Compressed solid composition for MRI

Abstract

The present invention relates to a compressed solid composition for MRI containing a physiologically acceptable manganese(II) compound, its preparation and use for preparing an oral solution.

Description

[Technical field]

[0001] The present invention relates to a compressed solid composition for magnetic resonance imaging (MRI) comprising a physiologically acceptable manganese(II) compound, its preparation and use for preparing oral solutions. [Background technology]

[0002] Manganese is one of the most abundant metals on earth, found as a constituent of more than 100 different minerals. In addition to being an essential trace element linked to metabolic processes in the body, manganese is also a paramagnetic metal with properties similar to gadolinium with respect to T1-weighted (T1-w) magnetic resonance imaging (MRI). Manganese in the form of manganese(II) chloride tetrahydrate is the active substance in the targeted oral contrast agent Mangoral, indicated for hepatobiliary MRI. Under physiological circumstances, manganese is poorly absorbed from the intestine after oral ingestion, but by using certain absorption enhancers, L-alanine and vitamin D3, it is possible to obtain a sufficiently high concentration in the liver to achieve a significant signal enhancement effect. In the liver, manganese is subject to a very high first-pass effect of up to 98%, which prevents the metal from reaching the systemic circulation, thereby reducing the number of systemic side effects. Manganese is one of the least toxic trace elements and, because of its favorable safety profile, may in the future be an attractive alternative to gadolinium-based contrast agents for patients undergoing MRI evaluation of the liver, specifically for patients with severe renal failure or acute kidney injury.

[0003] Liver metastases are the most common type of malignant localized liver lesion. Metastases to the liver occur frequently in advanced cancer disease and are associated with a substantial decrease in survival. In fact, the liver is one of the most common - and often the first - sites of metastasis. Approximately 70% of all patients with colorectal cancer will develop liver metastases at some point in their lives, and one third of them will have metastases limited to the liver alone. Early detection and localization of liver metastases is important for optimal patient management.

[0004] Mangoral is the first contrast agent to receive Orphan Drug Designation from the FDA for use in liver MRI in patients where the use of gadolinium-based contrast agents is medically inadvisable or who cannot administer gadolinium-based contrast agents.

[0005] Mangoral is administered orally and consists of manganese combined with an absorption enhancer that increases manganese absorption in the small intestine; the prerequisite of high uptake of manganese into liver tissue is optimal for obtaining high image quality. Manganese is a natural trace element and is efficiently taken up by liver cells after absorption from the gastrointestinal tract. Due to the retention of manganese in liver cells and its paramagnetic properties, the contrast agent clearly highlights liver tissue on MR imaging, while liver metastatic cancer does not accumulate manganese. Thus, liver metastases will be clearly detectable against the highlighted liver tissue on MR images.

[0006] Currently, Mangoral is provided in a two-powder formulation that contains manganese salts in one sachet and one or more absorption enhancers in another sachet, as powders are considered incompatible. The contents of the two sachets are then placed into a glass of water to provide an oral MRI solution.

[0007] Although two-part formulations work well, a compressed solid composition containing the active ingredient of Mangoral would facilitate patient handling of the compressed solid composition, potentially allowing home administration with lower risk of inaccurate dosing of the contrast agent composition, thereby reducing MRI-related hospitalizations.Therefore, there is a need in the art to provide a one-part formulation of Mangoral, particularly in the form of a compressed solid composition. Summary of the Invention

[0008] The inventors have found that the active ingredient of Mangoral can be prepared in a one-dose formulation as a compressed solid composition for MRI suitable for preparing an oral solution.By preparing the compressed solid composition at low relative humidity (rH), such as less than 25% rH, and by carefully selecting water-soluble excipients with low hygroscopicity, the inventors have successfully prepared water-soluble and effervescent tablets containing manganese(II) chloride.

[0009] In a first aspect, there is provided a magnetic resonance imaging (MRI) contrast agent composition comprising a physiologically acceptable manganese(II) compound, one or more absorption enhancers, and one or more water-soluble excipients, wherein the compressed solid composition is suitable for preparing an oral solution.

[0010] In a second aspect, there is provided a method for preparing a compressed solid composition as defined herein, the method comprising: a. providing a physiologically acceptable manganese(II) compound, optionally as a granule, and optionally drying the physiologically acceptable manganese(II) compound; b. providing one or more absorption enhancers; c. providing one or more water-soluble excipients to enable compression; d. mixing a physiologically acceptable manganese(II) compound with one or more absorption enhancers and one or more water-soluble excipients to provide an aqueous mixture; e. compressing the aqueous mixture to provide a compressed solid composition as defined herein; Includes.

[0011] In a third aspect, there is provided a compressed solid composition prepared by the method defined herein.

[0012] In a fourth aspect, there is provided a method for preparing an oral MRI solution, comprising the steps of: a. providing a compressed solid composition as defined herein; b. providing a suitable amount of water; c. adding said compressed solid composition to said water; Thereby forming an oral MRI solution. A method is provided, comprising: [Brief description of the drawings]

[0013] [Figure 1] Effect of temperature on effervescent tablets (volume 200 ml of water). Effervescent tablets disintegrate rapidly and the dissolution time decreases with increasing temperature. [Diagram 2] Disintegration time to a clear solution at different volumes of water (at 20° C.) for the effervescent tablet and the two-component powder formulation, respectively. The effervescent tablet shows significantly faster and therefore superior dissolution and disintegration rates compared to the two-component powder formulation. [Diagram 3] Visual inspection of a glass of water to which (A) the effervescent tablet or (B) the two-part powder formulation was exposed. (A) The effervescent tablet provides a clear solution with no sediment after 5 minutes, and (B) the two-part powder formulation provides a clear solution with sediment after 5 minutes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] definition The term "water-soluble" is used herein to describe compounds that dissolve in water at room temperature, such as about 25° C. The degree of water solubility ranges from infinitely soluble (no limit) (completely miscible), such as ethanol in water, to sparingly soluble, such as silver chloride in water. The term insoluble is often applied to poorly or very poorly soluble compounds.

[0015] The term "water-insoluble" is used herein to describe a compound that does not dissolve in water at room temperature, such as about 25°C.

[0016] Several other descriptive terms are also used to quantify the degree of solubility of a given solute, i.e., a compound undergoing dissolution: [Table 1]

[0017] The water solubility of a given solute typically depends on temperature. Depending on the nature of the solute, the solubility may increase or decrease with temperature. For most solids and liquids, their water solubility increases with temperature.

[0018] The term "poorly soluble in cold water" is used herein to describe a compound that does not completely dissolve in cold water, such as a glass of water at about 2 to about 15°C.

[0019] The terms "slowly soluble" and "very slowly soluble" are used herein to describe compounds that have a low rate of solubilization in water. In this context, "slow rate" is intended to mean a rate that does not allow complete solubilization of the compound in water, such as a glass of water, within 8 minutes.

[0020] The term "hygroscopic" is used herein to describe compounds that, at 40-60% relative humidity (rH), sorb water, either by absorption, adsorption, or a combination of the two processes, to a significant extent, e.g., to the extent that the mass and / or volume of said compound increases by about 5% or more within a certain period of time, such as after about 1 hour.

[0021] The term "relative humidity" or "rH" refers to the ratio, expressed as a percentage, of the partial pressure of water vapor to the equilibrium water vapor pressure at a given temperature.

[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" to refer to compounds capable of enhancing manganese transport across membranes of the gastrointestinal tract. These compounds are well known in the art, for example from WO 96 / 05867, and include physiologically acceptable reduced 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.

[0024] The term "effervescent couple" as used herein refers to a pair of pharma- ceutically acceptable excipients, one of which is a basic component and the other of which is an acidic component. The basic component liberates carbon dioxide upon contact with the acidic component and water. An example of a basic component is bicarbonate.

[0025] The term "clear solution," as used herein, refers to a solution that appears clear upon visual inspection in sunlight.

[0026] Detailed Description The present disclosure provides a magnetic resonance imaging (MRI) contrast agent composition comprising a physiologically acceptable manganese(II) compound, one or more absorption enhancers, and one or more water soluble excipients, wherein the compressed solid composition is suitable for preparing an oral solution.

[0027] Difficulties in the production of compressed hygroscopic solids. The design and manufacture of pharmaceutical compressed solids, such as tablets, is a complex, multi-step process that requires careful control of several parameters: delivering the correct amount of drug substance, in the right formulation, at the right time, in the right ratio, and at the desired location, with its chemical integrity protected throughout the process.

[0028] The main objectives of the tablet manufacturing process include: Formulating tablets that are strong and hard to withstand the mechanical shocks encountered during manufacture, packaging, shipping, dispensing, and use; Formulating tablets with uniform weight and drug content; Formulating bioavailable tablets according to the requirements of the indication; - Formulating tablets that are chemically and physically stable over a long period of time; Formulate tablets with proper product identity without tablet defects.

[0029] During tablet compression, it is generally preferred to have a relatively high moisture content so that higher tablet hardness can be produced with lower compression forces. However, limitations exist because higher moisture contents tend to have two deleterious consequences: Increased moisture will cause a decrease in powder flow rate which in turn will increase powder particle sticking resulting in unstable tablet weight uniformity. Increased moisture will cause increased adhesion failures, which can be particularly difficult on stamped compression tooling as there are more pockets where the powder can stick.

[0030] In terms of chemical stability, a relatively low water content is favorable to reduce the degree of drug decomposition, make microbial growth more difficult to occur, and prevent clogging of the compound. Effervescent tablets, for example, are very sensitive to water content. The chemical reaction between organic acids and inorganic bases is autocatalytic, resulting in gaseous carbon dioxide and water. A very low water content is therefore necessary to prevent the reaction from starting, but once started, the water produced thereby promotes the reaction until the compound is used up.

[0031] With hygroscopic materials, tablet production can be very difficult and may require careful optimization of excipient selection and the tabletting process.

[0032] Moisture absorption Hygroscopicity is the phenomenon of attracting and retaining water molecules from the surrounding environment, usually at ordinary or room temperature. This is accomplished by either absorption or adsorption in the adsorbent material, which undergoes a physical change. This can be an increase in volume, boiling point, viscosity, or other physical property or characteristic of the material, since the water molecules can disperse between the molecules of the material in the process.

[0033] The total amount of water that can be taken up by a hygroscopic material will be a function of the temperature and humidity of the atmosphere in which it is located, and will ultimately be determined by the sorption isotherm of the system.

[0034] The term "hygroscopic" is used herein to describe compounds that, at 40-60% relative humidity (rH), sorb water either by absorption, adsorption, or a combination of the two processes to a significant extent, e.g., to the extent that the mass and / or volume of said compound increases by about 5% or more after a period of time, such as after about 1 hour.

[0035] Relative Humidity (rH) Poor environmental control, especially in terms of air humidity, can directly affect pharmaceutical production lines in many ways. Humidity levels below 45% rH will cause static charge to build up in machines and materials. This can have significant effects in processes where flammable solvents are used, so that electrical coupling between machines is critical. Low humidity can also cause products to dry out, affecting their performance. Charge build-up on powders can result in poor power flow and charged products can cause adhesion to each other, resulting in packaging problems.

[0036] High humidity also causes products to absorb moisture during production and final packaging. If a product is sensitive to long-term moisture, it will decompose over time if packaged under the wrong conditions.

[0037] The issue of humidity is complicated because at different stages of the manufacturing process there will likely be different requirements for the moisture content of the atmosphere.

[0038] Air conditioning and air handling equipment based on the refrigeration cycle - Heating, ventilation, and air conditioning (HVAC) systems are generally constructed to condition the working environment to maintain a relative humidity level of 40-60% at a temperature of approximately 21-25°C.

[0039] In the context of the present disclosure, it is important to control the relative humidity of the atmosphere throughout the tablet production area to below 35% rH, such as below 34%, for example below 33%, such as below 32%, for example below 31%, such as below 30%, for example below 29%, such as below 28%, for example below 27%, such as below 26%, for example below 25%, such as below 24%, for example below 23%, such as below 22%, for example below 21%, such as below 20%, for example below 19%, such as below 18%, for example below 17%, such as below 16%, for example below 15%, such as below 14%, for example below 13%, such as below 12%, for example below 11%, such as below 10%.

[0040] In one embodiment, the relative humidity (rH) is kept below 30%. In one embodiment, the relative humidity (rH) is kept below 25%. In one embodiment, the relative humidity (rH) is kept below 20%. In one embodiment, the relative humidity (rH) is kept below 15%, for example below 10%.

[0041] Relative humidity levels below 40% can be achieved with rotary desiccant dryers. These machines have been around for many years and can be sized according to the working area required for drying. They work by passing an ambient air stream through a solid desiccant (typically silica gel) located within a rotating wheel or platform. The exit air from a rotary dryer may have a relative humidity of 1% or less, and it may be necessary to mix this air stream with another to achieve the humidity level required for a particular manufacturing facility or process. Flow control is therefore important. Water absorbed from the air by the desiccant is released into the hot air stream by the rotating desiccant bed. The resulting moist air is usually exhausted outside the building.

[0042] Pharmaceutical Excipients Pharmaceutical excipients are substances that are formulated with the active ingredient of a drug and are included for the purpose of long-term stabilization, to add bulk to solid dosage forms containing small amounts of potent active ingredients (and thus are often called "bulking agents," "fillers," or "diluents"), or to provide therapeutic enhancements to the active ingredient in the final dosage form, such as, but not limited to, facilitating drug absorption, reducing viscosity, or increasing solubility. Pharmaceutical excipients can also be useful in aiding in the handling of the active agent of interest during the manufacturing process, such as by promoting powder flow or anti-adherence, in addition to aiding in in vitro stability, such as preventing denaturation or aggregation over the expected shelf life.

[0043] Those skilled in the art will understand that some excipients are preferred and some are not preferred for inclusion in compositions as disclosed herein, but it may be possible to produce tablets containing non-preferred excipients if the relative amounts of the excipients are carefully controlled. Some excipients may contain about 5% moisture and therefore are not preferred, but may still be included in small amounts if the other excipients included are non-hygroscopic and dry. The following section outlines the different groups of excipients according to the present disclosure and points out which excipients are preferred for inclusion in a mixed blend that provides a compressed solid composition with desired properties.

[0044] In one embodiment, a compressed solid 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.

[0045] The excipients of the present disclosure should collectively be able to: · Efficient production of a plurality of compressed solid compositions (tablets) that are uniform in size and all contain essentially the same amount of active ingredients (manganese(II) compound and absorption enhancer(s)). Rapid and essentially complete dissolution of compressed solid compositions in water without stirring or agitation. Formation of a clear oral solution having an acceptable taste for oral consumption.

[0046] Filler / Diluent: A "filler" or "diluent" according to the present disclosure is preferably a water-soluble and non-hygroscopic filler. In one embodiment, a compressed solid composition is provided as defined herein, wherein the non-hygroscopic filler is selected from the group consisting of isomalt, lactose such as spray-dried lactose, α-lactose, or β-lactose, maltitol, maltose, and mannitol.

[0047] Dextrin and lactitol may be used in small amounts as alternative fillers, but typically contain 5% moisture and are therefore not preferred for inclusion.

[0048] Dextrates, dextrose, fructose, hypromellose, maltodextrin, sucrose, sorbitol, and xylitol are also water-soluble fillers, but are all hygroscopic and therefore not preferred for inclusion in a compressed solid composition as defined herein. In one embodiment, a compressed solid composition is provided as defined herein, wherein the compressed solid composition does not comprise a hygroscopic filler selected from the group consisting of dextrates, dextrose, fructose, hypromellose, maltodextrin, sucrose, sorbitol, and xylitol.

[0049] In one embodiment, the compressed solid composition does not include a water-insoluble filler. In one embodiment, the water-insoluble filler is selected from the group consisting of calcium carbonate, calcium phosphate (e.g., basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate), calcium silicate, cellulose powder, cellulose acetate, magnesium carbonate, magnesium oxide, medium chain triglycerides, microcrystalline cellulose, silicified microcrystalline cellulose, polymethacrylates, starch, calcium sulfate, and pregelatinized starch. In one embodiment, a compressed solid composition is provided as defined herein, wherein the compressed solid composition does not include a water-insoluble filler selected from the group consisting of 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, polymethacrylates, starch, calcium sulfate, and pregelatinized starch.

[0050] 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 hydroxyethyl methylcellulose, maltose, povidone, and dextrin. In one embodiment, the binder is povidone.

[0051] Sodium carboxymethylcellulose, dextrates, dextrose, hydroxyethyl cellulose, hydroxypropyl cellulose, maltodextrin, poloxamer, polydextrose, and sucrose may be used in small amounts as alternative water-soluble binders, but are all hygroscopic and therefore not preferred.

[0052] Acacia, hypromellose, methylcellulose, and sodium alginate are water soluble but dissolve very slowly in water and are not very useful. Pregelatinized starch, inulin, agar, gelatin, starch, alginic acid, cellulose acetate phthalate, ethyl cellulose, hydrogenated vegetable oil, magnesium aluminum silicate, microcrystalline cellulose, and polymethacrylates are poorly soluble in cold water and therefore are not preferred binders.

[0053] In one embodiment, a pressed solid composition is provided as defined herein, wherein the pressed solid composition does not comprise 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.

[0054] Disintegrants: "Disintegrants" are known in the art to swell and dissolve when wet, causing a compressed pharmaceutical composition, such as a tablet, to break apart.

[0055] Povidone is a water-soluble disintegrant, but a very strong disintegrant. In one embodiment, a compressed solid composition is provided that includes a non-hygroscopic disintegrant, wherein the non-hygroscopic disintegrant is povidone.

[0056] Carboxymethylcellulose calcium, croscarmellose sodium, and crospovidone are insoluble in water, but are very strong disintegrants and can be applied at very low levels, which is preferred. In one embodiment, a compressed solid composition is provided as defined herein, further comprising a water-insoluble disintegrant. In one embodiment, the water-insoluble disintegrant is selected from the group consisting of carboxymethylcellulose calcium, croscarmellose sodium, and crospovidone.

[0057] Sodium carboxymethylcellulose and hydroxypropylcellulose are water-soluble disintegrants, but are not preferred because they are hygroscopic. In one embodiment, the compressed solid composition does not include a hygroscopic disintegrant selected from the group consisting of sodium carboxymethylcellulose and hydroxypropylcellulose.

[0058] Methylcellulose, sodium alginate, pregelatinized starch, starch, alginic acid, calcium alginate, magnesium aluminum silicate, microcrystalline cellulose, polacrilin potassium, and sodium starch glycolate may be applied as disintegrants, but are not preferred because they are slowly soluble or insoluble in water and require addition at high levels.

[0059] Lubricant: A "lubricant" prevents ingredients from sticking to and clogging the tablet punch or capsule filling machine. During tablet production, lubricants also ensure that tablet formation and ejection can occur with low friction between the solids and the die walls.

[0060] Polyethylene glycol 6000 and sodium benzoate are preferred water-soluble and non-hygroscopic binders. In one embodiment, a compressed solid composition is provided as defined herein, and the non-hygroscopic lubricant is selected from the group consisting of polyethylene glycol 6000 and sodium benzoate.

[0061] Sodium lauryl sulfate imparts a bitter taste and is therefore not preferred.

[0062] Poloxamer and polyethylene glycol 4000 are water soluble but hygroscopic lubricants and are not preferred. In one embodiment, a compressed solid composition is provided as defined herein, wherein the compressed solid composition does not comprise a hygroscopic lubricant selected from the group consisting of poloxamer and polyethylene glycol 4000.

[0063] Sodium stearyl fumarate, calcium stearate, colloidal silica, 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 therefore not preferred for inclusion in a compressed solid composition as defined herein. In one embodiment, the compressed solid composition does not include a water insoluble lubricant selected from the group consisting of sodium stearyl fumarate, calcium stearate, colloidal silica, 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.

[0064] Properties of the compressed solid composition In accordance with the present disclosure, a carefully selected blend of water-soluble excipients is provided that can be compressed into a solid composition together with a physiologically acceptable manganese(II) compound and one or more absorption enhancers.

[0065] It is important that the multiple tablets produced from a batch by the methods disclosed herein all have substantially the same amounts of the ingredients.

[0066] Additionally, dissolution of the compressed solid composition in water, such as about 0.2 L of water, should provide a clear solution, except for residual vitamin D that may or may not be present in the compressed solid composition. When added to water, vitamin D generally exists as an oil phase on top of the water phase. It is further desirable that the dissolved solid composition have a neutral taste. In one embodiment, vitamin D is in the form of vitamin D3 100,000. In one embodiment, vitamin D3 is in the form of dry vitamin D3 100 SD / S.

[0067] In one embodiment, the compressed solid composition has sufficient hardness and low water content.In one embodiment, the hardness of the compressed solid composition is 35N to 110N, for example, more than 40N, for example, more than 45N, for example, more than 50N, for example, more than 55N, for example, more than 60N, for example, more than 65N, for example, more than 70N, for example, more than 75N, for example, more than 80N, for example, more than 85N, for example, more than 90N, for example, more than 95N, for example, more than 100N, for example, more than 105N, for example, about 110N.

[0068] In one embodiment, the compressed solid composition is for use in preparing an oral solution.

[0069] In one embodiment, the compressed solid composition is for use as a magnetic resonance imaging (MRI) contrast agent composition.

[0070] Dissolution rate In one embodiment, the compressed solid composition provides a clear aqueous solution within 8 minutes, such as within 7 minutes, such as within 6 minutes, such as within 5 minutes, such as within 4 minutes, such as within 3 minutes, at room temperature without stirring or agitating the solution. Preferably, a clear solution is formed within 5 minutes, more preferably within 3 minutes.

[0071] In one embodiment, the compressed solid composition provides 0.2 L of a clear aqueous solution within 8 minutes, such as within 7 minutes, for example within 6 minutes, such as within 5 minutes, for example within 4 minutes, for example within 3 minutes, at room temperature without stirring or agitating the solution. Preferably, a clear solution is formed within 5 minutes, more preferably within 3 minutes.

[0072] In one embodiment, the pressed solid composition is completely soluble in water within 8 minutes, such as within 7 minutes, for example within 6 minutes, such as within 5 minutes, for example within 4 minutes, for example within 3 minutes, at room temperature without stirring or agitating the solution. Preferably, the pressed solid composition is completely soluble in water within 5 minutes, more preferably within 3 minutes.

[0073] In one embodiment, the compressed solid composition is completely soluble in cold water, such as at about 2 to about 15° C., within 8 minutes. In one embodiment, the compressed solid composition is completely soluble in 0.2 L of water at 5° C. within about 8 minutes.

[0074] Decay Speed In one embodiment, the compressed solid composition disintegrates in water at room temperature within less than 3.0 minutes, such as within less than 2.5 minutes, such as within less than 2 minutes, such as within less than 1.5 minutes, such as within less than 1 minute, without stirring or agitating the solution. Preferably, the compressed solid composition disintegrates within 2 minutes, more preferably within 1 minute.

[0075] In one embodiment, the compressed solid composition disintegrates in 0.2 L of water at room temperature without stirring or agitation of the solution within less than 3.0 minutes, such as within less than 2.5 minutes, for example within less than 2 minutes, such as within less than 1.5 minutes, for example within less than 1 minute.

[0076] pH of the resulting solution Manganese-containing effervescent tablets, when dispensed into water, can result in the formation of a precipitate consisting of manganese carbonates. These salts can be redissolved by acidifying the resulting solution, preferably by adjusting the pH of the resulting solution to between 2 and 7.

[0077] In one embodiment, the compressed solid composition provides a pH of 2-7 in 0.2 L of water after complete dissolution of 0.5 g to 1 g of manganese(II) chloride tetrahydrate, or an equimolar amount of any corresponding manganese(II) salt.

[0078] Physiologically acceptable manganese(II) compounds In one embodiment, a compressed solid composition is provided as defined herein, wherein the physiologically acceptable manganese(II) compound is a salt of an inorganic or 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, kojic acid, salicylate, and gluconate.

[0079] In one embodiment, a compressed solid 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.

[0080] In one embodiment a compressed solid composition is provided as defined herein, wherein the physiologically acceptable manganese(II) compound is manganese(II) chloride tetrahydrate.

[0081] In one embodiment a compressed solid composition is provided as defined herein, wherein the compressed solid composition comprises 0.5 g to 1.2 g of manganese(II) chloride tetrahydrate, or an equimolar amount of any corresponding manganese(II) salt.

[0082] In an embodiment a compressed solid composition is provided as defined herein, wherein the compressed solid composition comprises from 0.6g to 1g, such as from 0.65g to 0.95g, for example from 0.70g to 0.90g, such as from 0.75g to 0.85g, for example 0.80g manganese(II) chloride tetrahydrate.

[0083] In one embodiment, a compressed solid composition is provided as defined herein, wherein the compressed solid composition comprises 0.8 g of manganese(II) chloride tetrahydrate, or an equimolar amount of any corresponding manganese(II) salt.

[0084] In one embodiment, a compressed solid composition is provided as defined herein, wherein the compressed solid composition comprises 0.8 g of manganese(II) chloride tetrahydrate, or an equimolar amount of the corresponding anhydrate or dihydrate.

[0085] In one embodiment, a compressed solid composition is provided as defined herein, the composition comprising: a) manganese(II) chloride tetrahydrate or dihydrate; b) alanine, such as L-alanine; c) Isomalt; d) Croscarmellose, such as croscarmellose sodium, e) Polyethylene glycol such as PEG6000 Includes.

[0086] In one embodiment, the compressed solid composition further comprises vitamin D, such as vitamin D3.

[0087] Absorption enhancers Under physiological circumstances, physiologically acceptable manganese(II) compounds are poorly absorbed from the intestine after oral ingestion, but by using certain absorption enhancers such as L-alanine and vitamin D3, it is possible to obtain concentrations in the liver high enough to achieve significant signal enhancement effects during MRI.

[0088] The term "absorption enhancer" is used interchangeably herein with the term "uptake enhancer" to refer to compounds capable of enhancing manganese transport across membranes of the gastrointestinal tract. These compounds are well known in the art, for example from WO 96 / 05867, and include physiologically acceptable reduced 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.

[0089] In one embodiment a compressed solid 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.

[0090] In one embodiment a compressed solid composition is provided as defined herein, wherein the proteinogenic amino acids are 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.

[0091] In one embodiment a compressed solid composition is provided as defined herein, wherein the proteinogenic amino acid is a neutral amino acid.

[0092] In one embodiment a compressed solid composition is provided as defined herein, wherein the proteinogenic amino acid is L-alanine.

[0093] In one embodiment, a compressed solid composition is provided as defined herein, wherein the vitamin D is vitamin D3.

[0094] In one embodiment, a compressed solid composition is provided as defined herein and comprises two absorption enhancers, hi one embodiment, the two absorption enhancers are L-alanine and vitamin D3.

[0095] In one embodiment a compressed solid composition is provided as defined herein, wherein the compressed solid composition comprises between 0.25g and 0.75g, such as between 0.30g and 0.70g, for example between 0.35g and 0.65g, such as between 0.40g and 0.60g, for example between 0.45g and 0.55g, such as 0.50g of a proteinogenic amino acid, such as L-alanine.

[0096] Foamable Composition In one embodiment, the compressed solid composition as provided herein is in the form of an effervescent solid composition, such as an effervescent tablet. The effervescent composition as disclosed herein comprises an effervescent couple.

[0097] The term "effervescent couple" as used herein refers to a pair of pharma- ceutically acceptable excipients, one of which is a basic component and the other of which is an acidic component. The basic component liberates carbon dioxide when in contact with the acidic component and water. An example of a basic component is bicarbonate, also known as hydrogen carbonate.

[0098] In one embodiment, the acidic component is citric acid, such as citric acid anhydride, hi one embodiment, the acidic component is malic acid.

[0099] In one embodiment, the basic component of the effervescent couple is selected from sodium bicarbonate, anhydrous sodium carbonate, and mixtures thereof.

[0100] In one embodiment, the basic component is sodium bicarbonate and the acidic component is citric acid, such as citric acid anhydride.

[0101] In one embodiment the effervescent tablet has a mass of between 1.8 g and 4.0 g, such as between 1.9 g and 3.9 g, for example between 2.0 g and 3.8 g, such as between 2.1 g and 3.7 g, for example between 2.2 g and 3.6 g, for example between 2.3 g and 3.5 g.

[0102] In one embodiment the compressed solid composition has a mass of from 1.8 g to 8.0 g, such as from 1.9 g to 6.0 g, for example from 2.0 g to 4.0 g.

[0103] In one embodiment, the effervescent tablet comprises manganese(II) chloride dihydrate.

[0104] In one embodiment, the compressed solid composition is provided as an effervescent tablet comprising bicarbonate, such as granular bicarbonate.

[0105] In one embodiment, the effervescent tablet comprises citric acid, such as anhydrous citric acid or citric acid monohydrate.

[0106] In one embodiment a compressed solid composition is provided as defined herein, wherein the weight ratio of citric acid to sodium bicarbonate in the effervescent tablet is at least 1.2 to 1, such as at least 1.3 to 1, for example at least 1.4 to 1, such as at least 1.5 to 1, for example at least 1.6 to 1, such as at least 1.7 to 1, for example at least 1.8 to 1, such as at least 1.9 to 1, for example at least 1.9 to 1, such as at least 2.0 to 1, for example at least 2.1 to 1, such as at least 2.2 to 1, for example at least 2.3 to 1, such as at least 2.4 to 1, for example at least 2.5 to 1.

[0107] In one embodiment, the effervescent tablet comprises a sweetener such as isomalt, optionally granulated isomalt, which is primarily used as a filler in the context of this disclosure.

[0108] In one embodiment, the effervescent tablet is configured such that the effervescent period ends when dissolution of the compressed solid composition is complete after dispensing in water, and thus the end of effervescence can be an indication of when the oral solution is ready for use.

[0109] In one embodiment, the compressed solid composition comprises: a) manganese chloride tetrahydrate or dihydrate; b) alanine, such as L-alanine; c) Isomalt; d) a bicarbonate, such as sodium bicarbonate; e) citric acid, such as citric acid monohydrate; f) polyethylene glycol, such as polyethylene glycol 6000 (PEG6000); The present invention is provided as an effervescent tablet comprising:

[0110] In one embodiment, the effervescent tablet further comprises vitamin D, such as vitamin D3.

[0111] In one embodiment, the effervescent tablet is prepared from granules, such as sodium bicarbonate granules.

[0112] In one embodiment, the granules comprise sodium bicarbonate, isomalt, and povidone. In one embodiment, the granules comprise 68.7% by weight sodium bicarbonate, 26.7% by weight isomalt, and 4.6% by weight povidone.

[0113] In a preferred embodiment, the effervescent tablet has a mass of about 2.5 g, for example 2.44 g.

[0114] In one embodiment, the effervescent tablet comprises: [Table 2]

[0115] In a preferred embodiment, the effervescent tablet comprises: [Table 3]

[0116] In one embodiment, the composition of Vitamin D3 powder 100 000 IU is as follows: [Table 4]

[0117] In one embodiment, the effervescent tablet contains 480-1120 IU of vitamin D3.

[0118] packaging The compressed solid compositions as defined herein are preferably packaged using a waterproof or moisture-proof material, such as a blister pack, optionally made of aluminum, of a suitable waterproof or moisture-proof material known to those skilled in the art. A blister pack is a preformed package used for solid compositions, such as the compressed solid compositions provided herein. A blister pack is useful for protecting the drug from external factors, such as humidity and contamination, for extended periods of time.

[0119] In one embodiment, A compressed solid composition as defined herein; A waterproof package that protects the compressed solid composition from moisture. A kit of parts is provided that includes:

[0120] Preparation of compressed solid compositions In one embodiment there is provided a method for preparing a compressed solid composition as defined herein, the method comprising: a) providing a physiologically acceptable manganese(II) compound, optionally as a granule, and optionally drying the physiologically acceptable manganese(II) compound; b) providing one or more water-soluble excipients to enable compression; c) mixing a physiologically acceptable manganese(II) compound with one or more absorption enhancers and one or more water-soluble excipients to provide an aqueous mixture; d) compressing the aqueous mixture to provide a compressed solid composition as defined herein; Includes.

[0121] In an embodiment there is provided a method as defined herein, wherein the relative humidity (rH) is kept below 35%, such as below 34%, for example below 33%, such as below 32%, for example below 31%, such as below 30%, for example below 29%, for example below 28%, such as below 27%, for example below 26%, such as below 25%, for example below 24%, such as below 23%, for example below 22%, such as below 21%, for example below 20%, such as below 19%, for example below 18%, such as below 17%, for example below 16%, for example below 15%, such as below 14%, for example below 13%, for example below 12%, such as below 11%, for example below 10%.

[0122] In one embodiment, the relative humidity (rH) is kept below 30%.

[0123] In one embodiment, the relative humidity (rH) is kept below 25%.

[0124] In one embodiment, the relative humidity (rH) is kept below 20%.

[0125] In one embodiment there is provided a compressed solid composition as prepared by the method defined herein.

[0126] item I-1. A compressed solid composition comprising a physiologically acceptable manganese(II) compound, one or more absorption enhancers, and one or more water-soluble excipients.

[0127] I-2. 2. A compressed solid composition according to item 1 for use in the preparation of an oral solution.

[0128] I-3. A compressed solid composition for use as a magnetic resonance imaging (MRI) contrast agent composition.

[0129] I-4. Item 11. The compressed solid composition of any one of the preceding items, wherein the one or more water-soluble excipients are non-hygroscopic water-soluble excipients.

[0130] I-5. 13. The compressed solid composition of any one of the preceding items, wherein 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.

[0131] I-6. Item 11. The compressed solid composition of any one of the preceding items, wherein the non-hygroscopic filler is selected from the group consisting of isomalt, spray-dried lactose, lactose such as α-lactose, or β-lactose, maltitol, maltose, and mannitol.

[0132] I-7. 13. The compressed solid composition of any one of the preceding items, wherein the compressed solid composition does not contain a hygroscopic filler selected from the group consisting of dextrates, dextrose, fructose, hypromellose, maltodextrin, sucrose, sorbitol, and xylitol.

[0133] I-8. 13. The compressed solid composition of any one of the preceding items, wherein the compressed solid composition does not contain a water insoluble filler selected from the group consisting of 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, polymethacrylates, starch, calcium sulfate, and pregelatinized starch.

[0134] I-9. Item 11. The compressed solid composition of any one of the preceding items, wherein the non-hygroscopic binder is selected from the group consisting of hydroxyethyl methylcellulose, maltose, povidone, and dextrin.

[0135] I-10. 13. The compressed solid composition of any one of the preceding items, wherein the compressed solid 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.

[0136] I-11. Item 11. The compressed solid composition of any one of the preceding items, wherein the non-hygroscopic disintegrant is povidone.

[0137] I-12. Item 11. The compressed solid composition of any one of the preceding items, further comprising a water-insoluble disintegrant.

[0138] I-13. Item 11. The compressed solid composition of any one of the preceding items, wherein the water-insoluble disintegrant is selected from the group consisting of calcium carboxymethylcellulose, croscarmellose sodium, and crospovidone.

[0139] I-14. Item 11. The compressed solid composition of any one of the preceding items, wherein the compressed solid composition does not comprise a hygroscopic disintegrant selected from the group consisting of sodium carboxymethylcellulose and hydroxypropylcellulose.

[0140] I-15. Item 11. The compressed solid composition of any one of the preceding items, wherein the non-hygroscopic lubricant is selected from the group consisting of polyethylene glycol 6000 and sodium benzoate.

[0141] I-16. Item 11. The compressed solid composition of any one of the preceding items, wherein the compressed solid composition does not contain a hygroscopic lubricant selected from the group consisting of poloxamer and polyethylene glycol 4000.

[0142] I-17. 13. The compressed solid composition of any one of the preceding items, wherein the compressed solid composition is free of a water-insoluble lubricant selected from the group consisting of sodium stearyl fumarate, calcium stearate, colloidal silica, 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.

[0143] I-18. Item 11. The compressed solid composition of any one of the preceding items, wherein the physiologically acceptable manganese(II) compound is a salt of an inorganic anion or an organic anion.

[0144] I-19. Item 11. The compressed solid composition of any one of the preceding items, wherein the inorganic anion is selected from the group consisting of chloride, fluoride, bromide, iodide, sulfate, and phosphate.

[0145] I-20. Item 11. The compressed solid composition of any one of the preceding items, wherein the organic anion is selected from the group consisting of ascorbate, kojic acid, salicylate, and gluconate.

[0146] I-21. 11. The compressed solid composition of any one of the preceding claims, 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.

[0147] I-22. Item 11. The compressed solid composition of any one of the preceding items, wherein the physiologically acceptable manganese(II) compound is manganese(II) chloride tetrahydrate.

[0148] I-23. 13. The compressed solid composition of any one of the preceding items, wherein the one or more absorption enhancers are selected from the group consisting of proteinogenic amino acids and vitamin D.

[0149] I-24. 13. The compressed solid composition of any one of the preceding items, wherein the proteinogenic amino acids are 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.

[0150] I-25. 13. The compressed solid composition of any one of the preceding items, wherein the proteinogenic amino acid is a neutral amino acid.

[0151] I-26. 13. The compressed solid composition of any one of the preceding items, wherein the proteinogenic amino acid is L-alanine.

[0152] I-27. Item 11. The compressed solid composition of any one of the preceding items, wherein the vitamin D is vitamin D3.

[0153] I-28. Item 11. A compressed solid composition according to any one of the preceding items, comprising two absorption enhancers.

[0154] I-29. 13. The compressed solid composition of any one of the preceding items, wherein the two absorption enhancers are L-alanine and vitamin D3.

[0155] I-30. 13. The compressed solid composition of any one of the preceding items, wherein the compressed solid composition comprises 0.5 g to 1.2 g of manganese(II) chloride tetrahydrate, or an equimolar amount of any corresponding manganese(II) salt.

[0156] I-31. 13. A compressed solid composition according to any one of the preceding items, comprising 0.6g to 1g, such as 0.65g to 0.95g, for example 0.70g to 0.90g, such as 0.75g to 0.85g, for example 0.80g of manganese(II) chloride tetrahydrate.

[0157] I-32. 8. The compressed solid composition of claim 1, wherein the compressed solid composition comprises 0.8 g of manganese(II) chloride tetrahydrate, or an equimolar amount of any corresponding manganese(II) salt.

[0158] I-33. 8. The compressed solid composition of claim 1, wherein the compressed solid composition comprises 0.8 g of manganese(II) chloride tetrahydrate, or an equimolar amount of the corresponding anhydrate or dihydrate.

[0159] I-34. 13. The compressed solid composition according to any one of the preceding items, wherein the compressed solid composition comprises 0.25g to 0.75g, such as 0.30g to 0.70g, for example 0.35g to 0.65g, such as 0.40g to 0.60g, for example 0.45g to 0.55g, for example 0.50g L-alanine.

[0160] I-35. Item 14. The compressed solid composition according to any one of the preceding items, wherein the compressed solid composition provides a clear aqueous solution within 8 minutes, such as within 7 minutes, for example within 6 minutes, such as within 5 minutes, for example within 4 minutes, such as within 3 minutes, at room temperature without stirring or agitating the solution.

[0161] I-36. Item 14. The compressed solid composition according to any one of the preceding items, wherein the compressed solid composition provides 0.2 L of a clear aqueous solution within 8 minutes, such as within 7 minutes, for example within 6 minutes, such as within 5 minutes, for example within 4 minutes, such as within 3 minutes, at room temperature without stirring or agitating the solution.

[0162] I-37. 13. A compressed solid composition according to any one of the preceding items, wherein the compressed solid composition dissolves completely in water within 8 minutes, such as within 7 minutes, for example within 6 minutes, such as within 5 minutes, for example within 4 minutes, such as within 3 minutes, at room temperature without stirring or agitation of the solution.

[0163] I-38. Item 1. The compressed solid composition according to any one of the preceding items, wherein the compressed solid composition disintegrates in water at room temperature within less than 3.0 minutes, such as within less than 2.5 minutes, such as within less than 2 minutes, such as within less than 1.5 minutes, for example within less than 1 minute, without stirring or agitation of the solution.

[0164] I-39. 13. The compressed solid composition according to any one of the preceding items, wherein the compressed solid composition disintegrates in 0.2 L of water at room temperature without stirring or agitation of the solution within less than 3.0 minutes, such as within less than 2.5 minutes, for example within less than 2 minutes, such as within less than 1.5 minutes, for example within less than 1 minute.

[0165] I-40. 13. The compressed solid composition of any one of the preceding items, wherein the compressed solid composition provides a pH of 2 to 7 in 0.2 L of water after complete dissolution of 0.5 g to 1 g of manganese(II) chloride tetrahydrate, or an equimolar amount of any corresponding manganese(II) salt.

[0166] I-41. 13. The compressed solid composition according to any one of the preceding items, wherein the compressed solid composition is a foamable composition.

[0167] I-42. 10. The compressed solid composition according to any one of the preceding items, wherein the effervescent tablet has a mass of from 1.8 g to 4.0 g, such as from 1.9 g to 3.9 g, for example from 2.0 g to 3.8 g, such as from 2.1 g to 3.7 g, for example from 2.2 g to 3.6 g, for example from 2.3 g to 3.5 g.

[0168] I-43. 13. The compressed solid composition of any one of the preceding items, wherein the effervescent tablet comprises manganese(II) chloride dihydrate.

[0169] I-44. Item 11. The compressed solid composition of any one of the preceding items, wherein the effervescent tablet comprises a bicarbonate, such as a granular bicarbonate.

[0170] I-45. Item 11. The compressed solid composition of any one of the preceding items, wherein the effervescent tablet comprises citric acid, such as anhydrous citric acid or citric acid monohydrate.

[0171] I-46. 13. A compressed solid composition according to any one of the preceding items, wherein the weight ratio of citric acid to sodium bicarbonate in the effervescent tablet is at least 1.2 to 1, such as at least 1.3 to 1, for example at least 1.4 to 1, such as at least 1.5 to 1, for example at least 1.6 to 1, such as at least 1.7 to 1, for example at least 1.8 to 1, such as at least 1.9 to 1, for example at least 1.9 to 1, such as at least 2.0 to 1, for example at least 2.1 to 1, such as at least 2.2 to 1, for example at least 2.3 to 1, such as at least 2.4 to 1, for example at least 2.5 to 1.

[0172] I-47. Effervescent tablets are a. manganese chloride tetrahydrate, dihydrate, or anhydrous; B alanine, c. Isomalt; d. a bicarbonate, such as sodium bicarbonate; e. citric acid, such as citric acid monohydrate; f. Polyethylene glycol such as polyethylene glycol 6000 (PEG6000) Item 11. The compressed solid composition of any one of the preceding items, comprising:

[0173] I-48. 48. The compressed solid composition of item 47, further comprising vitamin D3.

[0174] I-49. The composition comprises: a. Manganese(II) chloride tetrahydrate, dihydrate, or anhydrous; B alanine, c. Isomalt; d. Croscarmellose, such as croscarmellose sodium; e. Polyethylene glycol such as PEG6000 Item 11. The compressed solid composition of any one of the preceding items, comprising:

[0175] I-50. 50. The compressed solid composition of item 49, further comprising vitamin D3.

[0176] I-51. a) a compressed solid composition as defined in any one of the preceding items; b) Waterproof packaging Including parts kit.

[0177] I-52. A method for preparing a compressed solid composition as defined in any one of the preceding items, comprising: a. providing a physiologically acceptable manganese(II) compound, optionally as a granule, and optionally drying the physiologically acceptable manganese(II) compound; b. providing one or more absorption enhancers; c. providing one or more water-soluble excipients to enable compression; d. mixing a physiologically acceptable manganese(II) compound with one or more absorption enhancers and one or more water-soluble excipients to provide an aqueous mixture; e. compressing the aqueous mixture to provide a compressed solid composition as defined in any one of the preceding items; A method comprising:

[0178] I-53. 13. The method according to any one of the preceding items, wherein the relative humidity (RH) is kept below 35%, such as below 34%, for example below 33%, such as below 32%, for example below 31%, such as below 30%, for example below 29%, such as below 28%, for example below 27%, such as below 26%, for example below 25%, such as below 24%, for example below 23%, such as below 22%, for example below 21%, such as below 20%, for example below 19%, such as below 18%, for example below 17%, such as below 16%, for example below 15%, such as below 14%, for example below 13%, such as below 12%, for example below 11%, such as below 10%.

[0179] I-54. 2. A compressed solid composition prepared by the method of any one of the preceding items.

[0180] I-55. 1. A method for preparing an oral MRI solution, comprising: a. providing a compressed solid composition as defined in any one of the preceding items; b. providing a suitable amount of water; c. adding said compressed solid composition to said water; Thereby forming an oral MRI solution. A method comprising:

[0181] Item II 1. 1. A compressed solid composition comprising a physiologically acceptable manganese(II) compound, one or more absorption enhancers, and one or more water-soluble excipients, optionally wherein the compressed solid composition is for preparing an oral solution, e.g., for magnetic resonance imaging (MRI).

[0182] 2. 2. The compressed solid composition according to item 1, wherein 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.

[0183] 3. Item 11. The compressed solid composition of any one of the preceding items, wherein the non-hygroscopic filler is selected from the group consisting of isomalt, spray-dried lactose, lactose such as α-lactose, or β-lactose, maltitol, maltose, and mannitol.

[0184] 4. Item 11. The compressed solid composition of any one of the preceding items, wherein the non-hygroscopic binder is selected from the group consisting of hydroxyethyl methylcellulose, maltose, povidone, and dextrin.

[0185] 5. Item 11. The compressed solid composition of any one of the preceding items, wherein the non-hygroscopic disintegrant is povidone.

[0186] 6. Item 11. The compressed solid composition of any one of the preceding items, wherein the non-hygroscopic lubricant is selected from the group consisting of polyethylene glycol 6000 and sodium benzoate.

[0187] 7. 11. The compressed solid composition of any one of the preceding claims, 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.

[0188] 8. 13. The compressed solid composition of any one of the preceding items, wherein the one or more absorption enhancers are selected from the group consisting of proteinogenic amino acids and vitamin D, and optionally the compressed solid composition comprises two absorption enhancers, such as L-alanine and vitamin D3.

[0189] 9. 13. The compressed solid composition of any one of the preceding items, wherein the compressed solid composition comprises 0.5 g to 1.2 g of manganese(II) chloride tetrahydrate, or an equimolar amount of any corresponding manganese(II) salt.

[0190] 10. 13. The compressed solid composition according to any one of the preceding items, wherein the compressed solid composition provides a clear solution and / or dissolves completely, e.g. in 0.2 L of water, within 8 minutes, such as within 7 minutes, for example within 6 minutes, such as within 5 minutes, for example within 4 minutes, such as within 3 minutes, at room temperature without stirring or agitation of the solution.

[0191] 11. 13. The compressed solid composition of any one of the preceding items, wherein the compressed solid composition provides a pH of 2 to 7 in 0.2 L of water after complete dissolution of 0.5 g to 1 g of manganese(II) chloride tetrahydrate, or an equimolar amount of any corresponding manganese(II) salt.

[0192] 12. 13. The compressed solid composition according to any one of the preceding items, wherein the compressed solid composition is a foamable composition.

[0193] 13. A method for preparing a compressed solid composition as defined in any one of the preceding items, comprising: a. providing a physiologically acceptable manganese(II) compound, optionally as a granule, and optionally drying the physiologically acceptable manganese(II) compound; b. providing one or more absorption enhancers; c. providing one or more water-soluble excipients to enable compression; d. mixing a physiologically acceptable manganese(II) compound with one or more absorption enhancers and one or more water-soluble excipients to provide an aqueous mixture; e. compressing the aqueous mixture to provide a compressed solid composition as defined in any one of the preceding items; A method comprising:

[0194] 14. 13. The method according to any one of the preceding items, wherein the relative humidity (RH) is kept below 35%, such as below 34%, for example below 33%, such as below 32%, for example below 31%, such as below 30%, for example below 29%, such as below 28%, for example below 27%, such as below 26%, for example below 25%, such as below 24%, for example below 23%, such as below 22%, for example below 21%, such as below 20%, for example below 19%, such as below 18%, for example below 17%, such as below 16%, for example below 15%, such as below 14%, for example below 13%, such as below 12%, for example below 11%, such as below 10%.

[0195] 15. 1. A method for preparing an oral MRI solution, comprising: a. providing a compressed solid composition as defined in any one of the preceding items; b. providing a suitable amount of water; c. adding said compressed solid composition to said water; Thereby forming an oral MRI solution. A method comprising:

[0196] Item III 1. a) manganese(II) chloride tetrahydrate in the range of 0.50 g to 1.2 g, or an equimolar amount of the corresponding anhydrate or dihydrate; b) L-alanine in the range of 0.25 g to 0.75 g; c) one or more water-soluble excipients; d) effervescent couples containing a basic component and an acidic component; An effervescent tablet for magnetic resonance imaging (MRI), comprising: Effervescent tablets are for preparing oral solutions for MRI, Effervescent MRI tablets.

[0197] 2. 2. The effervescent MRI tablet according to item 1, wherein the one or more water-soluble excipients are selected from the group consisting of non-hygroscopic fillers, non-hygroscopic binders, non-hygroscopic disintegrants, non-hygroscopic lubricants, and combinations thereof.

[0198] 3. 3. The effervescent MRI tablet according to item 2, comprising a non-hygroscopic filler, the non-hygroscopic filler being selected from the group consisting of isomalt, lactose, maltitol, maltose, and mannitol.

[0199] 4. 3. The effervescent MRI tablet according to item 2, comprising a non-hygroscopic binder, the non-hygroscopic binder being selected from the group consisting of hydroxyethyl methylcellulose, maltose, povidone, and dextrin.

[0200] 5. 3. The effervescent MRI tablet according to item 2, comprising the non-hygroscopic disintegrant povidone.

[0201] 6. 3. The effervescent MRI tablet according to item 2, comprising a non-hygroscopic lubricant, the non-hygroscopic lubricant being selected from the group consisting of polyethylene glycol 6000 and sodium benzoate.

[0202] 7. 2. The effervescent MRI tablet according to item 1, further comprising vitamin D3.

[0203] 8. 2. The effervescent MRI tablet according to item 1, wherein the effervescent MRI tablet contains 0.50 g of L-alanine.

[0204] 9. 2. The effervescent MRI tablet according to item 1, which provides 0.2 L of a clear aqueous solution within 5 minutes at room temperature without stirring or agitating the solution.

[0205] 10. 2. The effervescent MRI tablet according to item 1, wherein the effervescent MRI tablet dissolves completely in water within 5 minutes at room temperature without stirring or agitating the solution.

[0206] 11. 2. The effervescent MRI tablet according to item 1, wherein the effervescent MRI tablet disintegrates in 0.2 L of water in less than 3.0 minutes at room temperature without stirring or agitation of the solution.

[0207] 12. 2. The effervescent MRI tablet according to item 1, which after complete dissolution of 0.5 g to 1 g of manganese(II) chloride tetrahydrate, or an equimolar amount of the corresponding anhydrate or dihydrate, results in a pH of 2 to 7 in 0.2 L of water.

[0208] 13. Item 1. The effervescent MRI tablet according to item 1, wherein the effervescent MRI tablet has a mass in the range of 1.8 g to 4.0 g.

[0209] 14. 2. The effervescent MRI tablet according to item 1, wherein the effervescent MRI tablet comprises granular bicarbonate.

[0210] 15. 2. The effervescent MRI tablet according to item 1, wherein the effervescent MRI tablet comprises citric acid.

[0211] 16. Item 2. The effervescent MRI tablet according to item 1, comprising citric acid and sodium bicarbonate, wherein the mass ratio of citric acid to sodium bicarbonate in the effervescent MRI tablet is 1.2 to 1.

[0212] 17. Effervescent MRI tablets are: a. manganese chloride tetrahydrate, dihydrate, or anhydrous; b L-alanine, c. Isomalt; d. sodium bicarbonate; e. citric acid; f.PEG6000 and 2. The effervescent MRI tablet according to item 1, comprising:

[0213] 18. Effervescent MRI tablets are: a. manganese chloride tetrahydrate, dihydrate, or anhydrous; b L-alanine, c. Isomalt; d. sodium bicarbonate; e. citric acid; f.PEG6000 and g. Povidone, h. Vitamin D3 and Item 2. The effervescent MRI tablet according to item 1, comprising:

[0214] 19. A process for preparing an effervescent MRI tablet as defined in item 1, comprising: a) providing a physiologically acceptable manganese(II) compound; b) providing one or more absorption enhancers; c) providing one or more water-soluble excipients to enable compression; d) mixing a physiologically acceptable manganese(II) compound with one or more absorption enhancers and one or more water-soluble excipients to provide an aqueous mixture; e) compressing the aqueous mixture to provide an effervescent MRI tablet. Including, Relative humidity (RH) is kept below 30%. method.

[0215] 20. 1. A method for preparing an oral MRI solution, comprising: a. Providing an effervescent MRI tablet as defined in paragraph 1; b. providing a suitable amount of water; c. adding said effervescent MRI tablet to said water; d. Thereby forming an oral MRI solution. A method comprising:

[0216] Working Example In the following examples, Examples 1-9 relate to non-effervescent tablets, referred to herein as "soluble tablets", and Examples 10-18 relate to effervescent tablets, referred to herein as "effervescent tablets". Examples 1-3 are examples of formulations that provide a clear solution within 5 minutes after introduction into water. Examples 4 and 7-8 demonstrate the problems associated with too high air humidity. Example 5 demonstrates that drying manganese chloride before mixing can lead to problems with high hygroscopicity. Examples 6 and 9 are examples of compositions that do not result in a clear solution after introduction into water. Examples 10-12 demonstrate the preparation of effervescent tablets produced under low relative humidity conditions that work well. Examples 13-14 demonstrate how effervescent tablets prepared at higher relative humidity do not perform as well. Examples 11 and 15-18 demonstrate the effect of drying manganese chloride, either directly or during the granulation process. Examples 16-18 demonstrate the effect of granulating the tablet ingredients to modify the dissolution profile.

[0217] Example 1: Soluble tablets based on isomalt with a tablet weight of 2000 mg Manganese chloride tetrahydrate, alanine, isomalt, croscarmellose sodium, and PEG6000 were mixed for 5 minutes, where the relative humidity (rH) in the air was 24%rH. Tablets were compressed in a single punch tablet press using 20mm flat tooling to give a tablet weight of 2000mg and a hardness of 40N. The manganese chloride tetrahydrate content was 800mg / tablet and the alanine content was 500mg / tablet. One tablet was placed in a glass of 200ml water at room temperature, the tablet disintegrated within 1 minute and quickly dissolved completely within 3 minutes to give a clear solution.

[0218] conclusion At low relative humidity in the air, tablets can be produced according to the above method that will rapidly disintegrate and dissolve to form a clear solution with a bland taste.

[0219] Example 2: Soluble tablets based on isomalt with a tablet weight of 2500 mg Manganese chloride tetrahydrate, alanine, isomalt, croscarmellose sodium, and PEG 6000 were mixed for 5 minutes. Tablets were compressed using 20 mm flat tooling in a single punch tablet press to a tablet weight of 2500 mg and hardness of 90 N. The manganese chloride tetrahydrate content was 800 mg / tablet and the alanine content was 500 mg / tablet. One tablet was placed in a glass of 200 ml water at room temperature; the tablet disintegrated within 3 minutes and completely dissolved within 5 minutes to give a clear solution.

[0220] Example 3: Soluble tablets based on isomalt with added vitamin D, tablet weight 2000 mg Manganese chloride tetrahydrate, alanine, dry vitamin D3 100 SD / S, isomalt, croscarmellose sodium, and PEG 6000 were mixed for 5 minutes. Tablets were compressed using 20 mm flat tooling in a single punch tablet press to a tablet weight of 2000 mg. Manganese chloride tetrahydrate content was 800 mg / tablet, alanine content was 500 mg / tablet, and vitamin D content was 20 μg / tablet plus 20% excess. One tablet was placed in a glass of 200 ml water at room temperature, and the tablet completely dissolved within 5 minutes to give a clear solution with a small shadow on the surface due to vitamin D.

[0221] Example 4: Soluble tablets based on isomalt with added vitamin D, tablet weight 2000 mg, adsorb moisture at 35% rH Manganese chloride tetrahydrate, alanine, dry vitamin D3 100 SD / S, isomalt, croscarmellose sodium, and PEG 6000 were mixed for 5 minutes, where the relative humidity in the air was 35% rH. Tablets were compressed in a single punch tablet press using 20 mm flat tooling to a tablet weight of 2000 mg and hardness of 85 N. During processing, the granules absorbed moisture from the air, forming lumps and making them difficult to inject into the tablet press. The manganese chloride tetrahydrate content was 800 mg / tablet, the alanine content was 500 mg / tablet, and the vitamin D content was 20 μg / tablet plus 20% excess. One tablet was placed in a glass of 200 ml water at room temperature, the tablet disintegrated within 4 minutes and completely dissolved within 9 minutes, giving a clear solution.

[0222] conclusion The humidity in the air in the production area needs to be kept low, such as less than 25% rH, otherwise the mixture will absorb moisture and form lumps, and tablet dissolution times will increase.

[0223] Example 5: Manganese chloride dried, soluble tablets based on isomalt Manganese chloride tetrahydrate was dried at 100°C overnight to constant weight. Approximately 22% of the weight was lost. Dry manganese chloride, alanine, dry vitamin D3 100 SD / S, isomalt, croscarmellose sodium, and PEG 6000 were mixed for 5 minutes, where the relative humidity in the air was 17% rH. Tablets were compressed using a 20mm flat tool in a single punch tablet press to a tablet weight of 2000mg and hardness of 61N. The manganese chloride tetrahydrate content was 800mg / tablet, the alanine content was 500mg / tablet, and the vitamin D content was 20μg / tablet plus 20% excess. One tablet was placed in a glass of 200ml water at room temperature, the tablet did not disintegrate but slowly dissolved from the surface. The tablet completely dissolved within 8 minutes, giving a clear solution with a small shadow on the surface due to vitamin D.

[0224] conclusion This example demonstrates that manganese chloride tetrahydrate becomes more hygroscopic upon drying, picking up water from the disintegrant and causing the disintegrant to lose its effectiveness, however the tablets were still able to dissolve to give a clear solution in addition to the oily vitamin D3 on the surface.

[0225] [Table 5]

[0226] Example 6: Soluble tablets based on isomalt with a tablet weight of 2000 mg containing a water-insoluble disintegrant Manganese chloride tetrahydrate, alanine, isomalt, crospovidone, and PEG 6000 were mixed for 5 minutes, where the relative humidity in the air was 24% rH. Tablets were compressed in a single punch tablet press using 20 mm flat tooling to a tablet weight of 2000 mg and hardness of 40 N. The manganese chloride tetrahydrate content was 800 mg / tablet and the alanine content was 500 mg / tablet. One tablet was placed in a glass of 200 ml water at room temperature; the tablet disintegrated within 1 minute and dissolved completely rapidly within 3 minutes, giving a clear solution containing undissolved crospovidone particles.

[0227] conclusion Based on this example, it appears that the use of a water-insoluble disintegrant such as crospovidone does not provide a clear solution even at low levels of disintegrant.

[0228] Example 7: Soluble tablets based on mannitol at high humidity Manganese chloride tetrahydrate, alanine, mannitol, crospovidone, and PEG6000 were mixed for 5 minutes, where the relative humidity in the air was 45% rH. Tablets were compressed using 12 mm flat tooling in a single punch tablet press to a tablet weight of 666. During processing, the granules absorbed moisture from the air, resulting in severe adhesion to the punch and die. The manganese chloride tetrahydrate content was 800 mg / 3 tablets and the alanine content was 500 mg / 3 tablets. Three tablets were placed in a glass of 200 ml water at room temperature, and the tablets completely dissolved within 5 minutes to give a clear solution with a sweet taste.

[0229] conclusion The humidity in the air in the production area needs to be kept low, such as below 25% rH, otherwise the mix will absorb moisture and form lumps, which will result in an ineffective tableting process and introduce uncertainty as to the final dosage in the tablets.

[0230] Example 8: Maltitol-based soluble tablets at high humidity Manganese chloride tetrahydrate, alanine, maltitol, crospovidone, and PEG6000 were mixed for 5 minutes, where the relative humidity in the air was 45%rH. Tablets were compressed in a single punch tablet press using 12mm flat tooling to a tablet weight of 666. During processing, the granules absorbed moisture from the air, forming lumps and becoming difficult to feed into the tablet press. The manganese chloride tetrahydrate content was 800mg / 3 tablets and the alanine content was 500mg / 3 tablets. Three tablets were placed in a glass of 200ml water at room temperature, and the tablets completely dissolved within 7 minutes to give a clear solution with a bitter taste.

[0231] conclusion The humidity in the air in the production area should be kept low, such as less than 25% rH, to prevent the mix from becoming moisture-adsorbing.

[0232] [Table 6]

[0233] Example 9: Soluble tablets based on isomalt with a tablet weight of 2000 mg, containing a non-water-soluble lubricant Manganese chloride tetrahydrate, alanine, isomalt, croscarmellose sodium, and PEG6000 were mixed for 5 minutes, where the relative humidity in the air was 23%rH. Magnesium stearate was added and mixed for 1 minute. Tablets were compressed in a single punch tablet press using 20mm flat tooling to a tablet weight of 2000mg and hardness of 88N. The manganese chloride tetrahydrate content was 800mg / tablet and the alanine content was 500mg / tablet. One tablet was placed in a glass of 200ml water at room temperature, the tablet disintegrated within 4 minutes and dissolved within 7 minutes.

[0234] conclusion This example demonstrates that a water-insoluble lubricant such as magnesium stearate, when added to water, provided a tablet that resulted in an opaque, off-white, milky solution with air bubbles on the surface.

[0235] Example 10: Effervescent tablets with small amounts of isomalt that work well Manganese chloride tetrahydrate, alanine, isomalt, sodium bicarbonate, citric acid anhydrous, and PEG 6000 were mixed for 5 minutes, where the relative humidity in the air was 24% rH. Tablets were compressed in a single punch tablet press using 20 mm flat tooling to a tablet weight of 2565 mg and hardness of 56 N. The manganese chloride tetrahydrate content was 800 mg / tablet and the alanine content was 500 mg / tablet. One tablet was placed in a glass of 200 ml water at room temperature and the tablet was allowed to effervescent for about 3.5 minutes. Manganese ions formed a precipitate with carbonate ions, so a precipitate of manganese carbonate was formed. At an acidic pH, this precipitate could be redissolved, which was achieved after 4.5 minutes, giving a clear solution with a slightly sour taste.

[0236] conclusion This example demonstrates that tablets can be produced that will rapidly disintegrate and dissolve in water at low relative humidity in the air, such as 24% rH, to provide a clear solution with an acceptable taste.

[0237] Example 11: Effervescent tablets with more isomalt work well Manganese chloride tetrahydrate, alanine, isomalt, sodium bicarbonate, citric acid anhydrous, and PEG 6000 were mixed for 5 minutes, where the relative humidity in the air was 24% rH. Tablets were compressed in a single punch tablet press using 20 mm flat tooling to a tablet weight of 2990 mg and hardness of 90 N. The manganese chloride tetrahydrate content was 800 mg / tablet and the alanine content was 500 mg / tablet. One tablet was placed in a glass of 200 ml water at room temperature and the tablet effervescent for approximately 3 minutes. A precipitate of manganese carbonate formed and redissolved after 5 minutes to give a clear solution with a slightly sour taste.

[0238] conclusion This example demonstrates that at low relative humidity in air, such as 24% rH, tablets can be produced that will rapidly disintegrate and dissolve to provide a clear solution with an acceptable taste.

[0239] Example 12: Effervescent tablets containing dried manganese chloride Manganese chloride tetrahydrate was dried at 100°C overnight to constant weight. Approximately 22% of the weight was lost. The dried manganese chloride tetrahydrate, alanine, isomalt, sodium bicarbonate, citric anhydride, and PEG6000 were mixed for 5 minutes, where the relative humidity in the air was 35% rH. Tablets were compressed using 20mm flat tooling in a single punch tablet press to a tablet weight of 2420mg and a hardness of 55N. Sticking was observed as the mixture absorbed moisture from the air. The manganese chloride tetrahydrate content was 800mg / tablet and the alanine content was 500mg / tablet. One tablet was placed in a glass of 200ml water at room temperature and the tablet effervescent for approximately 3 minutes. A precipitate of manganese carbonate formed and redissolved after 3.5 minutes to give a clear solution with a slightly sour taste.

[0240] conclusion This example demonstrates that drying manganese chloride tetrahydrate makes it more hygroscopic. The hygroscopic manganese chloride picked up moisture from the air, causing problems during tableting, but the tablets still went into solution quickly.

[0241] Example 13: Effervescent tablets with high levels of "effervescent mixture" at high humidity Manganese chloride tetrahydrate, alanine, sodium bicarbonate, citric acid anhydrous, and PEG 6000 were mixed for 5 minutes, where the relative humidity in the air was 44% rH. Tablets were compressed using 12 mm flat tooling in a single punch tablet press, resulting in a tablet weight of approximately 867 mg. During compression, the mixture absorbed moisture and adhesion was observed after compressing a few tablets. The manganese chloride tetrahydrate content was 800 mg / 3 tablets and the alanine content was 500 mg / 3 tablets. Three tablets were dispensed into a glass of 200 ml water at room temperature, and the tablets efferved for approximately 2 minutes. A precipitate of manganese carbonate formed and redissolved after 5 minutes, giving a clear solution with a slightly sour taste.

[0242] conclusion This example demonstrates that the relative humidity of the air in the production area must be kept low to ensure an efficient tableting process. Production of tablets at 44% rH caused the mix to absorb moisture and stick during compression.

[0243] Example 14: Effervescent tablets with low levels of "effervescent mixture" at high humidity Manganese chloride tetrahydrate, alanine, sodium bicarbonate, citric acid anhydrous, and PEG 6000 were mixed for 5 minutes, where the relative humidity in the air was 52% rH. Tablets were compressed using 12 mm flat tooling in a single punch tablet press to a tablet weight of approximately 692 mg. During compression, the mixture absorbed moisture and severe adhesion was observed. The manganese chloride tetrahydrate content was 800 mg / 3 tablets, and the alanine content was 500 mg / 3 tablets. Three tablets were placed in a glass of 200 ml water at room temperature, and the tablets efferved for approximately 3 minutes. A precipitate of manganese carbonate formed and redissolved after 5 minutes to give a clear solution with a slightly sour taste.

[0244] conclusion This example demonstrates that the relative humidity of the air in the production area must be kept low to ensure an efficient tableting process. Production of tablets at 52% rH caused the mix to absorb moisture and stick severely during compression.

[0245] [Table 7]

[0246] Example 15: Effervescent tablets containing manganese chloride / citric acid granulation 28.1 g manganese chloride tetrahydrate, 21.1 g citric acid monohydrate, and 0.9 g povidone were mixed in a high shear mixer. 96% ethanol was added as a granulation aid with stirring until the powder was fully wetted (5.3 g). The granules were dried overnight at 100° C. to a constant weight and sieved through a 710 μm sieve. The manganese chloride / citric acid granules, alanine, isomalt, sodium bicarbonate, and PEG6000 were mixed for 5 minutes, where the relative humidity in the air was 24% rH. Tablets were compressed on a single punch tablet press using 20 mm flat tooling to a tablet weight of 2395 mg and hardness of 70 N. The manganese chloride tetrahydrate content was 800 mg / tablet, the alanine content was 500 mg / tablet, and the citric acid anhydrous content was 600 mg / tablet. One tablet was placed in a glass of 200 ml water at room temperature and the tablet effervescent for approximately 3 minutes. A precipitate of manganese carbonate formed (less than in the previous example) and redissolved after 4 minutes to give a clear solution with a slightly sour taste.

[0247] conclusion This example demonstrates that manganese chloride / citric acid granulation can be beneficial as it reduces the amount of precipitate formed and provides a short tablet dissolution time.

[0248] Example 16: Effervescent tablets containing sodium bicarbonate granulations Manganese chloride tetrahydrate was dried overnight at 100° C. to constant weight. Approximately 22% of the weight was lost. 68.74 g sodium bicarbonate, 26.7 g isomalt, and 4.58 g povidone were mixed in a high shear mixer. 96% ethanol was added as a granulation aid with stirring until the powder was fully wetted (19.7 g). The granules were dried overnight at 100° C. and sieved through a 710 μm sieve. The dried manganese chloride tetrahydrate, alanine, sodium bicarbonate granules, citric acid anhydride, and PEG 6000 were mixed for 5 minutes, where the relative humidity in the air was 24% rH. Tablets were compressed on a single punch tablet press using 20 mm flat tooling to a tablet weight of 2445 mg and a hardness of 68 N. The manganese chloride tetrahydrate content was 800 mg / tablet, the alanine content was 500 mg / tablet, and the sodium bicarbonate content was 375 mg / tablet. One tablet was placed in a glass of 200 ml water at room temperature and the tablet effervescent for approximately 2.5 minutes. A small precipitate of manganese carbonate formed (less than in the previous example) and redissolved after 3.5 minutes to give a clear solution with a slightly sour taste.

[0249] conclusion This example demonstrates that granulation of sodium bicarbonate reduces the amount of precipitate formed and still provides short tablet dissolution times.

[0250] Example 17: Effervescent tablets containing lower levels of sodium bicarbonate granulation Dried manganese chloride tetrahydrate (from Example 16), alanine, sodium bicarbonate granules (from Example 16), citric acid anhydrous, and PEG 6000 were mixed for 5 minutes. Magnesium stearate was added and mixed for 1 minute. Tablets were compressed in a single punch tablet press using 20 mm flat tooling to a tablet weight of 2420 mg and hardness of 85 N. Manganese chloride tetrahydrate content was 800 mg / tablet, alanine content was 500 mg / tablet, and sodium bicarbonate content was 281 mg / tablet. One tablet was placed in a glass of 200 ml water at room temperature and the tablet effervescent for approximately 3 minutes. A small precipitate of manganese carbonate formed (as in Example 16) and redissolved after 4 minutes. The solution became milky white and effervescent. Adding even a small amount of magnesium stearate seemed to impoverish the solution.

[0251] Example 18: Effervescent tablets containing low levels of sodium bicarbonate granulation Dried manganese chloride tetrahydrate (from Example 16), alanine, dried vitamin D3 100 SD / S, sodium bicarbonate granules (from Example 16), citric acid anhydrous, and PEG 6000 were mixed for 5 minutes. Tablets were compressed using 20 mm flat tooling in a single punch tablet press to a tablet weight of 2440 mg and hardness of 80 N. Manganese chloride tetrahydrate content was 800 mg / tablet, alanine content was 500 mg / tablet, vitamin D content was 20 μg / tablet plus 20% overage, and sodium bicarbonate content was 253 mg / tablet. One tablet was placed in a glass of 200 ml water at room temperature and the tablet effervescent for approximately 3 minutes. A small precipitate of manganese carbonate (as in Example 16) formed and redissolved after 4 minutes to give a clear solution. The level of sodium bicarbonate was reduced to slow effervescence and reduce the time from end of effervescence to complete dissolution.

[0252] [Table 8]

[0253] Example 19: Comparison of "effervescent tablet" and "stick pack formulation" in terms of time to disintegrate and time to form a clear solution as a function of temperature material The materials used in this study are listed below: Effervescent tablets (see Table 4): Batch RD1901-7-T1 Stick pack formulation containing per dose: L-Alanine - batch: 1809009 (500 mg) Vitamin D3 dry powder - batch: 1809013 (10 mg) Manganese chloride tetrahydrate - batch: 1912002 (800 mg) Tap water

[0254] The stick pack formulation is an oral dry powder formulation in which manganese chloride tetrahydrate (800 mg) is packed in one stick pack and a homogenous blend of L-alanine (500 mg) and dry vitamin D3 powder (10 mg, 800 IU equivalent) is packed in another stick pack. The dual form of manganese chloride tetrahydrate in one pack and L-alanine and dry vitamin D3 powder in another pack is referred to herein as a powder formulation.

[0255] As used herein, an effervescent tablet contains: [Table 9]

[0256] Effect of temperature on disintegration time and time to form a clear solution method Two different formulations, the effervescent tablet and the powder formulation, were dissolved in 200 ml of water at three different temperatures: 5° C., 15° C., and 20° C. No stirring was used for the effervescent tablet, whereas the powder formulation was stirred. The disintegration time (few visible particles) and the time to a clear solution (no visible particles) were measured. For each formulation and temperature, three samples were tested.

[0257] result The results of the study are shown in Table 5. It should be noted that disintegration applies only to effervescent tablets. Figure 1 shows the effect of temperature on disintegration time and time to form a clear solution for effervescent tablets. At every temperature tested, the effervescent tablets disintegrated and completely dissolved more rapidly than the powder formulation. Furthermore, the lower the temperature, the longer the disintegration time and the complete dissolution time. [Table 10]

[0258] conclusion The test demonstrates that the effervescent tablet of the present disclosure disintegrates in 0.2 L of water in less than 5 minutes at temperatures between 5°C and 20°C, with faster disintegration at higher temperatures. A temperature of 5°C is preferred from the patient's perspective, as the aqueous solution at 5°C is easier to drink. The test also demonstrates that the time to dissolve the effervescent tablet is significantly shorter than the time to dissolve the powder formulation. Thus, the compressed solid composition works better than the powder formulation for preparing an oral solution for use in MRI.

[0259] Example 20: Comparison of "effervescent tablet" and "stick pack formulation" in terms of time to disintegrate and time to form a clear solution as a function of volume method The two different formulations, the effervescent tablet and the powder formulation of Example 19, were dissolved in 50 ml or 200 ml of water at 20° C. No stirring was used for the effervescent tablet, but the powder formulation was stirred. The disintegration time (few visible particles) and the time to a clear solution (no visible particles) were measured. Three samples of each formulation at different volumes were tested.

[0260] result The results are shown in Table 6. It should be noted that disintegration applies only to the effervescent tablets. Figure 2 shows the effect of water volume. As can be seen from the results, the volume range studied does not affect the disintegration time or the time to form a clear solution. The effervescent tablets formed a clear solution, while the powder formulation has undissolved particles. [Table 11]

[0261] The results in Table 6 show the difference between the two formulations after 5 minutes in either 50 ml or 200 mL of tap water at 20° C.

[0262] conclusion This example demonstrates that the compressed solid composition (e.g., effervescent tablet) exhibits significantly faster and therefore superior dissolution and disintegration rates compared to the two-dose powder formulation. Thus, the compressed solid composition performs better than the powder formulation for preparing an oral solution for use in MRI. Furthermore, the volume of 50mL to 200mL does not significantly affect the disintegration / dissolution time.

Claims

1. a. 0.5 g to 1.2 g of manganese(II) chloride tetrahydrate, or an equimolar amount of any corresponding manganese(II) salt; b. 0.25 g to 0.75 g of L-alanine; c. one or more water-soluble excipients; d. An effervescent couple comprising a basic component and an acidic component; 1. An effervescent MRI tablet comprising:

2. 2. The effervescent MRI tablet of claim 1, wherein 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.

3. the non-hygroscopic filler is selected from the group consisting of lactose, such as isomalt, spray-dried lactose, α-lactose, or β-lactose, maltitol, maltose, and mannitol; the non-hygroscopic binder is selected from the group consisting of hydroxyethyl methylcellulose, maltose, povidone, and dextrin; The non-hygroscopic disintegrant is povidone, and The non-hygroscopic lubricant is selected from the group consisting of polyethylene glycol 6000 and sodium benzoate; 3. The effervescent MRI tablet according to claim 2.

4. The effervescent MRI tablet according to any one of claims 1 to 3, further comprising a water-insoluble disintegrant.

5. 5. The effervescent MRI tablet of claim 4, wherein the water-insoluble disintegrant is selected from the group consisting of calcium carboxymethylcellulose, croscarmellose sodium, and crospovidone.

6. An effervescent MRI tablet as described in any one of claims 1 to 5, wherein the basic component is bicarbonate and the acidic component is citric acid.

7. An effervescent MRI tablet described in any one of claims 1 to 6, further containing PEG 6000.

8. The effervescent MRI tablet of claim 7, further comprising isomalt.

9. An effervescent MRI tablet according to any one of claims 1 to 8, further comprising vitamin D.

10. The vitamin D is vitamin D ３ 10. The effervescent MRI tablet according to claim 9, wherein

11. The effervescent MRI tablet according to any one of claims 1 to 10, comprising 0.8 g of manganese(II) chloride tetrahydrate or an equimolar amount of the corresponding anhydrate or dihydrate.

12. 12. The effervescent MRI tablet of any one of claims 1 to 11, wherein the effervescent MRI tablet provides 0.2 L of a clear aqueous solution within 8 minutes at room temperature without stirring or agitating the solution.

13. 13. The effervescent MRI tablet according to any one of claims 1 to 12, wherein the effervescent MRI tablet disintegrates in 0.2 L of water in less than 3.0 minutes at room temperature without stirring or agitating the solution.

14. A process for preparing an effervescent MRI tablet as defined in any one of claims 1 to 13, comprising: a) providing a physiologically acceptable manganese(II) compound, optionally as a granule, and optionally drying said physiologically acceptable manganese(II) compound; b) providing one or more absorption enhancers; c) providing one or more water-soluble excipients to enable compression; d) mixing said physiologically acceptable manganese(II) compound with said one or more absorption enhancers and said one or more water-soluble excipients to provide an aqueous mixture; e) compressing said aqueous mixture to provide an effervescent MRI tablet as defined in any one of claims 1 to 13. Including, Relative humidity (RH) is kept below 35%. method.

15. 1. A method for preparing an oral MRI solution comprising: a. providing an effervescent MRI tablet as defined in any one of claims 1 to 13; b. providing a suitable amount of water; c. adding the effervescent MRI tablet to the water; thereby forming said oral MRI solution. A method comprising:

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