about 1 hour prior to administration of the MRI composition, such as within about 45 minutes, such as within about 30 minutes prior to administration of the MRI composition.

11. 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.

12. The MRI composition for use according to any one of the preceding claims, wherein the meal is a snack.

13. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of carbohydrates in the meal is 20 to 50 grams, such as 20 to 22 grams, such as 22 to 24 grams, such as 24 to 26 grams, such as 26 to 28 grams, such as 28 to 30 grams, such as 30 to 32 grams, such as 32 to 34 grams, such as 34 to 36 grams, such as 36 to 38 grams, such as 38 to 40 grams, such as 40 to 42 grams, such as 42 to 44 grams, such as 44 to 46 grams, such as 46 to 48 grams, such as 48 to 50 grams.

14. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of carbohydrates in the meal is about 30 grams or about 31 grams.

15. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of carbohydrates in the meal is 60 to 200 kcal, such as 60 to 70 kcal, such as 70 to 80 kcal, such as 80 to 90 kcal, such as 90 to 100 kcal, such as 100 to 110 kcal, such as 110 to 120 kcal, such as 120 to 130 kcal, such as 130 to 140 kcal, such as 140 to 150 kcal, such as 150 to 160 kcal, such as 160 to 170 kcal, such as 170 to 180 kcal, such as 180 to 190 kcal, such as 190 to 200 kcal.

16. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of carbohydrates in the meal is 50 kcal% to 70 kcal%, such as 50 kcal% to 52 kcal%, such as 52 kcal% to 54 kcal%, such as 54 kcal% to 56 kcal%, such as 56 kcal% to 58 kcal%, such as 58 kcal% to 60 kcal%, such as 60 kcal% to 62 kcal%, such as 62 kcal% to 64 kcal%, such as 64 kcal% to 66 kcal%, such as 66 kcal% to 68 kcal%, such as 68 kcal% to 70 kcal%.

17. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of carbohydrates in the meal is about 59% of the total calories in the meal.

18. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of fat in the meal is 5 to 30 grams, such as 5 to 10 grams, such as 10 to 15 grams, such as 15 to 20 grams, such as 20 to 25 grams, such as 25 to 30 grams.

19. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of fat in the meal is about 7 grams, about 8 grams, about 9 grams or about 10 grams.

20. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of fat in the meal is 30 to 150 kcal, such as 30 to 40 kcal, such as 40 to 50 kcal, such as 50 to 60 kcal, such as 60 to 70 kcal, such as 70 to 80 kcal, such as 80 to 90 kcal, such as 90 to 100 kcal, such as 100 to 110 kcal, such as 110 to 120 kcal, such as 120 to 130 kcal, such as 130 to 140 kcal, such as 140 to 150 kcal.

21. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of fat in the meal is 25 kcal% to 45 kcal%, such as 25 kcal% to 27 kcal%, such as 27 kcal% to 29 kcal%, such as 29 kcal% to 31 kcal%, such as 31 kcal% to 33 kcal%, such as 33 kcal% to 35 kcal%, such as 35 kcal% to 37 kcal%, such as 37 kcal% to 39 kcal%, such as 39 kcal% to 41 kcal%, such as 41 kcal% to 43 kcal%, such as 43 kcal% to 45 kcal%.

22. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of fat in the meal is about 36% of the total calories in the meal.

23. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of protein in the meal is 0 to 10 grams, such as 0 to 2 grams, such as 2 to 4 grams, such as 4 to 6 grams, such as 6 to 8 grams, such as 8 to 10 grams.

24. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of protein in the meal is about 0 grams, about 1 gram, about 2 grams or about 3 grams.

25. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of protein in the meal is 0 to 50 kcal, such as 0 to 5 kcal, such as 5 to 10 kcal, such as 10 to 15 kcal, such as 15 to 20 kcal, such as 20 to 25 kcal, such as 25 to 30 kcal, such as 30 to 35 kcal, such as 35 to 40 kcal, such as 40 to 45 kcal, such as 45 to 50 kcal.

26. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of protein in the meal is 0 kcal% to 10 kcal%, such as 0 kcal% to 1 kcal%, such as 1 kcal% to 2 kcal%, such as 2 kcal% to 3 kcal%, such as 3 kcal% to 4 kcal%, such as 4 kcal% to 5 kcal%, such as 5 kcal% to 6 kcal%, such as 6 kcal% to 7 kcal%, such as 7 kcal% to 8 kcal%, such as 8 kcal% to 9 kcal%, such as 9 kcal% to 10 kcal% of the total calories in the meal.

27. The MRI composition for use according to any one of the preceding claims, wherein the predetermined amount of protein in the meal is about 5% of the total calories in the meal.

28. The MRI composition for use according to any one of the preceding claims, wherein the meal comprises one or more food items selected from the group consisting of bread, such as toast, and fruit juice, such as lime juice.

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

30. The MRI composition for use according to any one of the preceding claims, wherein the caloric content of the meal is 100 kcal to 500 kcal, such as 100 to 110 kcal, such as 110 kcal to 120 kcal, such as 120 kcal to 130 kcal, such as 130 kcal to 140 kcal, such as 140 kcal to 150 kcal, such as 150 kcal to 160 kcal, such as 160 kcal to 170 kcal, such as 170 kcal to 180 kcal, such as 180 kcal to 190 kcal, such as 190 kcal to 200 kcal, such as 200 kcal to 210 kcal, such as 210 kcal to 220 kcal, such as 220 kcal to 230 kcal, such as 230 kcal kcal, such as 240 kcal to 250 kcal, such as 250 kcal to 260 kcal, such as 260 kcal to 270 kcal, such as 270 kcal to 280 kcal, such as 280 kcal to 290 kcal, such as 290 kcal to 300 kcal, such as 300 kcal to 310 kcal, such as 310 kcal to 320 kcal, such as 320 kcal to 330 kcal, such as 330 kcal to 340 kcal, such as 340 kcal to 350 kcal, such as 350 kcal to 360 kcal, such as 360 kcal to 370 kcal, such as 370 kcal to 380 kcal, such as 380 kcal to 390 kcal, such as 390 kcal to 400 kcal.

31. The MRI composition for use according to any one of the preceding claims, wherein the caloric content of the meal is about 300 kcal or less, and wherein the predetermined amount of carbohydrates in the meal constitutes at least 50% of the caloric content of the meal.

32. A method for magnetic resonance imaging (MRI) of a subject, the method comprising administering to the subject a composition comprising, alone or together, manganese (II) chloride tetrahydrate, L-alanine and vitamin D, and optionally one or more water-soluble excipients; and performing MRI on the subject; wherein the subject consumes a meal 0 to 8 hours before or up to 2 hours after administration of the MRI composition, and wherein the caloric content of the meal is about 500 kcal or less.

33. A method of reducing or preventing nausea, diarrhea and / or headache in a subject receiving an MRI composition comprising, alone or together, manganese (II) chloride tetrahydrate, L-alanine and vitamin D and optionally one or more water-soluble excipients; the method comprising: i) administering a meal to the subject; as well as ii) administering the MRI composition to the subject; wherein the meal is administered 0 to 8 hours before administration of the MRI composition or up to 2 hours after administration of the MRI composition.

34. The method of claim 33, wherein the meal is administered 0 to 6 hours prior to administration of the MRI composition, 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.

35. The method of any one of claims 32 to 34, wherein image quality is not affected compared to a method wherein the MRI composition is administered to a fasting subject who has not eaten for more than 8 hours.

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