Preparation of plasma kallikrein inhibitors

Abstract

The present invention provides a pharmaceutical dosage form in the form of an orodispersible tablet comprising a plasma kallikrein inhibitor, a mixture used in the process for producing the orodispersible tablet of the invention, and the use of such an orodispersible tablet. The orodispersible tablet of the invention is particularly suitable for patients who may have difficulty swallowing tablets. The present invention provides on-demand treatment of bradykinin-mediated angioedema by orally administering a plasma kallikrein inhibitor in the form of an orodispersible tablet to a patient in need of treatment.

Description

[Technical field]

[0001] The present invention relates to the treatment of bradykinin-mediated angioedema with a plasma kallikrein inhibitor. In particular, the present invention provides a pharmaceutical dosage form in the form of an orodispersible tablet comprising a plasma kallikrein inhibitor, a mixture used in the method for producing the orodispersible tablet of the present invention, and the use of such an orodispersible tablet. The orodispersible tablet of the present invention is particularly suitable for patients who may have difficulty swallowing tablets. The present invention provides on-demand treatment of bradykinin-mediated angioedema by orally administering a plasma kallikrein inhibitor in the form of an orodispersible tablet to a patient in need of treatment. [Background technology]

[0002] Inhibitors of plasma kallikrein have many therapeutic applications, particularly in the treatment of bradykinin-mediated angioedema, such as hereditary angioedema and non-hereditary bradykinin-mediated angioedema (BK-AEnH).

[0003] Plasma kallikrein is a trypsin-like serine protease that can liberate kinins from kininogens (see KD Bhoola et al., "Kallikrein-Kinin Cascade", Encyclopedia of Respiratory Medicine, p483-493; JW Bryant et al., "Human plasma kallikrein-kinin system: physiological and biochemical parameters" Cardiovascular and haematological agents in medicinal chemistry, 7, p234-250, 2009; KD Bhoola et al., Pharmacological Rev., 1992, 44, 1; and DJ Campbell, "Towards understanding the kallikrein-kinin system: insights from the measurement of kinin peptides", Brazilian Journal of Medical and Biological Research 2000, 33, 665-677). Plasma kallikrein is an essential component of the intrinsic blood coagulation cascade, although its role in this cascade does not involve the release or enzymatic cleavage of bradykinin. Plasma prekallikrein is encoded by a single gene and can be synthesized in the liver and other tissues. It is secreted by hepatocytes as inactive plasma prekallikrein and circulates in plasma as a heterodimeric complex bound to high molecular weight kininogen (HK), which is activated to generate active plasma kallikrein.This contact activation system (or contact system) can be activated by negatively charged surfaces that activate factor XII (FXII) to factor XIIa (FXIIa), or by certain proteases that may not require a negatively charged surface, such as plasmin (Hofman et al., Clin Rev Allergy Immunol 2016), or by misfolded proteins (Maas et al., J Clinical Invest 2008). FXIIa mediates the conversion of plasma prekallikrein to plasma kallikrein and the subsequent cleavage of high molecular weight kininogen (HK) to generate bradykinin, a potent inflammatory hormone. Kinins are potent inflammatory mediators that act through G protein-coupled receptors and kinin antagonists (e.g., bradykinin receptor antagonists) have been investigated as potential therapeutic agents in the treatment of many diseases (F. Marceau and D. Regoli, Nature Rev., Drug Discovery, 2004, 3, 845-852).

[0004] Plasma kallikrein is believed to play a role in many inflammatory diseases. The major inhibitor of plasma kallikrein is serpin C1 esterase inhibitor. Patients with genetic deficiencies in C1 esterase inhibitor suffer from hereditary angioedema (HAE), which results in intermittent swelling of the face, hands, throat, gastrointestinal tract, and genitals. The blisters formed during acute attacks contain high concentrations of plasma kallikrein, which cleaves high molecular weight kininogen (HK) to liberate bradykinin, leading to increased vascular permeability. Treatment with an inhibitor of the high molecular weight protein plasma kallikrein has been shown to effectively treat HAE by preventing the release of bradykinin, which causes increased vascular permeability (A. Lehmann "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery" Expert Opin. Biol. Ther. 8, p1187-99). However, a risk of anaphylactic reactions has been reported with ecallantide.

[0005] Hereditary angioedema is a rare genetic disease characterized by recurrent acute attacks in which fluid accumulates outside of blood vessels, disrupting the normal flow of blood or lymph, causing rapid swelling of tissues such as the hands, feet, limbs, face, intestinal tract, or airways. Thus, "hereditary angioedema" can be defined as any disorder characterized by recurrent attacks of bradykinin-mediated angioedema (e.g., severe swelling) caused by a genetic malfunction / defect / mutation. Currently, three categories of HAE are known: (i) HAE type 1, (ii) HAE type 2, and (iii) normal C1 inhibitor HAE (normal C1-Inh HAE). However, the field of HAE is rapidly evolving, and it is likely that additional types of HAE will be defined in the future.

[0006] Without wishing to be bound by theory, HAE type 1 is believed to be caused by a mutation in the SERPING1 gene that leads to a decrease in the level of C1 inhibitor in the blood. Without wishing to be bound by theory, HAE type 2 is believed to be caused by a mutation in the SERPING1 gene that leads to a malfunction of C1 inhibitor in the blood. Without wishing to be bound by theory, the cause of normal C1-Inh HAE is less clearly defined, and the underlying gene malfunction / defect / mutation may sometimes remain unknown. It has been found that the cause of normal C1-Inh HAE is not related to a decrease in the level or malfunction of C1 inhibitor (unlike HAE types 1 and 2). Normal C1-Inh HAE can be diagnosed by investigating the family history and finding that angioedema has been inherited from a previous generation (hence, hereditary angioedema). Normal C1-Inh HAE may also be diagnosed by determining that there is a malfunction / defect / mutation in a gene other than the one related to C1 inhibitor. For example, it has been reported that plasminogen dysfunction / defects / mutations can cause normal C1-Inh HAE (see, e.g., Veronez et al., Front Med(Lausanne). 2019 Feb 21;6:28. doi: 10.3389 / fmed.2019.00028; or Recke et al., Clin Transl Allergy. 2019 Feb 14;9:9. doi: 10.1186 / s13601-019-0247-x).It has also been reported that factor XII dysfunction / defects / mutations can cause normal C1-Inh HAE (see, e.g., Mansi et al., The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine, 2015, 277;585-593; or Maat et al. J Thromb Haemost. 2019 Jan;17(1):183-194. doi: 10.1111 / jth.14325).

[0007] Acute HAE attacks usually progress through three important clinically distinct phases: an initial prodromal phase (which can usually last up to 12 hours), followed by a swelling phase, and then a resorption phase. The majority of HAE attacks show prodromal symptoms. Two-thirds of prodromal symptoms appear within 6 hours before the HAE attack, and no prodromal symptoms occur more than 24 hours before the HAE attack (Magerl et al, Clinical and Experimental Dermatology 2014, 39, 298-303). For example, the following prodromal symptoms may begin to be observed: slight swelling (especially seen in the face and neck), typical abdominal pain, and a typical reddening of the skin called "erythema marginata". The attack is in full expression when it reaches maximum swelling and maximum expression of pain (e.g. abdominal attack), discomfort (e.g. peripheral attack), or life-threatening danger (e.g. laryngeal attack). Once the attack has peaked, the period of time until normalization thereafter is determined by the time it takes for the swelling to subside and for the fluid that has infiltrated the tissues to be reabsorbed.

[0008] However, angioedema is not necessarily hereditary. In fact, another class of angioedema is non-hereditary bradykinin-mediated angioedema (BK-AEnH), which is not caused by an inherited gene malfunction / defect / mutation. In many cases, the underlying cause of BK-AEnH is unknown and / or undefined. However, the signs and symptoms of BK-AEnH are similar to HAE and, without being bound by theory, are thought to result from a bradykinin-mediated pathway shared between HAE and BK-AEnH. Specifically, BK-AEnH is characterized by recurrent acute attacks in which fluid accumulates outside of blood vessels, disrupting the normal flow of blood or lymph, causing rapid swelling in tissues such as the hands, feet, limbs, face, intestinal tract, airways, or genitals. Attacks of BK-AEnH are acute and usually progress through three important clinically distinct phases: an initial prodromal phase (which can usually last up to 12 hours), followed by a swelling phase, and then a resorption phase. The majority of attacks show prodromal symptoms. Two-thirds of prodromal symptoms appear within 6 hours before the attack, and no prodromal symptoms occur more than 24 hours before the attack (Magerl et al. Clinical and Experimental Dermatology (2014) 39, pp298-303). For example, the following prodromal symptoms may begin to be observed: slight swelling (especially seen in the face and neck), typical abdominal pain, and a typical reddening of the skin called "erythema marginata". Attacks are in full expression when they reach maximum swelling and maximum expression of pain (e.g. abdominal attacks), discomfort (e.g. peripheral attacks), or life-threatening danger (e.g. laryngeal attacks). Once the attack has peaked, the period of time until normalization thereafter is determined by the time it takes for the swelling to subside and for the fluid that has infiltrated the tissues to be reabsorbed.

[0009] Specific types of BK-AEnH include non-hereditary angioedema with normal C1 inhibitor (AE-nC1 Inh), which can be induced by the environment, hormones, or drugs, acquired angioedema, anaphylaxis-related angioedema, angiotensin-converting enzyme (ACE) inhibitor-induced angioedema, dipeptidyl peptidase-4 inhibitor-induced angioedema, and tPA-induced angioedema (tissue plasminogen activator-induced angioedema). However, it is unclear why these factors and conditions cause angioedema in only a relatively small population.

[0010] Environmental factors that can induce AE-nC1 Inh include air pollution (Kedarisetty et al., Otolaryngol Head Neck Surg. 2019 Apr 30:194599819846446. doi: 10.1177 / 0194599819846446) and silver nanoparticles used as antimicrobial components in, for example, healthcare, biomedical and consumer products (Long et al., Nanotoxicology. 2016;10(4):501-11. doi: 10.3109 / 17435390.2015.1088589).

[0011] Various publications have suggested a link between the bradykinin and contact system pathways and BK-AEnH, and the potential efficacy of treatment (see, for example, Bas et al. (N Engl J Med 2015); Leibfried and Kovary. (J Pharm Pract 2017); van den Elzen et al. (Clinic Rev Allerg Immunol 2018); Han et al. (JCI 2002)).

[0012] tPA-induced angioedema has been discussed in various publications as a potentially life-threatening complication after thrombolytic therapy in acute stroke patients (e.g., Simao et al., Blood.2017 Apr 20;129(16):2280-2290. doi: 10.1182 / blood-2016-09-740670;Froehlich et al., Stroke.2019 Jun 11:STROKEAHA119025260.doi: 10.1161 / STROKEAHA.119.025260;Rathbun, Oxf Med Case Reports.2019 Jan 24;2019(1):omy112. doi: 10.1093 / omcr / omy112;Lekoubou et al., Neurol Res.2014 Jul;36(7):687-94. doi: 10.1179 / 1743132813Y.0000000302;see Hill et al., Neurology.2003 May 13;60(9):1525-7).

[0013] Stone et al. (Immunol Allergy Clin North Am. 2017 Aug;37(3):483-495.) report that certain drugs can cause angioedema.

[0014] Scott et al. (Curr Diabetes Rev. 2018;14(4):327-333. doi: 10.2174 / 1573399813666170214113856) report a case of angioedema induced by a dipeptidyl peptidase-4 inhibitor.

[0015] Hermanrud et al. (BMJ Case Rep. 2017 Jan 10;2017. pii: bcr2016217802) report recurrent angioedema associated with pharmacological inhibition of dipeptidyl peptidase IV and also discuss acquired angioedema associated with angiotensin-converting enzyme inhibitors (ACEI-AAE). Kim et al. (Basic Clin Pharmacol Toxicol.2019 Jan;124(1):115-122. doi: 10.1111 / bcpt.13097) report angioedema associated with angiotensin II receptor blockers (ARBs). Reichman et al. (Pharmacoepidemiol Drug Saf. 2017 Oct;26(10):1190-1196. doi: 10.1002 / pds.4260) also reported a risk of angioedema in patients taking ACE inhibitors, ARB inhibitors, and beta-blockers. Diestro et al. (J Stroke Cerebrovasc Dis. 2019 May;28(5):e44-e45. doi: 10.1016 / j.jstrokecerebrovasdis.2019.01.030) also reported a possible association between certain angioedema and ARBs.

[0016] Giard et al. (Dermatology. 2012;225(1):62-9. doi: 10.1159 / 000340029) report that bradykinin-mediated angioedema can be caused by estrogen contraceptives.

[0017] The snow-white snow-white snowflakes are available at Garr etc. are described above (“Peptide aldehyde....”J. Peptide Res. 52, 62-71(1998)), T. Griesbacher et al.(“Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats” British Journal of Pharmacology 137, 692-700(2002)), Evans(“Selective dipeptide inhibitors of kallikrein” WO03 / 076458), Szelke et al.(“Kininogenase inhibitors” WO92 / 04371), DM Evans et al.(Immunopharmacology, 32, p115-116(1996)), Szelke et al.(“Kininogen inhibitors” WO95 / 07921), Antonsson et al.(“New peptide derivatives” WO94 / 29335), J. Corte et al.(“Six membered heterocycles useful as serine protease inhibitors” WO2005 / 123680), J. Stuerzbecher et al.(Brazilian J. Med. Biol. Res 27, p1929-34(1994)), Kettner et al al.(US 5,187,157), N. Teno et al.(Chem. Pharm. Bull. 41, p1079-1090(1993)), WB Young et al.(“Small molecule inhibitors of plasma kallikrein” Bioorg. Med. Chem. Letts. 16, p2034-2036(2006)), Okada et al.(“Development of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship” Chem. Pharm. Bull. 48, p1964-72(2000)), Steinmetzer et al.(“Trypsin-like serine protease inhibitors and their preparation and use” WO08 / 049595), Zhang et al.(“Discovery of highly potent small molecule kallikrein "Medicinal Chemistry 2, p545-553(2006)), Sinha et al. ("Inhibitors of plasma kallikrein" WO08 / 016883), Shigenaga et al. ("Plasma Kallikrein Inhibitors" WO2011 / 118672), and Kolte et al. ("Biochemical characterization of a novel high-affinity and specific kallikrein inhibitor”, British Journal of Pharmacology (2011), 162(7), 1639-1649). Steinmetzer et al. ("Serine protease inhibitors" WO2012 / 004678) also describe cyclized peptide analogs that are inhibitors of human plasmin and plasma kallikrein.

[0018] As explained above, HAE can develop in patients who exhibit genetic deficiency or dysfunction of C1 esterase inhibitor. Thus, some of the current treatments for HAE include administering C1 esterase inhibitor to correct the deficiency or dysfunction of C1 esterase inhibitor. Such treatments can be preventative (i.e., administered when there are no symptoms of acute HAE attack to prevent / reduce the likelihood of acute HAE attack) and / or acute treatment (i.e., administered when symptoms of acute HAE attack are identified and attempt to stop or reduce the severity of acute HAE attack).

[0019] Cinryze® and Haegarda® contain C1 esterase inhibitors and are approved to prevent acute HAE attacks (i.e., prophylactic treatment). Treatment with Cinryze® requires preparation of a powder into a solution that is injected every 3 or 4 days. Similarly, treatment with Haegarda® requires preparation of a powder into a solution that is injected twice weekly. These treatments are not always self-administered by patients, and patients must then undergo outpatient treatment. Thus, both of these prophylactic treatments are burdensome to patients. Furthermore, the FDA insert for Haegarda® states that it "should not be used to treat acute HAE attacks," and therefore patients may require additional treatment if an HAE attack occurs.

[0020] Berinert® and Ruconest® contain C1 esterase inhibitors and are approved for treating acute HAE attacks. Both of these treatments still involve the preparation of an injection solution followed by injection. This method can be burdensome for patients, especially when they have an acute HAE attack. Self-administration of the dosage is not always possible, and when self-administration is not possible, administration of the drug can be significantly delayed, which increases the severity of the patient's acute HAE attack.

[0021] Kalbitor® (active substance ecallantide) and Takhzyro® (active substance lanadelumab) are selective plasma kallikrein inhibitors approved for medical use in the treatment of HAE. Both therapeutics are formulated as injectable solutions. Ecallantide is a high molecular weight protein plasma kallikrein inhibitor with a risk of anaphylactic reactions. In fact, the EU marketing authorization application for Kalbitor® was recently withdrawn because the benefits of Kalbitor® did not outweigh its risks. Lanadelumab is a recombinant fully human IgG1 kappa light chain monoclonal antibody. Reported adverse reactions of lanadelumab treatment include hypersensitivity, pain at the injection site, erythema at the injection site, and subcutaneous bleeding at the injection site. The approved EMA label for Takhzyro® (active substance lanadelumab) states that it is ``not intended for the treatment of acute HAE attacks'' and that ``in the event of a breakthrough attack of HAE, individualized treatment with an approved rescue therapy should be initiated.'' Furthermore, as injectables, both of these treatments are burdensome to patients.

[0022] In some countries, berotralstat (BCX7353) has been approved for preventive (not on-demand) treatment of HAE, for example under the product name Orladeyo®. Hwang et al. (Immunotherapy (2019) 11(17), 1439-1444) note that higher doses are associated with greater gastrointestinal side effects, indicating greater toxicity at higher doses.

[0023] Furthermore, many molecules in the prior art have highly polar and ionizable guanidine or amidine functional groups. It is well known that such functional groups can limit intestinal permeability and therefore oral availability. For example, Tamie J. Chilcote and Sukanto Sinha ("ASP-634: An Oral Drug Candidate for Diabetic Macular Edema", ARVO 2012 May 6th-May 9th, 2012, Fort Lauderdale, Florida, Presentation 2240) have reported that the oral availability of ASP-440, a benzamidine, is low. In addition, it has been reported that the absorption rate can be improved by creating prodrugs such as ASP-634. However, it is well known that prodrugs can have some disadvantages, such as low chemical stability and potential toxicity due to inactive carriers or unexpected metabolites. Another report claims indole amides as compounds that may overcome the challenges associated with drugs with low or inadequate ADME-tox and physicochemical properties, but does not demonstrate or claim inhibition of plasma kallikrein (Griffioen et al., “Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases”, WO2010142801).

[0024] Other plasma kallikrein inhibitors known in the art are generally small molecules, some of which have highly polar, ionizable functional groups such as guanidine or amidine. Recently, plasma kallikrein inhibitors that do not have the guanidine or amidine functional groups have been reported. For example, Brandl et al. (“N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein” WO2012 / 017020), Evans et al. (“Benzylamine derivatives as inhibitors of plasma kallikrein” WO2013 / 005045), Allan et al. (“Benzylamine derivatives” WO2014 / 108679), Davie et al. (“Heterocyclic derivates” WO2014 / 188211), Davie et al. (“N-((het)arylmethyl)-heteroaryl-carboxamides compounds as plasma kallikrein inhibitors” WO2016 / 083820).

[0025] The applicant has developed a series of novel compounds that are inhibitors of plasma kallikrein, as disclosed in WO2016 / 083820 (PCT / GB2015 / 053615). These compounds show good selectivity for plasma kallikrein. One such compound is N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide. A particular dosage form containing this compound is disclosed in Collett et al. WO2019 / 106361. The name N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide refers to the structure shown below and is known by its code name "KVD900". The INN of KVD900 is sevetralstat.

[0026] [ka]

[0027] As already mentioned, hereditary angioedema (HAE) is a rare genetic condition characterized by recurrent attacks of severe swelling. The swelling is typically of the face, hands, throat, gastrointestinal tract and / or genitals. If untreated, attacks of swelling can be extremely uncomfortable and dangerous, sometimes causing abdominal pain, diarrhea, vomiting and even death. Existing medications for the treatment of HAE are administered on demand or as prophylactics. On-demand treatments are administered in response to a specific attack to reduce its severity, for example at the first signs of attack symptoms. In prophylactic treatments, treatment is administered on an ongoing and regular basis (i.e., not in response to one specific attack) to reduce the likelihood of an attack occurring. Prophylactic treatments are generally not completely effective, and patients treated with prophylactic treatment often experience breakthrough attacks. For this reason, HAE patients on prophylactic treatments typically receive on-demand treatment as a back-up against such breakthrough attacks (such treatments are often referred to as "rescue treatments"). Therefore, all HAE patients, regardless of their current treatment regimen (or lack of treatment regimen), would benefit from having access to an effective, on-demand treatment for HAE, which is one of the needs that the present invention aims to address.

[0028] Therefore, there is a need for a treatment for bradykinin-mediated angioedema (e.g., HAE or BK-AEnH) that is less burdensome to the patient to improve patient compliance. In particular, there is a need for an orally administered drug for the treatment of bradykinin-mediated angioedema (e.g., HAE or BK-AEnH). Because HAE attacks resolve more quickly and are shorter after early treatment (Maurer M et al. PLoS ONE 2013;8(2): e53773. doi:10.1371 / journal.pone.0053773), early intervention when attacks are anticipated or in progress is essential for successful management of the disease. Thus, there is also a need for oral treatments for acute bradykinin-mediated angioedema (e.g., HAE or BK-AEnH) attacks that are on-demand (e.g., used once symptoms of acute bradykinin-mediated angioedema (e.g., HAE or BK-AEnH) are recognized) and do not require regular (or ongoing) administration (e.g., treatments that do not require twice-weekly injections). There is a need, particularly for effective oral treatments in younger patients (e.g., under 2-18 years of age). Existing injection treatments can cause pain at the injection site, and the injections themselves can cause stress in children. Additionally, there is a need for specific oral dosage forms that are more suitable for patients who may have difficulty swallowing tablets (e.g., children, elderly, patients with conditions such as laryngeal attacks or dysphagia).

[0029] Currently, there are no approved oral treatments for bradykinin-mediated angioedema (e.g., HAE or BK-AEnH) (see, e.g., Craig et al. Int Arch Allergy Immunol. 2014;165(2):119-27. doi: 10.1159 / 000368404;Mager et al., Immunol Allergy Clin North Am. 2017 Aug;37(3):571-584). There are no approved on-demand oral treatments for bradykinin-mediated angioedema disease (e.g., HAE or BK-AEnH). Instead, the majority of current treatments are injectables. Injectables have many disadvantages compared to oral treatments, primarily with respect to patient compliance. For example, injectables are less convenient than oral treatments, for example, the patient must be in a suitable environment to compound and then administer the injection, and they also cause pain at the injection site. A decrease in patient compliance can lead to delays in patient treatment, which typically leads to worsening of attack symptoms or even stopping treatment all together. In fact, many patients suffering from HAE simply hope that the attacks will go away on their own because they do not want to take an injection. Injectable treatments are problematic in that they are administered late, as the patient may need to prepare the dosage form or even travel to the hospital to administer the treatment. Thus, HAE treatments are often hindered by administration delays brought about by a large burden on the patient. In fact, Maurer M et al. (PLoS ONE 2013;8(2):e53773.doi:10.1371 / journal.pone.0053773) explain that over 60% of patients administer HAE injectables more than an hour after the onset of an attack. Since HAE drugs are often used off-label to treat certain types of BK-AEnH, the problems associated with HAE treatments apply equally to the treatment of BK-AEnH.

[0030] The primary on-demand treatment for HAE is icatibant (sold as Firazyr®), which is administered by subcutaneous injection. In a real-world study of HAE patients for which icatibant was available (Maurer M et al. PLoS ONE 2013;8(2): e53773. doi:10.1371 / journal.pone.0053773), less than 40% of attacks treated were administered within 1 hour of onset, and 30% were not treated until more than 5 hours after onset. Furthermore, 45% of attacks in this study were not treated at all. Thus, there is an unmet need to provide patients with improved therapeutic options to treat HAE attacks on demand.

[0031] As mentioned above, there are no approved oral on-demand treatments for bradykinin-mediated angioedema diseases such as HAE and BK-AEnH. KVD900 is currently undergoing Phase 3 clinical trials (known as the KONFIDENT trial, https: / / konfidentstudy.com / ) and has met all efficacy and safety endpoints of its Phase 2 trials (see Clinical Trial NCT04208412). In these trials, KVD900 was administered as a swallowed tablet.

[0032] However, there remains a need to provide treatment options that allow for early intervention, which is known to reduce the duration of bradykinin-mediated attacks (e.g., HAE attacks) and the time to rapid attack resolution. Additionally, there remains a need to provide treatment options for individuals who may have difficulty swallowing, for example, those who are young or elderly, who have laryngeal attacks, who do not have access to water, and / or who have conditions such as dysphagia. Additionally, there is a risk of vomiting during abdominal attacks, which creates uncertainty as to how much of the dose will be absorbed, and the act of drinking water, which is desirable for swallowing a pill, can often exacerbate nausea. [Prior art documents] [Patent documents]

[0033] [Patent Document 1] International Publication No. 2003 / 076458 [Patent Document 2] International Publication No. 92 / 004371 [Patent Document 3] International Publication No. 95 / 007921 [Patent Document 4] WO 94 / 029335 [Patent Document 5] International Publication No. 2005 / 123680 [Patent Document 6] U.S. Pat. No. 5,187,157 [Patent Document 7] International Publication No. 2008 / 049595 [Patent Document 8] International Publication No. 2008 / 016883 [Patent Document 9] International Publication No. 2011 / 118672 [Patent Document 10] International Publication No. 2012 / 004678 [Patent Document 11] International Publication No. 2010 / 142801 [Patent Document 12] International Publication No. 2012 / 017020 [Patent Document 13] International Publication No. 2013 / 005045 [Patent Document 14] International Publication No. 2014 / 108679 [Patent Document 15] International Publication No. 2014 / 188211 [Patent Document 16] International Publication No. 2016 / 083820 [Patent Document 17] International Publication No. 2019 / 106361 [Non-patent literature]

[0034] [Non-Patent Document 1] KD Bhoola et al., “Kallikrein-Kinin Cascade”, Encyclopedia of Respiratory Medicine, p483-493

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[0035] The present invention aims to solve the above problems, and in particular to provide a therapeutic agent for bradykinin-mediated angioedema diseases such as HAE and BK-AEnH, which is particularly suitable for patients who require a dosage form that is easy to administer orally. Such patients include younger patients (e.g., patients under the age of 2-18, particularly those under the age of 2-12), older patients (e.g., patients over 70 years old), patients who frequently suffer from bradykinin-mediated attacks that are laryngeal attacks, patients who do not usually have ready access to liquids (e.g., water) to aid in the swallowing of oral dosage forms, or patients with conditions such as dysphagia. Oral dispersible tablets are also beneficial for treating other patients who prefer the convenience of an easy-to-swallow dosage form, and patients who may have difficulty in complying with medication (e.g., due to psychiatric disorders).

[0036] The present invention addresses these needs by providing a first-line orodispersible tablet (ODT) for on-demand treatment of bradykinin-mediated angioedema diseases such as HAE and BK-AEnH. The orodispersible tablet of the present invention has been developed to enable early intervention and reduce barriers to treatment.

[0037] Orodispersible tablets (e.g. orodispersible minitablets) are intended to be placed directly in the oral cavity and disintegrate rapidly in saliva before being swallowed. ODTs are not swallowable tablets, such as traditional swallowable tablets or capsules.

[0038] Developing an ODT formulation poses several challenges, such as the need for the ODT to have sufficient mechanical strength while also providing a fast disintegration time. In particular, since the ODT must have a feasible tablet size and drug load, drugs with high dose strengths (>200 mg) may be less suitable for ODTs, as the ODT is limited by the amount of drug that can be contained in each unit dose. This was a particularly challenging development process for KVD900, as the dose of KVD900 that was proven safe and effective in phase 2 was 600 mg, and this dose needs to be given in as few unit doses as possible to ensure patient compliance.

[0039] Moreover, KVD900 is also classified as a BCS class IV compound (according to the ICH guideline: BIOPHARMACEUTICS CLASSIFICATION SYSTEM-BASED BIOWAIVERS M9 Final Version adopted on November 20, 2019), making it particularly difficult to formulate as an ODT. BCS class IV drugs are considered to be poorly soluble and poorly permeable, which means that they may have low oral bioavailability and / or may not be able to be administered by oral route due to too low oral absorption rate. BCS class IV drugs are particularly difficult to formulate as oral dosage forms, especially ODTs, due to their many unfavorable properties. In fact, ODTs for BCS class IV drugs are not generally known in the art.

[0040] Applicants have overcome these difficulties and provided ODTs of KVD900, which are ODTs described herein as part of the present invention. These ODTs have been manufactured and administered to humans in Phase 1 trials.

[0041] For an ODT to be viable for clinical use, it must be capable of being mass-produced. To this end, the mixture of active ingredient and excipients must have sufficient processability and flowability to provide an ODT that meets the above requirements. These depend on the specific physicochemical properties of the candidate drug, including compressibility, solubility and particle size, the desired pharmacokinetic and pharmacodynamic properties of the drug and excipients, and flow properties. These properties are specific to the active ingredient and cannot be accurately predicted before formulation development has taken place. In addition, the ODT must have a pleasant taste, must not disintegrate into large particles in the mouth, and must be formulated to leave minimal or no residue in the mouth after oral administration.

[0042] In developing the ODT of the present invention, the inventors faced problems in providing a suitable ODT. Initial attempts to produce an ODT of KVD900 were unsuccessful as the inventors faced problems with degradation of KVD900 and processability problems such as poor flowability. The inventors have solved these problems by using, for example, the mixture of KVD900 and excipients and the method for producing the ODT described herein.

[0043] As explained above, the safety and efficacy of KVD900 has been demonstrated, meeting all of its Phase 2 safety and efficacy endpoints. Advantageously, the subsequent ODT formulation has a pharmacokinetic and pharmacodynamic profile comparable to formulations of KVD900 already tested in clinical trials (e.g., the immediate release (IR) formulation of KVD900 used in the Phase 2 and Phase 3 trials described herein).

[0044] definition As used herein, unless otherwise specified, the term "compound" refers to "KVD900." KVD900 may exist as its pharma- ceutically acceptable salts and / or solvates. The structure of KVD900 is shown below, and its name is N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide.

[0045] [ka]

[0046] The KVD900 used in the present invention may be in a preferred crystalline form (Form 1), which exhibits at least approximately the following characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees (2θ)): (1) 11.2, 12.5, 13.2, 14.5, and 16.3, or (2) 11.2, 12.5, 13.2, 14.5, 16.3, 17.4, and 17.9, or (3) 11.2, 12.5, 13.2, 14.5, 16.3, 17.4, 17.9, 21.2 and 22.0.

[0047] The term "approximately" in this context means that the measurement of the angle (2θ) has an uncertainty of ±0.3 (expressed in degrees 2θ), preferably ±0.2 (expressed in degrees 2θ).

[0048] Form 1 may also have an X-ray powder diffraction pattern including characteristic peaks (expressed in degrees 2-theta) at approximately 4.4, 11.2, 12.5, 13.2, 14.5, 16.3, 17.4, 17.9, 21.2, 22.0 and 22.6.

[0049] Form 1 may also have an X-ray powder diffraction pattern approximately similar to that shown in FIG.

[0050] "Pharmaceutically acceptable salts thereof and / or solvates thereof" shall be understood to mean "a pharma-ceutically acceptable salt thereof", "a pharma-ceutically acceptable solvate thereof", and "a pharma-ceutically acceptable solvate of a salt thereof". The preferred form of KVD900 is the free base form, particularly the anhydrous free base form (where it is possible to keep the free base anhydrous).

[0051] The term "pharmaceutical acceptable salt" refers to a physiologically or toxicologically acceptable salt, and may be, for example, a pharmaceutical acceptable acid addition salt. For example, since KVD900 has a basic group, such as a basic nitrogen, the pharmaceutical acceptable acid addition salts that may be formed include hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, lactate, tartrate, mesylate, succinate, oxalate, phosphate, esylate, tosylate, benzenesulfonate, naphthalenedisulfonate, maleate, adipate, fumarate, hippurate, camphorate, xinafoate, p-acetamidobenzoate, dihydroxybenzoate, hydroxynaphthoate, succinate, ascorbate, oleate, or bisulfate. The preferred pharmaceutical acceptable salt of the compound is hydrochloride.

[0052] Hemi-salts of the acids may also be formed, such as hemi-sulfates.

[0053] For a general discussion of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0054] The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharma- ceutically acceptable solvent molecules, such as, for example, ethanol or water. The term "hydrate" is used when the solvent is water, and for the avoidance of any doubt, the term "hydrate" is subsumed within the term "solvate".

[0055] "KVD900" can include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, hydrogen is replaced by deuterium or tritium, or carbon is replaced by 13 C or 14 Compounds where C is substituted are also within the scope of the invention.

[0056] As used herein, the term "orodispersible tablet" (ODT) refers to a tablet that is intended to be placed directly in the oral cavity and that disintegrates rapidly in saliva before being swallowed. An ODT is not a swallowable tablet, such as a traditional swallowable tablet or capsule.

[0057] The term "blend" as used herein in relation to embodiments of the present invention relates to a mixture of KVD900 and excipients used in the manufacturing process to provide the ODT of the present invention. For example, the mixture of KVD900 and excipients may include a blend of KVD900 and the excipients that is manufactured prior to compression into the ODT. The "blend" may be a powder mixture.

[0058] The terms "acute attack of bradykinin-mediated angioedema", "acute bradykinin-mediated angioedema attack", "bradykinin-mediated angioedema attack", or "attack of bradykinin-mediated angioedema" are used interchangeably herein. "Bradykinin-mediated angioedema" may be HAE or BK-AEnH. Preferably, the bradykinin-mediated angioedema is HAE, and if so, "acute attack of bradykinin-mediated angioedema" is an "acute attack of HAE" and may be used interchangeably with "acute HAE attack", "HAE attack", or "attack of HAE".

[0059] The term "hereditary angioedema" (abbreviated as HAE) refers to any bradykinin-mediated angioedema caused by an inherited genetic dysfunction, defect, or mutation. As a result, the term "HAE" includes at least HAE type 1, HAE type 2, and normal C1 inhibitor HAE (normal C1-Inh HAE).

[0060] The term "non-hereditary bradykinin-mediated angioedema" or "BK-AEnH" is bradykinin-mediated angioedema that is not caused by an inherited gene malfunction / defect / mutation (i.e., not hereditary angioedema (HAE)). Although the cause of BK-AEnH may be unknown and / or unclear, the signs and symptoms of BK-AEnH are similar to HAE and, without wishing to be bound by theory, are thought to result from a bradykinin-mediated pathway shared between HAE and BK-AEnH. Specific BK-AEnH treatable by the present invention are selected from non-hereditary angioedema with normal C1 inhibitor (AE-nC1 Inh), which may be induced by the environment, hormones, or drugs, acquired angioedema, anaphylaxis-related angioedema, angiotensin-converting enzyme (ACE or ace) inhibitor-induced angioedema, dipeptidyl peptidase-4 inhibitor-induced angioedema, and tPA-induced angioedema (tissue plasminogen activator-induced angioedema).

[0061] In the context of bradykinin-mediated angioedema (BK-AEnH or preferably HAE), "on-demand" treatment will be understood by those skilled in the art to mean that KVD900 is administered as needed for treatment associated with one particular bradykinin-mediated angioedema attack (BK-AEnH attack or preferably HAE attack). As described herein, this one particular bradykinin-mediated angioedema attack (BK-AEnH attack or preferably HAE attack) may be in progress (e.g., treatment is initiated when symptoms of a bradykinin-mediated angioedema attack are recognized) or may be likely to occur (e.g., when the patient expects that a bradykinin-mediated angioedema attack may be induced or triggered). Multiple doses of KVD900 may be administered as part of on-demand treatment, but these multiple doses are administered in conjunction with the same one bradykinin-mediated angioedema attack (BK-AEnH attack or preferably HAE attack). In other words, "on demand" does not require that KVD900 be administered continuously at regular intervals (e.g., once a week, twice a week, etc.) regardless of the onset of a bradykinin-mediated angioedema attack (BK-AEnH attack, or preferably HAE attack). In the treatment of the present invention, KVD900 is taken when a patient requires an immediate therapeutic effect. Particular "on-demand" treatments of the present invention include (i) on-demand treatment of a bradykinin-mediated angioedema attack (BK-AEnH attack or preferably an HAE attack) by administering KVD900 once symptoms of a bradykinin-mediated angioedema attack (BK-AEnH attack or preferably an HAE attack) are recognized, and (ii) on-demand prophylactic reduction of the likelihood of a bradykinin-mediated angioedema attack (BK-AEnH attack or preferably an HAE attack) when, for example, it is anticipated that a bradykinin-mediated angioedema attack (BK-AEnH attack or preferably an HAE attack) may be induced (or may be caused), as discussed in more detail below.

[0062] In any of the treatments of the invention described herein, the patient is preferably a human. Bradykinin-mediated angioedema (e.g., BK-AEnH or preferably HAE) can affect patients of any age. Thus, the human patient can be a child (0 to under 18 years old) or an adult (18 years old or older). In any of the treatments described herein, the patient may have a predisposition to angioedema. Specifically, the patient can be 12 years old or older. The patient may be 2 years old or older.

[0063] The human patient may be between 2 and under 18 years of age. The human patient may be between 2 and under 12 years of age. The human patient may be between 12 and under 18 years of age. The patient may be at least 70 years of age.

[0064] As used herein, the term "bioequivalent" refers to a dosage form that is therapeutically equivalent to the innovator's reference product (e.g., any approved dosage form, including KVD900) when administered under the same conditions in a pharmacokinetic evaluation. For example, they may meet the FDA guidance on bioequivalence testing (https: / / www.fda.gov / files / drugs / published / Bioavailability-and-Bioequivalence-Studies-Submitted-in-NDAs-or-INDs-%E2%80%94-General-Considerations.pdf) or the EMA guidance (https: / / www.ema.europa.eu / en / documents / scientific-guideline / guideline-investigation-bioequivalence-rev1_en.pdf). As used herein, a "bioequivalent" value is meant to refer to a pharmacokinetic value (e.g., Cmax or AUC of the formulations described herein) that exhibits a substantially similar pharmacokinetic profile or therapeutic effect. Bioequivalence can be demonstrated by in vivo and in vitro methods. These methods can include, for example, pharmacokinetic studies, pharmacodynamic studies, clinical trials, and in vitro studies. Bioequivalence can be demonstrated using any suitable pharmacokinetic measure or combination of pharmacokinetic measures known in the art, including the drug's loading dose, steady-state dose, initial or steady-state concentration, biological half-life, elimination rate, area under the curve (AUC), clearance, peak blood or plasma concentration (Cmax), time to peak concentration (Tmax), bioavailability, and efficacy. A value may be bioequivalent to a reference pharmacokinetic value if the geometric mean of AUC(0-t) (area under the plasma concentration curve from administration to the last observed concentration at time t), AUC(0-∞) (area under the plasma concentration curve extrapolated to time infinity), and Cmax (maximum plasma concentration) is 80%-125% (e.g., with a 90% confidence interval) of the reference pharmacokinetic value.

[0065] Thus, the present invention provides an orodispersible tablet that is bioequivalent to any of the orodispersible tablets described herein, where "bioequivalent" means that one or more of AUC(0-t), AUC(0-∞), Cmax are 80%-125% (e.g., with a 90% confidence interval) of the orodispersible tablets described herein.

[0066] Thus, in any of the Therapeutic Agents of the invention disclosed herein, in addition to inhibiting plasma kallikrein, particularly following a dose of KVD900 of at least about 30 mg (more specifically, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg or about 80 mg, e.g., about 80 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to 600 mg, or about 400 mg to 600 mg, specifically about 600 mg or about 400 mg to about 500 mg, specifically 500 mg), the Therapeutic Agent may also, following administration, reduce the cleavage of plasma prekallikrein to produce plasma kallikrein and / or reduce the production of factor XIIa (FXIIa). Thus, in some embodiments, particularly following a dosage of at least about 30 mg (more specifically, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg or about 80 mg, e.g., about 80 mg to about 900 mg, about 100 mg to about 800 mg, about 200 mg to about 700 mg, about 300 mg to 600 mg, or about 400 mg to 600 mg, specifically about 600 mg or about 400 mg to about 500 mg, specifically 500 mg) of KVD900, the Therapeutic Agent may also inhibit cleavage of plasma prekallikrein to produce plasma kallikrein and / or reduce cleavage of FXIIa to produce FXIIa.

[0067] Orodispersible tablets according to the present invention The orodispersible tablets of the present invention are advantageous because they have been developed to enable early intervention and reduce barriers to treatment of attacks of bradykinin-mediated angioedema (e.g., HAE). Furthermore, the orodispersible tablets of the present invention can be manufactured on a large scale because the underlying mixture / blend used to manufacture the ODT has excellent flow and compression properties.

[0068] The KVD900 in the orodispersible tablets of the present invention is administered at safe and effective doses and has a pharmacokinetic profile comparable to the swallowable immediate release tablets used in Phase 2 trials.

[0069] The present invention provides an orodispersible tablet comprising KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof).

[0070] The orodispersible tablet of the present invention may contain about 25 mg to about 1000 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 100 mg to about 1000 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). Unless expressly stated otherwise, the amount of KVD900 expressed in mg in the orodispersible tablets and mixtures of the present invention should be understood to mean the amount of KVD900 in its free base form (i.e., without taking into account the weight of any counterion, if present). The orodispersible tablet of the present invention may contain about 150 mg to about 1000 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 100 mg to about 700 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 200 mg to about 600 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 200 mg to about 350 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 250 mg to about 300 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 250 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). Alternatively, the orodispersible tablet of the present invention may contain about 275 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). Alternatively, the orodispersible tablet of the present invention may contain about 300 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof).

[0071] The orodispersible tablet of the present invention may contain about 25 mg to about 500 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 25 mg to about 200 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 25 mg to about 150 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 150 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof).

[0072] The orodispersible tablet of the present invention may contain about 25 mg to about 100 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 25 mg to about 80 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 25 mg to about 75 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 75 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). Alternatively, the orodispersible tablet of the present invention may contain about 50 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). Alternatively, the orodispersible tablet of the present invention may contain about 25 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof).

[0073] The orodispersible tablet of the present invention may contain about 10 to about 70% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 15 to about 60% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 20 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 26 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 25 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 25 to about 35% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 26 to about 35% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 25 to about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 26 to about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 15 to about 25% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The orodispersible tablet of the present invention may contain about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof).

[0074] The orodispersible tablets of the present invention may comprise one or more of a filler, a binder, a disintegrant, a lubricant, a flow enhancer, a sweetener, and a flavoring agent.

[0075] The orodispersible tablet of the present invention may also comprise a filler. The orodispersible tablet of the present invention may also comprise one or more fillers. The filler may be selected from isomalt, lactose and its derivatives (e.g., lactose monohydrate, spray-dried lactose, anhydrous lactose), mannitol (e.g., granular mannitol, powdered mannitol, spray-dried mannitol (e.g., Mannogem EZ®)), sorbitol, sucrose, starch, pregelatinized starch, and mixtures thereof. Preferably, the filler may be selected from isomalt, lactose and its derivatives (e.g., lactose monohydrate, spray-dried lactose, anhydrous lactose), mannitol (e.g., granular mannitol, powdered mannitol, spray-dried mannitol (e.g., Mannogem EZ®)), sorbitol, and pregelatinized starch. The one or more fillers may be mannitol (e.g., granular mannitol, powdered mannitol, spray-dried mannitol (e.g., Mannogem EZ®)). Even more preferably, the one or more fillers may be selected from granular mannitol and spray-dried mannitol (e.g., Mannogem EZ®). The one or more fillers may be granular mannitol. The one or more fillers may be spray-dried mannitol (e.g., Mannogem EZ®).

[0076] The one or more fillers can be present at about 30 to about 80% by weight of the orodispersible tablet. The one or more fillers can be present at about 40 to about 70% by weight of the orodispersible tablet. The one or more fillers can be present at about 40 to about 65% by weight of the orodispersible tablet. The one or more fillers can be present at about 50 to about 65% by weight of the orodispersible tablet. The one or more fillers can be present at about 50 to about 60% by weight of the orodispersible tablet. The one or more fillers can be present at about 50 to about 55% by weight of the orodispersible tablet. The one or more fillers can be present at about 53 to about 54% by weight of the orodispersible tablet. Preferably, the one or more fillers can be present at about 53.7% by weight of the orodispersible tablet.

[0077] The orodispersible tablet of the present invention may also include a binder. The orodispersible tablet of the present invention may also include one or more binders. The binder may also be selected from sugars (e.g., glucose, sucrose, fructose, dextrose, lactose), sugar alcohols (e.g., xylitol, maltitol, erythritol, sorbitol), polysaccharides (e.g., crystalline cellulose, microcrystalline cellulose (e.g., silicified microcrystalline cellulose), powdered cellulose, methylcellulose, carboxymethylcellulose and salts, hydroxypropylmethylcellulose), corn starch, starch 1500, acacia, other natural polymers (e.g., gelatin), polyethylene glycol, crosslinked acrylic acid and acrylic acid copolymers (e.g., Carbopol®), inorganic compounds (e.g., calcium carbonate), calcium phosphates (e.g., anhydrous dibasic calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate), tricalcium citrate, and mixtures thereof. More specifically, the binder can be selected from glucose, lactose, corn starch, starch 1500, gelatin, acacia, methylcellulose, carboxymethylcellulose and salt, hydroxypropylmethylcellulose, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) and mixtures thereof.Preferably, the binder is microcrystalline cellulose or hydroxypropylmethylcellulose.Even more preferably, the binder is silicified microcrystalline cellulose.

[0078] The one or more binders may be present at about 5 to about 40% by weight of the orodispersible tablet. The one or more binders may be present at about 5 to about 30% by weight of the orodispersible tablet. The one or more binders may be present at about 5 to about 20% by weight of the orodispersible tablet. The one or more binders may be present at about 5 to about 15% by weight of the orodispersible tablet. The one or more binders may be present at about 5 to about 10% by weight of the orodispersible tablet. The one or more binders may be present at about 8 to about 10% by weight of the orodispersible tablet. Preferably, the one or more fillers may be present at about 10% by weight of the orodispersible tablet (e.g., 10.01%, 9.74% or 9.69% by weight).

[0079] In the orodispersible tablet of the present invention, the one or more fillers and the one or more binders may be present at about 50 to about 90% by weight of the orodispersible tablet. In the orodispersible tablet of the present invention, the one or more fillers and the one or more binders may be present at about 50 to about 70% by weight of the orodispersible tablet. In the orodispersible tablet of the present invention, the one or more fillers and the one or more binders may be present at about 50 to about 65% by weight of the orodispersible tablet. In the orodispersible tablet of the present invention, the one or more fillers and the one or more binders may be present at about 55 to about 65% by weight of the orodispersible tablet. Preferably, the one or more fillers and the one or more binders may be present at about 64% by weight of the orodispersible tablet. Even more preferably, the one or more fillers and the one or more binders may be present at about 63.7% by weight of the orodispersible tablet.

[0080] In the orodispersible tablet of the present invention, the weight % ratio of one or more fillers to one or more binders may be about 3:1 to about 8:1. In the orodispersible tablet of the present invention, the weight % ratio of one or more fillers to one or more binders may be about 4:1 to about 7:1. In the orodispersible tablet of the present invention, the weight % ratio of one or more fillers to one or more binders may be about 4:1 to about 6:1. In the orodispersible tablet of the present invention, the weight % ratio of one or more fillers to one or more binders may be about 5:1 to about 6:1. In the orodispersible tablet of the present invention, the weight % ratio of one or more fillers to one or more binders may be about 4:1 to about 7:1. Preferably, in the orodispersible tablets of the present invention, the weight percent ratio of the one or more fillers to the one or more binders may be from about 5:1 to about 5.5:1, more specifically from about 5.3:1 to about 5.4:1 (e.g., 5.37:1).

[0081] More specifically, in the orodispersible tablet of the present invention, the weight percent ratio of mannitol to microcrystalline cellulose is about 3:1 to about 8:1, about 4:1 to about 7:1, about 4:1 to about 6:1, about 5:1 to about 6:1, or about 4:1 to about 7:1. Preferably, in the orodispersible tablet of the present invention, the weight percent ratio of mannitol to microcrystalline cellulose may be about 5:1 to about 5.5:1, more specifically about 5.3:1 to about 5.4:1 (e.g., 5.37:1).

[0082] The orodispersible tablet of the present invention may also include a disintegrant. The orodispersible tablet of the present invention may also include one or more disintegrants. The disintegrant may be starch USP, starch 1500, cellulose derivatives (e.g., carboxymethylcellulose and salts, hydroxypropylmethylcellulose), guar gum, alginic acid and salts, sodium starch glycolate, crosslinked cellulose (e.g., croscarmellose sodium, such as those sold under the names Croscarmellose®, Ac-Di-Sol®, Nymce ZSX®, Primellose®, Solutab®, Vivasol®), crosslinked polyvinylpyrrolidone (e.g., crospovidone, Crospovidon M®, Kollidon®, Polyplasdone®), synthetic polymers, soybean polysaccharides, calcium silicate, PEARLITOL Flash (co-processed mannitol / corn starch), and mixtures thereof. More specifically, the disintegrant is selected from cross-linked cellulose (e.g., Croscarmellose®, Ac-Di-Sol®, Nymce ZSX®, Primellose®, Solutab®, Vivasol®), synthetic polymers such as cross-linked polyvinylpyrrolidone (e.g., crospovidone, Crospovidon M®, Kollidon®, Polyplasdone®), sodium starch glycolate, and mixtures thereof. Preferably, the disintegrant is selected from polyvinylpyrrolidone (crospovidone), sodium starch glycolate, croscarmellose sodium. Even more preferably, the disintegrant is polyvinylpyrrolidone (crospovidone).

[0083] The one or more disintegrants may be present at about 1 to about 15% by weight of the orodispersible tablet. The one or more disintegrants may be present at about 1 to about 14% by weight of the orodispersible tablet. The one or more disintegrants may be present at about 1 to about 10% by weight of the orodispersible tablet. The one or more disintegrants may be present at about 5 to about 10% by weight of the orodispersible tablet. The one or more disintegrants may be present at about 1 to about 9% by weight of the orodispersible tablet. The one or more disintegrants may be present at about 2 to about 8% by weight of the orodispersible tablet. The one or more disintegrants may be present at about 2 to about 7% by weight of the orodispersible tablet. The one or more disintegrants may be present at about 3 to about 6% by weight of the orodispersible tablet. The one or more disintegrants may be present at about 4 to about 6% by weight of the orodispersible tablet. The one or more disintegrants may be present at about 4 to about 5% by weight of the orodispersible tablet. Preferably, the one or more disintegrants may be present in about 5% by weight of the orodispersible tablet.

[0084] The orodispersible tablet of the present invention may also include a lubricant. The orodispersible tablet of the present invention may not include a lubricant. The orodispersible tablet of the present invention may also include a lubricant. The lubricant may be selected from magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, glyceryl behenate, glyceryl palmitate, polyethylene glycol, polyoxyethylene stearate, lauryl sulfate, talc, paraffin, sodium stearyl fumarate, and mixtures thereof. Preferably, the lubricant is selected from magnesium stearate, sodium stearyl fumarate, and talc. Even more preferably, the lubricant is magnesium stearate.

[0085] Lubricant can be internal or external lubricant.Preferably, lubricant is external lubricant.As used herein, external lubricant means lubricant that aids in the flow of manufacturing process and thus is not actively added to blend / mixture, although it may be present in trace amount in final ODT.Even more preferably, lubricant used in orodispersible tablet of the present invention is only external lubricant.

[0086] The one or more lubricants may be present at about 0 to about 3% by weight of the orodispersible tablet. The one or more lubricants may be present at about 0.5 to about 3% by weight of the orodispersible tablet. The one or more lubricants may be present at about 0.5 to about 1% by weight of the orodispersible tablet. The one or more lubricants may be present at about 0.5 to about 1.25% by weight of the orodispersible tablet. The one or more lubricants may be present at about 0.75 to about 1.25% by weight of the orodispersible tablet. The one or more lubricants may be present at about 1 to about 2% by weight of the orodispersible tablet. The one or more lubricants may be present at about 0.5 to about 1% by weight of the orodispersible tablet. Preferably, the one or more lubricants are present in trace amounts. Even more preferably, the lubricant is one and is present in trace amounts (e.g., less than 0.05% by weight).

[0087] In preferred orodispersible tablets of the present invention, the lubricant is an external lubricant and is present in minor amounts (eg, less than 0.05% by weight).

[0088] The orodispersible tablets of the present invention may also comprise a flow improver. Preferably, the flow improver is silicon dioxide.

[0089] The flow improver may be present at about 0.5 to about 3% by weight of the orodispersible tablet. The flow improver may be present at about 0.5 to about 2% by weight of the orodispersible tablet. The flow improver may be present at about 0.5 to about 1% by weight of the orodispersible tablet. The flow improver may be present at about 0.6 to about 0.9% by weight of the orodispersible tablet. The flow improver may be present at about 0.6 to about 0.8% by weight of the orodispersible tablet. The flow improver may be present at about 0.7 to about 0.8% by weight of the orodispersible tablet. The flow improver may be present at about 0.6 to about 0.75% by weight of the orodispersible tablet. The flow improver may be present at about 0.75 to about 0.8% by weight of the orodispersible tablet. Preferably, the flow improver may be present at about 0.75% by weight of the orodispersible tablet.

[0090] The orodispersible tablet of the present invention may also contain a sweetener. The orodispersible tablet of the present invention may also contain one or more sweeteners. The sweetener may be selected from sucralose, aspartame, sugar derivatives, dextrose, polydextrose, xylitol, fructose, sucrose, lactitol, maltitol, and sodium saccharin (and mixtures thereof). Preferably, the sweetener is selected from sucralose, aspartame, sugar derivatives, dextrose, polydextrose, fructose, lactitol, and maltitol. Even more preferably, the sweetener is sucralose.

[0091] The one or more sweeteners may be present at about 0.1 to about 10% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.1 to about 7% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.1 to about 4% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.1 to about 3% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.1 to about 2% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.1 to about 1% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.2 to about 1% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.2 to about 0.9% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.2 to about 0.8% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.2 to about 0.7% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.3 to about 0.7% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.3 to about 0.6% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.4 to about 0.6% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.4 to about 0.5% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.5 to about 0.6% by weight of the orodispersible tablet. The one or more sweeteners may be present at about 0.45 to about 0.55% by weight of the orodispersible tablet. Preferably, the one or more sweeteners may be present at about 0.5% by weight of the orodispersible tablet.

[0092] The orodispersible tablet of the present invention may also include a flavoring. The orodispersible tablet of the present invention may also include one or more flavorings. The flavoring may be selected from lemon flavoring, mixed berry flavoring, grape flavoring, peppermint natural flavoring, mint flavoring, banana flavoring, chocolate flavoring, maple flavoring, strawberry flavoring, raspberry flavoring, cherry flavoring, orange flavoring, and vanilla flavoring, and mixtures thereof. The flavoring may be selected from lemon flavoring, mixed berry flavoring, grape flavoring, peppermint natural flavoring, mint flavoring, banana flavoring, chocolate flavoring, maple flavoring, and orange flavoring. In one embodiment, the flavoring is peppermint natural flavoring. In another embodiment, the flavoring is lemon flavoring. Preferably, the flavoring is grape flavoring. Even more preferably, the flavoring is mixed berry flavoring. Alternatively, the orodispersible tablet may be flavorless.

[0093] The one or more flavorings may be present at about 0.03 to about 1% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.03 to about 0.8% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.03 to about 0.5% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.03 to about 0.4% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.03 to about 0.3% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.05 to about 0.2% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.05 to about 0.1% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.03 to about 0.09% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.03 to about 0.08% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.03 to about 0.07% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.03 to about 0.06% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.04 to about 0.06% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.04 to about 0.05% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.05 to about 0.06% by weight of the orodispersible tablet. The one or more flavorings may be present at about 0.045 to about 0.055% by weight of the orodispersible tablet. Preferably, the one or more flavorings may be present at about 0.05% by weight of the orodispersible tablet.

[0094] For example, if the flavor is selected from lemon flavor or mixed berry flavor, the flavor may be present at about 0.2% to about 0.5% by weight of the orodispersible tablet. The flavor may be present at about 0.2 to about 0.4% by weight of the orodispersible tablet. The flavor may be present at about 0.3 to about 0.4% by weight of the orodispersible tablet. The one or more flavors may be present at about 0.36% by weight of the orodispersible tablet. The one or more flavors may be present at about 0.31% by weight of the orodispersible tablet.

[0095] The orodispersible tablet of the present invention may contain about 0.2 to about 0.5% grape flavor.The orodispersible tablet of the present invention may contain about 0.36% by weight lemon flavor.The orodispersible tablet of the present invention may contain about 0.31% by weight mixed berry flavor.

[0096] The orodispersible tablets of the present invention may comprise one or more of mannitol as a filler (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose as a binder (e.g., silicified microcrystalline cellulose), and polyvinylpyrrolidone (crospovidone) as a disintegrant.

[0097] The orodispersible tablets of the present invention may comprise two or more of mannitol as a filler (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose as a binder (e.g., silicified microcrystalline cellulose), and polyvinylpyrrolidone (crospovidone) as a disintegrant.

[0098] The orodispersible tablets of the present invention may comprise three or more of mannitol as a filler (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose as a binder (e.g., silicified microcrystalline cellulose), and polyvinylpyrrolidone (crospovidone) as a disintegrant.

[0099] The orodispersible tablets of the present invention may comprise one or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and peppermint natural flavor as a flavor.

[0100] The orodispersible tablets of the present invention may comprise one or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and lemon flavor as a flavoring.

[0101] The orodispersible tablets of the present invention may comprise one or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and mixed berry flavor as a flavor.

[0102] The orodispersible tablets of the present invention may comprise one or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and grape flavor as a flavor.

[0103] The orodispersible tablets of the present invention may comprise two or more of mannitol as a filler (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and peppermint natural flavor as a flavor.

[0104] The orodispersible tablets of the present invention may comprise two or more of mannitol as a filler (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and lemon flavor as a flavor.

[0105] The orodispersible tablets of the present invention may comprise two or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and mixed berry flavor as a flavor.

[0106] The orodispersible tablets of the present invention may comprise two or more of mannitol as a filler (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and grape flavor as a flavor.

[0107] The orodispersible tablets of the present invention may comprise three or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and peppermint natural flavor as a flavor.

[0108] The orodispersible tablets of the present invention may comprise three or more of mannitol as a filler (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and lemon flavor as a flavor.

[0109] The orodispersible tablets of the present invention may comprise three or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and mixed berry flavor as a flavor.

[0110] The orodispersible tablets of the present invention may comprise three or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and grape flavor as a flavor.

[0111] The orodispersible tablets of the present invention may comprise one or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, magnesium stearate as a lubricant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and peppermint natural flavor as a flavor.

[0112] The orodispersible tablets of the present invention may comprise one or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, magnesium stearate as a lubricant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and lemon flavor as a flavoring.

[0113] The orodispersible tablets of the present invention may comprise one or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, magnesium stearate as a lubricant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and mixed berry flavor as a flavor.

[0114] The orodispersible tablets of the present invention may comprise one or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, magnesium stearate as a lubricant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and grape flavor as a flavoring.

[0115] The orodispersible tablets of the present invention may comprise two or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, magnesium stearate as a lubricant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and peppermint natural flavor as a flavor.

[0116] The orodispersible tablets of the present invention may comprise two or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, magnesium stearate as a lubricant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and lemon flavor as a flavoring.

[0117] The orodispersible tablets of the present invention may comprise two or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, magnesium stearate as a lubricant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and mixed berry flavor as a flavor.

[0118] The orodispersible tablets of the present invention may comprise two or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, magnesium stearate as a lubricant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and grape flavor as a flavor.

[0119] The orodispersible tablets of the present invention may comprise three or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, magnesium stearate as a lubricant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and peppermint natural flavor as a flavor.

[0120] The orodispersible tablets of the present invention may comprise three or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, magnesium stearate as a lubricant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and lemon flavor as a flavor.

[0121] The orodispersible tablets of the present invention may comprise three or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, magnesium stearate as a lubricant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and mixed berry flavor as a flavor.

[0122] The orodispersible tablets of the present invention may comprise three or more of mannitol (e.g., granular mannitol and / or spray dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, magnesium stearate as a lubricant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and grape flavor as a flavor.

[0123] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose), polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and peppermint natural flavor.

[0124] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose), polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and lemon flavor.

[0125] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose), polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and mixed berry flavor.

[0126] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose), polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and grape flavor.

[0127] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose), polyvinylpyrrolidone (crospovidone), magnesium stearate, silicon dioxide, sucralose, and peppermint natural flavor.

[0128] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose), polyvinylpyrrolidone (crospovidone), magnesium stearate, silicon dioxide, sucralose, and lemon flavor.

[0129] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose), polyvinylpyrrolidone (crospovidone), magnesium stearate, silicon dioxide, sucralose, and mixed berry flavor.

[0130] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose), polyvinylpyrrolidone (crospovidone), magnesium stearate, silicon dioxide, sucralose, and grape flavor.

[0131] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), silicified microcrystalline cellulose, polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and peppermint natural flavor.

[0132] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), silicified microcrystalline cellulose, polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and lemon flavor.

[0133] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), silicified microcrystalline cellulose, polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and mixed berry flavor.

[0134] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), silicified microcrystalline cellulose, polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and grape flavor.

[0135] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), silicified microcrystalline cellulose, polyvinylpyrrolidone (crospovidone), magnesium stearate, silicon dioxide, sucralose, and peppermint natural flavor.

[0136] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), silicified microcrystalline cellulose, polyvinylpyrrolidone (crospovidone), magnesium stearate, silicon dioxide, sucralose, and lemon flavor.

[0137] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), silicified microcrystalline cellulose, polyvinylpyrrolidone (crospovidone), magnesium stearate, silicon dioxide, sucralose, and mixed berry flavor.

[0138] The orodispersible tablets of the present invention may comprise one or more of granular mannitol, spray dried mannitol (e.g., Mannogem EZ®), silicified microcrystalline cellulose, polyvinylpyrrolidone (crospovidone), magnesium stearate, silicon dioxide, sucralose, and grape flavor.

[0139] The orodispersible tablets of the present invention may comprise about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the orodispersible tablet.

[0140] The orodispersible tablets of the present invention may comprise about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the orodispersible tablet.

[0141] The orodispersible tablets of the present invention may comprise about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)), present at 1 to about 10% by weight of the orodispersible tablet.

[0142] The orodispersible tablets of the present invention may comprise about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the orodispersible tablet, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at 1 to about 10% by weight of the orodispersible tablet.

[0143] The orodispersible tablets of the present invention may comprise about 26 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the orodispersible tablet.

[0144] The orodispersible tablets of the present invention may comprise about 26 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the orodispersible tablet.

[0145] The orodispersible tablets of the present invention may comprise about 26 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)), present at 1 to about 10% by weight of the orodispersible tablet.

[0146] The orodispersible tablets of the present invention may comprise about 26 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the orodispersible tablet, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at 1 to about 10% by weight of the orodispersible tablet.

[0147] The orodispersible tablets of the present invention may comprise about 25 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 40 to about 70% by weight of the orodispersible tablet.

[0148] The orodispersible tablets of the present invention may comprise about 25 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 20% by weight of the orodispersible tablet.

[0149] The orodispersible tablets of the present invention may comprise about 25 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)), present at 1 to about 7% by weight of the orodispersible tablet.

[0150] The orodispersible tablets of the present invention may comprise about 25 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 40 to about 70% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 20% by weight of the orodispersible tablet, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at 1 to about 7% by weight of the orodispersible tablet.

[0151] The orodispersible tablets of the present invention may comprise about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 40 to about 70% by weight of the orodispersible tablet.

[0152] The orodispersible tablets of the present invention may comprise about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 20% by weight of the orodispersible tablet.

[0153] The orodispersible tablets of the present invention may comprise about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)), present at 1 to about 7% by weight of the orodispersible tablet.

[0154] The orodispersible tablets of the present invention may comprise about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 40 to 70% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 20% by weight of the orodispersible tablet, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at 1 to about 7% by weight of the orodispersible tablet.

[0155] The orodispersible tablets of the present invention may comprise about 25 to about 35% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 50 to about 60% by weight of the orodispersible tablet.

[0156] The orodispersible tablets of the present invention may comprise about 25 to about 35% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 15% by weight of the orodispersible tablet.

[0157] The orodispersible tablets of the present invention may comprise about 25 to about 35% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)), present at about 4 to about 6% by weight of the orodispersible tablet.

[0158] The orodispersible tablets of the present invention may comprise about 25 to about 35% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 50 to about 60% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 15% by weight of the orodispersible tablet, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 4 to about 6% by weight of the orodispersible tablet.

[0159] The orodispersible tablets of the present invention may comprise about 25 to about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 50 to about 55% by weight of the orodispersible tablet.

[0160] The orodispersible tablets of the present invention may comprise about 25 to about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 10% by weight of the orodispersible tablet.

[0161] The orodispersible tablets of the present invention may comprise about 25 to about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)), present at about 4 to about 5% by weight of the orodispersible tablet.

[0162] The orodispersible tablets of the present invention may comprise about 25 to about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 50 to about 55% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 10% by weight of the orodispersible tablet, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 4 to about 5% by weight of the orodispersible tablet.

[0163] The orodispersible tablet of the present invention may contain about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof).

[0164] The orodispersible tablet of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof) and one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present in about 54% by weight (e.g., about 53.7% by weight) of the orodispersible tablet.

[0165] The orodispersible tablets of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof) and one or more binders (e.g., silicified microcrystalline cellulose) present at about 10% by weight of the orodispersible tablet.

[0166] The orodispersible tablets of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof) and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)), present in about 5% by weight of the orodispersible tablet.

[0167] The orodispersible tablets of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 54% by weight (e.g., about 53.7% by weight) of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 10% by weight of the orodispersible tablet, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 5% by weight of the orodispersible tablet.

[0168] The orodispersible tablet of the present invention may contain about 15 to about 25% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof).

[0169] The orodispersible tablets of the present invention may comprise about 15 to about 25% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present in about 54% by weight (e.g., about 53.7% by weight) of the orodispersible tablet.

[0170] The orodispersible tablets of the present invention may comprise about 15 to about 25% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more binders (e.g., silicified microcrystalline cellulose) present at about 10% by weight of the orodispersible tablet.

[0171] The orodispersible tablets of the present invention may comprise about 15 to about 25% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)), present in about 5% by weight of the orodispersible tablet.

[0172] The orodispersible tablets of the present invention may comprise about 15 to about 25% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 54% by weight (e.g., about 53.7% by weight) of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 10% by weight of the orodispersible tablet, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 5% by weight of the orodispersible tablet.

[0173] The orodispersible tablets of the present invention may comprise about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the orodispersible tablet, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at 1 to about 10% by weight of the orodispersible tablet, and a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the orodispersible tablet.

[0174] The orodispersible tablets of the present invention may comprise about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the orodispersible tablet, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at 1 to about 10% by weight of the orodispersible tablet, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 1% by weight of the orodispersible tablet, and one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the orodispersible tablet.

[0175] The orodispersible tablets of the present invention comprise about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present in about 30 to about 80% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present in about 5 to about 30% by weight of the orodispersible tablet, one or more disintegrants (e.g., silicified microcrystalline cellulose) present in about 1 to about 10% by weight of the orodispersible tablet, and one or more disintegrants (e.g., silicified microcrystalline cellulose) present in about 1 to about 10% by weight of the orodispersible tablet. A disintegrant (e.g., polyvinylpyrrolidone (crospovidone)), a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the orodispersible tablet, one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the orodispersible tablet, and one or more flavorings (e.g., lemon flavor, mixed berry flavor, grape flavor, or peppermint natural flavor) present at 0.01 to about 1% by weight of the orodispersible tablet.

[0176] The orodispersible tablets of the present invention may comprise about 25 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 40 to 70% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 20% by weight of the orodispersible tablet, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at 1 to about 7% by weight of the orodispersible tablet, and a flow enhancer (e.g., silicon dioxide) present at about 0.5 to about 1% by weight of the orodispersible tablet.

[0177] The orodispersible tablets of the present invention may comprise about 25 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 40 to 70% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 20% by weight of the orodispersible tablet, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at 1 to about 7% by weight of the orodispersible tablet, a flow enhancer (e.g., silicon dioxide) present at about 0.5 to about 1% by weight of the orodispersible tablet, and one or more sweeteners (e.g., sucralose) present at about 0.3 to about 0.7% by weight of the orodispersible tablet.

[0178] The orodispersible tablets of the present invention may comprise about 25 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 40 to 70% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 20% by weight of the orodispersible tablet, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at 1 to about 7% by weight of the orodispersible tablet, one or more flow enhancers (e.g., silicon dioxide) present at about 0.5 to about 1% by weight of the orodispersible tablet, one or more sweeteners (e.g., sucralose) present at about 0.3 to about 0.7% by weight of the orodispersible tablet, and one or more flavors (e.g., peppermint natural flavor) present at about 0.03 to about 0.06% by weight of the orodispersible tablet.

[0179] The orodispersible tablets of the present invention comprise about 25 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present in about 40 to 70% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present in about 5 to about 20% by weight of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present in about 1 to about 7 ... disintegrants (e.g., polyvinylpyrrolidone (crospovidone)), a flow enhancer (e.g., silicon dioxide) present at about 0.5 to about 1% by weight of the orodispersible tablet, one or more sweeteners (e.g., sucralose) present at about 0.3 to about 0.7% by weight of the orodispersible tablet, and one or more flavoring agents (e.g., lemon flavor, mixed berry flavor, or grape flavor) present at about 0.2 to about 0.5% by weight of the orodispersible tablet.

[0180] The orodispersible tablets of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 54% by weight (e.g., about 53.7% by weight) of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 10% by weight of the orodispersible tablet, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 5% by weight of the orodispersible tablet, and a flow enhancer (e.g., silicon dioxide) present at about 0.75% by weight of the orodispersible tablet.

[0181] The orodispersible tablets of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 54% by weight (e.g., about 53.7% by weight) of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 10% by weight of the orodispersible tablet, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 5% by weight of the orodispersible tablet, a flow enhancer (e.g., silicon dioxide) present at about 0.75% by weight of the orodispersible tablet, and one or more sweeteners (e.g., sucralose) present at about 0.5% by weight of the orodispersible tablet.

[0182] The orodispersible tablets of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 54% by weight (e.g., about 53.7% by weight) of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 10% by weight of the orodispersible tablet, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 5% by weight of the orodispersible tablet, one or more flow enhancers (e.g., silicon dioxide) present at about 0.75% by weight of the orodispersible tablet, one or more sweeteners (e.g., sucralose) present at about 0.5% by weight of the orodispersible tablet, and one or more flavors (e.g., peppermint natural flavor) present at about 0.05% by weight of the orodispersible tablet.

[0183] The orodispersible tablets of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray dried mannitol) present at about 54% by weight (e.g., about 53.7% by weight) of the orodispersible tablet, one or more binders (e.g., silicified microcrystalline cellulose) present at about 10% by weight of the orodispersible tablet, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 5% by weight of the orodispersible tablet, a flow enhancer (e.g., silicon dioxide) present at about 0.75% of the orodispersible tablet, one or more sweeteners (e.g., sucralose) present at about 0.5% by weight of the orodispersible tablet, and one or more flavorings (e.g., lemon flavoring or mixed berry flavoring) present at about 0.3 to about 0.4% by weight of the orodispersible tablet.

[0184] The orodispersible tablet of the present invention may contain about 27% by weight of granular mannitol. The orodispersible tablet of the present invention may contain about 26.87% by weight of granular mannitol. Preferably, the orodispersible tablet of the present invention may contain about 26.85% by weight of granular mannitol.

[0185] The orodispersible tablet of the present invention may comprise about 27% by weight of spray-dried mannitol (e.g., Mannogem EZ®). The orodispersible tablet of the present invention may comprise about 26.87% by weight of spray-dried mannitol (e.g., Mannogem EZ®). Preferably, the orodispersible tablet of the present invention may comprise about 26.85% by weight of spray-dried mannitol (e.g., Mannogem EZ®).

[0186] The orodispersible tablet of the present invention may contain about 10% by weight of microcrystalline cellulose. Preferably, the orodispersible tablet of the present invention may contain about 10% by weight (e.g., 10.01%, 9.74% or 9.69% by weight) of silicified microcrystalline cellulose.

[0187] The orodispersible tablets of the present invention may contain about 5% by weight of polyvinylpyrrolidone (crospovidone).

[0188] The orodispersible tablet of the present invention may contain about 0.75% by weight of silicon dioxide.

[0189] The orodispersible tablets of the present invention may contain about 0.5% by weight of sucralose.

[0190] The orodispersible tablets of the present invention may contain about 0.05% by weight of peppermint natural flavour.

[0191] The orodispersible tablets of the present invention may contain from about 0.2 to about 0.5 grape flavor.

[0192] The orodispersible tablets of the present invention may contain about 0.36% by weight of lemon flavour.

[0193] The orodispersible tablets of the present invention may contain about 0.31% by weight of mixed berry flavour.

[0194] The orodispersible tablets of the present invention may contain trace amounts of magnesium stearate.

[0195] The orodispersible tablet of the present invention may comprise about 30% by weight KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.85% by weight granular mannitol, about 26.85% by weight spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight silicified microcrystalline cellulose, and about 5% by weight polyvinylpyrrolidone (crospovidone).

[0196] The orodispersible tablet of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.87% by weight of granular mannitol, about 26.87% by weight of spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight (e.g., 10.01% by weight) of silicified microcrystalline cellulose, about 5% by weight of polyvinylpyrrolidone (crospovidone), about 0.75% by weight of silicon dioxide, and about 0.5% by weight of sucralose.

[0197] The orodispersible tablet of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.85% by weight of granular mannitol, about 26.85% by weight of spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight of silicified microcrystalline cellulose, about 5% by weight of polyvinylpyrrolidone (crospovidone), about 0.75% by weight of silicon dioxide, about 0.5% by weight of sucralose, and about 0.05% by weight of peppermint natural flavor.

[0198] The orodispersible tablet of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.85% by weight of granular mannitol, about 26.85% by weight of spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight (e.g., 9.69%) of silicified microcrystalline cellulose, about 5% by weight of polyvinylpyrrolidone (crospovidone), about 0.75% by weight of silicon dioxide, about 0.5% by weight of sucralose, and about 0.36% by weight of lemon natural flavor.

[0199] The orodispersible tablet of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.85% by weight of granular mannitol, about 26.85% by weight of spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight (e.g., 9.74%) of silicified microcrystalline cellulose, about 5% by weight of polyvinylpyrrolidone (crospovidone), about 0.75% by weight of silicon dioxide, about 0.5% by weight of sucralose, and about 0.31% by weight of mixed berry natural flavor.

[0200] The orodispersible tablet of the present invention may comprise about 30% by weight KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.85% by weight granular mannitol, about 26.85% by weight spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight silicified microcrystalline cellulose, about 5% by weight polyvinylpyrrolidone (crospovidone), about 0.75% by weight silicon dioxide, about 0.5% by weight sucralose, about 0.05% by weight peppermint natural flavor, and trace amounts of magnesium stearate.

[0201] The orodispersible tablet of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.85% by weight of granular mannitol, about 26.85% by weight of spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight (e.g., 9.69%) of silicified microcrystalline cellulose, about 5% by weight of polyvinylpyrrolidone (crospovidone), about 0.75% by weight of silicon dioxide, about 0.5% by weight of sucralose, about 0.36% by weight of lemon natural flavor, and a trace amount of magnesium stearate.

[0202] The orodispersible tablet of the present invention may comprise about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.85% by weight of granular mannitol, about 26.85% by weight of spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight (e.g., 9.74%) of silicified microcrystalline cellulose, about 5% by weight of polyvinylpyrrolidone (crospovidone), about 0.75% by weight of silicon dioxide, about 0.5% by weight of sucralose, about 0.31% by weight of mixed berry flavor, and a trace amount of magnesium stearate.

[0203] The orodispersible tablet of the present invention may be round, oval, caplet, or oblong. The orodispersible tablet of the present invention may be round. The orodispersible tablet of the present invention may be oval. The orodispersible tablet of the present invention may be caplet shaped. The orodispersible tablet of the present invention may contain 300 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof) and may be round. The orodispersible tablet of the present invention may contain 150 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof) and may be oval shaped. The orodispersible tablet of the present invention may contain about 25 mg to about 75 mg (e.g., 25 mg, 50 mg, or 75 mg) of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof) and may be caplet shaped or oblong shaped. The orodispersible tablet of the present invention may contain about 25 mg and may be caplet shaped. The orodispersible tablet of the present invention may contain about 50 mg and may be in the form of a caplet. The orodispersible tablet of the present invention may contain about 75 mg and may be in the form of a caplet.

[0204] A particular advantage of the orodispersible tablet of the present invention is that the tablet can be debossed. The orodispersible tablet of the present invention can be debossed with a logo, tablet strength and / or one or more score lines. The orodispersible tablet of the present invention can be debossed with a logo. The orodispersible tablet of the present invention can be debossed with a tablet strength. The orodispersible tablet of the present invention can be debossed with a logo and tablet strength. Preferably, the orodispersible tablet of the present invention can be debossed with one or more score lines. The orodispersible tablet of the present invention can be debossed with a logo and one or more score lines. The orodispersible tablet of the present invention can be debossed with a logo and a score line. The phrase "debossed with one or more score lines" means that the orodispersible tablet of the present invention is debossed with one or more marks across the plane of the orodispersible tablet, thereby allowing the orodispersible tablet to be easily, accurately and uniformly divided into a plurality of sub-divided tablets. The orodispersible tablet of the present invention can be debossed with a single score line. The orodispersible tablet of the present invention may be embossed with two score lines. The orodispersible tablet of the present invention may be embossed with two score lines forming a cross.

[0205] The orodispersible tablets of the present invention can be debossed with a score line and then broken. Tablet breaking is the act of breaking a single hard tablet into multiple smaller tablets to obtain a desired dose of active ingredient. Tablet breaking is particularly useful for facilitating dose adjustment and facilitating administration of the dose in certain populations.

[0206] More specifically, the orodispersible tablet of the present invention can be debossed with a score line for dividing into a plurality of sub-divided tablets. The orodispersible tablet of the present invention can be debossed with a score line for dividing into four sub-divided tablets. The orodispersible tablet of the present invention can be debossed with a score line for dividing into two sub-divided tablets. The orodispersible tablet of the present invention can be debossed with a score line for dividing into two approximately equal halves of the sub-divided tablets.

[0207] An advantage of the orodispersible tablets of the invention with embossed score lines is that when they are divided, the multiple subdivided tablets retain acceptable content uniformity. For example, when an orodispersible tablet of the invention with embossed score lines for dividing into two sub-divided tablets of approximately equal halves is divided in half, each half retains acceptable content uniformity.

[0208] Thus, the present invention also provides sub-divided tablets obtainable by breaking an orodispersible tablet of the present invention along one or more score lines.

[0209] The orodispersible tablet of the present invention may contain about 300 mg, may be round, and may be debossed with a logo and a score line. The orodispersible tablet of the present invention may contain about 150 mg, may be oval, and may be debossed with a logo and a score line. The orodispersible tablet of the present invention may contain about 25 mg, may be caplet shaped, and may be debossed with a score line. The orodispersible tablet of the present invention may contain about 50 mg, may be caplet shaped, and may be debossed with a score line. The orodispersible tablet of the present invention may contain about 75 mg, may be caplet shaped, and may be debossed with a score line.

[0210] Disintegration and dissolution As used herein, disintegration specifications are defined as follows: <701> and obtained according to the standard procedure of Ph Eur 2.9.1 (measured in purified water USP). The disintegration specification can be greater than 80% in less than about 3 minutes. More specifically, the disintegration specification can be greater than 80% in less than about 2 minutes. More specifically, the disintegration specification can be greater than 80% in less than about 1 minute. The disintegration specification can be greater than 80% in less than about 45 seconds. Preferably, the disintegration specification can be greater than 80% in less than about 30 seconds. Even more preferably, the disintegration specification can be greater than 80% in less than about 20 seconds. The disintegration specification can be greater than 80% in less than about 15 to about 20 seconds. The disintegration specification can be greater than 80% in less than about 15 seconds.

[0211] As used herein, dissolution specifications are defined as follows: <711> and is obtained in compliance with the standard procedures of Ph Eur 2.9.3. The dissolution specification may be 99% or more in less than about 45 minutes. The dissolution specification may be 97% or more in less than about 45 minutes. The dissolution specification may be 95% or more in less than about 45 minutes. The dissolution specification may be 90% or more in less than about 45 minutes. The dissolution specification may be 80% or more in less than about 45 minutes. More specifically, the dissolution specification may be 80% or more in less than about 30 minutes. More specifically, the dissolution specification may be 80% or more in less than about 20 minutes. More specifically, the dissolution specification may be 80% or more in less than about 10 minutes. More specifically, the dissolution specification may be 80% or more in less than about 5 minutes.

[0212] The disintegration specification can be greater than 80% in less than about 20 seconds, and the dissolution specification can be greater than about 99% in less than about 45 minutes. The disintegration specification can be greater than 80% in less than about 15 to about 20 seconds, and the dissolution specification can be greater than about 97% in less than about 45 minutes. The disintegration specification can be greater than 80% in less than about 30 seconds, and the dissolution specification can be greater than 95% in less than about 45 minutes. The disintegration specification can be greater than 80% in less than about 20 seconds, and the dissolution specification can be greater than 90% in less than about 45 minutes. The disintegration specification can be greater than 80% in less than about 15 seconds, and the dissolution specification can be greater than 80% in less than about 45 minutes. The disintegration specification can be greater than 80% in less than about 30 seconds, and the dissolution specification can be greater than 80% in less than about 20 minutes. The disintegration specification can be greater than 80% in less than about 20 seconds, and the dissolution specification can be greater than 80% in less than about 10 minutes. Disintegration specifications can be greater than 80% in less than about 15 seconds, and dissolution specifications can be greater than 80% in less than about 5 minutes.

[0213] The present invention also provides ODTs that are bioequivalent to those described herein. Thus, the present invention provides ODTs that contain KVD900 as described herein, or bioequivalent formulations thereof.

[0214] Mixtures of the invention The present invention provides a blend used in the manufacturing process to provide the orodispersible tablet of the present invention. The blend of the present invention has improved flowability, compression and processing properties, for example, it can be compressed into a stable orodispersible tablet. Furthermore, the blend of the present invention can be manufactured on a large scale because the blend has excellent flowability and compression properties.

[0215] The mixtures of the present invention are particularly advantageous due to their versatility, in particular because they can be used to produce orodispersible tablets of various sizes and / or strengths without compromising the fast disintegration times or dosage unit uniformity provided by the orodispersible tablets of the present invention.

[0216] For example, lower tablet strengths may result in narrower compression force tolerances, making it difficult to use the same mixture to produce orodispersible tablets of various sizes and / or strengths. The Applicant has overcome these difficulties and provided the mixtures of the present invention that can withstand compression even at lower strengths (e.g. 75 mg, 50 mg or 25 mg), which allows these mixtures to be used to produce orodispersible tablets of lower strengths that have suitable compression forces and resulting hardness while maintaining a fast disintegration time.

[0217] The present invention provides a mixture comprising KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The present invention provides a mixture comprising about 25 mg to about 1000 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may comprise about 100 mg to about 1000 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may comprise about 150 mg to about 1000 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may comprise about 100 mg to about 700 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may comprise about 200 mg to about 600 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may comprise about 250 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). Alternatively, the mixture of the present invention may comprise about 275 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). Alternatively, the mixture of the present invention may comprise about 300 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof).

[0218] The mixture of the present invention may contain about 25 mg to about 500 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 25 mg to about 200 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 25 mg to about 150 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 150 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof).

[0219] The mixture of the present invention may contain about 25 mg to about 100 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 25 mg to about 80 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 25 mg to about 75 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 75 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). Alternatively, the mixture of the present invention may contain about 50 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). Alternatively, the mixture of the present invention may contain about 25 mg of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof).

[0220] The mixture of the present invention may contain about 10 to about 70% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 15 to about 60% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 20 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 26 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 25 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 25 to about 35% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 26 to about 35% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 25 to about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 26 to about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 15 to about 25% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof). The mixture of the present invention may contain about 30% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof).

[0221] The mixture of the present invention may include one or more of a filler, a binder, a disintegrant, a lubricant, a flow improver, a sweetener, and a flavoring agent.

[0222] The mixture of the present invention may also include a filler. The mixture of the present invention may also include one or more fillers.

[0223] The filler may be selected from isomalt, lactose and its derivatives (e.g., lactose monohydrate, spray-dried lactose, anhydrous lactose), sorbitol, mannitol (e.g., granular mannitol, powdered mannitol, spray-dried mannitol (e.g., Mannogem EZ®)), sorbitol, sucrose, starch, pregelatinized starch, and mixtures thereof. Preferably, the filler may be selected from isomalt, lactose and its derivatives (e.g., lactose monohydrate, spray-dried lactose, anhydrous lactose), mannitol (e.g., granular mannitol, powdered mannitol, spray-dried mannitol (e.g., Mannogem EZ®)), sorbitol, and pregelatinized starch. One or more fillers may be mannitol (e.g., granular mannitol, powdered mannitol, spray-dried mannitol (e.g., Mannogem EZ®)). Even more preferably, the one or more fillers may be selected from granular mannitol and spray-dried mannitol (e.g., Mannogem EZ®). The one or more fillers may be granular mannitol. The one or more fillers may be spray-dried mannitol (e.g., Mannogem EZ®).

[0224] The one or more fillers can be present at about 30 to about 80% by weight of the mixture. The one or more fillers can be present at about 40 to about 70% by weight of the mixture. The one or more fillers can be present at about 40 to about 65% by weight of the mixture. The one or more fillers can be present at about 50 to about 65% by weight of the mixture. The one or more fillers can be present at about 50 to about 60% by weight of the mixture. The one or more fillers can be present at about 50 to about 55% by weight of the mixture. The one or more fillers can be present at about 53 to about 54% by weight of the mixture. Preferably, the one or more fillers can be present at about 53.7% by weight of the mixture.

[0225] The mixture of the present invention may also include a binder. The mixture of the present invention may also include one or more binders. The binder may also be selected from sugars (e.g., glucose, sucrose, fructose, dextrose, lactose), sugar alcohols (e.g., xylitol, maltitol, erythritol, sorbitol), polysaccharides (e.g., crystalline cellulose, microcrystalline cellulose (e.g., silicified microcrystalline cellulose), powdered cellulose, methylcellulose, carboxymethylcellulose and salts, hydroxypropylmethylcellulose), corn starch, starch 1500, acacia, other natural polymers (e.g., gelatin), polyethylene glycol, crosslinked acrylic acid and acrylic acid copolymers (e.g., Carbopol®), inorganic compounds (e.g., calcium carbonate), calcium phosphates (e.g., anhydrous dibasic calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate), tricalcium citrate, and mixtures thereof. More specifically, the binder can be selected from glucose, lactose, corn starch, starch 1500, gelatin, acacia, methylcellulose, carboxymethylcellulose and salt, hydroxypropylmethylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose, and mixtures thereof.Preferably, the binder is microcrystalline cellulose or hydroxypropylmethylcellulose.Even more preferably, the binder is silicified microcrystalline cellulose.

[0226] The one or more binders can be present at about 5 to about 40% by weight of the mixture. The one or more binders can be present at about 5 to about 40% by weight of the mixture. The one or more binders can be present at about 5 to about 20% by weight of the mixture. The one or more binders can be present at about 5 to about 15% by weight of the mixture. The one or more binders can be present at about 5 to about 14% by weight of the mixture. The one or more binders can be present at about 5 to about 10% by weight of the mixture. The one or more binders can be present at about 8 to about 10% by weight of the mixture. The one or more fillers can be present at about 10% by weight (e.g., 10.01%, 9.74% or 9.69% by weight) of the orodispersible tablet. Preferably, the one or more fillers can be present at about 10% by weight of the mixture.

[0227] In the mixture of the present invention, the one or more fillers and the one or more binders can be present at about 50 to about 90% by weight of the mixture. In the mixture of the present invention, the one or more fillers and the one or more binders can be present at about 50 to about 70% by weight of the mixture. In the mixture of the present invention, the one or more fillers and the one or more binders can be present at about 50 to about 65% by weight of the mixture. In the mixture of the present invention, the one or more fillers and the one or more binders can be present at about 55 to about 65% by weight of the mixture. Preferably, the one or more fillers and the one or more binders can be present at about 64% by weight of the mixture. Even more preferably, the one or more fillers and the one or more binders can be present at about 63.7% by weight of the mixture.

[0228] In the mixture of the present invention, the weight % ratio of the one or more fillers to the one or more binders may be about 3:1 to about 8:1. In the mixture of the present invention, the weight % ratio of the one or more fillers to the one or more binders may be about 4:1 to about 7:1. In the mixture of the present invention, the weight % ratio of the one or more fillers to the one or more binders may be about 4:1 to about 6:1. In the mixture of the present invention, the weight % ratio of the one or more fillers to the one or more binders may be about 5:1 to about 6:1. In the mixture of the present invention, the weight % ratio of the one or more fillers to the one or more binders may be about 4:1 to about 7:1. Preferably, in the mixture of the present invention, the weight % ratio of the one or more fillers to the one or more binders may be about 5:1 to about 5.5:1, more preferably about 5.3:1 to about 5.4:1 (e.g., 5.37:1).

[0229] More specifically, in the mixture of the present invention, the weight percent ratio of mannitol to microcrystalline cellulose is about 3:1 to about 8:1, about 4:1 to about 7:1, about 4:1 to about 6:1, about 5:1 to about 6:1, or about 4:1 to about 7:1. Preferably, in the mixture of the present invention, the weight percent ratio of mannitol to microcrystalline cellulose may be about 5:1 to about 5.5:1, more preferably about 5.3:1 to about 5.4:1 (e.g., 5.37:1).

[0230] The mixture of the present invention may also include a disintegrant. The mixture of the present invention may also include one or more disintegrants. The disintegrant is selected from synthetic polymers such as crosslinked cellulose (e.g., Croscarmellose®, Ac-Di-Sol®, Nymce ZSX®, Primellose®, Solutab®, Vivasol®), crosslinked polyvinylpyrrolidone (e.g., Crospovidone, Crospovidon M®, Kollidon®, Polyplasdone®), sodium starch glycolate, and mixtures thereof. More specifically, the disintegrant may be starch USP, starch 1500, cellulose derivatives (e.g., carboxymethylcellulose and salts, hydroxypropylmethylcellulose), guar gum, alginic acid and salts, sodium starch glycolate, crosslinked cellulose (e.g., croscarmellose sodium, such as those marketed under the names Croscarmellose®, Ac-Di-Sol®, Nymce ZSX®, Primellose®, Solutab®, Vivasol®), crosslinked polyvinylpyrrolidone (e.g., crospovidone, Crospovidon M®, Kollidon®, Polyplasdone®), soy polysaccharides, calcium silicate, PEARLITOL Flash (co-processed mannitol / corn starch), and mixtures thereof. Preferably, the disintegrant is selected from polyvinylpyrrolidone (crospovidone), sodium starch glycolate, and croscarmellose sodium. Even more preferably, the disintegrant is polyvinylpyrrolidone (crospovidone).

[0231] The one or more disintegrants can be present at about 1 to about 15% by weight of the mixture. The one or more disintegrants can be present at about 1 to about 14% by weight of the mixture. The one or more disintegrants can be present at about 1 to about 10% by weight of the mixture. The one or more disintegrants can be present at about 1 to about 9% by weight of the mixture. The one or more disintegrants can be present at about 2 to about 8% by weight of the mixture. The one or more disintegrants can be present at about 1 to about 7% by weight of the mixture. The one or more disintegrants can be present at about 2 to about 7% by weight of the mixture. The one or more disintegrants can be present at about 3 to about 6% by weight of the mixture. The one or more disintegrants can be present at about 4 to about 6% by weight of the mixture. The one or more disintegrants can be present at about 4 to about 5% by weight of the mixture. Preferably, the one or more disintegrants can be present at about 5% by weight of the mixture.

[0232] The mixture of the present invention may also include a flow improver. Preferably, the flow improver is silicon dioxide.

[0233] The flow improver can be present at about 0.5 to about 3% by weight of the mixture. The flow improver can be present at about 0.5 to about 2% by weight of the mixture. The flow improver can be present at about 0.5 to about 1% by weight of the mixture. The flow improver can be present at about 0.6 to about 0.9% by weight of the mixture. The flow improver can be present at about 0.6 to about 0.8% by weight of the mixture. The flow improver can be present at about 0.7 to about 0.8% by weight of the mixture. The flow improver can be present at about 0.6 to about 0.75% by weight of the mixture. The flow improver can be present at about 0.75 to about 0.8% by weight of the mixture. Preferably, the flow improver can be present at about 0.75% by weight of the mixture.

[0234] The mixture of the present invention may also contain a sweetener. The mixture of the present invention may also contain one or more sweeteners. The sweetener may be selected from sucralose, aspartame, sugar derivatives, dextrose, polydextrose, xylitol, fructose, sucrose, lactitol, maltitol, and sodium saccharin (and mixtures thereof). Preferably, the sweetener is selected from sucralose, aspartame, sugar derivatives, dextrose, polydextrose, fructose, lactitol, and maltitol. Even more preferably, the sweetener is sucralose.

[0235] The one or more sweeteners can be present at about 0.1 to about 10% by weight of the mixture. The one or more sweeteners can be present at about 0.1 to about 7% by weight of the mixture. The one or more sweeteners can be present at about 0.1 to about 4% by weight of the mixture. The one or more sweeteners can be present at about 0.1 to about 3% by weight of the mixture. The one or more sweeteners can be present at about 0.1 to about 2% by weight of the mixture. The one or more sweeteners can be present at about 0.1 to about 1% by weight of the mixture. The one or more sweeteners can be present at about 0.2 to about 1% by weight of the mixture. The one or more sweeteners can be present at about 0.2 to about 0.9% by weight of the mixture. The one or more sweeteners can be present at about 0.2 to about 0.8% by weight of the mixture. The one or more sweeteners can be present at about 0.2 to about 0.7% by weight of the mixture. The one or more sweeteners may be present at about 0.3 to about 0.7% by weight of the mixture. The one or more sweeteners may be present at about 0.3 to about 0.6% by weight of the mixture. The one or more sweeteners may be present at about 0.4 to about 0.6% by weight of the mixture. The one or more sweeteners may be present at about 0.4 to about 0.5% by weight of the mixture. The one or more sweeteners may be present at about 0.5 to about 0.6% by weight of the mixture. The one or more sweeteners may be present at about 0.45 to about 0.55% by weight of the mixture. Preferably, the one or more sweeteners may be present at about 0.5% by weight of the mixture.

[0236] The mixtures of the present invention may also include a fragrance. The mixtures of the present invention may also include one or more fragrances.

[0237] The flavoring may be selected from lemon flavor, mixed berry flavor, grape flavor, peppermint natural flavor, mint flavor, banana flavor, chocolate flavor, maple flavor, strawberry flavor, raspberry flavor, cherry flavor, orange flavor, and vanilla flavor, and mixtures thereof. The flavoring may be selected from lemon flavor, mixed berry flavor, grape flavor, peppermint natural flavor, mint flavor, banana flavor, chocolate flavor, maple flavor, and orange flavor. In one embodiment, the flavoring is peppermint natural flavor. In another embodiment, the flavoring is lemon flavor. Preferably, the flavoring is grape flavor. Even more preferably, the flavoring is mixed berry flavor. Alternatively, the orodispersible tablet may be unflavored.

[0238] The one or more fragrances can be present at about 0.03 to about 1% by weight of the mixture. The one or more fragrances can be present at about 0.03 to about 0.8% by weight of the mixture. The one or more fragrances can be present at about 0.03 to about 0.5% by weight of the mixture. The one or more fragrances can be present at about 0.03 to about 0.4% by weight of the mixture. The one or more fragrances can be present at about 0.03 to about 0.3% by weight of the mixture. The one or more fragrances can be present at about 0.05 to about 0.2% by weight of the mixture. The one or more fragrances can be present at about 0.05 to about 0.1% by weight of the mixture. The one or more fragrances can be present at about 0.03 to about 0.09% by weight of the mixture. The one or more fragrances can be present at about 0.03 to about 0.08% by weight of the mixture. The one or more fragrances may be present at about 0.03 to about 0.07% by weight of the mixture. The one or more fragrances may be present at about 0.03 to about 0.06% by weight of the mixture. The one or more fragrances may be present at about 0.04 to about 0.06% by weight of the mixture. The one or more fragrances may be present at about 0.04 to about 0.05% by weight of the mixture. The one or more fragrances may be present at about 0.05 to about 0.06% by weight of the mixture. The one or more fragrances may be present at about 0.045 to about 0.055% by weight of the mixture. Preferably, the one or more fragrances may be present at about 0.05% by weight of the mixture.

[0239] For example, if the flavor is selected from lemon flavor or mixed berry flavor, the flavor may be present at about 0.2% to 0.5% by weight of the orodispersible tablet. The flavor may be present at about 0.2 to 0.4% by weight of the orodispersible tablet. The flavor may be present at about 0.3 to 0.4% by weight of the orodispersible tablet. The one or more flavors may be present at about 0.36% by weight of the orodispersible tablet. The one or more flavors may be present at about 0.31% by weight of the orodispersible tablet.

[0240] The orodispersible tablet of the present invention may contain about 0.2 to about 0.5% grape flavor.The orodispersible tablet of the present invention may contain about 0.36% by weight lemon flavor.The orodispersible tablet of the present invention may contain about 0.31% by weight mixed berry flavor.

[0241] The mixture of the present invention may include one or more of mannitol (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and peppermint natural flavor as a flavoring.

[0242] The mixture of the present invention may include one or more of mannitol as a filler (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and lemon flavor as a flavoring.

[0243] The mixture of the present invention may include one or more of mannitol (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®) as a filler, microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and mixed berry flavor as a flavor.

[0244] The mixture of the present invention may include one or more of mannitol as a filler (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and grape flavor as a flavoring.

[0245] The mixture of the present invention may include two or more of mannitol as a filler (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and peppermint natural flavor as a flavoring.

[0246] The mixture of the present invention may include two or more of mannitol as a filler (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and lemon flavor as a flavoring.

[0247] The mixture of the present invention may include two or more of mannitol as a filler (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and mixed berry flavor as a flavor.

[0248] The mixture of the present invention may include two or more of mannitol as a filler (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and grape flavor as a flavoring.

[0249] The mixture of the present invention may include three or more of mannitol as a filler (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and peppermint natural flavor as a flavor.

[0250] The mixture of the present invention may include three or more of mannitol as a filler (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and lemon flavor as a flavoring.

[0251] The mixture of the present invention may include three or more of mannitol as a filler (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and mixed berry flavor as a flavor.

[0252] The mixture of the present invention may include three or more of mannitol as a filler (e.g., granular mannitol and / or spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose) as a binder, polyvinylpyrrolidone (crospovidone) as a disintegrant, silicon dioxide as a flow enhancer, sucralose as a sweetener, and grape flavor as a flavor.

[0253] The blends of the present invention may include one or more of granular mannitol, spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose), polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and peppermint natural flavor.

[0254] The blends of the present invention may include one or more of granular mannitol, spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose), polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and lemon flavor.

[0255] The blends of the present invention may include one or more of granular mannitol, spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose), polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and mixed berry flavor.

[0256] The blends of the present invention may include one or more of granular mannitol, spray-dried mannitol (e.g., Mannogem EZ®), microcrystalline cellulose (e.g., silicified microcrystalline cellulose), polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and grape flavor.

[0257] The blends of the present invention may include one or more of granular mannitol, spray-dried mannitol (e.g., Mannogem EZ®), silicified microcrystalline cellulose, polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and peppermint natural flavor.

[0258] The blends of the present invention may include one or more of granular mannitol, spray-dried mannitol (e.g., Mannogem EZ®), silicified microcrystalline cellulose, polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and lemon flavor.

[0259] The blends of the present invention may include one or more of granular mannitol, spray-dried mannitol (e.g., Mannogem EZ®), silicified microcrystalline cellulose, polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and mixed berry flavor.

[0260] The blend of the present invention may include one or more of granular mannitol, spray-dried mannitol (e.g., Mannogem EZ®), silicified microcrystalline cellulose, polyvinylpyrrolidone (crospovidone), silicon dioxide, sucralose, and grape flavor.

[0261] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture.

[0262] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, and a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture.

[0263] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, and one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture.

[0264] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture, and one or more flavorings (e.g., lemon flavoring, mixed berry flavoring, grape flavoring, or peppermint natural flavoring) present at 0.01 to about 1% by weight of the mixture.

[0265] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture.

[0266] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, and a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture.

[0267] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, and one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture.

[0268] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture, and one or more flavorings (e.g., lemon flavoring, mixed berry flavoring, grape flavoring, or peppermint natural flavoring) present at 0.01 to about 1% by weight of the mixture.

[0269] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture.

[0270] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, and a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture.

[0271] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, and one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture.

[0272] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture, and one or more flavorings (e.g., lemon flavoring, mixed berry flavoring, grape flavoring, or peppermint natural flavoring) present at 0.01 to about 1% by weight of the mixture.

[0273] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture.

[0274] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, and a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture.

[0275] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, and one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture.

[0276] The mixtures of the present invention may include about 15 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, one or more flow enhancers (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture, and one or more flavorings (e.g., lemon flavoring, mixed berry flavoring, grape flavoring, or peppermint natural flavoring) present at 0.01 to about 1% by weight of the mixture.

[0277] The mixtures of the present invention may comprise about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture.

[0278] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, and a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture.

[0279] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, and one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture.

[0280] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture, and one or more flavorings (e.g., lemon flavoring, mixed berry flavoring, grape flavoring, or peppermint natural flavoring) present at 0.01 to about 1% by weight of the mixture.

[0281] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture.

[0282] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, and a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture.

[0283] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, and one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture.

[0284] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture, and one or more flavorings (e.g., lemon flavoring, mixed berry flavoring, grape flavoring, or peppermint natural flavoring) present at 0.01 to about 1% by weight of the mixture.

[0285] The mixtures of the present invention may comprise about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture.

[0286] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, and a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture.

[0287] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, and one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture.

[0288] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture, and one or more flavorings (e.g., lemon flavoring, mixed berry flavoring, grape flavoring, or peppermint natural flavoring) present at 0.01 to about 1% by weight of the mixture.

[0289] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture.

[0290] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, and a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture.

[0291] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, and one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture.

[0292] The mixtures of the present invention may include about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, one or more flow enhancers (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture, and one or more flavorings (e.g., lemon flavoring, mixed berry flavoring, grape flavoring, or peppermint natural flavoring) present at 0.01 to about 1% by weight of the mixture.

[0293] The mixtures of the present invention may comprise about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture.

[0294] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, and a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture.

[0295] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, and one or more sweeteners (e.g., sucralose) present at about 0.1 to about 1% by weight of the mixture.

[0296] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture, and one or more flavorings (e.g., lemon flavoring, mixed berry flavoring, grape flavoring, or peppermint natural flavoring) present at 0.01 to about 1% by weight of the mixture.

[0297] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture.

[0298] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, and a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture.

[0299] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, and one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture.

[0300] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 10% by weight of the mixture, one or more flow enhancers (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture, and one or more flavorings (e.g., lemon flavoring, mixed berry flavoring, grape flavoring, or peppermint natural flavoring) present at 0.01 to about 1% by weight of the mixture.

[0301] The mixtures of the present invention may comprise about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture.

[0302] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, and a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture.

[0303] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, and one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture.

[0304] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 30% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture, and one or more flavorings (e.g., lemon flavoring, mixed berry flavoring, grape flavoring, or peppermint natural flavoring) present at 0.01 to about 1% by weight of the mixture.

[0305] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture.

[0306] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, and a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture.

[0307] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to about 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, and one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture.

[0308] The mixtures of the present invention may include about 26 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), one or more fillers (e.g., granular mannitol and / or spray-dried mannitol) present at about 30 to 80% by weight of the mixture, one or more binders (e.g., silicified microcrystalline cellulose) present at about 5 to about 14% by weight of the mixture, one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 1 to about 7% by weight of the mixture, a flow enhancer (e.g., silicon dioxide) present at about 0.1 to about 5% by weight of the mixture, one or more sweeteners (e.g., sucralose) present at about 0.1 to about 5% by weight of the mixture, and one or more flavorings (e.g., lemon flavoring, mixed berry flavoring, grape flavoring, or peppermint natural flavoring) present at 0.01 to about 1% by weight of the mixture.

[0309] The mixtures of the present invention may comprise about 25 to about 50% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)), present at about 5 to about 10% by weight of the mixture.

[0310] The mixtures of the present invention may comprise about 25 to about 40% by weight of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), and one or more disintegrants (e.g., polyvinylpyrrolidone (crospovidone)) present at about 5 to about 10% by weight of the mixture.

[0311] The mixture of the present invention may contain about 27% by weight of granular mannitol. The mixture of the present invention may contain about 26.87% by weight of granular mannitol. Preferably, the mixture of the present invention may contain about 26.85% by weight of granular mannitol.

[0312] The mixture of the present invention may comprise about 27% by weight of spray-dried mannitol (e.g., Mannogem EZ®). The mixture of the present invention may comprise about 26.87% by weight of spray-dried mannitol (e.g., Mannogem EZ®). Preferably, the mixture of the present invention may comprise about 26.85% by weight of spray-dried mannitol (e.g., Mannogem EZ®).

[0313] The mixture of the present invention may contain about 10% by weight of microcrystalline cellulose. Preferably, the mixture of the present invention may contain about 10% by weight of silicified microcrystalline cellulose.

[0314] The mixture of the present invention may contain about 5% by weight of polyvinylpyrrolidone (crospovidone).

[0315] The mixture of the present invention may include about 0.75% by weight of silicon dioxide.

[0316] The mixture of the present invention may contain about 0.5% by weight of sucralose.

[0317] The mixture of the present invention may include about 0.36% by weight of lemon flavor.

[0318] The mixture of the present invention may include about 0.31% by weight of mixed berry flavor.

[0319] The mixture of the present invention may contain about 0.05% by weight of peppermint natural flavor.

[0320] The mixture of the present invention may comprise about 30% by weight KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.85% by weight granular mannitol, about 26.85% by weight spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight silicified microcrystalline cellulose, and about 5% by weight polyvinylpyrrolidone (crospovidone).

[0321] The mixture of the present invention may comprise about 30% by weight KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.87% by weight granular mannitol, about 26.87% by weight spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight silicified microcrystalline cellulose, and about 5% by weight polyvinylpyrrolidone (crospovidone).

[0322] The mixture of the present invention may comprise about 30% by weight KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.85% by weight granular mannitol, about 26.85% by weight spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight silicified microcrystalline cellulose, about 5% by weight polyvinylpyrrolidone (crospovidone), about 0.75% by weight silicon dioxide, about 0.5% by weight sucralose, and about 0.05% by weight peppermint natural flavor.

[0323] The mixture of the present invention may comprise about 30% by weight KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.87% by weight granular mannitol, about 26.87% by weight spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight silicified microcrystalline cellulose, about 5% by weight polyvinylpyrrolidone (crospovidone), about 0.75% by weight silicon dioxide, and about 0.5% by weight sucralose.

[0324] The mixture of the present invention may comprise about 30% by weight KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.85% by weight granular mannitol, about 26.85% by weight spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight silicified microcrystalline cellulose, about 5% by weight polyvinylpyrrolidone (crospovidone), about 0.75% by weight silicon dioxide, about 0.5% by weight sucralose, and about 0.36% by weight lemon flavor.

[0325] The mixture of the present invention may comprise about 30% by weight KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), about 26.85% by weight granular mannitol, about 26.85% by weight spray-dried mannitol (e.g., Mannogem EZ®), about 10% by weight silicified microcrystalline cellulose, about 5% by weight polyvinylpyrrolidone (crospovidone), about 0.75% by weight silicon dioxide, about 0.5% by weight sucralose, and about 0.31% by weight mixed berry flavor.

[0326] The manufacturing method of the present invention As mentioned above, the method of making the ODT described herein is a method to overcome the instability and decomposition problems initially observed when the inventors attempted to make the ODT of KVD900.

[0327] The present invention provides a method for producing an ODT of the present invention from a mixture of the present invention, comprising blending the components of the mixture to form a powder mixture and compressing into an orodispersible tablet.

[0328] In particular, the present invention relates to a method for producing an orodispersible tablet according to the invention from a mixture according to the invention, comprising the steps of: a) combining and blending KVD900, one or more binders, and one or more disintegrants to form a powder mixture; b) adding one or more fillers to the powder mixture from step a) and blending to form a final blend; and c) compressing the mixture into an orodispersible tablet.

[0329] More specifically, the method of manufacture comprises: a) combining and blending about 26 to about 40% by weight of KVD900, about 5 to about 30% by weight of one or more binders selected from microcrystalline cellulose or hydroxypropyl methylcellulose, and about 1 to about 10% by weight of one or more disintegrants selected from polyvinylpyrrolidone (crospovidone), sodium starch glycolate, and croscarmellose sodium to form a powder mixture; b) adding to the powder mixture from step a) about 30 to about 80% by weight of one or more fillers selected from mannitol (e.g., granular mannitol and spray-dried mannitol (e.g., Mannogem EZ®) and blending to form a final blend; c) compressing into an orodispersible tablet.

[0330] More specifically, the method of manufacture comprises: a) combining and blending about 30% by weight of KVD900, about 10% by weight of silicified microcrystalline cellulose, and about 5% by weight of polyvinylpyrrolidone (crospovidone) to form a powder mixture; b) adding about 26.85% by weight of granular mannitol and 26.85% by weight of spray-dried mannitol (e.g., Mannogem EZ®) to the powder mixture from step a) and blending to form a final blend; c) compressing into an orodispersible tablet.

[0331] Alternatively, the method of manufacture comprises: a) combining and blending about 30% by weight of KVD900, about 10% by weight of silicified microcrystalline cellulose, and about 5% by weight of polyvinylpyrrolidone (crospovidone) to form a powder mixture; b) adding about 26.87% by weight of granular mannitol and 26.87% by weight of spray-dried mannitol (e.g., Mannogem EZ®) to the powder mixture from step a) and blending to form a final blend; c) compressing into an orodispersible tablet.

[0332] In another embodiment of the present invention, the method of manufacture comprises the steps of: a) combining and blending KVD900, one or more binders, one or more disintegrants, a flow improver, one or more sweeteners, and one or more flavoring agents to form a powder mixture; b) adding one or more fillers to the powder mixture from step a) and blending to form a final blend; c) compressing into an orodispersible tablet.

[0333] More specifically, the method of manufacture comprises: a) adding and blending about 26 to about 40% by weight of KVD900, about 5 to about 30% by weight of one or more binders selected from microcrystalline cellulose or hydroxypropyl methylcellulose, about 1 to about 10% by weight of one or more disintegrants selected from polyvinylpyrrolidone (crospovidone), sodium starch glycolate, and croscarmellose sodium, about 0.5 to about 1% by weight of a flow improver, about 0.1 to about 1% by weight of one or more sweeteners, and about 0.01 to about 1% by weight of one or more flavorings to form a powder mixture; b) adding to the powder mixture from step a) about 30 to about 80% by weight of one or more fillers selected from mannitol (e.g., granular mannitol and spray-dried mannitol (e.g., Mannogem EZ®) and blending to form a final blend; c) compressing into an orodispersible tablet.

[0334] More specifically, the method of manufacture comprises: a) combining and blending about 30% by weight KVD900, about 10% by weight silicified microcrystalline cellulose, about 5% by weight polyvinylpyrrolidone (crospovidone), about 0.75% by weight silicon dioxide, about 0.5% by weight sucralose, and about 0.05% by weight peppermint natural flavor to form a powder mixture; b) adding about 26.85% by weight of granular mannitol and 26.85% by weight of spray-dried mannitol (e.g., Mannogem EZ®) to the powder mixture from step a) and blending to form a final blend; c) compressing into an orodispersible tablet.

[0335] Alternatively, the method of manufacture comprises: a) combining and blending about 30% by weight KVD900, about 10% by weight silicified microcrystalline cellulose, about 5% by weight polyvinylpyrrolidone (crospovidone), about 0.75% silicon dioxide, and about 0.5% sucralose to form a powder mixture; b) adding about 26.87% by weight of granular mannitol and 26.87% by weight of spray-dried mannitol (e.g., Mannogem EZ®) to the powder mixture from step a) and blending to form a final blend; c) compressing into an orodispersible tablet.

[0336] In another embodiment, the method of manufacture comprises: a) combining and blending about 30% by weight KVD900, about 10% by weight silicified microcrystalline cellulose, about 5% by weight polyvinylpyrrolidone (crospovidone), about 0.75% silicon dioxide, about 0.5% sucralose, and about 0.36% by weight lemon natural flavor to form a powder mixture; b) adding about 26.85% by weight of granular mannitol and 26.85% by weight of spray-dried mannitol (e.g., Mannogem EZ®) to the powder mixture from step a) and blending to form a final blend; c) compressing into an orodispersible tablet.

[0337] In another embodiment, the method of manufacture comprises: a) combining and blending about 30% by weight KVD900, about 10% by weight silicified microcrystalline cellulose, about 5% by weight polyvinylpyrrolidone (crospovidone), about 0.75% by weight silicon dioxide, about 0.5% by weight sucralose, and about 0.31% by weight mixed berry flavor to form a powder mixture; b) adding about 26.85% by weight of granular mannitol and 26.85% by weight of spray-dried mannitol (e.g., Mannogem EZ®) to the powder mixture from step a) and blending to form a final blend; c) compressing into an orodispersible tablet.

[0338] In some embodiments, the manufacturing method includes using an external lubricant. By external lubricant, we mean a lubricant that aids in the flow of the manufacturing process and is therefore not actively added to the blend / mixture, although trace amounts may be present in the final ODT. Preferably, the external lubricant is magnesium stearate.

[0339] The manufacturing method of the present invention may further comprise a step of debossing the orodispersible tablet. The manufacturing method of the present invention may further comprise a step of debossing the orodispersible tablet with a logo, tablet strength and / or one or more score lines. In one embodiment, the manufacturing method of the present invention further comprises a step of debossing the orodispersible tablet with a logo. In another embodiment, the manufacturing method of the present invention further comprises a step of debossing the orodispersible tablet with a tablet strength. Preferably, the manufacturing method of the present invention further comprises a step of debossing the orodispersible tablet with one or more score lines. The manufacturing method of the present invention further comprises a step of debossing the orodispersible tablet with one score line. The manufacturing method of the present invention further comprises a step of debossing the orodispersible tablet with two score lines. The manufacturing method of the present invention further comprises a step of debossing the orodispersible tablet with two score lines in a cross shape.

[0340] Kits of the Invention The present invention also provides a kit for providing a predetermined dose of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof), comprising a plurality of orodispersible tablets according to the present invention.

[0341] In some embodiments of the present invention, a kit for providing a predetermined dose of KVD900 (or a pharma- ceutically acceptable salt and / or solvate thereof) comprises two orodispersible tablets according to the present invention.

[0342] The total dose of the multiple orodispersible tablets in the kit of the invention can be about 500 mg (e.g., by providing a kit containing two orodispersible tablets as described herein, each containing about 250 mg of KVD900).

[0343] The total dose of the multiple orodispersible tablets in the kit of the invention can be about 550 mg (e.g., by providing a kit containing two orodispersible tablets as described herein, each containing about 275 mg of KVD900).

[0344] The total dose of the multiple orodispersible tablets in the kit of the invention can be about 600 mg (e.g., by providing a kit containing two orodispersible tablets as described herein, each containing about 300 mg of KVD900).

[0345] In the kit of the present invention, the plurality of orodispersible tablets can be packaged in a blister pack (e.g., Alu / Alu blister, Aclar / Alu blister, Amcor AmSky blister). The blister pack can be in a peel-back or push-through format. The plurality of orodispersible tablets can also be packaged in other configurations known in the art.

[0346] When the kit comprises an orodispersible tablet embossed with a score line(s) as described herein, the kit of the invention may also comprise instructions for breaking the orodispersible tablet into sub-scored tablets.

[0347] On-demand treatment of attacks of bradykinin-mediated angioedema (e.g., BK AEnH attacks, preferably HAE attacks) As mentioned above, the "bradykinin-mediated angioedema" may be selected from HAE and BK-AEnH. The bradykinin-mediated angioedema may be BK-AEnH. Preferably, the bradykinin-mediated angioedema is HAE.

[0348] The present invention provides an improved treatment for bradykinin-mediated angioedema compared to currently available treatments for bradykinin-mediated angioedema. The present invention provides an oral treatment for HAE that is particularly useful as an on-demand treatment for and / or to reduce the likelihood of a bradykinin-mediated angioedema attack. Specifically, as described herein, the therapeutic agents of the present invention have (i) a rapid onset of action, (ii) potency, (iii) a favorable safety profile, and (iv) sustained pharmacodynamic effect.

[0349] Thus, according to the present invention there is provided a method for the on-demand treatment of bradykinin-mediated angioedema, comprising administering on-demand one or more orodispersible tablets comprising KVD900 according to the present invention to a patient in need of treatment.

[0350] According to one aspect of the present invention, there is provided a method for treating an attack of bradykinin-mediated angioedema on demand, comprising administering to a patient in need of treatment one or more orodispersible tablets comprising KVD900 according to the present invention, wherein the one or more orodispersible tablets are administered on demand upon recognition of symptoms of an attack of bradykinin-mediated angioedema.

[0351] If the bradykinin-mediated angioedema is HAE, the "bradykinin-mediated angioedema attack" is an "HAE attack." If the bradykinin-mediated angioedema is BK-AEnH, the "bradykinin-mediated angioedema attack" is a "BK-AEnH attack." As noted above, the bradykinin-mediated angioedema is preferably HAE.

[0352] Although each bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) may differ in terms of severity and affected areas, patients suffering from bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE), medical personnel knowledgeable in bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE), and caregivers of patients with bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE) have the observation skills to identify symptoms of a bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack), which may include, but are not limited to, tissue swelling, such as in the hands, feet, extremities, face, intestinal tract and / or airways, fatigue, headache, muscle pain, tingling skin, abdominal pain, nausea, vomiting, diarrhea, difficulty swallowing, hoarseness, shortness of breath, and / or mood changes. Thus, in some embodiments, administration of KVD900 can occur once at least one of the above symptoms is recognized.

[0353] The treatment of the present invention can treat patients with laryngeal attacks.

[0354] The treatment of the present invention may treat patients having abdominal attacks, particularly patients having abdominal attacks and experiencing emetic symptoms.

[0355] The treatment of the present invention can further treat patients with dysphagia.

[0356] It will also be understood by those skilled in the art that "administered at the time of recognition of symptoms of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack)" means administered as soon as possible after the symptoms of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) are recognized. For example, patients are expected to have KVD900 at all times (most likely in the form of a pharma- ceutically acceptable composition) readily and readily available to ensure that treatment is administered at the time of recognition of symptoms of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack). In other words, treatment is on demand. For example, in some embodiments, KVD900 can be administered within 1 hour of symptoms of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) being recognized, preferably within 30 minutes, within 20 minutes, within 10 minutes, or within 5 minutes of symptoms of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) being recognized.

[0357] In the case where symptoms of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) are recognized in the prodromal phase, one embodiment of the present invention is that KVD900 can be administered in the prodromal phase of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack). In these circumstances, the recognized symptoms may be mild swelling, particularly mild swelling affecting the face and neck. Additionally or alternatively, the symptom may be abdominal pain, particularly abdominal pain is considered to be characteristic of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack). Additionally or alternatively, the symptom may be skin redness, such as erythema marginatum.

[0358] Treatment according to the present invention can prevent the severity of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack). In some circumstances, treatment can shorten the attack duration, and in some cases, can completely stop the attack. For example, treatment can stop the progression of peripheral bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) or abdominal bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack). In some embodiments, treatment according to the present invention can inhibit the development of subsequent swelling, possibly completely, particularly when treatment is started in the prodromal phase. In particular, in some embodiments, treatment can prevent bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) from progressing to the swelling phase, particularly when treatment is started in the prodromal phase.

[0359] KVD900 may be sufficient to treat a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) alone (i.e., without the need to administer any active pharmaceutical ingredient other than KVD900 to the patient). Thus, in some embodiments of the present invention, no active pharmaceutical ingredient other than KVD900 is administered to the patient to treat a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack). In particular, in some embodiments, the treatment of the present invention does not require the administration of any active pharmaceutical ingredient other than KVD900 to treat a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) (e.g., without the need for a rescue drug such as pdC1INH, rhC1INH, or icatibant). More specifically, in some embodiments, no active pharmaceutical ingredient for treating a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) other than KVD900 is administered to the patient (e.g., no rescue medication such as pdC1INH, rhC1INH, or icatibant is required).

[0360] Alternatively, in some embodiments, the treatment of the present invention can be used in combination with other treatments for bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE). For example, in some embodiments, the on-demand acute therapy described herein can be used as a "top-up treatment" for another treatment for bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE). In some embodiments, the patient may be taking a preventive treatment for bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE), and the on-demand therapy described herein can be used to treat a bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) that was not prevented by the other preventive treatment for bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack).

[0361] For example, in some embodiments, a method is provided for treating bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE) in a patient already taking a prophylactic C1 inhibitor (e.g., Cinryze®, Haegarda®, Berinert®), comprising administering KVD900 orally on demand to the patient once symptoms of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) are recognized. In another embodiment, a method is provided for treating bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE) in a patient already taking prophylactic lanadelumab, comprising administering KVD900 orally on demand to the patient once symptoms of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) are recognized. In another embodiment, a method is provided for treating bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE) in a patient already taking berotralstat for prophylaxis, comprising orally administering KVD900 on demand to the patient upon recognition of symptoms of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack).

[0362] In any of the above treatments, the symptoms can be recognized by the patient. In any of the above treatments, the symptoms can be recognized by a medical professional, such as a medical professional knowledgeable in bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE). In any of the above treatments, the symptoms can be recognized by a caregiver of the patient.

[0363] Treatment according to the invention can reduce the proportion of bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) that progress to one or more levels on the 5-point Likert scale (5LS). Treatment according to the invention can reduce the proportion of bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) that progress to one or more levels on the 5LS within 12 hours of administering the compound. Treatment according to the invention can improve the time to resolution of bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) to "none" on the 5LS. The 5LS is a scale well known in the art that can be used to report the severity of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) (see, e.g., Allergy Asthma Proc. 2018 Jan 1;39(1):74-80.doi:10.2500 / aap.2018.39.4095), for example, using this scale, attacks can be reported as "none," "mild," "moderate," "severe," or "very severe."

[0364] Treatment according to the invention can reduce the proportion of bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) that are rated as "worse" or "very worse" on the 7-point transition question (7TQ). Treatment according to the invention can increase the proportion of bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) that are rated as "better than before" or "much better than before". The 7TQ is a well-known index in the art that can be used to score the progression of bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks), and can be used to report attacks as "much better than before", "better than before", "slightly better than before", "no change", "slightly worse", "worse", or "much worse".

[0365] In some embodiments of the on-demand treatment of any of the bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) of the present invention, a single dose of KVD900 can be administered to the patient to treat the bradykinin-mediated angioedema attack (e.g., BK-AEnH attacks, preferably HAE attacks). In some other embodiments of the on-demand treatment of any of the bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) of the present invention, multiple doses of KVD900 can be administered to the patient to treat the acute bradykinin-mediated angioedema attack (e.g., BK-AEnH attacks, preferably HAE attacks). For example, the on-demand treatment can include administering two doses of KVD900 within 24 hours from the time the first dose is taken. Alternatively, the on-demand treatment can include administering three doses of KVD900 within 24 hours from the time the first dose is taken. Alternatively, on-demand treatment may involve administering four doses of KVD900 within 24 hours of taking the first dose. If multiple doses are taken, the doses can be evenly spaced such that there is approximately an equal amount of time between each dose (e.g., subsequent doses taken 8 hours, 16 hours, and 24 hours after the first dose).

[0366] In some embodiments of the on-demand treatment of any of the bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) of the present invention, the patient can be administered a daily dosage in two doses per day. These two doses can be administered simultaneously, separately, or sequentially. In some embodiments, the two doses can be administered at any time during the day, with the interval between the two doses being specific to the patient and the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attacks, preferably HAE attacks). In some embodiments, the second dose can be administered within about 2 hours of the first dose (more specifically, about 1 to 2 hours after the first dose). In some embodiments, the second dose can be administered about 1 to about 4 hours after the first dose (more specifically, about 1 to 3 hours, about 2 to 3 hours, or 3 to about 4 hours after the first dose). In some embodiments, the second dose can be administered about 4 to about 12 hours after the first dose (more specifically, about 4 to about 8 hours, or about 6 hours after the first dose). In some embodiments, the second dose can be administered about 2 to about 6 hours after the first dose (more specifically, about 3 to about 6 hours after the first dose). In some embodiments, the second dose can be administered within about 8 hours after the first dose (more specifically, about 4 to about 8 hours after the first dose). In some embodiments, the second dose can be administered within about 12 hours after the first dose (more specifically, about 8 to about 12 hours after the first dose). In some embodiments, the second dose can be administered within about 16 hours after the first dose (more specifically, about 12 to about 16 hours after the first dose). In some embodiments, the second dose can be administered within about 20 hours of the first dose (more specifically, about 16 to about 20 hours after the first dose). In some embodiments, the second dose can be administered within about 24 hours of the first dose (more specifically, about 20 to about 24 hours after the first dose). In some embodiments, each of the two doses can be 500 mg of KVD900.Alternatively, each of the two doses can be 550 mg of KVD 900. Alternatively, each of the two doses can be 600 mg of KVD 900.

[0367] In any on-demand treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) of the present invention, the patient can be administered the daily dose in two doses per day, with the second dose being administered at least about 6 hours after the first dose. The patient can be administered the daily dose in two doses per day, with the second dose being administered about 5 to about 7 hours after the first dose. More specifically, the patient can be administered the daily dose in two doses per day, with the second dose being administered about 6 hours after the first dose. In these embodiments, each of the two doses can be 500 mg of KVD900. Each of these 500 mg doses can be two orodispersible tablets containing 250 mg of KVD900. In these embodiments, each of the two doses can be 550 mg of KVD900. Each of these 550 mg doses can be two orodispersible tablets containing 275 mg of KVD900. In these embodiments, each of the two doses can be 600 mg of KVD900. Each of these 600 mg doses can be two orodispersible tablets containing 300 mg of KVD900.

[0368] In some embodiments of the on-demand treatment of any of the bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) of the present invention, the patient can be administered a daily dose in three doses per day. These three doses can be administered simultaneously, separately, or sequentially. In some embodiments, the three doses can be administered at any time during the day, with the interval between the three doses being specific to the patient and the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attacks, preferably HAE attacks). In some embodiments, both the second and third doses can be administered within about 4 hours of the first dose. More specifically, the second dose can be administered about 1 to 3 hours after the first dose, and the third dose can be administered about 3 to about 4 hours after the first dose. The second dose can be administered about 4 to about 12 hours after the first dose (more specifically, about 4 to about 8 hours or about 6 hours after the first dose), and the third dose can be administered about 4 to about 12 hours after the second dose (more specifically, about 4 to about 8 hours or about 6 hours after the second dose). Even more specifically, the second dose can be administered about 2 hours after the first dose, and the third dose can be administered about 4 hours after the first dose. In some embodiments, both the second and third doses can be administered within about 8 hours after the first dose. More specifically, the second dose can be administered about 3 to 5 hours after the first dose, and the third dose can be administered about 7 to about 8 hours after the first dose. Even more specifically, the second dose can be administered about 4 hours after the first dose, and the third dose can be administered about 8 hours after the first dose. In some embodiments, both the second and third doses can be administered within about 16 hours of the first dose. More specifically, the second dose can be administered about 7 to 9 hours after the first dose, and the third dose can be administered about 15 to about 16 hours after the first dose.Even more specifically, the second dose can be administered about 8 hours after the first dose, and the third dose can be administered about 16 hours after the first dose. In some embodiments, each of the three doses can be 500 mg of KVD900. Alternatively, each of the three doses can be 550 mg of KVD900. Alternatively, each of the three doses can be 600 mg of KVD900.

[0369] In any on-demand treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) of the present invention, the patient may be administered the daily dose in three doses per day, with the second and third doses administered at least about 6 hours after the previous dose. The patient may be administered the daily dose in three doses per day, with the second dose administered about 5 hours to about 7 hours after the first dose, and the third dose administered about 11 hours to about 13 hours after the first dose. More specifically, the patient may be administered the daily dose in three doses per day, with the second dose administered about 6 hours after the first dose, and the third dose administered about 12 hours after the first dose. In these embodiments, each of the three doses may be 500 mg of KVD900. Each of these 500 mg doses may be two orodispersible tablets containing 250 mg of KVD900. In these embodiments, each of the three doses can be 550 mg of KVD900. Each of these 550 mg doses can be two orodispersible tablets containing 275 mg of KVD900. In these embodiments, each of the three doses can be 600 mg of KVD900. Each of these 600 mg doses can be two orodispersible tablets containing 300 mg of KVD900.

[0370] For example, if the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) continues after the administration of the first dose, multiple doses can be administered. "Continue" as used in this context can mean, for example, that the first dose does not prevent the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) from increasing, or that the first dose does not completely stop the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack), or that the first dose does not reduce the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack). Thus, the on-demand treatment of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention can include administering a first dosage, and then administering a second dosage if the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) persists after administration of the first dosage. The on-demand treatment of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention can also include administering a first dosage, and then administering a second dosage if the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) persists after administration of the first dosage, and then administering a third dosage if the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) persists after administration of the second dosage. In either case, each subsequent dose can be administered simultaneously, separately or sequentially. In either case, each subsequent dose can be administered at least about 6 hours (e.g., about 6 hours) after the previous dose. In either case, each dose can contain 500 mg of KVD900, for example administered as two orodispersible tablets containing 250 mg of KVD900. Alternatively, each dose can contain 550 mg of KVD900, for example administered as two orodispersible tablets containing 275 mg of KVD900.Alternatively, each dose may contain 600 mg of KVD900, administered as two orodispersible tablets, for example containing 300 mg of KVD900.

[0371] Thus, the on-demand treatment of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention can include administering a first dose containing 500 mg of compound (e.g., as two orodispersible tablets containing 250 mg of compound), and then administering a second dose containing 500 mg of compound (e.g., as two orodispersible tablets containing 250 mg of compound) if bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) persists after administration of the first dose. The second dose can be administered at least about 6 hours (e.g., about 6 hours) after the first dose. If the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) persists after the second dose, the on-demand treatment of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention can include administering a third dose containing 500 mg of the compound (e.g., as two orodispersible tablets containing 250 mg of the compound). The third dose can be administered at least about 6 hours (e.g., about 6 hours) after the second dose.

[0372] Alternatively, the on-demand treatment of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention can include administering a first dose containing 550 mg of compound (e.g., as two orodispersible tablets containing 275 mg of compound), and then administering a second dose containing 550 mg of compound (e.g., as two orodispersible tablets containing 275 mg of compound) if bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) persists after administration of the first dose. The second dose can be administered at least about 6 hours (e.g., about 6 hours) after the first dose. If the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) persists after the second dose, the on-demand treatment of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention can include administering a third dose containing 550 mg of the compound (e.g., as two orodispersible tablets containing 275 mg of the compound). The third dose can be administered at least about 6 hours (e.g., about 6 hours) after the second dose.

[0373] Alternatively, the on-demand treatment of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention can include administering a first dose containing 600 mg of compound (e.g., as two orodispersible tablets containing 300 mg of compound), and then administering a second dose containing 600 mg of compound (e.g., as two orodispersible tablets containing 300 mg of compound) if bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) persists after administration of the first dose. The second dose can be administered at least about 6 hours (e.g., about 6 hours) after the first dose. If the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) persists after the second dose, the on-demand treatment of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention can include administering a third dose containing 600 mg of the compound (e.g., as two orodispersible tablets containing 300 mg of the compound). The third dose can be administered at least about 6 hours (e.g., about 6 hours) after the second dose.

[0374] Even if the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) appears to decrease (or even stop completely) after administration of the first dose, multiple doses can be administered to prevent the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) from increasing again. For example, multiple doses can be used to reassure the patient (e.g., to ease the patient's anxiety). Thus, an on-demand treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) of the present invention may include administering a first dosage and then administering a second dosage to prevent the severity of the bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) from increasing again, even if the severity of the bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) appears to have decreased (or even stopped completely) after administration of the first dosage. Even if the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) appears to decrease (or even stop completely) after administration of the first and / or second dose, the on-demand treatment of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention may include administering a third dose to prevent the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) from increasing again. In either case, each subsequent dose may be administered simultaneously, separately or sequentially. In either case, each subsequent dose may be administered at least about 6 hours (e.g., about 6 hours) after the previous dose. In either case, each dose may contain 500 mg of the compound, for example, administered as two tablets containing 250 mg of the compound. Alternatively, each dose may contain 550 mg of the compound, administered as two tablets containing, for example, 275 mg of the compound.Alternatively, each dose can contain 600 mg of the compound, administered as two tablets containing, for example, 300 mg of the compound.

[0375] Specifically, the on-demand treatment of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention can include administering a first dosage containing 500 mg of the compound (e.g., as two tablets containing 250 mg of the compound), and then administering a second dosage containing 500 mg of the compound (e.g., as two tablets containing 250 mg of the compound) to prevent the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) from increasing again, even if the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) appears to decrease (or even completely stop) after administration of the first dosage. The second dosage can be administered at least about 6 hours (e.g., about 6 hours) after the first dosage. Even if the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) appears to decrease (or even stop completely) after administration of the first and / or second dose, the on-demand treatment of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention may include administering a third dose containing 500 mg of the compound (e.g., as two tablets containing 250 mg of the compound) to prevent the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) from increasing again. The third dose may be administered at least about 6 hours (e.g., about 6 hours) after the second dose.

[0376] Alternatively, the on-demand treatment of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention can include administering a first dosage containing 550 mg of compound (e.g., as two tablets containing 275 mg of compound), and then administering a second dosage containing 550 mg of compound (e.g., as two tablets containing 275 mg of compound) to prevent the severity of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) from increasing again, even if the severity of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) appears to decrease (or even completely stop) after administration of the first dosage. The second dosage can be administered at least about 6 hours (e.g., about 6 hours) after the first dosage. Even if the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) appears to decrease (or even stop completely) after administration of the first and / or second dose, the on-demand treatment of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention may include administering a third dose containing 550 mg of the compound (e.g., as two tablets containing 275 mg of the compound) to prevent the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) from increasing again. The third dose may be administered at least about 6 hours (e.g., about 6 hours) after the second dose.

[0377] Alternatively, the on-demand treatment of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention can include administering a first dosage containing 600 mg of compound (e.g., as two tablets containing 300 mg of compound), and then administering a second dosage containing 600 mg of compound (e.g., as two tablets containing 300 mg of compound) to prevent the severity of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) from increasing again, even if the severity of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) appears to decrease (or even completely stop) after administration of the first dosage. The second dosage can be administered at least about 6 hours (e.g., about 6 hours) after the first dosage. Even if the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) appears to decrease (or even stop completely) after administration of the first and / or second dose, the on-demand treatment of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) of the present invention may include administering a third dose containing 600 mg of the compound (e.g., as two tablets containing 300 mg of the compound) to prevent the severity of the bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) from increasing again. The third dose may be administered at least about 6 hours (e.g., about 6 hours) after the second dose.

[0378] The on-demand treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) of the present invention can include not administering more than three doses (e.g., three doses containing 500 mg of the compound, optionally as six tablets each containing 250 mg of the compound) in a 24-hour period. Alternatively, the on-demand treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) of the present invention can include not administering more than three doses (e.g., three doses containing 550 mg of the compound, optionally as six tablets each containing 275 mg of the compound) in a 24-hour period. Alternatively, on-demand treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) of the present invention may include administering no more than three doses in a 24-hour period (e.g., three doses containing 600 mg of the compound, optionally as six tablets each containing 300 mg of the compound).

[0379] On-demand prophylactic treatment of bradykinin-mediated angioedema attacks (e.g., BK AEnH attacks, preferably HAE attacks) According to one aspect of the present invention, there is provided a method of treating bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE) on demand, comprising administering one or more orodispersible tablets comprising KVD900 according to the present invention to a patient in need of treatment, wherein the one or more orodispersible tablets are administered on demand to prophylactically reduce the likelihood of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack).

[0380] In some embodiments, KVD900 can be administered to prevent a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack). As described above, preferably, the bradykinin-mediated angioedema is HAE.

[0381] As mentioned above, the treatment according to the present invention does not require the administration of KVD900 at regular intervals to provide preventive treatment. In fact, in some embodiments, KVD900 can be administered on demand. For example, when it is expected that a bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) will be induced (or caused) (i.e., the patient is expected to develop a bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack)), KVD900 can be administered on demand, for example, to reduce the possibility of a bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) (e.g., to prevent a bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack)). In some embodiments, a patient may predict that a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) will be induced (or caused). In some embodiments, a medical professional, such as a medical professional with knowledge of bradykinin-mediated angioedema (e.g., a BK-AEnH attack, preferably an HAE attack) may predict that a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) will be induced (or caused). In some embodiments, a patient's caregiver may predict that a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) will be induced (or caused). For example, a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) can be triggered (or caused) by a variety of stimuli, such as physical trauma (e.g., a medical, dental, or surgical procedure) and / or stress (e.g., a high-stress situation, such as mental stress, as may be associated with undergoing an examination or mental stress related to a medical, dental, or surgical procedure).For example, when a patient may expect to have a bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack), the patient's high stress / anxiety level may induce (or cause) a bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack). Furthermore, the frequency of occurrence of bradykinin-mediated angioedema attacks (e.g., BK-AEnH attack, preferably HAE attack) may vary over time in the same patient. Patients often have periods in which they have a higher frequency of occurrence of bradykinin-mediated angioedema attacks (e.g., BK-AEnH attack, preferably HAE attack) than usual. Therefore, during periods in which a patient has a higher frequency of occurrence of bradykinin-mediated angioedema attacks (e.g., BK-AEnH attack, preferably HAE attack) compared to usual, a bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) may be expected. Those familiar with bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE) will recognize that a bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) may be induced (or caused) in this manner. Patients, medical personnel with knowledge of bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE), and patient caregivers may also be observant to anticipate such triggers. Thus, in accordance with the present invention, a therapeutic agent may be administered on demand when the patient is expected to be exposed to one or more of these stimuli or situations.

[0382] As mentioned above, patients can be administered KVD900 as part of the on-demand prophylactic treatment of bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks).As mentioned above, this treatment reduces the likelihood of bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks).However, in some circumstances, patients still have the likelihood of developing bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks). Thus, one embodiment of the present invention is that a patient can be administered KVD900 as part of an on-demand prophylactic treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack), as described above, further comprising taking an on-demand dosage of KVD900 to treat a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) when symptoms of the bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) are recognized if they occur. These on-demand treatments of bradykinin-mediated angioedema attacks (e.g., a BK-AEnH attack, preferably an HAE attack) are described above.

[0383] Thus, in some embodiments, there is provided a method for treating bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE) on demand, comprising administering one or more orodispersible tablets containing KVD900 according to the present invention to a patient in need of treatment, wherein the one or more orodispersible tablets are administered on demand to prophylactically reduce the likelihood of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack), and further comprising administering the one or more orodispersible tablets on demand upon recognition of symptoms of an acute HAE attack.

[0384] In some embodiments of the on-demand treatment of any of the bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) of the present invention, a single dose of KVD900 can be administered to the patient to treat the bradykinin-mediated angioedema attack (e.g., BK-AEnH attacks, preferably HAE attacks). In some other embodiments of the on-demand treatment of any of the bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) of the present invention, multiple doses of KVD900 can be administered to the patient to treat the bradykinin-mediated angioedema attack (e.g., BK-AEnH attacks, preferably HAE attacks). For example, the on-demand treatment can include administering two doses of KVD900 within 24 hours from the time the first dose is taken. Alternatively, the on-demand treatment can include administering three doses of KVD900 within 24 hours from the time the first dose is taken. Alternatively, on-demand treatment may involve administering four doses of KVD900 within 24 hours of taking the first dose. If multiple doses are taken, the doses can be evenly spaced such that there is approximately an equal amount of time between each dose (e.g., subsequent doses taken 8 hours, 16 hours, and 24 hours after the first dose).

[0385] In some embodiments of the on-demand prophylactic treatment of any of the bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) described herein, the patient may be administered two doses per day. These two doses may be administered simultaneously, separately, or sequentially. In some embodiments, the two doses may be administered at any time during the day, with the interval between the two doses being patient specific. In some embodiments, the second dose may be administered within about 2 hours of the first dose (more specifically, about 1 to 2 hours after the first dose). In some embodiments, the second dose may be administered about 1 to about 4 hours after the first dose (more specifically, about 1 to 3 hours, about 2 to 3 hours, or about 3 to about 4 hours after the first dose). In some embodiments, the second dose may be administered about 4 to about 12 hours after the first dose (more specifically, about 4 to about 8 hours, or about 6 hours after the first dose). In some embodiments, the second dose can be administered about 2 to about 6 hours after the first dose (more specifically, about 3 to about 6 hours after the first dose). In some embodiments, the second dose can be administered within about 8 hours after the first dose (more specifically, about 4 to about 8 hours after the first dose). In some embodiments, the second dose can be administered within about 12 hours after the first dose (more specifically, about 8 to about 12 hours after the first dose). In some embodiments, the second dose can be administered within about 16 hours after the first dose (more specifically, about 12 to about 16 hours after the first dose). In some embodiments, the second dose can be administered within about 20 hours after the first dose (more specifically, about 16 to about 20 hours after the first dose). In some embodiments, the second dose can be administered within about 24 hours of the first dose (more specifically, about 20 to about 24 hours after the first dose). In some embodiments, each of the two doses can be 500 mg of KVD900. Alternatively, each of the two doses can be 550 mg of KVD900. Alternatively, each of the two doses can be 600 mg of KVD900.

[0386] In any on-demand prophylactic treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) described herein, the patient can be administered the daily dose in two doses per day, with the second dose administered at least about 6 hours after the first dose. The patient can be administered the daily dose in two doses per day, with the second dose administered about 5 to about 7 hours after the first dose. More specifically, the patient can be administered the daily dose in two doses per day, with the second dose administered about 6 hours after the first dose. In these embodiments, each of the two doses can be 500 mg of KVD900. Each of these 500 mg doses can be two orodispersible tablets containing 250 mg of KVD900. Alternatively, in these embodiments, each of the two doses can be 550 mg of KVD900. Each of these 550 mg doses can be two orodispersible tablets containing 275 mg of KVD900. Alternatively, in these embodiments, each of the two doses can be 600 mg of KVD900. Each of these 600 mg doses can be two orodispersible tablets containing 300 mg of KVD900.

[0387] In some embodiments of the on-demand prophylactic treatment of any of the bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) described herein, the patient can be administered a daily dose in three doses per day. These three doses can be administered simultaneously, separately, or sequentially. In some embodiments, the three doses can be administered at any time during the day, with the interval between the three doses being specific to the patient. In some embodiments, both the second and third doses can be administered within about four hours of the first dose. More specifically, the second dose can be administered about 1 to 3 hours after the first dose, and the third dose can be administered about 3 to about 4 hours after the first dose. The second dose can be administered about 4 to about 12 hours after the first dose (more specifically, about 4 to about 8 hours or about 6 hours after the first dose), and the third dose can be administered about 4 to about 12 hours after the second dose (more specifically, about 4 to about 8 hours or about 6 hours after the second dose). Even more specifically, the second dose can be administered about 2 hours after the first dose, and the third dose can be administered about 4 hours after the first dose. In some embodiments, both the second and third doses can be administered within about 8 hours after the first dose. More specifically, the second dose can be administered about 3 to 5 hours after the first dose, and the third dose can be administered about 7 to about 8 hours after the first dose. Even more specifically, the second dose can be administered about 4 hours after the first dose, and the third dose can be administered about 8 hours after the first dose. In some embodiments, both the second and third doses can be administered within about 16 hours of the first dose. More specifically, the second dose can be administered about 7 to 9 hours after the first dose, and the third dose can be administered about 15 to about 16 hours after the first dose. Even more specifically, the second dose can be administered about 8 hours after the first dose, and the third dose can be administered about 16 hours after the first dose.In some embodiments, each of the three doses can be 500 mg of KVD900. Alternatively, each of the three doses can be 550 mg of KVD900. Alternatively, each of the three doses can be 600 mg of KVD900.

[0388] In any on-demand prophylactic treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) described herein, the patient may be administered the daily dose in three doses per day, with the second and third doses administered at least about 6 hours after the previous dose. The patient may be administered the daily dose in three doses per day, with the second dose administered about 5 hours to about 7 hours after the first dose, and the third dose administered about 11 hours to about 13 hours after the first dose. More specifically, the patient may be administered the daily dose in three doses per day, with the second dose administered about 6 hours after the first dose, and the third dose administered about 12 hours after the first dose. In these embodiments, each of the three doses may be 500 mg of KVD900. Each of these 500 mg doses can be two orodispersible tablets containing 250 mg of KVD900. Alternatively, in these embodiments, each of the three doses can be 550 mg of KVD900. Each of these 550 mg doses can be two orodispersible tablets containing 275 mg of KVD900. Alternatively, in these embodiments, each of the three doses can be 600 mg of KVD900. Each of these 600 mg doses can be two orodispersible tablets containing 300 mg of KVD900.

[0389] For example, multiple doses can be administered if there is a continuing need to prophylactically reduce the likelihood of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack), for example, as described above, if the patient continues to expect that a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) may be induced. Thus, the on-demand treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) of the present invention can include administering a first dose, and then administering a second dose if there is a continuing need to prophylactically reduce the likelihood of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) after administration of the first dose. The on-demand treatment of bradykinin-mediated angioedema attacks (e.g., BK-AEnH attacks, preferably HAE attacks) of the present invention may also include administering a first dose, then administering a second dose if there is still a need to prophylactically reduce the likelihood of a bradykinin-mediated angioedema attack (e.g., BK-AEnH attacks, preferably HAE attacks) after administration of the first dose, and then administering a third dose if there is still a need to prophylactically reduce the likelihood of a bradykinin-mediated angioedema attack (e.g., BK-AEnH attacks, preferably HAE attacks) after administration of the second dose. In either case, each subsequent dose may be administered simultaneously, separately or sequentially. In either case, each dose may contain 500 mg of KVD900, for example, administered as two orodispersible tablets containing 250 mg of KVD900. Alternatively, each dose may contain 550 mg of KVD900, for example administered as two orodispersible tablets containing 275 mg of KVD900, or alternatively, each dose may contain 600 mg of KVD900, for example administered as two orodispersible tablets containing 300 mg of KVD900.

[0390] Specifically, the on-demand treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) described herein can include administering a first dose containing 500 mg of the compound (e.g., as two tablets each containing 250 mg of the compound), and then administering a second dose containing 500 mg of the compound (e.g., as two tablets each containing 250 mg of the compound) if there is still a need to prophylactically reduce the likelihood of an acute HAE attack after administration of the first dose. The second dose can be administered at least about 6 hours (e.g., about 6 hours) after the first dose. If there is still a need to prophylactically reduce the likelihood of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) after the second dose, the on-demand treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) of the present invention can include administering a third dose containing 500 mg of the compound (e.g., as two tablets each containing 250 mg of the compound). The third dose can be administered at least about 6 hours (e.g., about 6 hours) after the second dose.

[0391] Alternatively, the on-demand treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) described herein can include administering a first dose containing 550 mg of the compound (e.g., as two tablets each containing 275 mg of the compound), and then administering a second dose containing 550 mg of the compound (e.g., as two tablets each containing 275 mg of the compound) if there is still a need to prophylactically reduce the likelihood of an acute HAE attack after administration of the first dose. The second dose can be administered at least about 6 hours (e.g., about 6 hours) after the first dose. If there is still a need to prophylactically reduce the likelihood of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) after the second dose, the on-demand treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) of the present invention can include administering a third dose containing 550 mg of the compound (e.g., as two tablets each containing 275 mg of the compound). The third dose can be administered at least about 6 hours (e.g., about 6 hours) after the second dose.

[0392] Alternatively, the on-demand treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) described herein can include administering a first dose containing 600 mg of the compound (e.g., as two tablets each containing 300 mg of the compound), and then administering a second dose containing 600 mg of the compound (e.g., as two tablets each containing 300 mg of the compound) if there is still a need to prophylactically reduce the likelihood of an acute HAE attack after administration of the first dose. The second dose can be administered at least about 6 hours (e.g., about 6 hours) after the first dose. If there is still a need to prophylactically reduce the likelihood of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) after the second dose, the on-demand treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) of the present invention can include administering a third dose containing 600 mg of the compound (e.g., as two tablets each containing 300 mg of the compound). The third dose can be administered at least about 6 hours (e.g., about 6 hours) after the second dose.

[0393] The on-demand prophylactic treatment of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) described herein may include not administering more than three doses (e.g., three doses containing 500 mg of compound, optionally as six tablets each containing 250 mg of compound) in a 24-hour period. Alternatively, the on-demand prophylactic treatment of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) described herein may include not administering more than three doses (e.g., three doses containing 550 mg of compound, optionally as six tablets each containing 275 mg of compound) in a 24-hour period. Alternatively, on-demand prophylactic treatment of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) as described herein may include administering no more than three doses in a 24-hour period (e.g., three doses containing 600 mg of the compound, optionally as six tablets each containing 300 mg of the compound).

[0394] Ongoing and regular prophylactic treatment of bradykinin-mediated angioedema (e.g., BK AEnH, preferably HAE) According to one aspect of the present invention, there is provided a method of treating bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE), comprising administering one or more orodispersible tablets comprising KVD900 according to the present invention to a patient in need of treatment, wherein the one or more orodispersible tablets are administered to prophylactically reduce the likelihood of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack), and wherein the one or more orodispersible tablets of the present invention are administered periodically to the patient.

[0395] The term "administered periodically" is intended to mean that KVD900 is administered continuously at regular intervals (e.g., once a week, twice a week, etc.) to provide effective treatment. KVD900 is administered in one or more ODTs as described herein. A medical practitioner will readily understand what is meant by regular (or continuous) administration.

[0396] In some embodiments, KVD900 can be administered to prevent bradykinin-mediated angioedema attacks (eg, BK-AEnH attacks, preferably HAE attacks).

[0397] In some embodiments, one or more orodispersible tablets can be administered once a day. In other embodiments, one or more orodispersible tablets can be administered twice a day. In other embodiments, one or more orodispersible tablets can be administered three times a day. In other embodiments, one or more orodispersible tablets can be administered every other day.

[0398] As mentioned above, KVD900 can be administered to patients as part of the continuous and regular preventive treatment of bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE).As mentioned above, this treatment reduces the possibility of bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack).However, in some situations, patients still have the possibility of developing bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack). Thus, one embodiment of the present invention is that a patient may be administered KVD900 as part of an ongoing, regular preventative treatment of bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE) as described above, further comprising taking an on-demand dose of KVD900 to treat a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) when symptoms of the bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack) are recognized as occurring. These on-demand treatments of bradykinin-mediated angioedema attacks (e.g., a BK-AEnH attack, preferably an HAE attack) are described above.

[0399] Thus, in some embodiments, there is provided a method of treating bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE), comprising administering one or more orodispersible tablets containing KVD900 according to the present invention to a patient in need of treatment, wherein the one or more orodispersible tablets are administered to prophylactically reduce the likelihood of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack), and wherein the one or more orodispersible tablets of the present invention are administered periodically to the patient, and further comprising administering one or more orodispersible tablets on demand upon recognition of symptoms of a bradykinin-mediated angioedema attack (e.g., a BK-AEnH attack, preferably an HAE attack).

[0400] BK-AEnH As mentioned above, bradykinin-mediated angioedema may also be BK-AEnH.

[0401] If BK-AEnH is dipeptidyl peptidase-4 inhibitor-induced angioedema, it may be induced by the use of dipeptidyl peptidase-4 inhibitors as antidiabetic drugs.BK-AEnH may be dipeptidyl peptidase-4 inhibitor-induced by sitagliptin, metformin, saxagliptin, linagliptin, empagliflozin, alogliptin or pioglitazone.

[0402] When BK-AEnH is ACE inhibitor-induced angioedema, BK-AEnH is ACE inhibitor-induced induced by benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, or trandolapril.

[0403] When BK-AEnH is tPA-induced angioedema, it may be induced by thrombolytic therapy with tissue plasminogen activator. A patient may be undergoing thrombolytic therapy with tissue plasminogen activator to treat an acute stroke, such as an ischemic stroke.

[0404] When BK-AEnH is non-hereditary angioedema with normal C1 inhibitor (AE-nC1 Inh) and drug-induced (i.e., drug-induced AE-nC1 Inh), BK-AEnH can be drug-induced by at least one of a nonsteroidal anti-inflammatory agent, a β-lactam antibiotic, and a non-β-lactam antibiotic. The nonsteroidal anti-inflammatory agent can be at least one of aspirin, celecoxib, diclofenac, diflunisa I, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, and tolmetin.

[0405] When BK-AEnH is non-hereditary angioedema with normal C1 inhibitor (AE-nC1 Inh) and drug-induced (i.e., drug-induced AE-nC1 Inh), BK-AEnH may be induced by angiotensin II receptor blockers (ARBs). For example, BK-AEnH may be induced by azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, or valsartan.

[0406] If BK-AEnH is drug-induced AE-nC1 Inh, then BK-AEnH may be drug-induced by beta-blockers.

[0407] When BK-AEnH is non-hereditary angioedema with normal C1 inhibitor (AE-nC1 Inh) and is hormonally induced, AE-nC1 Inh can be hormonally induced by hormonal contraceptives. In some embodiments, AE-nC1 Inh can be hormonally induced by estrogen. For example, the patient may be a woman and may be taking estrogen as a contraceptive.

[0408] dosage In any of the treatments of the invention described herein, KVD900 is orally administered in a therapeutically effective amount in the form of an orodispersible tablet.

[0409] KVD900 can be administered at a daily dose of about 5 mg to about 2000 mg per day. The term "daily dose" refers to the total amount administered in one day. More specifically, the compound of formula A can be administered at a daily dose of about 100 mg to about 1500 mg, about 300 mg to about 1800 mg, about 100 mg to about 1400 mg, about 200 mg to about 1200 mg, about 300 mg to about 1200 mg, about 600 mg to about 1200 mg, about 550 mg to about 1200 mg, about 500 mg to about 1000 mg, about 450 mg to about 900 mg, about 450 mg to about 600 mg, about 500 mg to about 700 mg (more specifically 600 mg), about 800 mg to about 1000 mg per day, about 900 mg to about 1400 mg (more specifically 1200 mg), or about 900 mg to about 1200 mg. In a specific embodiment, the daily dose is 300 mg. In another particular embodiment, the daily dosage is 500 mg. In another particular embodiment, the daily dosage is 550 mg. In another particular embodiment, the daily dosage is 600 mg. In another particular embodiment, the daily dosage is 900 mg. In another particular embodiment, the daily dosage is 1000 mg. In another particular embodiment, the daily dosage is 1100 mg. In another particular embodiment, the daily dosage is 1200 mg. In another particular embodiment, the daily dosage is 1500 mg. In another particular embodiment, the daily dosage is 1650 mg. In another particular embodiment, the daily dosage is 1800 mg.

[0410] The daily dose can be administered as one single dose or divided into multiple doses administered periodically during the day.Furthermore, each dose can be administered as a single dosage form or divided into multiple dosage forms.When multiple doses and multiple dosage forms are used, they can be administered simultaneously, separately, or sequentially.

[0411] In some embodiments, each single unit dosage form comprising KVD900 comprises about 250 mg of KVD900. Alternatively, each single unit dosage form comprising KVD900 comprises about 275 mg of KVD900. Alternatively, each single unit dosage form comprising KVD900 comprises about 300 mg of KVD900.

[0412] Each dose administered to a patient may contain 500 mg of KVD900 and may be subdivided into two tablets containing 250 mg of KVD900. Alternatively, each dose administered to a patient may contain 550 mg of KVD900 and may be subdivided into two tablets containing 275 mg of KVD900. Alternatively, each dose administered to a patient may contain 600 mg of KVD900 and may be subdivided into two tablets containing 300 mg of KVD900.

[0413] Alternatively, each dose may contain 250 mg of the compound and may be one tablet containing 250 mg of the compound, alternatively, each dose may contain 275 mg of the compound and may be one tablet containing 275 mg of the compound, alternatively, each dose may contain 300 mg of the compound and may be one tablet containing 300 mg of the compound.

[0414] In a particular embodiment, the patient is administered a daily dose of 500 mg, administered as a single dose. In a particular embodiment, the patient is administered a daily dose of 550 mg, administered as a single dose. In another particular embodiment, the patient is administered a daily dose of 600 mg, administered as a single dose.

[0415] In another particular embodiment, the patient is administered a daily dose of 1000 mg, administered as two separate doses. In particular, the second dose is administered 2-6 hours after the first dose, preferably about 3-6 hours after the first dose. Alternatively, the patient is administered a daily dose of 1100 mg, administered as two separate doses. In particular, the second dose is administered 2-6 hours after the first dose, preferably about 3-6 hours after the first dose. Alternatively, the patient is administered a daily dose of 1200 mg, administered as two separate doses. In particular, the second dose is administered 2-6 hours after the first dose, preferably about 3-6 hours after the first dose.

[0416] In another specific embodiment, the patient is administered a daily dose of 1500 mg, administered as three doses. In particular, the second dose is administered between 2 and 8 hours (e.g., about 2 hours, about 4 hours, about 6 hours, or about 8 hours) from the first dose, and the third dose is administered between about 4 and 16 hours (e.g., about 4 hours, about 6 hours, about 8 hours, about 12 hours, or about 16 hours) from the first dose. Alternatively, the patient is administered a daily dose of 1650 mg, administered as three doses. In particular, the second dose is administered between 2 and 8 hours (e.g., about 2 hours, about 4 hours, about 6 hours, or about 8 hours) from the first dose, and the third dose is administered between about 4 and 16 hours (e.g., about 4 hours, about 6 hours, about 8 hours, about 12 hours, or about 16 hours) from the first dose. Alternatively, the patient is administered a daily dose of 1800 mg, administered as three doses. Specifically, the second dose is administered between 2 and 8 hours (e.g., about 2 hours, about 4 hours, about 6 hours, or about 8 hours) after the first dose, and the third dose is administered between about 4 and 16 hours (e.g., about 4 hours, about 6 hours, about 8 hours, about 12 hours, or about 16 hours) after the first dose.

[0417] Further details of the treatment of the present invention Thus, in the treatment of the present invention, one or more orodispersible tablets according to the present invention may be administered to a patient in need of treatment, the patient being aged between 2 and under 18 years, more particularly between 2 and under 12 years. Alternatively or additionally, one or more orodispersible tablets according to the present invention may be administered to a patient in need of treatment, the patient having a laryngeal attack.

[0418] Alternatively, one or more orodispersible tablets according to the invention may be administered to a patient in need of treatment, where the patient is an elderly patient who has difficulty swallowing tablets (e.g. a patient over 70 years of age). Alternatively or additionally, one or more orodispersible tablets according to the invention may be administered to a patient in need of treatment, where the patient has laryngeal attacks.

[0419] As shown herein, KVD900 acts rapidly. Specifically, KVD900 is a potent inhibitor of plasma kallikrein activity and is highly effective in interrupting the positive feedback loop of the contact activation system between plasma kallikrein, prekallikrein, factor XII (FXII), and factor XIIa (FXIIa). The pharmacokinetic and pharmacodynamic data described herein (as well as WO2020 / 249977 and WO2020 / 249979) show that these effects are rapidly demonstrated after oral administration of an orodispersible tablet containing KVD900. Thus, the treatment of the present invention is fast acting and therefore particularly suitable for on-demand treatment of bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE).

[0420] The treatment of the present invention is particularly advantageous when the plasma concentration of KVD900 is at least 500 ng / mL. Plasma concentrations of at least 500 ng / mL may be observed following administration of a dose of at least about 60 mg (more specifically at least about 70 mg or about 80 mg) of KVD900.

[0421] The treatment according to the present invention provides rapid protection from HK (high molecular weight kininogen) cleavage, which is particularly suitable for prophylactically reducing the probability of a bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) and / or reducing the severity (or even stopping) of an ongoing bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack). As described herein, the treatment according to the present invention also has a sustained pharmacodynamic effect. The pharmacodynamic effect of KVD900 related to the treatment of bradykinin-mediated angioedema (e.g., BK-AEnH, preferably HAE) includes providing protection from HK cleavage, which may cause a bradykinin-mediated angioedema attack (e.g., BK-AEnH attack, preferably HAE attack) as described above. For example, KVD900 can provide protection from HK cleavage by at least (i) inhibiting plasma kallikrein, (ii) reducing the cleavage of plasma prekallikrein, and / or (iii) reducing the generation of factor XIIa from factor XII.

[0422] In each figure, the term "compound" refers to KVD900. [Brief description of the drawings]

[0423] [Figure 1] 1 shows the X-ray powder diffraction pattern of KVD900 produced in Example 1. [Diagram 2] PK curves showing the PK profiles of 500 mg and 600 mg ODT equivalent to the 600 mg FCT used in the Phase 2 study are shown. [Diagram 3] The LogPK curve of the PK curve is shown in FIG. [Figure 4] Geometric means of plasma concentrations following single doses of 500 mg and 600 mg ODT or 600 mg FCT are shown.

[0424] Each of the embodiments presented herein can be better understood by reference to the following examples, which are intended to illustrate the treatments provided herein and are not intended to be limiting in any way. Indeed, the scope of the invention is defined by the claims.

[0425] While certain example embodiments have been described herein, it will be apparent to those skilled in the art that various changes and modifications can be made, and such modifications are intended to fall within the scope of the appended claims. EXAMPLES

[0426] General Experimental Details In the examples below, the following abbreviations and definitions are used: [Table 1]

[0427] Example 1 Preparation of KVD900 A. 1-(4-hydroxymethyl-benzyl)-1H-pyridin-2-one 4-(Chloromethyl)benzyl alcohol (5.0 g, 31.93 mmol) was dissolved in acetone (150 mL). 2-Hydroxypyridine (3.64 g, 38.3 mmol) and potassium carbonate (13.24 g, 95.78 mmol) were added and the reaction mixture was stirred at 50° C. for 3 h, after which the solvent was removed in vacuo and the residue was dissolved in chloroform (100 mL). The solution was washed with water (30 mL), brine (30 mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica) using 3% MeOH / 97% CHCl3 as eluent to give a white solid (5.30 g, 24.62 mmol, 77% yield), which was identified as 1-(4-hydroxymethyl-benzyl)-1H-pyridin-2-one. [M+Na] + =238

[0428] B. 1-(4-Chloromethyl-benzyl)-1H-pyridin-2-one 1-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one (8.45 g, 39.3 mmol), anhydrous DCM (80 mL) and triethylamine (7.66 ml, 55.0 mmol) were cooled in an ice bath. Methanesulfonyl chloride (3.95 ml, 51.0 mmol) was added and stirred in the ice bath for 15 min. The ice bath was removed and stirring was continued at room temperature overnight. The reaction mixture was partitioned between DCM (100 mL) and saturated aqueous NH4Cl (100 mL). The aqueous layer was further extracted with DCM (2 x 50 mL) and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give 1-(4-chloromethyl-benzyl)-1H-pyridin-2-one (8.65 g, 36.6 mmol, 93% yield) as a pale yellow solid. [MH] + =234.1

[0429] C. Methyl 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate To a solution of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (320 mg, 1.88 mmol; CAS number 318496-66-1 (synthesized according to the method described in WO2012 / 009009)) and 1-(4-(chloromethyl)benzyl)pyridin-2(1H)-one (527 mg, 2.26 mmol) in DMF (5 mL) was added potassium carbonate (519 mg, 3.76 mmol) and heated at 60 °C overnight. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (2 x 100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (40 g column, 0-100% EtOAc in isohexane) to give the two regioisomers. The second isomer eluted from the column was collected to give methyl 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (378 mg, 1.01 mmol, 53.7% yield) as a colorless gum. [MH] + =368.2

[0430] D. 3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid To a solution of 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (3.77 g, 10.26 mmol) in THF (5 mL) and MeOH (5 mL) was added 2M NaOH solution (15.39 ml, 30.8 mmol) and stirred overnight. 1M HCl (50 mL) was added and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (1.22 g, 3.45 mmol, 33.6% yield) as a white powder. [MH] + =354.2

[0431] E. 3-Fluoro-4-methoxy-pyridine-2-carbonitrile Copper(I) cyanide (1.304 g, 14.56 mmol) was added to a solution of 2-bromo-3-fluoro-4-methoxypyridine (1 g, 4.85 mmol) in DMF (5 mL) in a large microwave vial. The reaction vial was sealed and heated to 100° C. for 16 h. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The thick suspension was sonicated, and additional water (40 mL) and EtOAc (2×50 mL) were added and sonicated to break up the precipitated solids. The combined layers were filtered through a plug of Celite, and the organic layer was isolated, washed with brine (50 mL), dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to give a pale green solid that was identified as the desired compound, 3-fluoro-4-methoxy-pyridine-2-carbonitrile (100 mg, 0.578 mmol, 12% yield).

[0432] F. (3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester 3-Fluoro-4-methoxy-pyridine-2-carbonitrile (100 mg, 0.578 mmol) was dissolved in anhydrous methanol (10 mL, 247 mmol) and nickel chloride hexahydrate (14 mg, 0.058 mmol) was added followed by di-tert-butyl dicarbonate (255 mg, 1.157 mmol). The resulting pale green solution was cooled to -5°C in an ice-salt bath and then sodium borohydride (153 mg, 4.05 mmol) was added in small portions while maintaining the reaction temperature at about 0°C. The dark brown solution was left stirring at 0°C and slowly warmed to room temperature and then stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness at 40°C to give a black residue which was diluted with DCM (10 mL) and washed with sodium bicarbonate (10 mL). An emulsion formed so the organic layer was separated and concentrated by phase separation cartridge. The crude was purified by chromatography eluting with EtOAc / isohexane to give the title compound (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester as a clear yellow oil (108 mg, 62% yield). [MH] + =257

[0433] G. C-(3-Fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride (3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester (108 mg, 0.358 mmol) was dissolved in isopropyl alcohol (1 mL), then HCl (6N in isopropyl alcohol) (1 mL, 0.578 mmol) was added at room temperature and stirred for 2 hours at 40° C. The reaction mixture was concentrated under reduced pressure, then triturated with ether, sonicated, and decanted to give a cream-colored solid (75 mg, 55% yield), which was identified as C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride. [MH] + =157

[0434] Example 1a N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide (compound of formula A) 3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (825 mg, 2.34 mmol) and C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride (450 mg, 2.34 mmol) were dissolved in DCM while cooling to 0° C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (627.0 mg, 3.27 mmol), HOBt (378.8 mg, 2.80 mmol) and triethylamine (1.63 mL, 1182 mmol) were added under stirring and the mixture was allowed to warm to room temperature and stirring was continued for 20 h. Chloroform (50 mL) was added and the mixture was washed with saturated aqueous NaHCO3 and concentrated under vacuum. The crude material was purified by chromatography eluting with methanol / DCM. The solvent was removed under vacuum and the resulting solid was triturated with diethyl ether and collected by filtration to give the compound of formula A. [MH] + =492.0

[0435] NMR (CD3OD)δ: 3.41 (3H, s), 4.03 (3H, s), 4.65 (2H, s), 4.72 (2H, d, J=2.3Hz), 5.24 (2H, s), 5.37 (2H, s), 6.44 (1H, td, J = 1.4, 6.8Hz), 6.62 (1H, d, J = 9.0Hz), 7.18-7.22 (1H, m), 7.31-7.38 (4H, m), 7.56-7.60 (1H, m), 7.75 (1H, dd, J = 1.9, 7.1Hz), 8.18 (1H, s), 8.27 (1H, d, J = 5.6Hz)ppm.

[0436] The XRPD diffraction pattern of KVD900 obtained by the above procedure is shown in FIG.

[0437] [Table 2]

[0438] Example 2 Preparation of an orodispersible tablet containing KVD900 of the present invention The ODT of KVD900 was prepared according to the following method.

[0439] method 1. Add KVD900, silicified microcrystalline cellulose, crospovidone, sucralose NF, silicon dioxide, and peppermint natural flavor to a blender and blend to form a powder mixture.

[0440] 2. Add granular mannitol, spray dried mannitol (e.g., Mannogem EZ®) to the powder mixture from step 1 in a blender and blend.

[0441] 3. Compress the final blend with external magnesium stearate as a lubricant into tablets.

[0442] [Table 3]

[0443] The orodispersible tablets of the present invention according to Table 1 have been manufactured on a 5 kg scale.

[0444] The results shown in Examples 3 to 8 are for orodispersible tablets of the invention according to Table 1.

[0445] Example 3 Disintegration and dissolution of orodispersible tablets of the present invention method Disintegration test The disintegration test was performed according to the following protocol: USP <701> and Ph Eur 2.9.1.

[0446] Place one tablet in each of the six tubes in the basket and operate the apparatus with USP water maintained at 37±2°C. At the end of the specified time (see table below), lift the basket from the liquid and observe the tablets. If there are still palpable tablet cores in the basket, begin the test procedure again with new tablets.

[0447] When the tablet has completely disintegrated, the value recorded in the results column is reported.

[0448] [Table 4]

[0449] Dissolution Test The dissolution test was performed according to the following protocol: USP <711> (Type II) and Ph Eur 2.9.3.

[0450] The specific conditions are as follows:

[0451] [Table 5]

[0452] The chromatographic conditions are as follows:

[0453] [Table 6] [Table 7] [Table 8]

[0454] The disintegration specification of the orodispersible tablets of the present invention is greater than 80% in less than about 15-20 seconds. <701> and meets the acceptance criteria of 45 seconds or less (NMT) based on the standard procedure of Ph Eur 2.9.1. It also meets the FDA guidance for orodispersible tablets for disintegration times of approximately 30 seconds or less when based on the United States Pharmacopeia (USP) disintegration test method or an alternative method, and meets the European Pharmacopoeia requirement for disintegration times of 3 minutes or less for orodispersible tablets.

[0455] The dissolution specification of the orodispersible tablets of the present invention is greater than 95% in about 45 minutes. <711> and meets the acceptance criterion of Q=80% at 45 minutes in the QC dissolution test according to the standard procedure of Ph Eur 2.9.3.

[0456] Example 4 Homogeneity and moisture content of orodispersible tablets of the present invention Uniformity of dosage units is measured according to the following protocol: USP <905> and can be obtained using mass variation according to Ph Eur 2.9.40.

[0457] Moisture content is USP <921> and by the Karl Fischer volumetric titration method using an apparatus for determining water content that complies with the requirements described in Method 1c / Ph Eur 2.5.12.

[0458] [Table 9]

[0459] The uniformity of the dosage units of the orodispersible tablets of the present invention is determined according to USP <905> and meets the acceptance criteria according to Ph Eur 2.9.40.

[0460] The moisture content of the orodispersible tablets of the present invention is determined according to USP <921> and meets the acceptance criteria according to method 1c / Ph Eur 2.5.12.

[0461] Example 5 Stability Test Stability of the ODT of 300 mg of KVD900 of the present invention Samples of KVD900 300 mg ODT were packaged in Aclar / Alu blister packs and stored at 25° C. / 60% RH. Testing on samples of KVD900 300 mg ODT was performed as described in Table 3.

[0462] [Table 10]

[0463] A second sample of KVD900 300 mg ODT was packaged in an Aclar / Alu blister pack and stored at 40° C. / 75% RH. Testing on the KVD900 300 mg ODT sample was performed as described in Table 4.

[0464] [Table 11]

[0465] Stability of the ODT of 250 mg of KVD900 of the present invention Samples of KVD900 250 mg ODT were packaged in Aclar / Alu blister packs and stored at 25° C. / 60% RH. Testing on samples of KVD900 250 mg ODT was performed as described in Table 5.

[0466] [Table 12]

[0467] A second sample of KVD900 250 mg ODT was packaged in an Aclar / Alu blister pack and stored at 40° C. / 75% RH. Testing on the KVD900 250 mg ODT sample was performed as described in Table 6.

[0468] [Table 13]

[0469] Example 6 Hardness test of the orodispersible tablets of the present invention The hardness of the dosage units is USP <1217> One tablet is placed into the tablet hardness tester and the hardness value is recorded. This analysis is repeated 10 times and the average value is reported.

[0470] result The hardness data of the orodispersible tablets of the present invention are shown in Tables 7-10.

[0471] [Table 14] [Table 15] [Table 16] [Table 17]

[0472] Example 7 Assay of the orodispersible tablets of the present invention and testing of related substances [Table 18] [Table 19]

[0473] result Assay and related substance data for the orodispersible tablets of the present invention are shown in Tables 12 to 15. These data support the superior stability of the orodispersible tablets of the present invention.

[0474] [Table 20] [Table 21] [Table 22] [Table 23]

[0475] The assay of the orodispersible tablets of the present invention meets the acceptance criteria of 90-110% of the label claim. "Label claim" refers to the dose on the label. Thus, for the 300 mg ODT in Tables 12 and 13, the 90-110% acceptance limit is 270 mg to 330 mg. For the 250 mg ODT in Tables 14 and 15, the 90-110% acceptance limit is 225 mg to 275 mg.

[0476] The related substance analysis of the orodispersible tablet of the present invention meets the acceptance criteria for individual impurities of NMT 0.5% and total impurities of NMT 2.0%.

[0477] Example 8 Microbial Thresholds The total viable aerobic organism count was determined according to USP <61> The test for specific microorganisms on E. coli is performed according to the pour plate method in accordance with USP / Ph Eur 2.6.12. <62> / Ph Eur 2.6.13.

[0478] result The microbial limit data for the orodispersible tablets of the present invention are shown in Tables 16-19.

[0479] [Table 24] [Table 25] [Table 26] [Table 27]

[0480] The microbial limit data in Tables 16 to 19 show that the orodispersible tablets of the present invention have a TAMC≦103 CFU / g, TYMC≦10 2 This indicates that the acceptance criteria are met: CFU / g and no E. coli present per gram.

[0481] Example 9 Phase 1 Study: Pharmacokinetic (PK) Study the purpose To compare the PK of single doses of KVD900 following administration of orodispersible tablets (ODT) or film-coated tablets in healthy adult subjects.A secondary objective was to determine the safety and tolerability of single doses of KVD900 following administration of ODT or film-coated tablets to healthy adult subjects under fasting conditions.

[0482] method The study was an open-label, randomized, single-dose, three-way crossover pharmacokinetic study.

[0483] Thirty-six healthy adult male and female subjects were enrolled.

[0484] In a three-period crossover design, a single dose of KVD900 was administered in two different strengths on day 1 of each period, either as an ODT under fasting conditions (arms A or B) or as a film-coated tablet under fasting conditions (arm C).

[0485] Treatment groups A to C were as follows:

[0486] Treatment arm A: 600 mg KVD900 ODT (2 × 300 mg ODT) at time 0 on day 1.

[0487] Treatment arm B: 500 mg KVD900 ODT at time 0 on day 1 (2 × 250 mg ODT).

[0488] Treatment group C: 600 mg KVD900 film-coated tablets (2 × 300 mg tablets, FCT) at time 0 on day 1.

[0489] The film-coated tablets were those used in the Phase 2 study described herein (NCT04208412).

[0490] There was a washout period of at least 4 days between the doses in periods 1 and 2 and the doses in periods 2 and 3.

[0491] Pharmacokinetic sampling of KVD900 was performed pre-dose and up to 48 hours post-dose.

[0492] The following PK parameters were calculated for KVD900 in plasma: AUC 0-t , AUC 0-inf , AUC %extrap , C max , T lag , T max , Kel, t1 / 2, CL / F, and Vz / F.

[0493] Analysis of variance (ANOVA) was performed using appropriate statistical procedures to calculate the AUC transformed into natural logarithm (ln). 0-t , AUC 0-inf , AUC %extrap , and C max The natural logarithm transformed AUC of KVD900 was used for the following comparisons: 0-t , AUC 0-inf , AUC %extrap , and C max We estimated 90% confidence intervals (Cis) for the ratios of least squares means (LSM): Treatment Group A and Treatment Group C Treatment Group B and Treatment Group C

[0494] A comparison of the pharmacokinetic properties of KVD900 following administration of an orodispersible tablet (ODT) or a film-coated tablet (FCT) according to the present invention is shown in Table 20.

[0495] Preliminary PK data from the Phase 1 study are shown in Figures 2 and 3. Specifically, the PK curves are shown in Figure 2, and the LogPK curves are shown in Figure 3. These figures demonstrate that the ODT of the present invention has a PK profile comparable to that of FCT, the safety and efficacy of which has been demonstrated in a Phase 2 study of KVD900.

[0496] [Table 28]

[0497] Further PK data from the Phase 1 study are provided below.

[0498] A comparison of the pharmacokinetic properties of plasma KVD900 following administration of a single oral dose of an orodispersible tablet (ODT) or a film-coated tablet (FCT) according to the invention is shown in Table 21.

[0499] Further PK data from the Phase 1 study is presented in Figure 4. Specifically, Figure 4 shows the geometric mean plasma concentrations following a single dose of ODT or FCT of KVD900.

[0500] [Table 29]

[0501] A summary of the statistical comparison of plasma KVD900 pharmacokinetic parameters following administration of a single dose of 600 mg FCT and 600 mg ODT is shown in Table 22.

[0502] [Table 30]

[0503] A summary of the statistical comparison of plasma KVD900 pharmacokinetic parameters following administration of a single dose of 500 mg ODT and 600 mg FCT is shown in Table 23.

[0504] [Table 31]

[0505] A single dose of 500 mg or 600 mg of KVD900 administered in ODT or FCT was well tolerated in healthy adult participants enrolled in the study.

[0506] These additional data support that the ODT of the present invention has a PK profile comparable to that of the FCT, the safety and efficacy of which has been demonstrated in a Phase 2 study of KVD900.

[0507] Example 10 Preparation of an alternative orodispersible tablet of the present invention Alternative ODTs of KVD900 according to Tables 24-26 were prepared according to the method described in Example 2.

[0508] [Table 32] [Table 33] [Table 34]

[0509] Orodispersible tablets of the present invention according to Table 26 (75 mg, 50 mg, 25 mg) were manufactured using a single blend on a 4 kg scale. This 4 kg blend was then divided to obtain approximately equal numbers of tablets for each strength. 75mg: 1800g (7,200 tablets) 50mg: 1400g (8,...

Claims

1. Orally dispersible tablets comprising KVD900 or a pharmaceutically acceptable salt and / or solvate thereof, wherein KVD900 is: 【Chemistry 1】 The orally dispersible tablet described above.

2. Approximately 100 mg to approximately 1000 mg of KVD900 or a pharmaceutically acceptable salt and / or solvate thereof, Approximately 200 mg to approximately 350 mg of KVD900 or a pharmaceutically acceptable salt and / or solvate thereof, Approximately 250 mg of KVD900 or a pharmaceutically acceptable salt and / or solvate thereof, Approximately 275 mg of KVD900 or a pharmaceutically acceptable salt and / or solvate thereof, An orally dispersible tablet according to claim 1, comprising approximately 300 mg of KVD900 or a pharmaceutically acceptable salt and / or solvate thereof.

3. It contains approximately 26 to 40% by weight of KVD900 or a pharmaceutically acceptable salt and / or solvate, Preferably, the orally dispersible tablet according to claim 1 comprises about 30% by weight of KVD900 or a pharmaceutically acceptable salt and / or solvate thereof.

4. The orally dispersible tablet contains one or more disintegrants present in about 1 to about 10% by weight of the orally dispersible tablet, or The one or more disintegrants are present in the orally dispersible tablet in an amount of approximately 4 to approximately 5% by weight, or The one or more disintegrants are present in the orally dispersible tablet in an amount of approximately 5% by weight. The orally dispersible tablet according to claim 1.

5. The one or more disintegrants are selected from polyvinylpyrrolidone (crospovidone), sodium starch glycolate, and croscarmellose sodium. Preferably, the orally dispersible tablet contains polyvinylpyrrolidone (crospovidone), The orally dispersible tablet according to claim 4.

6. The orally dispersible tablet contains one or more fillers present in approximately 30 to approximately 80% by weight, or The orally dispersible tablet contains one or more fillers present in approximately 50 to approximately 60% by weight, or The orally dispersible tablet contains one or more fillers present in approximately 53 to 54% by weight, The orally dispersible tablet according to claim 1.

7. The one or more fillers are selected from isomalt, lactose and its derivatives (e.g., lactose monohydrate, spray-dried lactose, anhydrous lactose), sorbitol, mannitol (e.g., granular mannitol, powdered mannitol, spray-dried mannitol (e.g., Mannogem EZ®))), sorbitol, sucrose, starch, pregelatinized starch, and mixtures thereof. Preferably, the orally dispersible tablet contains one or more fillers selected from granular mannitol and spray-dried mannitol (e.g., Mannogem EZ®). The orally dispersible tablet according to claim 6.

8. The orally dispersible tablet contains one or more binders present in an amount of about 5 to about 40% by weight, or The orally dispersible tablet contains one or more binders present in approximately 5 to approximately 30% by weight, or The orally dispersible tablet contains one or more binders present in approximately 5 to approximately 10% by weight, or The orally dispersible tablet contains one or more binders present in approximately 10% by weight, The orally dispersible tablet according to claim 1.

9. The one or more binders are selected from microcrystalline cellulose (e.g., silicified microcrystalline cellulose) and hydroxypropyl methylcellulose. Preferably, the orally dispersible tablet contains silicified microcrystalline cellulose. The orally dispersible tablet according to claim 8.

10. It further contains a fluidity improver, Preferably, the fluidity enhancer is present in an amount of about 0.5 to about 3% by weight of the orally dispersible tablet, or the fluidity enhancer is present in an amount of about 0.75% by weight of the orally dispersible tablet. The orally dispersible tablet according to claim 1.

11. The orally dispersible tablet according to claim 10, wherein the fluidity enhancer is silicon dioxide.

12. It further contains one or more sweeteners, Preferably, one or more sweeteners are present in an amount of about 0.1 to about 1% by weight of the orally dispersible tablet. The orally dispersible tablet according to claim 1.

13. The one or more sweeteners are selected from sucralose, aspartame, sugar derivatives, dextrose, polydextrose, xylitol, fructose, sucrose, lactitol, maltitol, and sodium saccharin, as well as mixtures thereof. Preferably, the orally dispersible tablet contains sucralose as a sweetener. The orally dispersible tablet according to claim 12.

14. It further contains one or more fragrances, Preferably, one or more of the fragrances are present in an amount of about 0.03 to about 0.4% by weight of the orally dispersible tablet. The orally dispersible tablet according to claim 1.

15. The one or more flavors mentioned above are selected from lemon flavor, mixed berry flavor, grape flavor, natural peppermint flavor, mint flavor, banana flavor, chocolate flavor, maple flavor, strawberry flavor, raspberry flavor, cherry flavor, orange flavor, and vanilla flavor, as well as mixtures thereof. In some cases, the orally dispersible tablet contains natural peppermint flavoring. The orally dispersible tablet according to claim 14.

16. An orally dispersible tablet according to claim 1, comprising one or more of the following: granular mannitol, spray-dried mannitol (e.g., Mannogem EZ®), silicified microcrystalline cellulose, polyvinylpyrrolidone (e.g., crospovidone), sucralose, silicon dioxide, and natural peppermint flavoring.

17. The orally dispersible tablet according to claim 1, which is debossed and, in some cases, has one or more score lines debossed.

18. The orally dispersible tablet is A) 30% by weight of KVD900, B) 26.87% by weight of granular mannitol, C) 26.87% by weight of spray-dried mannitol, D) 10.01% by weight of silicified microcrystalline cellulose, E) 5% by weight of crospovidone, F) 0.5% by weight of sucralose, G) 0.75% by weight of silicon dioxide, An orally dispersible tablet according to claim 1, comprising, wherein KVD900 is in the form of a free base.

19. An orally dispersible tablet according to claim 18, comprising 300 mg of KVD900.

20. An orally dispersible tablet according to claim 19, comprising 268.7 mg of granular mannitol, 268.7 mg of spray-dried mannitol, 100.1 mg of silicified microcrystalline cellulose, 50 mg of crospovidone, 5 mg of sucralose, and 7.5 mg of silicon dioxide.

21. An orally dispersible tablet according to claim 18, comprising 150 mg of KVD900.

22. An orally dispersible tablet according to claim 18, comprising 75 mg of KVD900.

23. The orally dispersible tablet according to claim 18, further comprising a small amount of magnesium stearate as a lubricant.

24. a) Approximately 26 to 40% by weight of KVD900, b) One or more fillers in an amount of approximately 30 to approximately 80% by weight, c) One or more binders in an amount of approximately 5 to approximately 40% by weight, d) A mixture comprising one or more disintegrants in an amount of about 1 to about 10% by weight.

25. a) Approximately 30% by weight of KVD900, b) Approximately 26.85% by weight of granular mannitol and approximately 26.85% by weight of spray-dried mannitol (e.g., Mannogem EZ®), c) Approximately 10% by weight of silicified microcrystalline cellulose, d) The mixture according to claim 24, comprising about 5% by weight of polyvinylpyrrolidone (e.g., crospovidone).

26. A method for producing an orally dispersible tablet according to any one of claims 1 to 23 from a mixture according to claim 24 or 25, the method comprising blending the components of the mixture to form a powder mixture and compressing it into an orally dispersible tablet.

27. A kit for providing a predetermined dose of KVD900, comprising two or more orally dispersible tablets according to any one of claims 1 to 23.

28. The kit according to claim 27, comprising two orally dispersible tablets.

29. An orally dispersible tablet according to any one of claims 1 to 17 for on-demand treatment of bradykinin-mediated angioedema in patients who require on-demand treatment of bradykinin-mediated angioedema.

30. The orally dispersible tablet according to claim 29, wherein the bradykinin-mediated angioedema is hereditary angioedema (HAE), or the bradykinin-mediated angioedema is non-hereditary bradykinin-mediated angioedema.

31. The orally dispersible tablet according to claim 29, wherein the patient has a laryngeal seizure.

32. The tablet comprises a dose of approximately 500 mg of KVD900 or a pharmaceutically acceptable salt and / or solvate thereof. Depending on the circumstances, each dose may be subdivided into two orally dispersible tablets, each containing 250 mg of KVD900. The orally dispersible tablet according to claim 29.

33. The tablet comprises a dose of approximately 550 mg of KVD900 or a pharmaceutically acceptable salt and / or solvate thereof. Depending on the circumstances, each dose may be subdivided into two orally dispersible tablets, each containing 275 mg of KVD900. The orally dispersible tablet according to claim 29.

34. The tablet comprises a dose of approximately 600 mg of KVD900 or a pharmaceutically acceptable salt and / or solvate thereof. Depending on the circumstances, each dose may be subdivided into two orally dispersible tablets, each containing 300 mg of KVD900. The orally dispersible tablet according to claim 29.

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