New formulation

Abstract

The present disclosure relates to dispersible tablets that can disintegrate rapidly (e.g., within 3 minutes) in very small amounts of water to form suspensions with good flowability and an acceptable mouthfeel. Also disclosed are tablets and dispersible tablets for medical use of daprodustat.

Description

[Technical Field]

[0001] The present disclosure relates to dispersible tablets that can disintegrate rapidly (e.g., within 3 minutes) in very small amounts of water to form suspensions with good flowability and an acceptable mouthfeel. Also disclosed are tablets and dispersible tablets for medical use of daprodustat. [Background technology]

[0002] While most adult patients can swallow conventional tablets and capsules, there are still some patients for whom this poses a challenge. Pediatric patients, particularly those under the age of 8, often experience problems, as do elderly patients and patients with certain medical conditions that make swallowing difficult (e.g., neurological patients, patients with nasogastric tubes, and those with certain medical conditions such as head and neck cancer).

[0003] Alternative formulation types known in the art include suspensions, dispersible tablets, and orodispersible tablets. Dispersible tablets are tablets that disintegrate in water (or possibly other suitable vehicle such as milk or juice) to form a suspension, which may be swallowed by the patient.

[0004] For pediatric patients, it is important that the entire suspension be consumed, so it is important that the volume of the vehicle be kept low. Considering that some drugs need to be taken by infants as young as 3 months, a suspension volume of 5 ml or less is desirable. This may be important for certain other patients, such as dialysis patients, whose fluid intake must be limited.

[0005] Another important consideration, particularly for the pediatric population, is the palatability of the medication, which depends in part on the taste of the intended drug, but also in part on the texture of the resulting suspension, commonly referred to as mouthfeel.

[0006] Therefore, dispersible tablets that can disperse rapidly in very small volumes (1-5 ml) to produce pleasant-tasting suspensions with acceptable mouthfeel are highly desirable.

[0007] Daprodustat is a HIF prolyl hydroxylase inhibitor being developed for the treatment of chronic kidney disease-associated anemia in dialysis and non-dialysis patients. Chronic kidney disease-associated anemia rarely occurs in children, including infants as young as 3 months of age. As mentioned above, dialysis patients must limit their intake. Therefore, a dispersible tablet formulation of daprodustat that can be rapidly dispersed into very small amounts to produce a suspension with a good mouthfeel is highly desirable.

[0008] WO 2016 / 120258 A1 discloses dispersible tablets of bedaquiline fumarate, which, when dispersed in a small amount of liquid (1 ml to 5 ml), the resulting mixture can be described as a soft mass. Summary of the Invention

[0009] In a first aspect, the present invention provides a method for producing a pulp having a solids content of 0.9 or less and a pulp content of 615 mm 2 A dispersible tablet exhibiting the following surface area, said dispersible tablet comprising extragranular components and at least 40% (weight / weight of said dispersible tablet) of granules: a. the granules have a diameter of ≦140 microns, a density of 0.4-0.6 g / mL, and comprise ≦60% (weight / weight of the granules) of an active pharmaceutical ingredient, 20-60% (weight / weight of the granules) of microcrystalline cellulose, and a binder, wherein the ratio of microcrystalline cellulose to binder is ≧10:1; and b. the extragranular component comprises at least 20% (w / w of the dispersible tablet) of silicified microcrystalline cellulose and a disintegrant; Dispersible tablets are provided.

[0010] In another aspect, the present invention provides a method for producing the dispersible tablets of the present invention.

[0011] In a further aspect, the present invention provides a dispersible tablet of daprodustat, or a pharmaceutically acceptable salt thereof, and medical uses of said tablet. [Brief explanation of the drawings]

[0012] [Figure 1] 1 is a graph showing the effect of tablet solids content on disintegration. Each line represents a different manufacturing batch of tablets having formulation 24 or 25, with the formulations in each line differing only in solids content. Specific Description of the Invention

[0013] definition The requirement that "the granules are ≦140 microns in size" means that the granules have a d50 of ≦140 microns.

[0014] term d 50 has its conventional meaning and can be measured by established techniques including sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction or disk centrifugation. 50 may relate to the volume distribution of the particles, in which case the phrase "the granules are ≦140 microns in diameter" refers to the condition where at least 50% of the granules by volume have a diameter ≦140 microns. Techniques based on volume or weight distribution usually yield roughly the same values for the average particle size.

[0015] In the context of the present invention, the term "insoluble material" refers to a polymeric additive that has a solubility in water at 25°C of 0.1 mg / mL or less.

[0016] In the context of the present invention, the term "soluble filler" denotes a polyol or sugar that exhibits a solubility in water at 25°C of 200 mg / ml or more.

[0017] In the context of the present invention, the term "binder" refers to a water-soluble polymer (e.g., having a solubility in water of 100 mg / mL or more) that facilitates wet granulation. Typically, such polymers have a molecular weight in the range of 500 Da to 2 MDa and an apparent viscosity in the range of 1 to 15,000 mPa·sec as a 2% aqueous solution at 20°C.

[0018] The term "disintegrant" is a term of art. In one embodiment, the term refers to an additive that promotes the disintegration (breakdown into small pieces) of a dispersible tablet when it comes into contact with a liquid medium.

[0019] The term "sweetener" is a term of art. In one embodiment, the term refers to an additive added to a dispersible tablet to mask the unpleasant taste of an active pharmaceutical ingredient or to enhance the perception of sweetness, improving overall palatability.

[0020] The term "lubricant" is a term of art. In one embodiment, the term refers to an additive to reduce friction between the tablet press tools (punches and dies) and the tablet.

[0021] When used herein in connection with a numerical value, the term "about" is intended to have its ordinary meaning in connection with the numerical value. Where appropriate, the word "about" may be replaced by the numerical value ±5%.

[0022] Percent solids is a technical term. Percent solids is determined by the tablet density (g / cm 3 ) to the true density (g / cm) of the input material or compressed compound 3 Tablet density is calculated by dividing the tablet weight (mg) by the tablet volume (mm 3 ) The tablet volume is determined using the tablet dimensions and shape. The true density of the input compression blend can be measured using a pycnometer or calculated from the true densities of all individual components previously measured or obtained from the literature.

[0023] Description of the invention The dispersible tablets of the present invention can completely disintegrate very quickly in a small amount of water. In one embodiment, the dispersible tablets of the present invention can completely disintegrate in 5 ml of water within 3 minutes to produce a suspension with an acceptable mouthfeel. In contrast to the dispersible tablets described in WO 2016 / 120258, the resulting suspension is liquid and easy to flow. To achieve the desired combination of properties, the inventors identified several key parameters essential for 1) rapid disintegration and 2) acceptable mouthfeel, including meeting the European Pharmacopoeia Good Quality Dispersion Test Standard. This work is described in the Examples.

[0024] As explained in WO 2016 / 12058, somewhat counterintuitively, tablets composed primarily of soluble material exhibit long disintegration times, which are attributed to the fact that tablets can absorb water and create a saturated layer that prevents further diffusion of electrolytes from the saturated stagnation layer (according to the Noyes-Whitney diffusion layer theory). This phenomenon was also observed by the present inventors. WO 2016 / 12058 recognized that insoluble additives were necessary to function as a core that allowed water to penetrate the tablet formulation. However, the results of human sensory analysis studies shown in Example 13 demonstrated that the total amount of insoluble material present in the formulation is relevant to mouthfeel. It is believed that large amounts of insoluble material may result in dispersion of the tablets in WO 2016 / 12058, forming a soft mass instead of a free-flowing liquid. In contrast, the tablets of the present invention are free-flowing and can be easily administered via syringe or refill tube.

[0025] In one embodiment, the dispersible tablet of the present invention has a total level of insoluble material of 200 mg or less, which is considered to be a critical level for acceptable mouthfeel (see Example 13). In the context of the present invention, insoluble material is as defined above. In a more specific embodiment, when the dispersible tablet contains only microcrystalline cellulose, silicified microcrystalline cellulose, binder, disintegrant, soluble filler, lubricant, and optionally sweetener as additives, the total weight of microcrystalline cellulose and silicified microcrystalline cellulose should not exceed 200 mg. It has also been observed that the particle size of insoluble material is important for mouthfeel, and in one embodiment, the total weight of microcrystalline cellulose and silicified microcrystalline cellulose should not exceed 200 mg, and the median particle size (d50) of microcrystalline cellulose and silicified microcrystalline cellulose should not exceed 125 microns.

[0026] Several parameters in the tablet are important to enable fast disintegration.

[0027] As shown in Examples 1 and 2, the surface area and solids content of the tablets are important parameters to ensure disintegration within 3 minutes. 2 In other words, the tablet must be small. This is because a small tablet has a relatively high surface area to volume ratio, reducing the distance that water must travel to penetrate the "core" of the tablet. In one embodiment, the surface area is between 96 and 615 mm 2 The solids content is important for similar reasons. The solids content of a tablet is related to the number of pores in the extragranular components of the tablet that allow water to penetrate quickly (without relying on the core action of insoluble material). Both of these parameters allow water to penetrate and the extragranular components to break down, liberating granules containing the active pharmaceutical ingredient. In one embodiment, the solids content is 0.8-0.9.

[0028] Tablet solids content is related to tablet tensile strength, which is presented in certain examples as a proxy for tablet solids content.

[0029] Granule size and density are important parameters for rapid disintegration, for reasons similar to tablet surface area and solid content. Granule size (like tablet surface area) determines the distance water must travel to penetrate the granule's "core." Example 4 shows that granules with a median diameter of ≤140 microns achieve tablet disintegration within 3 minutes. Granule density reflects the degree of pores and channels within the granule and also affects disintegration time by providing pores and channels that allow water to rapidly penetrate the granule. Example 18 shows that a granule density of 0.4 to 0.6 g / mL allows rapid water absorption into the granules, resulting in granule disintegration and release of the active pharmaceutical ingredient. Granule density is not significantly affected by compression for tableting and remains within the stated range. In one embodiment, granule density refers to the density of the granules before tableting. In one embodiment, a dispersible tablet comprises granules with a density of 0.5 to 0.6 mg / mL.

[0030] It is clear from the above that the physical structure of the tablet influences the disintegration rate. Furthermore, as discussed below, the composition of the granules and extragranular components also influence the disintegration rate.

[0031] Intragranular composition As explained above, the use of insoluble materials in granules promotes tablet disintegration. The tablets exemplified in WO 2016 / 12058 used silicified microcrystalline cellulose within the granules. However, the use of silicified microcrystalline cellulose within the granules is believed to hinder the wet granulation process and limit the process control required to obtain granules of the appropriate size and density. In fact, it should be noted that in WO 2016 / 12058, the granule production process was complicated, involving a separate binder portion consisting of a binder and a wetting agent, and an "intragranular" portion consisting of an active ingredient, silicified microcrystalline cellulose, a disintegrant, and a glidant. Wet granulation is much simpler when silicified microcrystalline cellulose and a glidant are omitted from the granules. Therefore, the dispersible tablets of the present invention utilize microcrystalline cellulose within the granules. In one embodiment, the granules do not contain silicified microcrystalline cellulose. In one embodiment, the granules do not contain a glidant. In one embodiment, the granules do not contain either silicified microcrystalline cellulose or a glidant.

[0032] While Example 5 demonstrates that granules may contain 20-60% (wt / wt) (in the granule) of microcrystalline cellulose (MCC; e.g., AVICEL PH101 or CEOLUS KG-1000), it should be noted that in embodiments where the total level of insoluble material remains below 200 mg, the granule percentage or MCC content of the granule may need to be limited. The inventors have determined that the most rapid disintegration time is observed with 20-60% (wt / wt) intragranular microcrystalline cellulose, which has also been observed to improve the robustness of the granulation process. Tablets with 20-30% (wt / wt) microcrystalline cellulose have the best mouthfeel. Thus, in one embodiment, the present invention provides a dispersible tablet in which the granules comprise 20-30% (wt / wt) microcrystalline cellulose. In a more specific embodiment, the present invention provides a dispersible tablet in which the granules comprise about 20% (wt / wt) microcrystalline cellulose. An MCC of 20% (wt / wt) indicates optimal granulation method robustness.

[0033] Several different grades of microcrystalline cellulose are available. Those skilled in the art will appreciate that the grade selected should exhibit excellent compressibility and mouthfeel. Mouthfeel depends, in part, on particle size. A particle size (d50) of 125 microns or less is desirable, with a size of 50 microns or less being ideal. AVICEL PH101 and CEOLUS KG-1000 are suitable grades. CEOLUS KG-1000 is the finest microcrystalline cellulose grade and provides improved mouthfeel.

[0034] In addition to containing the active pharmaceutical ingredient and microcrystalline cellulose, the granules must further comprise a binder. The binder may be a natural polymer such as a polysaccharide or polypeptide or its derivative, or a synthetic polymer such as a polyalkylene oxide (e.g., PEG), polyacrylate, polyvinylpyrrolidone, or a mixture thereof. Mixed polymers, such as block copolymers and glycopeptides, may also be used. In one embodiment, the binder may be selected from the group consisting of hydroxypropyl methylcellulose, povidone, maltodextrin, starch 1500, or a mixture thereof. In one embodiment, the binder may be selected from the group consisting of hydroxypropyl methylcellulose, povidone, maltodextrin, and starch 1500. In another embodiment, the binder may be selected from the group consisting of hydroxypropyl methylcellulose and povidone, or a mixture thereof. In another embodiment, the binder may be selected from the group consisting of hydroxypropyl methylcellulose and povidone.

[0035] In one embodiment, the binder is hydroxypropyl methylcellulose (HPMC). In one embodiment, HPMC contains sufficient hydroxypropyl and methoxy groups to render it water-soluble. HPMC with a methoxy degree of substitution of about 19.0 to about 30.0 and a hydroxypropyl molar substitution of about 4.0 to about 12.0 is generally water-soluble. The methoxy degree of substitution represents the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. The hydroxypropyl molar substitution represents the average number of moles of propylene oxide reacted with each anhydroglucose unit of the cellulose molecule. Preferred HPMC is hypromellose 2910 3 mPa·sec or hypromellose 2910 5 mPa·sec, particularly hypromellose 2910 3 mPa·sec. Hydroxypropyl methylcellulose is the U.S. nonproprietary name for hypromellose (see Martindale, The Extra Pharmacopoeia, 29th edition, page 1435). In the four-digit number "2910," the first two digits represent the approximate percentage of methoxy groups, the third and fourth digits represent the approximate percentage of hydroxypropoxyl groups; 3 mPa·sec or 5 mPa·sec refers to the apparent viscosity of a 2% aqueous solution at 20° C. In one embodiment, the hydroxypropyl methylcellulose binder is hypromellose 2910 3 cP (i.e., PHARMACOAT 603).

[0036] The use of a water-soluble polymeric binder may be primarily responsible for the formation of the saturated layer mentioned above. Furthermore, its use is necessary in wet granulation for granule formation. The inventors have confirmed that the binder level should be kept to a minimum. Example 6 indicates that in order to disintegrate in less than 3 minutes, the granules for tablets should have a microcrystalline cellulose:binder ratio of ≥ 10:1, which appears to be most important for tablets containing a high level of granules. In one embodiment, the present invention provides a dispersible tablet in which the granules comprise a binder selected from microcrystalline cellulose, hydroxymethylpropylcellulose, and povidone in a ratio of ≥ 10:1 (the ratio is calculated based on the mass of a) microcrystalline cellulose and b) binder present in the granule). In one embodiment, the present invention provides a dispersible tablet in which the granules comprise microcrystalline cellulose and hydroxymethylpropylcellulose in a ratio of ≥ 4:1. In one embodiment, the present invention provides a dispersible tablet in which the granules comprise microcrystalline cellulose and hydroxymethylpropylcellulose in a ratio of ≥ 10:1. In one embodiment, the present invention provides a dispersible tablet, wherein the granules comprise microcrystalline cellulose and a binder in a ratio of 15: 1 to 10: 1. In one embodiment, the present invention provides a dispersible tablet, wherein the granules comprise microcrystalline cellulose and a binder in a ratio of approximately 10: 1.

[0037] In addition, the granules may further comprise a soluble filler and a disintegrant. In one embodiment, the present invention provides a dispersible tablet in which the granules comprise microcrystalline cellulose, hydroxypropyl methylcellulose, one or more soluble fillers and one or more disintegrants, but do not contain any further classes of additives.

[0038] Suitable soluble fillers are polyols, such as mannitol, sorbitol, maltitol, xylitol, erythritol, isomalt, lactitol, and low-molecular-weight dextrins, as well as sugars such as lactose (including anhydrous lactose and lactose monohydrate), fructose, sucrose, dextrose, and maltose. Thus, in one embodiment, the present invention provides a dispersible tablet in which the granules further comprise one or more soluble fillers selected from the group consisting of mannitol, sorbitol, maltitol, xylitol, erythritol, isomalt, lactitol, low-molecular-weight dextrins, lactose (including anhydrous lactose and lactose monohydrate), fructose, sucrose, dextrose, and maltose. In a more specific embodiment, the present invention provides a dispersible tablet in which the granules further comprise mannitol. Mannitol is preferred over lactose because it is more tolerable, especially in pediatric populations. However, it is believed that active pharmaceutical ingredients may be limited in their choice of soluble fillers due to incompatibility.

[0039] The use of a soluble filler in granules is desirable to maintain a low total level of insoluble solids in the tablet to improve mouthfeel. Example 11 shows that 17-75% (wt / wt) of a soluble filler (e.g., mannitol) provides greater mechanical strength (lower levels of fines) for downstream processing into tablets. Thus, in one embodiment, the present invention provides a dispersible tablet in which the granules comprise 15-75% (wt / wt) of a soluble filler. In a further embodiment, the present invention provides a dispersible tablet in which the granules comprise 17-75% (wt / wt) of a soluble filler. In another embodiment, the present invention provides a dispersible tablet in which the granules comprise 15-75% (wt / wt) of mannitol. In yet another embodiment, the present invention provides a dispersible tablet in which the granules comprise 17-75% (wt / wt) of mannitol. As can be appreciated, since a wide variety of levels of soluble filler are acceptable, a wide variety of levels of active pharmaceutical ingredient can be tolerated in the granules, which can be compensated for by the varying levels of soluble filler.

[0040] Various grades of mannitol are available. Mannitol, PEARLITOL 160C, produces larger and better flowing granules compared to PEARLITOL 50C or 25C.

[0041] Those skilled in the art will appreciate that the total amount of mannitol in the daily dose (note that multiple tablets can be dissolved in the vehicle) should be within the recommended daily tolerance limit of 50 mg / kg / day (WHO Food additive series Toxicological monograph. 616. Mannitol) (WHO Food Additives Series 21) (inchem.org)).

[0042] Example 12 shows that tablets containing an intragranular disintegrant disperse in less than 3 minutes. Any suitable disintegrant may be used in the granules. Suitable disintegrants include cross-linked polyvinylpyrrolidone, modified cellulose gums such as croscarmellose sodium (e.g., AC-DI-SOL), sodium starch glycolate (e.g., GLYCOLYS), sodium carboxymethylcellulose, sodium dodecyl sulfate, modified corn starch, microcrystalline cellulose, magnesium aluminum silicate, alginic acid, alginate salts, powdered cellulose, and crospovidone (e.g., POLYPLASDONE XL). Other possible disintegrants include xanthan gum, gellan gum, soy polysaccharides, and the like. The optimal amount of disintegrant depends on the extragranular disintegrant selected and can be easily determined by one skilled in the art. The disintegrant promotes granule swelling and disintegration.

[0043] In one embodiment, the disintegrant is selected from croscarmellose sodium, crospovidone XL-10, and sodium starch glycolate. In one embodiment, the disintegrant is croscarmellose sodium (e.g., AC-DI-SOL). In a more specific embodiment, the disintegrant is croscarmellose sodium and is used in an amount of 1.5-3% (w / w) in the granules. In one embodiment, the disintegrant is crospovidone. In a more specific embodiment, the disintegrant is crospovidone and is used in an amount of 5-15% (w / w) in the granules. In a specific embodiment where the disintegrant is crospovidone, fine particle grade crospovidone (e.g., POLYPLASDONE XL-10) may be used. In one embodiment, the disintegrant is sodium starch glycolate (e.g., GLYCOLYS). In a more specific embodiment, the disintegrant is sodium starch glycolate and is used in an amount of 3-5% (w / w) in the granules. Again, it will be understood that the active pharmaceutical ingredient may influence the choice of disintegrant based on incompatibility. For example, sodium starch glycolate was selected for use in cabotegravir granules due to the incompatibility between cabotegravir and croscarmellose sodium.

[0044] Extragranular composition As explained above, the use of an insoluble material in the extragranular component promotes tablet disintegration. The dispersible tablets of the present invention utilize silicified microcrystalline cellulose as an extragranular component because it has an improved mouthfeel compared to microcrystalline cellulose. Example 7 shows that tablets comprising ≥ 20% silicified microcrystalline cellulose (SMCC) disperse in less than 3 minutes. In one embodiment, the dispersible tablet contains 20-50% (weight / weight of dispersible tablet) silicified microcrystalline cellulose.

[0045] Several different grades of silicified microcrystalline cellulose are available. Those skilled in the art will recognize that the grade selected should exhibit excellent flow, compressibility, and mouthfeel. Mouthfeel is dependent, in part, on particle size. A particle size (d50) of 125 microns or less is desirable. PROSOLV SMCC50 (d50=65 microns) and SMCC90 (d50=125 microns) are suitable grades.

[0046] In addition to containing silicified microcrystalline cellulose, the extragranular component must also contain a disintegrant. Disintegrants swell when wet, which contributes to the disintegration of the tablet, liberating the granules. Example 8 demonstrates that different disintegrants can be used. Suitable disintegrants include those listed above in connection with the intragranular composition, more particularly croscarmellose sodium or crospovidone XL-10. The optimal amount of disintegrant depends on the extragranular disintegrant selected and can be easily determined by one skilled in the art. Example 9 demonstrates that the disintegrant croscarmellose sodium is suitably used in an amount of 3-6% (w / w) of the extragranular component. Thus, in one embodiment, the present invention provides a dispersible tablet in which the disintegrant present in the extragranular component is croscarmellose sodium (e.g., AC-DI-SOL). In a more specific embodiment, the present invention provides a dispersible tablet in which croscarmellose sodium is present in the extragranular component in an amount of 3-6% (w / w) of the tablet. 3-4.5% (w / w) croscarmellose sodium was required in the formulation for optimal dispersibility. Thus, in one embodiment, the present invention provides a dispersible tablet in which croscarmellose sodium is present in the extragranular component in an amount of 3-4.5% (w / w) of the tablet.

[0047] In another embodiment, the disintegrant present in the extragranular component is crospovidone XL-10. In a more specific embodiment, the disintegrant present in the extragranular component is crospovidone XL-10 and is used in an amount of 10-15% (w / w) of the tablet. In a more specific embodiment, the disintegrant present in the extragranular component is crospovidone XL-10 and is used in an amount of approximately 10% (w / w) of the tablet. As noted above in connection with extragranular disintegrants, the selection of the extragranular disintegrant must take into account incompatibility with the active pharmaceutical ingredient.

[0048] The extragranular components may further comprise a lubricant and optionally a sweetener and a soluble filler.

[0049] Suitable lubricants are pharmaceutically acceptable lubricants such as magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, etc. In one embodiment, the lubricant is sodium stearyl fumarate. In a more specific embodiment, the lubricant is sodium stearyl fumarate (e.g., PRUV) used at a level of 2% (w / w) of the tablet. At this level, sodium stearyl fumarate provides effective lubrication during tableting and does not form scum during dispersion. The selection of a lubricant must take into account incompatibility with the active pharmaceutical ingredient. For example, low levels of magnesium stearate (0.5% (w / w)) have been successfully used in daprodustat dispersible tablets due to incompatibility with sodium stearyl fumarate. In one embodiment, the lubricant is magnesium stearate (e.g., LIGAMED). In a more particular embodiment, the lubricant is magnesium stearate, used at a level of 0.5% (w / w) of the tablet.

[0050] Whether a separate sweetener is necessary depends on factors such as the taste of the active pharmaceutical ingredient. Taste acceptability is important for chronic, once-daily administration, especially in pediatric populations. Therefore, a separate sweetener may be necessary in the extragranular component, but it should be noted that some potential additives for use as soluble intragranular fillers are sugars, which may also have a positive impact on palatability. Suitable sweeteners include sugars and artificial sweeteners, such as acesulfame potassium, neotame, or sucralose. In one embodiment, the sweetener is sucralose. In a more specific embodiment, the sweetener is sucralose, used at 1-2% (w / w) of the dispersible tablet formulation. In the presence of very bitter drugs, sucralose can also be used in combination with acesulfame potassium or neotame, or can be replaced by neotame alone, which is approximately 20 times sweeter than sucralose.

[0051] Example 7 demonstrates that the use of a soluble filler in the extragranular component is not necessary, while Formulation 15 demonstrates that the use of a soluble filler can be tolerated without adverse effects on disintegration time. Suitable soluble fillers for use in the extragranular component include those described above for use in the granules. In one embodiment, the soluble filler is mannitol (such as PEARLITOL 200SD). In a more specific embodiment, it is used in an amount of 10-75% of the dispersible tablet formulation.

[0052] Co-processed additives (commercially available additive mixtures) make it more difficult to obtain the parameters necessary for good disintegration, and although they can be used, they are not preferred.

[0053] tablet The dispersible tablets of the present invention contain a minimum of 40% (wt / wt) granules. Example 3 shows that tablets containing this percentage of granules have acceptable content uniformity. Those skilled in the art will recognize that content uniformity is more difficult to achieve for active pharmaceutical ingredients administered at very low doses. Because content uniformity improves with higher granule content, those skilled in the art will understand that tablets containing "low" doses of active pharmaceutical ingredients may require a higher percentage of granules to achieve acceptable content uniformity. In fact, as shown in Example 3, a dispersible tablet containing 83% (wt / wt) granules was found to disintegrate within 3 minutes and exhibit good content uniformity. In one embodiment, the dispersible tablets of the present invention contain 40-85% (wt / wt) granules. In one embodiment, the dispersible tablets of the present invention contain 40-83% (wt / wt) granules. In another embodiment, the dispersible tablets of the present invention contain 40-60% (wt / wt) granules.

[0054] In one embodiment, the present invention provides a method for producing a cellulose membrane comprising a cellulose membrane having a solids content of 0.9 or less and a cellulose membrane having a solids content of 615 mm or less. 2 A dispersible tablet exhibiting the following surface area, said dispersible tablet comprising extragranular components and at least 40% (w / w) of granules: The granules have a diameter of ≦140 microns and a density of 0.4 to 0.6 g / mL; i) 60% or less (weight / weight of the granules) of an active pharmaceutical ingredient; ii) 20-60% (weight / weight of the granules) of microcrystalline cellulose; iii) hydroxypropyl methylcellulose, wherein the ratio of crystalline cellulose to hydroxypropyl methylcellulose is ≧10:1; iv) a disintegrant; v) one or more soluble fillers; and Consists of; and The extragranular components are: i) at least 20% (weight / weight of said dispersible tablet) of silicified microcrystalline cellulose; ii) a disintegrant; iii) a lubricant; iv) optionally with a soluble filler; v) a sweetener, if desired; Consists of: Dispersible tablets are provided.

[0055] In one embodiment, the present invention provides a method for producing a cellulose membrane comprising a cellulose membrane having a solids content of 0.9 or less and a cellulose membrane having a solids content of 615 mm or less. 2 A dispersible tablet exhibiting the following surface area, said dispersible tablet comprising extragranular components and at least 40% (w / w) of granules: The granules have a diameter of ≦140 microns and a density of 0.4 to 0.6 g / mL; i) 60% or less (weight / weight of the granules) of an active pharmaceutical ingredient; ii) 20-30% (weight / weight of the granules) of microcrystalline cellulose; iii) hydroxypropyl methylcellulose, with a ratio of crystalline cellulose to hydroxypropyl methylcellulose of 10:1; iv) a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone XL-10, and sodium starch glycolate; v) a soluble filler which is mannitol; Consists of; and The extragranular components are: i) at least 20% (weight / weight of said dispersible tablet) of silicified microcrystalline cellulose; ii) a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone XL-10, sodium starch glycolate, and L-HPC; iii) a lubricant selected from the group consisting of magnesium stearate and sodium stearyl fumarate; iv) optionally with a soluble filler; v) a sweetener, if desired; Consists of: Dispersible tablets are provided.

[0056] In one embodiment, the present invention provides a method for producing a cellulose membrane comprising a cellulose membrane having a solids content of 0.9 or less and a cellulose membrane having a solids content of 615 mm or less. 2 A dispersible tablet exhibiting the following surface area, said dispersible tablet comprising extragranular components and at least 40% (w / w) of granules: The granules have a diameter of ≦140 microns and a density of 0.4 to 0.6 g / mL; i) 60% or less (weight / weight of the granules) of an active pharmaceutical ingredient; ii) 20-30% (weight / weight of the granules) of microcrystalline cellulose; iii) hydroxypropyl methylcellulose, with a ratio of crystalline cellulose to hydroxypropyl methylcellulose of 10:1; iv. a disintegrant which is croscarmellose sodium; v) a soluble filler which is mannitol; Consists of; The extragranular components are: i) at least 20% (weight / weight of said dispersible tablet) of silicified microcrystalline cellulose; ii) a disintegrant selected from the group consisting of croscarmellose sodium and crospovidone XL-10; iii) a lubricant selected from the group consisting of magnesium stearate and sodium stearyl fumarate; iv) optionally with a soluble filler; v) a sweetener, if desired; Consists of: Dispersible tablets are provided.

[0057] In certain embodiments where the intragranular disintegrant is croscarmellose sodium, the croscarmellose sodium is used in an amount of 1.5-3% (w / w) of the granule. In certain embodiments where the intragranular disintegrant is crospovidone XL-10, the crospovidone XL-10 is used in an amount of 5-15% (w / w) of the granule. In certain embodiments where the intragranular disintegrant is sodium starch glycolate, the sodium starch glycolate is used in an amount of 3-5% (w / w) of the granule.

[0058] In certain embodiments where the extragranular disintegrant is croscarmellose sodium, the croscarmellose sodium is used in an amount of 3-6% (w / w) of the dispersible tablet. In certain embodiments where the extragranular disintegrant is crospovidone XL-10, the crospovidone XL-10 is used in an amount of 10-15% (w / w) of the dispersible tablet. In certain embodiments where the extragranular disintegrant is sodium starch glycolate, the sodium starch glycolate is used in an amount of 5% (w / w) of the dispersible tablet. In certain embodiments where the extragranular disintegrant is L-HPC, the L-HPC is used in an amount of 15% (w / w) of the dispersible tablet.

[0059] In certain embodiments where the lubricant is magnesium stearate, the magnesium stearate is used in an amount of 0.5-1% (w / w) of the dispersible tablet. In certain embodiments where the lubricant is sodium stearyl fumarate, the magnesium stearate is used in an amount of 0.5-2% (w / w) of the dispersible tablet.

[0060] The tablet core may optionally be thin-coated to improve taste and / or provide a refined appearance. If present, the thin-coat is small and, by weight, accounts for approximately 3% (w / w) of the total tablet weight. Theoretically, the thin-coat retards water penetration into the extragranular components and the pores and channels therein, but has been found to dissolve rapidly enough that, in principle, it does not significantly affect disintegration time. Many suitable polymeric thin-coating materials are known in the art. A preferred thin-coating material is hydroxypropylmethylcellulose HPMC, particularly HPMC 2910 3, 5, and 6 mPa·sec. Other suitable film-forming polymers may also be used herein, including hydroxypropylcellulose and acrylate-methacrylate copolymers. In addition to the film-forming polymer, the thin-coat may further comprise a plasticizer (e.g., propylene 20 glycol) and, optionally, a pigment (e.g., titanium dioxide, iron oxide). In one embodiment of the present invention, the tablets of the present invention are thin-coated. In another embodiment, the tablets of the present invention are not thin-coated.

[0061] Suitability of dispersible tablets for different active pharmaceutical ingredients Those skilled in the art will readily recognize that the dispersible tablets of the present invention rapidly disintegrate, with the release of the active pharmaceutical ingredient (API) into the medium resulting from the disintegration of the tablet encasing it. Therefore, it is clear that the physical properties of the active pharmaceutical ingredient, and in particular the solubility of the active pharmaceutical ingredient, do not affect the disintegration time. The examples demonstrate that three very different APIs, namely, daprodustat (Formulations 1, 2, 5-14, 16-20, 24, and 25), cabotegravir (Formulations 3, 15, 21-23, and 26), and gepotidacin (Formulation 4), can be successfully formulated. These APIs have a wide range of solubility (0.127-175 mg / mL), ranging from nearly insoluble to very soluble. Thus, the examples demonstrate that a variety of APIs can be formulated with the dispersible tablets of the present invention and exhibit rapid disintegration.

[0062] Although suitable for essentially any active pharmaceutical ingredient, the small size of the tablet (determined by the maximum allowable surface area of the tablet) and the requirement that the granular and extragranular compositions contain minimum amounts of certain excipients are kept in mind, which places practical constraints on the amount of active pharmaceutical ingredient that can be contained within a single tablet, and can be calculated to allow the dispersible tablets of the present invention to accommodate a wide range of drug loads, from 0.1 to 56% (w / w). Example 14 demonstrates that four tablets exhibit a disintegration time of less than 3 minutes in 5 ml of water, and that increasing the volume of water to 10 ml can allow eight tablets to dissolve with an appropriate disintegration time. Dissolution of multiple tablets can increase the maximum theoretical dose of the active pharmaceutical ingredient (to at least 200 mg).

[0063] Thus, in one embodiment, the dispersible tablet of the present invention comprises 0.1 to 56% (w / w) of the active pharmaceutical ingredient. In another embodiment, the dispersible tablet of the present invention is suitable for active pharmaceutical compositions having a maximum dose of approximately 200 mg taken at one time. It is also particularly suitable for active pharmaceutical ingredients typically administered to pediatric patients (e.g., those under the age of 8) due to elderly patients and certain medical conditions that make swallowing difficult (e.g., patients with neurological disorders, patients with nasogastric tubes, and those with certain medical conditions such as head and neck cancer). Example 16 demonstrates acceptable recovery of the dose (API = daprodustat) from an administration device used in practice, although it is noted that a rinsing step may be important to ensure >90% recovery from the syringe and nasogastric tube.

[0064] Those skilled in the art will understand that wet granulation is used to form granules used in tablets. Compared to other formulation techniques (e.g., direct compression and dry granulation), wet granulation is complex and is usually only performed when other techniques are not suitable. Thus, in one embodiment, the active pharmaceutical ingredient is one that is not suitable for formulation by direct compression and dry granulation using low-shear blending methods. Wet granulation is particularly suitable in situations where the drug load is low, as this technique typically results in the drug substance being uniformly distributed and trapped in the granules. In addition, granules produced by wet granulation typically have better flow properties than ungranulated powders (used in direct compression) or roller-compacted granulation. This also contributes to content uniformity, as better-flowing granules ensure better tablet weight control during compression. Very low-dose tablets may require high-shear blending followed by high-shear wet granulation to ensure the drug substance is uniformly distributed and trapped in the granules.

[0065] Daprodustat dispersible tablets In one embodiment, the dispersible tablet of the present invention comprises daprodustat or a pharmaceutically acceptable salt thereof. Daprodustat has the USAN, INN, and JAN name for the compound N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine (the IUPAC name for this compound is N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine). Daprodustat exhibits keto / enol tautomerism. All tautomers of daprodustat, including mixtures thereof, are intended to be encompassed within the scope of the present invention. In a more specific embodiment, the daprodustat dispersible tablet of the present invention comprises 0.25 to 12 mg of daprodustat or a pharmaceutically acceptable salt thereof (measured as the free acid). In more specific embodiments, the daprodustat dispersible tablets of the invention comprise either 0.25 mg or 2 mg of daprodustat or a pharmaceutically acceptable salt thereof (measured as the free acid).

[0066] Daprodustat or a pharmaceutically acceptable salt thereof may be formulated according to the methods disclosed in WO 2007 / 150011. In one embodiment, the tablet contains 0.25 to 2 mg of daprodustat free acid.

[0067] In certain embodiments, daprodustat free acid is 1) a sharp melting point of 240-242°C as determined by thermogravimetric analysis; and / or 2) CuK α an X-ray powder diffraction (XRPD) pattern comprising at least five diffraction angles selected from the group consisting of 4.0±0.2, 6.4±0.2, 7.5±0.2, 8.0±0.2, 15.2±0.2, 17.2±0.2, 18.6±0.2, 19.3±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, and 24.1±0.2 degrees 2θ, when measured using radiation; It is an unsolvated crystalline form characterized by:

[0068] The crystalline form may be prepared according to the method described in Examples 1 to 4 of WO 2019 / 052133.

[0069] In certain embodiments, the unsolvated crystalline form of daprodustat free acid is CuK α The compound is characterized by an X-ray powder diffraction (XRPD) pattern, when measured using radioactive isotopic compositions, comprising at least five diffraction angles selected from the group consisting of 4.0±0.2, 6.4±0.2, 7.5±0.2, 8.0±0.2, 15.2±0.2, 17.2±0.2, 18.6±0.2, 19.3±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2 and 24.1±0.2 degrees 2θ.

[0070] In certain embodiments, the unsolvated crystalline form of daprodustat free acid is CuK αThe compound is characterized by an X-ray powder diffraction (XRPD) pattern, when measured using radioactive isotopic compositions, comprising at least 6, 7, 8, or 9 diffraction angles selected from the group consisting of 4.0±0.2, 6.4±0.2, 7.5±0.2, 8.0±0.2, 15.2±0.2, 17.2±0.2, 18.6±0.2, 19.3±0.2, 19.9±0.2, 20.4±0.2, 21.0±0.2, and 24.1±0.2 degrees 2θ.

[0071] In one embodiment, the unsolvated crystalline form of daprodustat free acid is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the following diffraction angles: 6.4±0.2, 7.5±0.2, and 8.0±0.2 degrees 2θ.

[0072] In one embodiment, the unsolvated crystalline form of daprodustat free acid is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the following diffraction angles: 6.4±0.2, 7.5±0.2, 8.0±0.2, 17.2±0.2, and 19.3±0.2 degrees 2θ.

[0073] In a more particular embodiment, the unsolvated crystalline form of daprodustat free acid is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the following diffraction angles: 6.4±0.2, 7.5±0.2, 8.0±0.2, 15.2±0.2, 17.2±0.2, and 19.3±0.2 degrees 2θ.

[0074] In one embodiment, the unsolvated crystalline form of daprodustat free acid is characterized by an X-ray powder diffraction (XRPD) pattern comprising characteristic XRPD peaks at 6.4°±0.2°, 7.5°±0.2°, and 7.9°±0.2° 2θ. The X-ray powder diffraction pattern may exhibit one or more additional characteristic peaks at 17.2°±0.2°, 21.0°±0.2°, 24.0°±0.2°, or 19.3°±0.2° 2θ.

[0075] In another embodiment, daprodustat free acid is an unsolvated crystalline form designated CS9. Form CS9 has an X-ray powder diffraction pattern with characteristic peaks at 4.6°±0.2°, 6.6°±0.2°, and 21.1°±0.2° 2θ using CuKα radiation. In a more particular embodiment, the X-ray powder diffraction pattern of Form CS9 has one or more additional characteristic peaks at 9.4°±0.2°, 20.2°±0.2°, and 24.2°±0.2° 2θ using CuKα radiation.

[0076] Form CS9 may be prepared from the free acid according to the methods described in WO 2019 / 052133.

[0077] In another embodiment, daprodustat free acid is a crystalline form designated Form 3. Form 3 has an X-ray powder diffraction pattern with peaks at 2θ values of 4.5°±0.2°, 5.6°±0.2°, 9.0°±0.2°, and 16.8°±0.2° using CuKα radiation. In a more particular embodiment, the X-ray powder diffraction pattern of Form 3 has one or more additional characteristic peaks at 2θ values selected from 8.5°±0.2°, 11.2°±0.2°, 20.6°±0.2°, and 24.7°±0.2° using CuKα radiation and / or a DSC endothermic peak with a phase change onset (T onset) at about 245.3°C.

[0078] In another embodiment, daprodustat free acid is a crystalline form designated Form 4. Form 4 has an X-ray powder diffraction pattern with peaks at 2θ values of 7.2°±0.2°, 11.5°±0.2°, 21.7°±0.2°, 22.9°±0.2°, 23.3°±0.2°, and 25.8°±0.2° using CuKα radiation. In a more particular embodiment, the X-ray powder diffraction pattern of Form 4 has one or more additional characteristic peaks at 2θ values selected from 6.3°±0.2°, 12.9°±0.2°, 16.5°±0.2°, 18.1°±0.2°, and 19.7°±0.2° using CuKα radiation and / or a DSC endothermic peak with a phase change onset (T onset) at about 243.9°C.

[0079] Forms 3 and 4 may be prepared as described in WO 2020 / 102302.

[0080] In another embodiment, daprodustat free acid is a crystalline form designated Form M. Form M has an X-ray powder diffraction pattern with characteristic peaks at 2θ values of 4.7°±0.2°, 6.5°±0.2°, and 6.8°±0.2° using CuKα radiation. Form M may be prepared as described in WO 2021 / 031102.

[0081] In one embodiment, the present invention provides a method for producing a cellulose membrane comprising a cellulose membrane having a solids content of 0.9 or less and a cellulose membrane having a solids content of 615 mm or less. 2 A dispersible tablet exhibiting the following surface area, said dispersible tablet comprising 70-83% (wt / wt) of granular and extragranular components: a. the granules have a diameter of ≦140 microns and a density of 0.4 to 0.6 g / mL; i) 3% or less (weight / weight of said granules) of daprodustat or a pharmaceutically acceptable salt thereof (measured as the free acid); ii) 20-30% (weight / weight of the granules) of microcrystalline cellulose; iii) hydroxypropyl methylcellulose, with a ratio of crystalline cellulose to hydroxypropyl methylcellulose of 10:1; iv) a disintegrant which is croscarmellose sodium or crospovidone XL-10; v) a soluble filler which is mannitol; Consists of; and b. The extragranular component is i) at least 20% (weight / weight of said dispersible tablet) of silicified microcrystalline cellulose; ii) a disintegrant selected from the group consisting of croscarmellose sodium and crospovidone XL-10; iii) a lubricant selected from the group consisting of magnesium stearate and sodium stearyl fumarate; iv) a sweetener which is sucralose; Consists of: Dispersible tablets are provided.

[0082] In certain embodiments where the intragranular disintegrant is croscarmellose sodium, the croscarmellose sodium is used in an amount of 1.5-3% (w / w) of the granule. In certain embodiments where the intragranular disintegrant is crospovidone XL-10, the crospovidone XL-10 is used in an amount of 5-15% (w / w) of the granule.

[0083] In certain embodiments where the extragranular disintegrant is croscarmellose sodium, the croscarmellose sodium is used in an amount of 3-6% (w / w) of the tablet. In certain embodiments where the extragranular disintegrant is crospovidone XL-10, the crospovidone XL-10 is used in an amount of 10-15% (w / w) of the dispersible tablet.

[0084] In certain embodiments where the lubricant is magnesium stearate, the magnesium stearate is used in an amount of 0.5-1% (w / w) of the dispersible tablet. In certain embodiments where the lubricant is sodium stearyl fumarate, the magnesium stearate is used in an amount of 0.5-2% (w / w) of the dispersible tablet.

[0085] In one embodiment, the dispersible tablet is film coated, in another embodiment, it is not film coated.

[0086] In another embodiment, the present invention provides a method for producing a cellulose membrane comprising a cellulose membrane having a solids content of 0.9 or less and a cellulose membrane having a solids content of 615 mm 2 A dispersible tablet exhibiting the following surface area, said dispersible tablet comprising 70-83% (wt / wt) of granular and extragranular components: a. the granules have a diameter of ≦140 microns and a density of 0.4 to 0.6 g / mL; i) 3% or less (weight / weight of said granules) of daprodustat or a pharmaceutically acceptable salt thereof (measured as the free acid); ii) 20-30% (weight / weight of the granules) of microcrystalline cellulose; iii) hydroxypropyl methylcellulose, with a ratio of crystalline cellulose to hydroxypropyl methylcellulose of 10:1; iv) a disintegrant which is croscarmellose sodium; v) a soluble filler which is mannitol; Consists of; and b. The extragranular component is i) at least 20% (weight / weight of said dispersible tablet) of silicified microcrystalline cellulose; ii) a disintegrant which is croscarmellose sodium; iii) a lubricant which is magnesium stearate; iv) a sweetener which is sucralose; It consists of Dispersible tablets are optionally thin-coated, Dispersible tablets are provided.

[0087] In a more specific embodiment, the present invention provides a method for producing a pulp having a solids content of 0.9 or less and a pulp having a solids content of 615 mm 2 A dispersible tablet exhibiting the following surface area, said dispersible tablet comprising 70-83% (wt / wt) of granular and extragranular components: a) the granules have a diameter of ≦140 microns and a density of 0.4 to 0.6 g / mL; i. 3% or less (weight / weight of said granules) of daprodustat or a pharmaceutically acceptable salt thereof (measured as the free acid); ii. 20-30% (weight / weight of the granules) of microcrystalline cellulose; iii. hydroxypropyl methylcellulose, wherein the ratio of hydroxypropyl methylcellulose to crystalline cellulose is 10:1; iv. 1.5-3% (weight / weight of the above granules) of croscarmellose sodium; v. a soluble filler which is mannitol; Consists of; and b) The extragranular components are i. at least 20% (weight / weight of the dispersible tablet) silicified microcrystalline cellulose; ii. 3-6% (weight / weight of the dispersible tablet) of croscarmellose sodium; iii. a lubricant which is magnesium stearate; iv. a sweetener which is sucralose; It consists of Dispersible tablets are optionally thin-coated, Dispersible tablets are provided.

[0088] In a more specific embodiment, the present invention provides a method for producing a pulp having a solids content of 0.9 or less and a pulp having a solids content of 615 mm 2 A dispersible tablet exhibiting the following surface area, said dispersible tablet comprising 70-83% (wt / wt) of granular and extragranular components: a) the granules have a diameter of ≦140 microns and a density of 0.4 to 0.6 g / mL; i. 3% or less (weight / weight of said granules) of daprodustat or a pharmaceutically acceptable salt thereof (measured as the free acid); ii. 20% (weight / weight of the granules) of microcrystalline cellulose; iii. hydroxypropyl methylcellulose, wherein the ratio of hydroxypropyl methylcellulose to crystalline cellulose is 10:1; iv. 1.5-3% (weight / weight of the above granules) of croscarmellose sodium; v. a soluble filler which is mannitol; Consists of; and b) The extragranular components are i. at least 20% (weight / weight of the dispersible tablet) silicified microcrystalline cellulose; ii. 3-6% (weight / weight of the dispersible tablet) of croscarmellose sodium; iii. a lubricant which is magnesium stearate; iv. a sweetener which is sucralose; It consists of Dispersible tablets are thin-coated, Dispersible tablets are provided.

[0089] In certain embodiments, the dispersible tablets are tablets comprising daprodustat as the API, which are Formulation 1 or Formulation 2 described in the Examples. As shown in Example 14, 4 tablets can be dissolved in 5 ml, and 8 tablets can be dissolved in 10 ml. This ability to dissolve multiple tablets in a small volume, resulting in a free-flowing solution with acceptable mouthfeel, allows for all dose levels in a given dosing regimen. As shown in Example 15, daprodustat dispersible tablets are stable after 3 months of storage at 40°C / 75% RH when packed in a 60 cc HDPE bottle containing 2 g of desiccant. Examples 16 and 17 demonstrate that daprodustat dispersible tablets are stable for 2 hours after dispersion in water, with good recovery achieved from various dosing devices (e.g., dosing cups, syringes, and refill tubes).

[0090] Medical uses of daprodustat dispersible tablets The dispersible tablets of daprodustat may be used in therapy, more particularly in the treatment of anemia. In certain embodiments, the dispersible tablets of daprodustat of the present invention may be used in the treatment of anemia associated with chronic kidney disease (also known as renal anemia).

[0091] Thus, in one embodiment, the present invention provides a daprodustat dispersible tablet of the present invention for use in therapy.

[0092] In another embodiment, the present invention provides the daprodustat dispersible tablet of the present invention for use in a method for treating anemia due to chronic kidney disease.

[0093] In yet another embodiment, the present invention provides the use of daprodustat or a pharmaceutically acceptable salt thereof in the manufacture of a daprodustat dispersible tablet of the present invention for use in the treatment of anemia due to chronic kidney disease.

[0094] In another embodiment, the present invention provides a method for treating anemia due to chronic kidney disease in a subject in need thereof, said method comprising administering to said subject a daprodustat dispersible tablet of the present invention.

[0095] In a specific embodiment, the subject is a human. In one embodiment, the human is a pediatric patient under the age of 18. In a more specific embodiment, the human is a pediatric patient under the age of 12. In one embodiment, the human is a pediatric patient between the ages of 3 months and 12. In another embodiment, the human is a pediatric patient under the age of 8. In a more specific embodiment, the human is a pediatric patient between the ages of 3 months and 8.

[0096] In one embodiment, the subject with anemia due to chronic kidney disease may be undergoing dialysis, such as hemodialysis or peritoneal dialysis. In an alternative embodiment, the subject is not undergoing dialysis. In certain embodiments, the subject may be iron deficient (TSAT≦20% and / or serum ferritin≦100 ng / ml) and may be receiving iron supplementation therapy.

[0097] In a further embodiment, the present invention provides a dosing regimen for treating anemia due to chronic kidney disease, with the goal of maintaining hemoglobin within the range of 10-12 g / dL and providing safe increases at lower hemoglobin levels. The dose is modified based on hemoglobin concentration determined at a clinical visit using an age-specific algorithm. Hemoglobin concentration may be measured by known methods, such as a complete blood count or HemoCue.

[0098] In one embodiment, the present invention provides a dosing regimen for treating anemia due to chronic kidney disease in patients aged 3 months to 2 years, comprising administering the dispersible tablet of the present invention at a once-daily equivalent of 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, or 8 mg (free acid dose), with the dose adjusted up or down by one dose step based on the patient's hemoglobin level to maintain the patient's hemoglobin level within the range of 10-12 g / dL. Note that the once-daily equivalent of 0.125 mg is achieved by administering 0.25 mg three times a week (TIW). All other dose steps include a once-daily dosing frequency.

[0099] In one embodiment, the present invention provides a dosing regimen for the treatment of anemia due to chronic kidney disease in a patient between 2 and 6 years of age, wherein the dispersible tablet of the present invention is administered in a once daily dose of either 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 or possibly 12 mg (free acid dose), the dose being titrated up or down based on the patient's hemoglobin level to maintain the patient's hemoglobin level within the range of 10-12 g / dL.

[0100] In one embodiment, the present invention provides a dosing regimen for the treatment of anemia due to chronic kidney disease in a patient aged 6-12 years, wherein the dispersible tablet of the present invention is administered in a once daily dose of any of 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and possibly 12 or 16 mg (free acid dose), the dose being titrated up or down based on the patient's hemoglobin level to maintain the patient's hemoglobin level within the range of 10-12 g / dL.

[0101] In certain embodiments, the patient's hemoglobin concentration is monitored at least once every three months. In more specific embodiments, the patient's hemoglobin concentration is monitored at least once every eight weeks. In even more specific embodiments, the patient's hemoglobin concentration is monitored monthly or every four weeks. Those skilled in the art will understand that monitoring may be more frequent when treatment is initiated, and that the frequency of monitoring will be reduced once the patient's hemoglobin concentration has stabilized within the target range (10-12 g / dL).

[0102] In embodiments where the patient experiences a rapid increase in hemoglobin concentration (e.g., greater than 2.0 g / dL within 4 weeks or an initial rise at initiation of greater than 1 g / dL within 2 weeks), the dose is reduced by one dose step or discontinued.

[0103] In embodiments where the patient's hemoglobin concentration exceeds the maximum of the target range, administration is discontinued and treatment resumed at the next lower dosage level until the hemoglobin concentration is within the target range.

[0104] Clinical judgment is also important when increasing or decreasing the dose. In embodiments where the patient is higher than the target range, the dose is decreased by one dose step or discontinued. In embodiments where the patient is symptomatic of anemia despite being in the 10-12 g / dL range, the dose can be increased by one dose step, but should not exceed 12 g / dL.

[0105] A dosing regimen is provided for the treatment of anemia due to chronic kidney disease to maintain hemoglobin levels within the range of 10-12 g / dL, wherein the daprodustat dispersible tablets of the present invention are administered in once-daily doses equivalent to 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and possibly 12 or 16 mg (free acid dose); a) If hemoglobin concentration is <10 g / dL and increases by <0.5 g / dL compared to the previous assessment, increase the dose by one dose step; b) If hemoglobin is within the target range of 10-12 g / dL but the patient is still symptomatic due to their anemia, increase the dose by one dose step; c) If hemoglobin concentration is within the range of >12 to ≤12.5 g / dL, reduce the dose by one dose step; d) Dose reduction by one dose step if there is an increase in hemoglobin concentration of >2 g / dL over 4 weeks or an increase in hemoglobin concentration of >1 g / dL over 2 weeks; e) If hemoglobin levels are stable within the target range of 10-12 g / dL, maintain the same dose; f) If the hemoglobin concentration is >12.5 g / dL, discontinue administration until the hemoglobin concentration is ≦12.0 g / dL and resume treatment at the next lower dose.

[0106] It will be apparent that a dose adjustment will result in the daprodustat dose being increased or decreased by one dose step at a time: those receiving the highest (maximum) dose of daprodustat who require a dose increase will maintain that dose, while those receiving the lowest dose of daprodustat who require a dose reduction will cease daprodustat treatment.

[0107] For the avoidance of doubt, it should be noted that any particular dose can be administered as a single tablet or multiple tablets. For example, a 4 mg dose can be administered as two 2 mg tablets. For Formulation 24 (0.25 mg daprodustat dispersible tablets) and Formulation 25 (2 mg daprodustat dispersible tablets) described in the Examples, it should be noted that up to four tablets can be suspended in a 5 mL volume. Dispersion of eight tablets requires a total volume of 10 mL.

[0108] For ESA-naive patients, appropriate starting doses are specified in Table 1.

[0109] [Table 1]

[0110] For non-dialysis patients switching from an ESA to daprodustat, appropriate starting doses are specified in Table 2.

[0111] [Table 2]

[0112] For dialysis patients switching from an ESA to daprodustat, appropriate starting doses are specified in Table 3.

[0113] [Table 3]

[0114] manufacturing One aspect of the present invention is a method for formulating dispersible tablets of the present invention, said method comprising: (a) formulating granules using intragranular ingredients as described herein; and (c) obtaining extragranular fractions using extragranular fraction ingredients as described herein, and formulating tablets of the present invention using these fractions. In one embodiment, the granules produced in (a) do not comprise silicified microcrystalline cellulose.

[0115] Granules may be prepared by any suitable method, such as direct compression, dry granulation, or wet granulation. In one embodiment, a wet granulation method is used. In wet granulation, granules may be prepared by contacting or mixing relevant components with a medium that may be aqueous or non-aqueous, or a combination. In one embodiment, the medium is water (quantity), more particularly purified water (quantity). In one embodiment, such a wet granulation method is a batch high shear granulation method. The use of a batch high shear granulation method results in better control of granule size and lower levels of fine particles compared to top spray granulation.

[0116] As shown in Example 11, the use of a soluble filler in the granules improves wet granulation; granules comprising 17-75% (wt / wt) soluble filler (e.g., mannitol) have greater mechanical strength (lower levels of fines) for downstream processing into tablets.

[0117] The use of batch high shear granulation methods results in improved granule characteristics (flow characteristics, particle size distribution control, fine particle level) for dispersible tablets. The resulting granules can then be dried and sized (or sieved) before being mixed or blended with the extragranular components (as defined herein). Such blends inherently require lubrication, with the extragranular layer also containing a lubricant. The blend can then be converted into tablets using a conventional tablet press. The equipment used for the tablet press determines the surface area of the tablet.

[0118] Numbered Embodiments The dispersible tablets are described by the following set of numbered embodiments:

[0119] Embodiment 1.0.9 or less solid content and 615mm 2 A dispersible tablet exhibiting the following surface area, said dispersible tablet comprising at least 40% (w / w) of granular and extragranular components: a. the granules have a diameter of ≦140 microns, a density of 0.4-0.6 g / mL, and comprise ≦60% (wt / wt) of an active pharmaceutical ingredient, 20-60% (wt / wt) of microcrystalline cellulose, and a binder, wherein the ratio of microcrystalline cellulose to binder is ≧10:1; and b. the extragranular component comprises at least 20% silicified microcrystalline cellulose and a disintegrant; Dispersible tablets.

[0120] Embodiment 2. The dispersible tablet of embodiment 1, wherein the granules comprise 20-30% (w / w) microcrystalline cellulose.

[0121] Embodiment 3. The dispersible tablet of embodiment 2, wherein the granules comprise about 20% (w / w) microcrystalline cellulose.

[0122] Embodiment 4. The dispersible tablet of any one of embodiments 1 to 3, wherein the binder is selected from hydroxypropyl methylcellulose and povidone.

[0123] Embodiment 5. The dispersible tablet of any one of embodiments 1 to 4, wherein the disintegrant in the extragranular component is croscarmellose sodium or crospovidone XL-10.

[0124] Embodiment 6. The dispersible tablet of embodiment 5, wherein croscarmellose sodium is used in an amount of about 3-6% (w / w) in the extragranular component.

[0125] Embodiment 7. A dispersible tablet according to any one of embodiments 1 to 6, wherein the granules further comprise one or more soluble fillers exhibiting a solubility of at least 200 mg / ml at 25° C.

[0126] Embodiment 8. The dispersible tablet of embodiment 7, wherein the granules further comprise one soluble filler, which is mannitol.

[0127] Embodiment 9. The dispersible tablet of any one of embodiments 1 to 8, wherein the granules further comprise a disintegrant.

[0128] Embodiment 10. A dispersible tablet according to any one of embodiments 1 to 9, wherein the extragranular component further comprises a sweetener and / or a lubricant.

[0129] Embodiment 11. A dispersible tablet according to any one of embodiments 1 to 10, wherein the 1 or more tablets can completely disintegrate in 5 ml of water within a time period of 3 minutes.

[0130] Embodiment 12. A dispersible tablet according to embodiment 11, wherein the suspension prepared after complete disintegration contains less than 200 mg of insoluble solid particles of 125 microns or less per dispersed unit dose.

[0131] Embodiment 13. The dispersible tablet of any one of embodiments 1 to 12, wherein the active pharmaceutical ingredient is daprodustat or a pharmaceutically acceptable salt thereof.

[0132] Embodiment 14.0.9 or less solid content and 615mm 2 A dispersible tablet exhibiting the following surface area, said dispersible tablet comprising 70-83% (w / w) of granular and extragranular components: b. the granules have a diameter of ≦140 microns, a density of 0.4-0.6 g / mL, and consist of 3% w / w or less daprodustat or a pharmaceutically acceptable salt thereof (measured as the free acid), 20-30% (w / w) of a disintegrant which is microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, or crospovidone XL-10, and a soluble filler which is mannitol, wherein the ratio of microcrystalline cellulose to hydroxypropyl methylcellulose is 10:1; and c. the extragranular component consists of at least 20% silicified microcrystalline cellulose, a disintegrant selected from the group consisting of croscarmellose sodium and crospovidone XL-10, a lubricant selected from the group consisting of magnesium stearate and sodium stearyl fumarate, and a sweetener which is sucralose; Dispersible tablets. [Example]

[0133] Disintegration time measurement protocol ·Method 1: USP method <701> The decay is measured using Method 2: Disperse 1-4 tablets in 5 mL of water or 5-8 tablets in 10 mL of water by gently swirling in a 30 mL dosing cup for 1-3 minutes.

[0134] We observe that disintegration times measured using Methods 1 and 2 show good correlation. In Examples 1, 2, and 4-16, the quoted disintegration times were measured by either Method 1 or Method 2.

[0135] Example 1 Table 4 shows the 615mm 2 Tablets with a total surface area of less than 1000 μm are shown to disperse in less than 3 minutes at an average tensile strength of 2 MPa (±0.5 MPa). [Table 4]

[0136] The compositions of Formulations 1 to 4 are shown in Table 5. The formulations were prepared in 615 mm 2 This demonstrates that tablets with a tablet surface area of less than 1000 MPa can be rapidly disintegrated. [Table 5]

[0137] Example 2 Table 6 and Figure 1 show that tablets with a solids fraction of 0.9 or less disperse in less than 3 minutes. The solids fraction is related to the tablet density (g / cm 3) to the true density (g / cm) of the input material or compressed compound 3 ) and is therefore unitless. Tablet density is calculated by dividing the tablet weight (mg) by the tablet volume (mm 3 ) The tablet volume is determined using the tablet dimensions and shape. The true density of the input compression blend can be measured using a pycnometer or calculated from the true densities of all individual components previously measured or obtained from the literature. [Table 6]

[0138] The composition of Formulation 2 is provided in Example 1.

[0139] The lines in Figure 1 relate to different production batches of tablets with formulation 24 or 25, each line differing only in percent solids.

[0140] USP <1062> According to the study, there is a direct relationship between tablet tensile strength (MPa) and tablet solids content. Tensile strength (Ts) is expressed in MPa and is calculated from tablet hardness, thickness, and die dimensions as shown in the following formula (Pitt and Heasley, 2013, Powder Technology, 238: 169-175):

number

[0141] where P is the tablet hardness, D is the length of the minor axis, T is the tablet thickness, and W is the median cylinder thickness (tablet wall height).

[0142] In terms of the relationship between tablet solid fraction and tablet tensile hardness, and the relationship between tablet solid fraction and tablet disintegration time, all of the formulations disclosed in Examples 1, 4-12, and 14-16 have similar tensile strengths and tablet solid fractions of 0.9 or less.

[0143] Example 3 Table 7 shows that tablets containing a minimum of 40% (wt / wt) granules comply with USP <905> According to the FDA, the content uniformity is acceptable with AV<15. Granule loadings in the range of 40-75% have been found to be suitable for producing fast-dispersing tablets. Granule loadings can be successfully increased to 83% in ultra-small 100 mg core weight dispersible tablets. [Table 7]

[0144] The compositions of Formulations 5-10 are shown in Table 8 and are for illustrative purposes only, as they are not dispersible tablets of the present invention, and are therefore intended to illustrate the effect of granule content on content uniformity. [Table 8]

[0145] Example 4 Table 9 shows that tablets comprising granules with a median size of ≦140 microns disperse in less than 3 minutes at a target average tablet tensile strength of 2 MPa (±0.5 MPa). [Table 9]

[0146] The compositions of Formulations 1 and 11 are shown in Table 10. [Table 10]

[0147] Example 5 Table 11 shows that tablets comprising granules containing 20-60% (wt / wt) microcrystalline cellulose (MCC) disperse in less than 3 minutes at a target average tablet tensile strength of 2 MPa (±0.5 MPa). The most rapid disintegration time was observed with 20% (wt / wt) microcrystalline cellulose, which was also optimal for granulation process robustness. [Table 11]

[0148] Table 12 shows the compositions of formulations 1, 2, 3, 13, and 14. [Table 12]

[0149] Example 6 Table 13 shows that the ratio of MCC to binder needs to be ≧10:1 in granules for tablets comprising high levels of granules (75-83% wt / wt) to disintegrate in less than 3 minutes at a target average tablet tensile strength of 2 MPa (±0.5 MPa). The ratio of MCC to binder can be ≧4:1 for tablets comprising lower levels of granules (e.g., 40% wt / wt granules) to disintegrate in less than 3 minutes at a target average tablet tensile strength of 2 MPa (±0.5 MPa). [Table 13]

[0150] The compositions of Formulations 1, 2, 7, 12 and 13 are shown in Table 14. [Table 14]

[0151] Example 7 Table 15 shows that tablets comprising ≧20% silicified microcrystalline cellulose (SMCC) disperse in less than 3 minutes at a target average tablet tensile strength of 2 MPa (±0.5 MPa). [Table 15]

[0152] Table 16 shows the compositions of formulations 1, 2, 11, 16 and 17. [Table 16]

[0153] Example 8 Table 17 shows that tablets comprising croscarmellose sodium, crospovidone XL-10, sodium starch glycolate and L-HPC as extragranular disintegrants disperse in less than 3 minutes at a target average tablet tensile strength of 2 MPa (±0.5 MPa). Crospovidone XL-10 disintegrant may be used at a level of 10-15% (w / w) in the extragranular composition of the dispersible tablet. [Table 17]

[0154] The compositions of Formulations 1, 2, 3, 21, 26, and 15 are shown in Table 18. Note that even though Formulations 15, 21, and 26 are not tablets of the present invention, they are still fast disintegrating and provide support for the use of sodium starch glycolate and L-HPC as extragranular disintegrants. [Table 18]

[0155] Example 9 Table 19 shows that tablets comprising 3-6% (w / w) extragranular croscarmellose sodium disintegrant disintegrate in less than 3 minutes at a target average tablet tensile strength of 2 MPa (±0.5 MPa). [Table 19]

[0156] The compositions of Formulations 1, 2, 18 and 19 are shown in Table 20. [Table 20]

[0157] Example 10 Table 21 shows that tablets comprising 10-15% (w / w) extragranular crospovidone XL-10 disintegrant disperse in less than 3 minutes at a target average tablet tensile strength of 2 MPa (±0.5 MPa). [Table 21]

[0158] Table 22 shows the compositions of Formulations 3, 20, and 21. Note that even though Formulations 20 and 21 are not tablets of the present invention, they are still fast disintegrating and provide support for the use of extragranular crospovidone XL-10 in 10% amounts. [Table 22]

[0159] Example 11 Table 23 shows that tablets comprising a second intragranular soluble filler in addition to MCC have a lower amount of insoluble solids and therefore improved mouthfeel. Granules comprising 17-75% (wt / wt) of a soluble filler (e.g., mannitol) have greater mechanical strength (lower levels of fines) for downstream processing into tablets. Disintegration is measured at a target average tablet tensile strength of 2 MPa (±0.5 MPa). [Table 23]

[0160] The compositions of Formulations 1, 3, 4 and 13 are shown in Table 24. [Table 24]

[0161] Example 12 Table 25 shows that tablets comprising intragranular disintegrants (e.g., croscarmellose sodium, sodium starch glycolate, and crospovidone XL-10) disperse in less than 3 minutes at a target average tablet tensile strength of 2 MPa (±0.5 MPa). 3% (w / w) croscarmellose sodium and 4% sodium starch glycolate were successfully used in the granules to produce a fast-dispersing formulation (dispersing in 30 seconds). [Table 25]

[0162] Table 26 shows the compositions of Formulations 1, 3 and 20. It is noted that while the SMCC content of Formulation 20 is <20%, the tablet still meets the disintegration time, demonstrating that a variety of disintegrants can be used within the granules. [Table 26]

[0163] Example 13 Table 27 shows that tablets containing 200 mg or less of MCC and SMCC have an acceptable mouthfeel. The MCC and SMCC grades used had a small size of 125 microns or less to improve mouthfeel. The mouthfeel is considered acceptable if the statistical average response from taste test participants is "acceptable" and the majority of participants perceive the mouthfeel as "acceptable." [Table 27]

[0164] Example 14 Table 28 shows that tablets of the present invention can be dispersed in 5 mL of water. The API in Formulations 24 and 25 is daprodustat free acid. Formulation 24 is a 0.25 mg daprodustat dispersible tablet and Formulation 25 is a 2 mg daprodustat dispersible tablet.

[0165] [Table 28]

[0166] The compositions of Formulations 24 and 25 are shown in Table 29. Note that Formulation 24 is a thin-coated version of Formulation 1, and Formulation 25 is a thin-coated version of Formulation 2. Note that purified water is removed during processing. Note that the weight of the thin-coat applied per tablet can vary depending on the efficiency of the process, but can typically be 3.0% (w / w) of the tablet core weight. [Table 29]

[0167] Example 15 Sixty tablets (Formulation 24 in Table 30 and Formulation 25 in Table 31) were packed in 60 cc HDPE bottles with induction seal caps and 2 g of desiccant. Tablet stability was evaluated over a range of conditions (RH = relative humidity; Amb = ambient; Exposed = tablets outside of the primary container, e.g., opened in a Petri dish). [Table 30] [Table 31]

[0168] Tables 30 and 31 demonstrate that formulations 24 and 25 have excellent stability when stored under 40°C / 75% RH conditions for 3 months.

[0169] Example 16 Dispersions (1 x 0.25 mg tablet (Formulation 24) and 4 x 2 mg tablets (Formulation 25)) were formulated by adding water, then the tablet, then vortexing for 2 minutes in the following dosing device: 30mL dosing cup Glass (soda lime) 10mL syringe + cup Nasogastric (GN) tube + syringe + cup

[0170] Dose recovery was assessed by measuring the drug content of each dispersion. The drug content of a 5 mL rinse was also measured. Acceptable recovery is considered to be an LC of 90% or greater for the sum of the combined contents of the recovery and rinse samples. Table 32 shows that acceptable recovery was demonstrated for the total volume, administration device, and administration device combination tested. Syringes and GN supply tubes showed less than 90% recovery from the recovery samples, suggesting that a rinse step is important to ensure achieving >90% recovery when using these administration devices. [Table 32]

[0171] Example 17 A dispersion (1 x 0.25 mg tablet (Formulation 24)) was formulated by adding water and then swirling for 2 minutes in the following dosing device: 30mL dosing cup Glass (soda lime)

[0172] The stability of the drug substance in the dispersion was evaluated by measuring the content and impurities at the following time points: 0, 30, 60 and 120 minutes. Table 33 shows that the dispersion is stable up to 120 minutes. [Table 33]

[0173] Example 18 Table 34 shows tablets comprising granules with a disintegrant density of 0.4 to 0.6 mg / mL in less than 3 minutes, particularly tablets comprising granules with a disintegrant density of 0.5 to 0.6 mg / mL in less than 60 seconds. [Table 34]

[0174] The composition of Formulation 1 is shown in Table 5.

Claims

1. Solid content of 0.9 or less and 615 mm ２ Dispersible tablets having the following surface area, The dispersible tablet comprises an extragranular component and at least 40% (by weight / weight) of granules in the dispersible tablet. a. The granules have a diameter of ≤140 microns, a density of 0.4 to 0.6 g / mL, and contain 60% or less (by weight / weight in the granules) of a pharmaceutical active ingredient, 20 to 60% (by weight / weight in the granules) of crystalline cellulose and a binder, wherein the ratio of crystalline cellulose to the binder is ≥10:1; and b. The extragranular component comprises at least 20% (by weight / weight in the dispersible tablet) of silicified crystalline cellulose and a disintegrant. Dispersible tablets.

2. The dispersible tablet according to claim 1, wherein the granules contain 20-30% (by weight) of crystalline cellulose.

3. The dispersible tablet according to claim 2, wherein the granules contain 20% (by weight) of crystalline cellulose.

4. The dispersible tablet according to claim 1, wherein the binder is selected from hydroxypropyl methylcellulose and povidone.

5. The dispersible tablet according to claim 1, wherein the disintegrant in the extragranular component is croscarmellose sodium or crospovidone XL-10.

6. The dispersible tablet according to claim 5, wherein croscarmellose sodium is used in an amount of 3 to 6% (by weight / by weight) of the extragranular components.

7. The dispersible tablet according to claim 1, wherein the granules further comprise one or more soluble fillers exhibiting a solubility of at least 200 mg / ml at 25°C.

8. The dispersible tablet according to claim 7, wherein the granules comprise one soluble filler, which is mannitol.

9. The dispersible tablet according to claim 1, wherein the granules further contain a disintegrant.

10. The dispersible tablet according to claim 1, wherein the extragranular component further comprises a sweetener and / or a lubricant.

11. The dispersible tablet according to claim 1, wherein one or more tablets can be completely disintegrated in 5 ml of water within a time of 3 minutes.

12. The dispersible tablet according to claim 11, wherein the suspension prepared after complete disintegration contains less than 200 mg of insoluble solid particles having a d50 of 125 microns or less per dispersed unit dose.

13. The dispersible tablet according to any one of claims 1 to 12, wherein the active pharmaceutical ingredient is daprodustat or a pharmaceutically acceptable salt thereof.

14. Solid content of 0.9 or less and 615 mm ２ Dispersible tablets having the following surface area, The dispersible tablet comprises an extragranular component and 70-83% (by weight / weight) of granules in the dispersible tablet. a. The granules have a diameter of ≤ 140 microns and a density of 0.4 to 0.6 g / mL. i. 3% or less (by weight / weight in the granules) of daprodustat or a pharmaceutically acceptable salt thereof (measured as free acid); ii. 20-30% (by weight / weight) of crystalline cellulose in the granules; iii. Hydroxypropyl methylcellulose and crystalline cellulose in a ratio of 10:1; iv. With a disintegrant that is croscarmellose sodium or crospovidone XL-10; v. A soluble filler that is mannitol, Consists of; and b. The extragranular components are, i. At least 20% (by weight / by weight in the dispersible tablet) of silicified crystalline cellulose; ii. A disintegrant selected from the group consisting of croscarmellose sodium and crospovidone XL-10; iii. A lubricant selected from the group consisting of magnesium stearate and sodium stearyl fumarate; iv. The sweetener is sucralose, Consists of, Dispersible tablets.

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