PDE9 inhibitors for treatment of sickle cell disease

Abstract

The present application relates to PDE9 inhibitors for the treatment of sickle cell disease. The present disclosure relates to a PDE9 inhibitor, a pharmaceutical composition comprising the PDE9 inhibitor. In one aspect, an oral pharmaceutical composition comprises from about 100 mg to about 300 mg of 6-[(3S, 4S)-4-methyl-1-(pyrimidin-2-ylmethyl) pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo [1, 5-a] pyrazin-8-one (Compound 1), or a pharmaceutically acceptable salt, solvate, or polymorph thereof; a filler selected from the group consisting of from about 4% to about 6% by weight of pregelatinized starch and / or from about 15% to about 50% by weight of microcrystalline cellulose; and a processing aid selected from the group consisting of from about 1% to about 2.5% by weight of colloidal silica and / or from about 0.5% to about 1.5% by weight of magnesium stearate, the pharmaceutical composition being in the form of a solid tablet suitable for administration to a patient.

Description

[0001] This application is a divisional application of an application filed on August 29, 2019, with application number 201980071992.8 and invention name “PDE9 inhibitors for treating sickle cell disease”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 725,725, filed on August 31, 2018, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to methods of making and using pharmaceutical compositions comprising cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 9 inhibitors (hereinafter referred to as PDE9 inhibitors). Background Art

[0004] Sickle cell disease (SCD, also known as sickle cell anemia (SCA)) is a genetic disorder that leads to a vaso-occlusive process and is responsible for the majority of deaths in SCD patients. SCD disease is caused by point mutations in the hemoglobin (HBB) gene that produce abnormal sickle hemoglobin (HbS or HbSS), which polymerizes and generates hard and sticky sickle-shaped red blood cells. Sickle-shaped red blood cells lead to chronic inflammation, increased cell adhesion, oxidative stress, and endothelial dysfunction, ultimately leading to a vaso-occlusive process.

[0005] There is currently no cure for SCD. Options include blood transfusions and treatment with the anticancer agent hydroxyurea. Blood transfusions correct anemia by increasing the number of normal, non-sickled red blood cells in circulation. Regular transfusion therapy can help prevent recurrent strokes in high-risk children. Hydroxyurea (HU) has been approved for the treatment of SCD and has been shown to reduce the frequency of painful crises and hospitalizations. Unfortunately, HU is often poorly tolerated, and its widespread use is limited by concerns about its potential effects on fertility and reproduction; challenges in achieving and maintaining effective doses due to its hematologic toxicity; and the need for monthly monitoring (Heeney et al., Pediatr Clin North Am., 2008, 55(2):483). In fact, it is estimated that only one-quarter of adult patients, and possibly even fewer, are treated with this drug (Stettler et al., JAMA, 2015, 313:1671). Furthermore, due to these challenges, many patients are given subeffective doses of HU. Therefore, there is an urgent need for new, safe, and effective treatments that can be safely used worldwide to prevent the morbid complications of SCD in patients of all ages.

[0006] There is still a need for treatment of SCD. Summary of the invention

[0007] The present disclosure provides methods of making and using Compound 1 and / or a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt or polymorph thereof for treating sickle cell disease.

[0008] In one aspect described herein, an oral pharmaceutical composition comprises: about 100 mg to about 300 mg of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one (Compound 1) or a pharmaceutically acceptable salt, solvate or polymorph thereof; a filler selected from about 4% to about 6% by weight of pregelatinized starch and / or about 15% to about 50% by weight of microcrystalline cellulose; and a processing aid selected from about 1% to about 2.5% by weight of colloidal silicon dioxide and / or about 0.5% to about 1.5% by weight of magnesium stearate, wherein the pharmaceutical composition is in the form of a solid tablet suitable for administration to a patient. In some embodiments, the composition has a friability of no more than about 0.3% weight loss, as determined by the USP friability and USP disintegration test, and a disintegration time of less than about 15 minutes. In some embodiments, the composition has at least one of a friability of no more than about 0.3% weight loss or a disintegration time of less than about 15 minutes, as determined by the USP friability and USP disintegration test. In some embodiments, the pharmaceutical composition further comprises hydroxypropyl cellulose (HPC). In some embodiments, the hydroxypropyl cellulose (HPC) is present in an amount of about 0.4% to about 0.5% by weight. In some embodiments, the hydroxypropyl cellulose (HPC) is present in an amount of about 0.5% by weight. In some embodiments, the composition has a hardness of about 10 kPa and / or a thickness of about 4.50 to about 4.80 mm. In some embodiments, about 100 mg, 200 mg, or about 300 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or polymorph thereof is contained. In some embodiments, about 300 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or polymorph thereof is included. In some embodiments, about 5% pregelatinized starch is included by weight. In some embodiments, about 20% microcrystalline cellulose is included by weight. In some embodiments, about 2% colloidal silicon dioxide is included by weight. In some embodiments, about 1% magnesium stearate is included by weight. In some embodiments, the composition comprises pregelatinized starch, colloidal silicon dioxide and magnesium stearate in a weight ratio of 5:2:1. In some embodiments, a coating selected from an enteric coating or an Opadry® II white film coating is also included. In some embodiments, the coating accounts for about 2.5% by weight of the total tablet.

[0009] In another aspect described herein, an oral pharmaceutical composition comprises: about 100 mg to about 300 mg of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one (Compound 1) or a pharmaceutically acceptable salt, solvate or polymorph thereof; about 5% by weight of pregelatinized starch; about 20% by weight of microcrystalline cellulose; about 2% by weight of colloidal silicon dioxide; and about 1% by weight of magnesium stearate, the pharmaceutical composition being in the form of a solid tablet. In some embodiments, the composition has a friability of no more than about 0.3% weight loss and / or a disintegration time of less than about 15 minutes as determined by the USP friability and USP disintegration tests. In some embodiments, about 0.5% by weight of hydroxypropyl cellulose (HPC) is also included. An oral pharmaceutical composition comprises 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one (Compound 1) or a pharmaceutically acceptable salt, solvate or polymorph thereof; the pharmaceutical composition is in the form of a solid tablet. In some embodiments, it also comprises at least a filler. In some embodiments, the filler is microcrystalline cellulose or pregelatinized starch. In some embodiments, the composition comprises about 4% to about 6% pregelatinized starch by weight. In some embodiments, the composition comprises about 15 mg to about 25 mg of pregelatinized starch per tablet. In some embodiments, the composition also comprises at least a processing aid. In some embodiments, the processing aid is colloidal silicon dioxide and / or magnesium stearate. In some embodiments, the composition comprises colloidal silicon dioxide of about 1% to about 2.5% by weight and / or magnesium stearate of about 0.5% to about 1.5% by weight. In some embodiments, the composition comprises colloidal silicon dioxide of about 6 mg to about 8 mg and / or magnesium stearate of about 2 mg to about 4 mg per tablet. In some embodiments, microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide and magnesium stearate are included. In some embodiments, a coating selected from enteric coating or Opadry® II white film coating is also included. In some embodiments, the coating accounts for about 2.5% by weight of the tablet. In some embodiments, the composition comprises about 20 mg to about 40 mg of the coating per tablet. In some embodiments, the composition comprises pregelatinized starch, colloidal silicon dioxide and magnesium stearate in a weight ratio of 5:2:1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or polymorph thereof, is present in an amount of about 30 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg.In some embodiments, compound 1 or a pharmaceutically acceptable salt or polymorph thereof is present in the composition in an amount of about 50% to about 80% or about 60% to about 75% by weight of the solid tablet. In some embodiments, compound 1 or a pharmaceutically acceptable salt or polymorph thereof is present in the composition in an amount of 65%, about 68%, about 70%, about 72% or about 75% by weight of the solid tablet. In some embodiments, the composition has friability and / or disintegration time. In some embodiments, the composition has a friability of no more than 0.3% weight loss and / or a disintegration time of less than about 15 minutes, and the friability and disintegration time are determined by USP testing. In some embodiments, the composition further comprises 0.4% to about 0.5% hydroxypropyl cellulose by weight.

[0010] In another aspect described herein, a method for treating sickle cell disease in a subject in need thereof comprises administering any of the pharmaceutical compositions described above. In some embodiments, the pharmaceutical composition is taken with food. In some embodiments, the pharmaceutical composition is administered once a day, twice a day, or three times a day. In some embodiments, the pharmaceutical composition is administered once a day. In some embodiments, the pharmaceutical composition is administered for at least 4 weeks, 12 weeks, 16 weeks, or 24 weeks. In some embodiments, the method further comprises administering hydroxyurea (HU). In some embodiments, the method comprises administering to the subject from about 0.3 mg / kg of subject weight to about 6.0 mg / kg of subject weight or from about 0.3 mg / kg of subject weight to about 1.0 mg / kg of subject weight of Compound 1 or a pharmaceutically acceptable salt or polymorph thereof per day or per dose. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 Compound 1 was shown to reduce myeloid and neutrophil inflammatory markers in the lungs of Townes mice.

[0012] Figure 2 Compound 1 was shown to reduce the adhesion of SCD patient neutrophils to endothelial cell-lined microfluidic chambers in vitro.

[0013] Figure 3 Compound 1 was shown to reduce the expression of CD11a, CD11b and CD18 integrins on neutrophils from SCD patients.

[0014] Figure 4 A comparison chart between Compound 1 and hydroxyurea is shown, demonstrating the superior efficacy of Compound 1.

[0015] Figure 5Shown are the results of a study comparing Compound 1 (30 mg / kg) in the Townes SCD model.

[0016] Figure 6 Shown are the results of a study comparing Compound 1 (30 mg / kg) in the Townes SCD model.

[0017] Figure 7 The clinical study design for Compound 1 is shown.

[0018] Figure 8 Described without limitation is a representative sampling of screen shots for use in a mobile device running software designed to track the effects of a drug on a person. DETAILED DESCRIPTION

[0019] Phosphodiesterases (PDEs) are a family of enzymes at the cellular level that degrade cyclic nucleotides and thus regulate second messengers throughout the body. PDEs represent attractive drug targets as evidenced by the numerous compounds that have been introduced into clinical trials and the market, respectively. PDEs are encoded by 21 genes and are functionally classified into 11 families that differ in their kinetic properties, substrate selectivity, expression, localization pattern, activation, regulators, and inhibitor sensitivity. The function of PDEs is to degrade cyclic nucleoside monophosphates, cyclic adenosine monophosphate (cAMP) and / or cyclic guanosine monophosphate (cGMP), which are important intracellular mediators involved in many important processes, including the control of neurotransmission and the contraction and relaxation of smooth muscle.

[0020] PDE9 is cGMP-specific (for cAMP, K m cAMP>1000x), and is hypothesized to be a key player in regulating cGMP levels because PDE9 has the lowest Km among PDEs for this nucleotide. PDE9 is expressed at low levels throughout the brain and has the potential to regulate basal cGMP.

[0021] In the periphery, PDE9 expression is highest in prostate, intestine, kidney, and hematopoietic cells, enabling therapeutic potential in various non-CNS indications.

[0022] In the present disclosure, pharmaceutical compositions comprising a PDE9 inhibitor are designed for the treatment of sickle cell disease (SCD).

[0023] Compounds of the Disclosure In the context of the present disclosure, a compound is considered to be a PDE9 inhibitor if the amount required to achieve a 50% inhibition level of PDE9 is 10 micromolar or less, preferably less than 9 micromolar, such as 8 micromolar or less, such as 7 micromolar or less, such as 6 micromolar or less, such as 5 micromolar or less, such as 4 micromolar or less, such as 3 micromolar or less, more preferably 2 micromolar or less, such as 1 micromolar or less, and in particular 500 nM or less. In a preferred embodiment, the amount of a PDE9 inhibitor required to achieve an IC50 level of PDE9 is 400 nM or less, such as 300 nM or less, 200 nM or less, 100 nM or less, or even 80 nM or less, such as 50 nM or less, for example 25 nM or less.

[0024] In this application, the symbol IC 50 and IC50 are used interchangeably.

[0025] In some embodiments, the PDE9 inhibitors of the present disclosure have low or no blood-brain barrier penetration. For example, the ratio of the concentration of the PDE9 inhibitor of the present disclosure in the brain to its concentration in plasma (brain / plasma ratio) may be less than about 0.50, about 0.40, about 0.30, about 0.20, about 0.10, about 0.05, about 0.04, about 0.03, about 0.02, or about 0.01. In some embodiments, the brain / plasma ratio is measured 30 min or 120 min after administration of the PDE9 inhibitor.

[0026] In some embodiments, the PDE9 inhibitor may be any imidazopyrazinone PDE9 inhibitor disclosed in WO 2013 / 053690 and / or any imidazotriazinone PDE9 inhibitor disclosed in WO 2013 / 110768, the contents of each of which are incorporated herein by reference in their entirety.

[0027] In some embodiments, the PDE9 inhibitor is Compound 1 or a pharmaceutically acceptable salt, co-crystal, solvate or polymorph thereof. The racemic form of Compound 1 and the anhydrous form of Compound 1 have been described in WO 2013 / 053690 and WO 2017 / 005786. In some embodiments, the PDE9 inhibitor is 6-[(3S, 4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one (Compound 1), or a pharmaceutically acceptable salt or polymorph thereof. In some embodiments, the anhydrous form of Compound 1 has the following structure:

[0028]

[0029] 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one; Formula C 21 H 26 N6O2; calculated molecular weight is about 394 g / mol. In some embodiments, Compound 1 is enantiomerically pure or substantially enantiomerically pure.

[0030] Pharmaceutical composition The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of any PDE9 inhibitor and a pharmaceutically acceptable carrier or diluent. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or polymorph thereof, and a pharmaceutically acceptable carrier or diluent or excipient.

[0031] Pharmaceutically acceptable salts The present disclosure also includes salts of PDE9 inhibitors, generally pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts. Acid addition salts include salts of inorganic acids and organic acids.

[0032] Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, sulfamic acid, nitric acid, etc. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, itaconic acid, lactic acid, methanesulfonic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylene salicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, theophylline acetic acid, and 8-halotheophylline, such as 8-bromotheophylline, etc. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Berge, SM et al., J. Pharm. Sci. 1977, 66, 2, the contents of which are incorporated herein by reference.

[0033] Additionally, the compounds of the disclosure may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present disclosure.

[0034] In some embodiments, the pharmaceutical composition comprises a solvated, unsolvated, or crystalline form of Compound 1. In some embodiments, Compound 1 is present in an unsolvated form. In some embodiments, Compound 1 is present in a crystalline form. In some embodiments, Compound 1 is present in a monohydrate crystalline form.

[0035] preparation The compound of the present disclosure can be used alone or in combination with a pharmaceutically acceptable carrier, diluent or excipient in a single dose or multiple doses. The pharmaceutical composition according to the present disclosure can be prepared with a pharmaceutically acceptable carrier or diluent and any other known adjuvant and excipient according to conventional techniques, such as those disclosed in Remington: The Science and Practice of Pharmacy, the 22nd edition, Gennaro, Mack Publishing Co., Easton, PA, 2013.

[0036] The pharmaceutical composition can be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) routes. It should be understood that the route will depend on the general health and age of the subject to be treated, the nature of the condition to be treated, and the active ingredient. In some embodiments, the pharmaceutical composition is formulated for oral administration to a subject. In some embodiments, the pharmaceutical composition is formulated as a tablet or pill. In some embodiments, the pharmaceutical composition is formulated as a solid tablet suitable for oral administration to a subject.

[0037] Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings, or they may be formulated to provide controlled release of the active ingredient, such as sustained release or extended release, according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs, which may be prepared either as is or in solid form for reconstitution prior to use.

[0038] Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injection solutions, dispersions, suspensions or emulsions, and sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Other suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, skin patches and implants.

[0039] The present disclosure also provides a process for preparing a pharmaceutical composition comprising mixing a therapeutically effective amount of a compound of the present disclosure with at least one pharmaceutically acceptable carrier or diluent.

[0040] The compounds of the present disclosure are generally used as free substances or as pharmaceutically acceptable salts thereof. Such salts are prepared in a conventional manner by treating a solution or suspension of a compound of the present disclosure with a pharmaceutically acceptable acid. Representative examples of suitable organic and inorganic acids are described above.

[0041] For parenteral administration, solutions of the compounds of the present disclosure in sterile aqueous solution, aqueous propylene glycol solution, aqueous vitamin E solution, or sesame or peanut oil may be used. Where necessary, such aqueous solutions should be appropriately buffered, and the liquid diluent first made isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. Compounds of the present disclosure may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.

[0042] Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, carclazyte, sucrose, cyclodextrin, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid and low alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or mixed with wax. Then, the pharmaceutical composition formed by combining the compound of the present disclosure with a pharmaceutically acceptable carrier can be easily administered in various dosage forms suitable for the disclosed route of administration. The preparation can be conveniently present in unit dosage form by methods known in the pharmaceutical field.

[0043] Pharmaceutical compositions of the present disclosure suitable for oral administration can be provided in discrete units (such as capsules or tablets), each discrete unit containing a predetermined amount of active ingredient and optionally suitable excipients. In addition, oral formulations can be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions.

[0044] If a solid carrier is used for oral administration, the preparation can be tableted, placed in a hard gelatin capsule in the form of a powder or pill, or the preparation can be in the form of a lozenge or troche. The amount of the solid carrier will vary widely, but the range will be from about 25 mg to about 1 g per dosage unit. In some embodiments, the solid carrier will be from about 10 mg to about 150 mg per dosage unit.In some embodiments, a solid carrier will be from about 10 mg to about 20 mg, from about 10 mg to about 30 mg, from about 10 mg to about 40 mg, from about 10 mg to about 50 mg, from about 10 mg to about 60 mg, from about 10 mg to about 70 mg, from about 10 mg to about 80 mg, from about 10 mg to about 90 mg, from about 10 mg to about 100 mg, from about 10 mg to about 125 mg, from about 10 mg to about 150 mg, from about 20 mg to about 30 mg, from about 20 mg to about 40 mg, from about 20 mg to about 50 mg, from about 20 mg to about 60 mg, from about 20 mg to about 70 mg, from about 20 mg to about 80 mg, from about 20 mg to about 90 mg, from about 20 mg to about 100 mg, from about 20 mg to about 125 mg, from about 20 mg to about 150 mg, from about 20 mg to about 40 mg, from about 30 mg to about 50 mg, from about 30 mg to about 60 mg, from about 30 mg to about 70 mg, from about 30 mg to about 80 about 30 mg to about 90 mg, about 30 mg to about 100 mg, about 30 mg to about 125 mg, about 30 mg to about 150 mg, about 40 mg to about 50 mg, about 40 mg to about 60 mg, about 40 mg to about 70 mg, about 40 mg to about 80 mg, about 40 mg to about 90 mg, about 40 mg to about 100 mg, about 40 mg to about 125 mg, about 40 mg to about 150 mg, about 50 mg to about 60 mg, about 50 mg to about 70 mg, about 50 mg to about 80 mg, about 50 mg to about 90 mg, about 50 mg to about 100 mg, about 50 mg to about 125 mg, about 50 mg to about 150 mg, about 60 mg to about 70 mg, about 60 mg to about 80 mg, about 60 mg to about 90 mg, about 60 mg to about 100 mg, about 60 mg to about 125 mg, about 60 mg to about 150 mg, about 70 mg to about 80 mg In some embodiments, the present invention relates to an oral dosage form of the present invention. The oral dosage form may be selected from the group consisting of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 24, 36, 48, 51, 62, 78, 79, 80, 800, 800, 800, 800, 1000, 1200, 15 ...500, 1000, 1000, 1500, 1500, 1500, 1500In some embodiments, the solid carrier will be about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, or about 150 mg. In some embodiments, the solid carrier will be at least about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or about 125 mg. In some embodiments, the solid carrier will be up to about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, or about 150 mg per dosage unit. In some embodiments, the solid carrier will be about 150 mg to about 1,000 mg per dosage unit.In some embodiments, a solid carrier will be from about 150 mg to about 175 mg, from about 150 mg to about 200 mg, from about 150 mg to about 300 mg, from about 150 mg to about 400 mg, from about 150 mg to about 500 mg, from about 150 mg to about 600 mg, from about 150 mg to about 700 mg, from about 150 mg to about 800 mg, from about 150 mg to about 900 mg, from about 150 mg to about 1,000 mg, from about 175 mg to about 200 mg, from about 175 mg to about 300 mg, from about 175 mg to about 400 mg, from about 175 mg to about 500 mg, from about 175 mg to about 600 mg, from about 175 mg to about 700 mg, from about 175 mg to about 800 mg, from about 175 mg to about 900 mg, from about 175 mg to about 1,000 mg, from about 200 mg to about 300 mg, from about 200 mg to about 400 mg, about 200 mg to about 500 mg, about 200 mg to about 600 mg, about 200 mg to about 700 mg, about 200 mg to about 800 mg, about 200 mg to about 900 mg, about 200 mg to about 1,000 mg, about 300 mg to about 400 mg, about 300 mg to about 500 mg, about 300 mg to about 600 mg, about 300 mg to about 700 mg, about 300 mg to about 800 mg, about 300 mg to about 900 mg, about 300 mg to about 1,000 mg, about 400 mg to about 500 mg, about 400 mg to about 600 mg, about 400 mg to about 700 mg, about 400 mg to about 800 mg, about 400 mg to about 900 mg, about 400 mg to about 1,000 mg, about 500 mg to about 600 mg, about 500 mg to about 700 In some embodiments, the present invention relates to an oral dosage form of at least one embodiment of the present invention. The oral dosage form of at least one embodiment of the present invention is at least one embodiment of the present invention.In some embodiments, the solid carrier will be about 150 mg, about 175 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg. In some embodiments, the solid carrier will be at least about 150 mg, about 175 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg. In some embodiments, the solid carrier will be at most about 175 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg per dosage unit.

[0045] In some embodiments, the solid carrier will be about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or about 1 g per dosage unit. If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable solution (such as an aqueous or non-aqueous liquid suspension or solution).

[0046] In some embodiments, the solid carrier will be from about 1 g to about 2 g per dosage unit. In some embodiments, the solid carrier will be from about 1 g to about 1.1 g, from about 1 g to about 1.2 g, from about 1 g to about 1.3 g, from about 1 g to about 1.4 g, from about 1 g to about 1.5 g, from about 1 g to about 1.6 g, from about 1 g to about 1.7 g, from about 1 g to about 1.8 g, from about 1 g to about 1.9 g, from about 1 g to about 2 g, from about 1.1 g to about 1.2 g, from about 1.1 g to about 1.3 g, from about 1.1 g to about 1.4 g, from about 1.1 g to about 1.5 g, from about 1.2 g to about 1.6 g, from about 1.1 g to about 1.7 g, from about 1.1 g to about 1.8 g, from about 1.1 g to about 1.9 g, g, about 1.2 g to about 1.8 g, about 1.2 g to about 1.9 g, about 1.2 g to about 2 g, about 1.3 g to about 1.4 g, about 1.3 g to about 1.5 g, about 1.3 g to about 1.6 g, about 1.3 g to about 1.7 g, about 1.3 g to about 1.8 g, about 1.3 g to about 1.9 g, about 1.3 g to about 2 g, about 1.4 g to about 1.5 g, about 1.4 g to about 1.6 g, about 1.4 g to about 1.7 g, about 1.4 g to about 1.8 g, about 1.4 g to about 1.9 g, about 1.4 g to about 2 g, about 1.5 g to about 1.6 g, about 1.5 g to about 1.7 g, about 1.5 g to about 1.8 g, about 1.5 g to about 1.9 g, about 1.5 g to about 2 g, about 1.6 g to about 1.7 g, about 1.6 g to about 1.8 g In some embodiments, the solid carrier will be about 1 g, about 1.1 g, about 1.2 g, about 1.3 g, about 1.4 g, about 1.5 g, about 1.6 g, about 1.7 g, about 1.8 g, about 1.9 g, or about 2 g. In some embodiments, the solid carrier will be at least about 1 g, about 1.1 g, about 1.2 g, about 1.3 g, about 1.4 g, about 1.5 g, about 1.6 g, about 1.7 g, about 1.8 g, or about 1.9 g.In some embodiments, the solid carrier will be up to about 1.1 g, about 1.2 g, about 1.3 g, about 1.4 g, about 1.5 g, about 1.6 g, about 1.7 g, about 1.8 g, about 1.9 g, or about 2 g per dosage unit.

[0047] The pharmaceutical composition of the present disclosure can be prepared by conventional methods in the art. For example, tablets can be prepared by mixing the active ingredient with a common adjuvant and / or diluent and then compressing the mixture in a conventional tablet press. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, etc. Any other adjuvant or additive commonly used for such purposes, such as coloring agents, flavoring agents, preservatives, etc., can be used as long as they are compatible with the active ingredient.

[0048] The pharmaceutical composition comprises PDE9 inhibitor compound 1. The pharmaceutical composition comprises at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% by weight of the PDE9 inhibitor of the present disclosure. The pharmaceutical composition comprises at least about 1% to about 90% by weight of the PDE9 inhibitor of the present disclosure. The pharmaceutical composition comprises at least about 1% to about 10%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about About 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90%, or about 80% to about 90%. The pharmaceutical composition contains at least about 1%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%. The pharmaceutical composition comprises at least about 1%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%. The pharmaceutical composition comprises at least or at most about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% of the PDE9 inhibitor of the present disclosure by weight. The pharmaceutical composition comprises at least about 90% to about 99.9% of the PDE9 inhibitor of the present disclosure by weight.The pharmaceutical composition comprises at least about 90% to about 91%, about 90% to about 92%, about 90% to about 93%, about 90% to about 94%, about 90% to about 95%, about 90% to about 96%, about 90% to about 97%, about 90% to about 98%, about 90% to about 99%, about 90% to about 99.9%, about 91% to about 92%, about 91% to about 93%, about 91% to about 94%, about 91% to about 95%, about 91% to about 96%, about 91% to about 97%, about 91% to about 98%, about 91% to about 99%, about 91% to about 99.9%, about 92% to about 93%, about 92% to about 94%, about 92% to about 95%, about 92% to about 96%, about 92% to about 97%, about 92% to about 98%, about 92% to about 99%, about 92% to about 99.9%, about 93% to about 93%, about 92% to about 94%, about 92% to about 95%, about 92% to about 96%, about 92% to about 97%, about 92% to about 98%, about 92% to about 99%, about 92% to about 99.9%, about 93% to about To about 94%, about 93% to about 95%, about 93% to about 96%, about 93% to about 97%, about 93% to about 98%, about 93% to about 99%, about 93% to about 99.9%, about 94% to about 95%, about 94% to about 96%, about 94% to about 97%, about 94% to about 98%, about 94% to about 99%, about 94% to about 99.9%, about 95% to about 96%, about 95% to about 97%, about 95% to about 98%, about 95% to about 99%, about 95% to about 99.9%, about 96% to about 97%, about 96% to about 98%, about 96% to about 99%, about 96% to about 99.9%, about 97% to about 98%, about 97% to about 99%, about 97% to about 99.9%, about 98% to about 99%, about 98% to about 99.9%, or about 99% to about 99.9%. The pharmaceutical composition comprises at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 99.9%. The pharmaceutical composition comprises at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99%. The pharmaceutical composition comprises at least about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 99.9% of the PDE9 inhibitor of the present disclosure by weight. The pharmaceutical composition comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the PDE9 inhibitor of the present disclosure by weight.

[0049] In some embodiments, compound 1 or a pharmaceutically acceptable salt or polymorph thereof is formulated as a pharmaceutical composition for oral administration. For example, it can be in the form of a solid tablet. The composition for oral administration comprises at least a filler and / or a processing aid. The processing aid can be a glidant or a lubricant. The composition for oral administration may also include a coating. In some embodiments, the composition for oral administration comprises microcrystalline cellulose and / or pregelatinized starch as a filler. In some embodiments, the composition for oral administration comprises colloidal silicon dioxide and / or magnesium stearate as a processing aid. In some embodiments, the composition for oral administration comprises Opadry® II white film coating. Opadry® II is a high-productivity, water-soluble, pH-independent complete dry powder film coating system containing polymers, plasticizers and pigments that allow immediate disintegration for rapid and effective release. In some embodiments, the composition for oral administration comprises purified water, which is removed during processing.

[0050] In some embodiments, the tablet comprises a coating of about 5% to about 20% by weight of the total weight of the tablet. In some embodiments, the tablet comprises a coating of about 0.5% to about 10%. In some embodiments, the tablet comprises about 0.5% to about 1%, about 0.5% to about 2%, about 0.5% to about 3%, about 0.5% to about 4%, about 0.5% to about 5%, about 0.5% to about 6%, about 0.5% to about 7%, about 0.5% to about 8%, about 0.5% to about 9%, about 0.5% to about 10%, about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about 1% to about 5%, about 1% to about 6%, about 1% to about 7%, about 1% to about 8%, about 1% to about 9%, about 1% to about 10%, about 2% to about 3%, about 2% to about 4%, about 2% to about 5%, about 2% to about 6%, about 2% to about 7%, about 2% to about 8%, about 2% to about 9%, From about 2% to about 10%, from about 3% to about 4%, from about 3% to about 5%, from about 3% to about 6%, from about 3% to about 7%, from about 3% to about 8%, from about 3% to about 9%, from about 3% to about 10%, from about 4% to about 5%, from about 4% to about 6%, from about 4% to about 7%, from about 4% to about 8%, from about 4% to about 9%, from about 4% to about 10%, from about 5% to about 6%, from about 5% to about 7%, from about 5% to about 8%, from about 5% to about 9%, from about 5% to about 10%, from about 6% to about 7%, from about 6% to about 8%, from about 6% to about 9%, from about 6% to about 10%, from about 7% to about 8%, from about 7% to about 9%, from about 7% to about 10%, from about 8% to about 9%, from about 8% to about 10%, or from about 9% to about 10% coating. In some embodiments, the tablet comprises about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% coating. In some embodiments, the tablet comprises at least about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 9% coating. In some embodiments, the tablet comprises at most about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% coating. In some embodiments, the tablet comprises about 0.5%, about 5%, about 10%, about 15%, or about 20% coating by weight of the total weight of the tablet.

[0051] In some embodiments, the composition further comprises an enteric coating. An enteric coating is a polymer barrier applied to oral drugs to prevent them from dissolving or disintegrating in the gastric environment. Tablets, mini-tablets, pills, and granules (usually contained in capsule shells) are the most common enteric dosage forms. The function of most enteric coatings is to provide a surface that is stable at the strongly acidic pH found in the stomach, but rapidly decomposes at higher pH (alkaline pH). For example, they will not dissolve in the gastric acid of the stomach (pH is about 3), but will dissolve in the alkaline (pH 7-9) environment present in the small intestine. By preventing the drug from dissolving into the stomach, the enteric coating can protect the gastric mucosa from the irritation of the drug itself. When the drug reaches the neutral or alkaline environment of the intestine, its active ingredient will then dissolve and become suitable for absorption into the bloodstream. Materials used for enteric coatings include, but are not limited to, fatty acids, waxes, shellac, plastics, and plant fibers. The conventional material used is a solution of film resin.

[0052] In some embodiments, the pharmaceutical composition comprises a filler. In some embodiments, the filler is a pregelatinized starch. In embodiments, the pharmaceutical composition comprises about 4% to about 6% by weight of pregelatinized starch of the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises about 4%, about 5%, or about 6% by weight of pregelatinized starch of the total weight of the pharmaceutical composition.

[0053] In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises microcrystalline cellulose of about 15% to about 50% by weight of the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises microcrystalline cellulose of about 50%, about 40%, about 30%, about 20%, or about 15% by weight of the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises about 20% by weight of microcrystalline cellulose.

[0054] In some embodiments, the pharmaceutical composition comprises a processing aid. In some embodiments, the processing aid is colloidal silicon dioxide. In embodiments, the pharmaceutical composition comprises colloidal silicon dioxide at about 1% to about 2.5% by weight of the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises colloidal silicon dioxide at about 1%, about 1.5%, about 2%, or about 2.5% by weight of the total weight of the pharmaceutical composition.

[0055] In some embodiments, the processing aid is magnesium stearate. In embodiments, the pharmaceutical composition comprises from about 0.5% to about 1.5% by weight of magnesium stearate of the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises about 0.5%, about 0.8%, about 1.0%, about 1.2%, or about 1.5% by weight of magnesium stearate of the total weight of the pharmaceutical composition.

[0056] In some embodiments, the pharmaceutical composition comprises pregelatinized starch, colloidal silicon dioxide, and magnesium stearate in a weight ratio of 5:2:1.

[0057] In some embodiments, a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is stored at a controlled room temperature (20-25 o C) storage.

[0058] In some embodiments, the pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt or polymorph thereof, is protected from light.

[0059] In some embodiments, the pharmaceutical composition has friability and / or disintegration time. As disclosed herein, friability is the tendency of a tablet to break, crumble or crack after compression. Fragility testing is a laboratory technique for testing the durability of a tablet. The test involves repeatedly dropping a tablet sample over a fixed time using a rotating wheel with a baffle. Fragility is determined by the USP (United States Pharmacopeia) standard test for tablet friability. In some embodiments, the pharmaceutical composition has a friability of no more than about 0.5% weight loss of the tablet. In some embodiments, the pharmaceutical composition has a friability of no more than about 0.4% weight loss of the tablet. In some embodiments, the pharmaceutical composition has a friability of no more than about 0.3% weight loss of the tablet. In some embodiments, the pharmaceutical composition has a friability of no more than about 0.25% weight loss of the tablet.

[0060] Disintegration testing is used to test how a drug in pill form disintegrates in solution. These tests can be related to the in vitro decomposition of powdered compounds for quality control purposes. Disintegration is defined as a state in which the residue of the unit being tested does not remain on the screen of the equipment, or if residue remains, it consists of fragments of the disintegrated portion of the tablet ingredient portion, such as the insoluble coating of the tablet, or the capsule shell, or any melted fatty substance. This test is usually performed on products with known absorption problems or known poor solubility. It can also be performed on sustained-release or delayed-release products, such as enteric-coated products. Dissolution testing can be performed on capsules or tablets. In some embodiments, the dissolution time of the pharmaceutical composition does not exceed 15 minutes.

[0061] In some embodiments, the pharmaceutical composition further comprises hydroxypropyl cellulose. Hydroxypropyl cellulose is a derivative of cellulose, which is water-soluble and organic-soluble. It is commonly used as a pharmaceutical excipient. Hydroxypropyl cellulose can be used as a tablet binder, thickener, tackifier, coating agent, and film former. In some embodiments, the pharmaceutical composition further comprises about 1% to about 6% of hydroxypropyl cellulose by weight of the tablet. In some embodiments, the pharmaceutical composition further comprises about 4% to about 5% of hydroxypropyl cellulose by weight of the tablet. In some embodiments, the hydroxypropyl cellulose accounts for about 4% of the tablet weight. In some embodiments, the hydroxypropyl cellulose accounts for about 5% of the tablet weight. In some embodiments, the hydroxypropyl cellulose accounts for about 6% of the tablet weight.

[0062] In some embodiments, the pharmaceutical composition has tablet hardness and / or tablet thickness. Tablet hardness testing is a laboratory technique used in the pharmaceutical industry to determine the breaking point and structural integrity of a tablet and to find out how the tablet changes under storage, transportation, packaging, and handling conditions before use. The breaking point of a tablet depends on its shape. In some embodiments, the hardness of the tablet is about 10 kPa. In some embodiments, the thickness of the tablet is about 4.5-5.0 mm. In some embodiments, the thickness of the tablet is about 4.65-4.85 mm.

[0063] In some other embodiments, the composition comprising Compound 1, or a pharmaceutically acceptable salt or polymorph thereof, is suitable for pediatric use and can be taken by a pediatric sickle cell anemia patient.

[0064] In some embodiments, the pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is taken with food. In some embodiments, the pharmaceutical composition is taken after a meal. In some embodiments, the pharmaceutical composition is not taken with food.

[0065] Drug administration In some embodiments, the oral dosage range is about 0.001 to about 100 mg per kg body weight per day. In some embodiments, the oral dosage range is about 0.01 to about 50 mg per kg body weight per day. In some embodiments, the oral dosage range is about 0.05 to about 10 mg per kg body weight per day. Oral dosages are usually administered in one or more doses, usually one to three doses per day. In some embodiments, the dosage is administered once, twice or three times a day. The exact dosage will depend on the frequency and mode of administration, the sex, age, weight and overall health of the subject being treated, the nature and severity of the condition being treated and any concomitant diseases to be treated, and other factors apparent to those skilled in the art.

[0066] In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered to a subject in need thereof at a dose of less than 6.0 mg or less than about 4.0 mg per kg of subject body weight. In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered at a dose of about 0.1 mg to about 6.0 mg per kg of subject body weight. For example, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered at a dose of about 0.3 to about 3.0 mg, or about 0.3 to about 1.0 mg per kg of subject body weight. The patient may have sickle cell disease. The patient may be an adult (≥18 years old) or a child (<18 years old). In some embodiments, the patient receives Compound 1 or a pharmaceutically acceptable salt or polymorph thereof at a dose of about 0.3 mg, about 0.2 mg, about 0.1 mg, or about 0.05 mg per kg of subject body weight. In some embodiments, the patient receives Compound 1 or a pharmaceutically acceptable salt or polymorph thereof at about 1 mg per kg of subject body weight. In some embodiments, the patient receives about 3 mg of Compound 1, or a pharmaceutically acceptable salt or polymorph thereof, per kg of subject body weight. In some embodiments, the patient receives about 6 mg of Compound 1, or a pharmaceutically acceptable salt or polymorph thereof, per kg of subject body weight.

[0067] In some embodiments, the patient receives Compound 1, or a pharmaceutically acceptable salt or polymorph thereof, at about 0.1 mg per kg of subject body weight.

[0068] In some embodiments, the patient receives Compound 1, or a pharmaceutically acceptable salt or polymorph thereof, at about 0.3 mg per kg of subject body weight.

[0069] In some embodiments, the patient receives Compound 1, or a pharmaceutically acceptable salt or polymorph thereof, at about 0.5 mg per kg of subject body weight.

[0070] In some embodiments, the patient receives Compound 1, or a pharmaceutically acceptable salt or polymorph thereof, at about 1 mg per kg of subject body weight.

[0071] In some embodiments, the patient receives Compound 1, or a pharmaceutically acceptable salt or polymorph thereof, at about 5 mg per kg of subject body weight.

[0072] In some embodiments, the patient receives Compound 1, or a pharmaceutically acceptable salt or polymorph thereof, at about 10 mg per kg of subject body weight.

[0073] In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered to a patient in need at a flat dose of about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg per day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered to a patient at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, or about 350 mg. In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered at a dose of about 50 mg. In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered at a dose of about 100 mg. In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered at a dose of about 150 mg. In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered at a dose of about 200 mg. In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered at a dose of about 250 mg. In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered at a dose of about 300 mg. In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered at a dose of about 350 mg. In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered at a dose of about 400 mg.

[0074] In some embodiments of the pharmaceutical composition, compound 1 is administered at a maximum dose per day or per dose. In some embodiments, a total combined dose of 1 g of compound 1 or a pharmaceutically acceptable salt, solvate, or polymorph thereof is administered per day or per dose. In some embodiments, a total combined dose of 600 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or polymorph thereof is administered per day or per dose. In some embodiments, a total combined dose of 500 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or polymorph thereof is administered per day or per dose. In some embodiments, a total combined dose of 400 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or polymorph thereof is administered per day or per dose. In some embodiments, a total combined dose of 300 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or polymorph thereof is administered per day or per dose. In some embodiments, a total combined dose of 200 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or polymorph thereof is administered per day or per dose. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or polymorph thereof, is administered to a patient, wherein Compound 1, or a pharmaceutically acceptable salt or polymorph thereof, is administered once a day. In some embodiments, the pharmaceutical composition is administered twice a day.

[0075] In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered to a patient, wherein Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered once a day with food. It has been found that food can significantly reduce adverse events. When Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is taken with food, the incidence and severity of side effects such as nausea, vomiting and headache can be reduced.

[0076] In some embodiments, Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered to a patient, wherein Compound 1 or a pharmaceutically acceptable salt or polymorph thereof is administered once a day for at least 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, or 2 years. In some embodiments, the patient is treated for 3 months. In some embodiments, the patient is treated for 6 months. In some embodiments, the patient is treated for 1 year. In some embodiments, the patient is treated for 1.5 years. In some embodiments, the patient is treated for 2 years, 3 years, 4 years, 5 years, more than 5 years, or for life.

[0077] In some embodiments, the pharmaceutical composition is in unit dosage form by methods known to those skilled in the art. For illustrative purposes, a typical unit dosage form for oral administration may contain about 0.01 to about 1000 mg, about 0.05 to about 500 mg, or about 0.5 mg to about 200 mg.

[0078] Combination therapy In one embodiment, a pharmaceutical composition comprising a compound of the present disclosure is used in combination with an additional active agent such as hydroxyurea (HU). The compound of the present disclosure and the additional active agent may be administered simultaneously, sequentially, or in any order. The compound of the present disclosure and the additional active agent may be administered in any suitable different doses, different dose frequencies, or by any suitable different routes.

[0079] As used herein, the term "simultaneous administration" is not particularly limited, and means that the compound of the present disclosure and the additional active agent are administered substantially simultaneously, for example, in a mixture or in a sequential order immediately thereafter.

[0080] As used herein, the term "sequential administration" is not particularly limited, and refers to that the compound of the present disclosure and another activating agent are not administered simultaneously, but are administered one by one or in groups, with a specific time interval between administrations. The time interval between each administration of the compound of the present disclosure and another activating agent may be the same or different, and may be selected from, for example, a range of 2 minutes to 96 hours, 1 to 7 days, or one, two or three weeks. Typically, the time interval between administrations may be in the range of a few minutes to several hours, such as 2 minutes to 72 hours, 30 minutes to 24 hours, or 1 to 12 hours. Further examples include time intervals in the range of 24 to 96 hours, 12 to 36 hours, 8 to 24 hours, and 6 to 12 hours.

[0081] The molar ratio of the compound of the present disclosure and other activating agent is not particularly limited. For example, when the compound of the present disclosure and a kind of other activating agent are combined in the composition, their molar ratio can be in the range of 1:500 to 500:1, or 1:100 to 100:1, or 1:50 to 50:1, or 1:20 to 20:1, or 1:5 to 5:1 or 1:1. When the compound of the present disclosure and two or more other activating agents are combined in the composition, similar molar ratio is applicable. The compound of the present disclosure can include about 1% to 10% of the composition, or about 10% to about 20%, or about 20% to about 30%, or about 30% to 40%, or about 40% to 50%, or about 50% to 60%, or about 60% to 70%, or about 70% to 80%, or about 80% to 90%, or about 90% to 99% of the predetermined molar weight percentage.

[0082] Methods of using the compounds of the present disclosure PDE9 is specifically expressed in the human hematopoietic system, including neutrophils, reticulocytes, and erythroleukemic cells. Furthermore, SCD patients exhibit significantly elevated PDE9 expression in reticulocytes and neutrophils compared to healthy individuals (Almeida et al., Br J Haematol. 2008 Sep;142(5), 836). Furthermore, there is evidence for a link between PDE9 and cell adhesion, as pharmacological PDE9 inhibition improves the increased adhesive properties of SCD neutrophils (Miguel et al., Inflamm Res. 2011 Jul;60(7), 633). The mechanism by which PDE9 inhibition reduces cell adhesion has been shown to be mediated by increased cGMP and decreased endothelial adhesion molecule expression. Importantly, in animal models of SCD, the reduction in cell adhesion mediated by PDE9 inhibitors has the functional effect of increasing cell survival. In addition to demonstrating reduced cell adhesion compared to HU, PDE9 inhibition also results in increased production of fetal non-sickled hemoglobin (HbF), which reduces the cellular concentration of abnormal hemoglobin (HbS) within red blood cells (RBCs), thereby reducing abnormal hemoglobin aggregation and its associated sequelae. Large studies such as the Sickle Cell Disease Collaborative Study, as well as studies in various patient populations outside the United States, have demonstrated the importance of increasing HbF in the treatment of SCD, showing that HbF is one of the most important modifiers of the disease (Alsultan et al., Am J Hematol. 2013, 88(6), 531), and data show that modifiers of HbF improve other hematological parameters (Akinsheye, Blood, 2011, 118(1):19). Finally, Almeida et al. demonstrated that in a mouse model of SCD, treatment with HU combined with PDE9 inhibition resulted in an additional beneficial amplification of the cGMP enhancing effects of HU (Almeida et al., Blood. 2012 Oct;120(14), 2879). In conclusion, PDE9 inhibitors can both regulate the expression of fetal hemoglobin production and reduce cell adhesion, and both mechanisms are critical for the treatment of SCD.

[0083] The PDE9 inhibitors of the present disclosure and hydroxyurea (HU) act through different mechanisms. HU increases nitric oxide (NO) levels, which activates soluble guanylate cyclase (sGC) to generate cGMP. The PDE9 inhibitors of the present disclosure block the degradation of cGMP by inhibiting PDE9 enzymatic activity, thereby increasing cGMP levels. In the erythroid lineage, cGMP binds to protein kinase G (PKG) and signals fetal gamma globin synthesis and ultimately HbF production. In hematopoietic cells with high PDE9 expression, direct inhibition of PDE9 activity increases cGMP levels, thereby promoting reduced leukocyte adhesion.

[0084] One aspect of the present disclosure provides methods of using the PDE9 inhibitors of the present disclosure and pharmaceutical compositions comprising the PDE9 inhibitors of the present disclosure.

[0085] The PDE9 inhibitors of the present disclosure may be used to treat sickle cell disease or any disease and / or symptom associated with sickle cell disease, such as anemia, sickle cell hemoglobin C disease (SC), vaso-occlusive crises, painful episodes (sickle cell crises), splenic sequestration crises, acute chest syndrome, aplastic crises, hemolytic crises, chronic pain, bacterial infections, and stroke.

[0086] In one embodiment, a PDE9 inhibitor of the present disclosure is used to increase hemoglobin levels in a subject.

[0087] In another embodiment, the PDE9 inhibitors of the present disclosure are used to increase cGMP levels in cells or plasma of a subject, wherein the subject has sickle cell disease. The cells may be, but are not limited to, red blood cells and / or white blood cells. The cGMP levels may be increased by at least 50%, at least 100%, or at least 150%. In some embodiments, the cGMP levels may be increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, or 25-fold.

[0088] In another embodiment, the PDE9 inhibitor of the present disclosure is used to increase the number of fetal hemoglobin (HbF) positive red blood cells in a subject, wherein the subject has sickle cell disease. The number of HbF positive red blood cells increases by at least 50%, at least 100%, or at least 150%. In some embodiments, the number of HbF positive red blood cells increases by at least 2 times, 3 times, 4 times, 5 times, 10 times, 15 times, 20 times, or 25 times.

[0089] In another embodiment, a PDE9 inhibitor of the present disclosure is used to reduce the percentage of sickled red blood cells (% sickle RBC), the percentage of stasis (% stasis), total bilirubin, or total white blood cell count in a subject, wherein the subject has sickle cell disease. The % sickle RBC, % stasis, total bilirubin, total white blood cell count, or spleen weight is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, or 70%.

[0090] cGMP levels can be measured by any suitable method in the art, such as an enzyme immunoassay.

[0091] As used herein, HbF-positive cells mean red blood cells having Hb F. HbF-positive cells can be measured from a blood sample using any suitable method in the art, such as electrophoresis and / or colorimetry.

[0092] As used herein, sickle erythrocytes, sickled erythrocytes, refer to erythrocytes having a crescent or sickle shape. % sickled erythrocytes can be measured from a blood sample by any suitable method in the art.

[0093] As used herein, stasis or microvascular stasis is a severe slowing or complete cessation of blood or lymph flow through blood vessels. % Stasis is the number of quiescent (no flow) venules divided by the number of flowing venules multiplied by 100. % Stasis can be measured by any suitable method in the art.

[0094] As used herein, total bilirubin means both unconjugated and conjugated bilirubin.Total bilirubin levels can be measured from a blood sample by any suitable method in the art.

[0095] As used herein, total white blood cell count or total leukocyte count is a blood test that measures the number of white blood cells in the body. It can be measured from a blood sample by any suitable method in the art.

[0096] Another aspect of the present disclosure provides a method of using a PDE9 inhibitor of the present disclosure in combination with at least one other active agent. They can be administered simultaneously or sequentially. They can exist as a mixture for simultaneous administration, or can each be present in a separate container for sequential administration.

[0097] As used herein, the term "simultaneous administration" is not particularly limited, and means that the PDE9 inhibitor of the present disclosure and at least one other active agent are administered substantially simultaneously, for example, as a mixture or in a sequential order immediately thereafter.

[0098] As used herein, the term "sequential administration" is not particularly limited and means that the PDE9 inhibitor of the present disclosure is not administered at the same time as at least one other active agent, but is administered one by one or in groups, with a specific time interval between administrations. The time interval between the respective administrations of the PDE9 inhibitor of the present disclosure and at least one other active agent may be the same or different, and may be selected from, for example, a range of 2 minutes to 96 hours, 1 to 7 days, or one, two or three weeks. Typically, the time interval between administrations may be in the range of a few minutes to several hours, such as in the range of 2 minutes to 72 hours, 30 minutes to 24 hours, or 1 to 12 hours. Other examples include time intervals in the range of 24 to 96 hours, 12 to 36 hours, 8 to 24 hours, and 6 to 12 hours.

[0099] The molar ratio of the PDE9 inhibitor of the present disclosure to at least one other active agent is not particularly limited. For example, when the PDE9 inhibitor of the present disclosure and one other active agent are combined in a composition, their molar ratio can be in the range of 1:500 to 500:1, or 1:100 to 100:1, or 1:50 to 50:1, or 1:20 to 20:1, or 1:5 to 5:1, or 1:1. When the PDE9 inhibitor of the present disclosure is combined with two or more other active agents in a composition, similar molar ratios apply. The PDE9 inhibitor of the present disclosure may include a predetermined molar weight percentage of about 1% to 10%, or about 10% to about 20%, or about 20% to about 30%, or about 30% to 40%, or about 40% to 50%, or about 50% to 60%, or about 60% to 70%, or about 70% to 80%, or about 80% to 90%, or about 90% to 99% of the composition.

[0100] The other active agent may be a PDE9 inhibitor or HU different from the present disclosure.The other active agent may also be an antibiotic agent such as penicillin, a nonsteroidal anti-inflammatory drug (NSAIDS) such as diclofenac or naproxen, an analgesic such as an opioid, or folic acid.

[0101] Yet another aspect of the present disclosure provides methods of using a PDE9 inhibitor of the present disclosure in combination with at least one other therapy, such as but not limited to blood transfusion, bone marrow transplant, or gene therapy.

[0102] Kits and Devices The present disclosure provides a variety of kits and devices for conveniently and / or effectively implementing the methods of the present disclosure. Typically, the kit will contain sufficient amounts and / or numbers of components to allow the user to perform a variety of treatments on a subject and / or perform a variety of experiments.

[0103] In one embodiment, the present disclosure provides a kit for treating sickle cell disease comprising a PDE9 inhibitor compound of the present disclosure or a combination of a PDE9 inhibitor compound of the present disclosure, optionally with any other active agent, e.g., HU, an antibiotic agent (e.g., penicillin), a nonsteroidal anti-inflammatory drug (NSAIDS) (e.g., diclofenac or naproxen), analgesics (e.g., opioids), or folic acid.

[0104] The kit may further include packaging and instructions and / or delivery agents to form a formulation composition. Delivery agents may include saline, buffered solutions or any delivery agents disclosed herein. The amount of each component may vary to achieve a consistent, reproducible higher concentration of saline or a simple buffer formulation. Components may also vary to increase the stability of the PDE9 inhibitor compound in the buffer over a period of time and / or under various conditions.

[0105] The present disclosure provides devices that can incorporate the PDE9 inhibitor compounds of the present disclosure. These devices contain stable drug formulations that can be used for immediate delivery to subjects in need, such as human patients with sickle cell disease.

[0106] Non-limiting examples of devices include pumps, catheters, needles, transdermal patches, pressurized olfactory delivery devices, iontophoresis devices, multilayer microfluidic devices. The device can be used to deliver the PDE9 inhibitor compounds of the present disclosure in a single, multiple or split dosing regimen. The device can be used to deliver the PDE9 inhibitor compounds of the present disclosure across biological tissues, intradermally, subcutaneously or intramuscularly. Further examples of devices suitable for delivering PDE9 inhibitor compounds include, but are not limited to, a medical device for intravesical drug delivery disclosed in International Publication WO 2014036555; a glass bottle made of Type I glass disclosed in U.S. Publication No. 20080108697; a drug eluting device disclosed in U.S. Publication No. 20140308336, comprising a membrane made of a degradable polymer and an active agent; an infusion device disclosed in U.S. Pat. No. 5716988, having an injection micropump, or a container containing a pharmaceutically stable formulation of an active agent; an implantable device disclosed in International Publication WO 2015023557, comprising a reservoir and a channelized member in fluid communication with the reservoir; a hollow fiber-based biocompatible drug delivery device having one or more layers disclosed in U.S. Publication No. 20090220612; an infusion device disclosed in International Publication WO An implantable device for drug delivery disclosed in 2013170069, comprising an elongated flexible device having a shell defining a reservoir containing a drug in solid or semisolid form; a bioresorbable implant device disclosed in U.S. Patent No. 7326421, the contents of each of which are incorporated herein by reference in their entirety.

[0107] definition As used herein, the articles "a" and "an" should be understood to mean "at least one", unless expressly indicated to the contrary.

[0108] As used herein, the phrase "and / or" should be understood to mean "either or both" of the elements so combined, i.e., the elements are present in combination in some cases and separately in other cases. Unless expressly indicated to the contrary, in addition to the elements specifically identified by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, when used in conjunction with open language such as "comprising", references to "A and / or B" may refer to A without B (optionally including elements other than B) in one embodiment; to B without A (optionally including elements other than A) in another embodiment; and to both A and B (optionally including other elements) in yet another embodiment.

[0109] As used herein, "or" should be understood to have the same meaning as "and / or" defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, that is, including at least one of a plurality of elements or a list of elements, but also including more than one, and optionally including additional unlisted items. Only terms that are explicitly indicated to the contrary, such as "only one of..." or "exactly one of...", or when "consisting of..." is used in the claims, will refer to including exactly one element of a plurality of elements or a list of elements.

[0110] In general, as used herein, the term "or" when preceding an exclusive term (such as "either," "one of," "only one of," or "exactly one of") should be interpreted only to indicate exclusive alternatives (i.e., "one or the other, but not both"). When used in a claim, "consisting essentially of" should have its ordinary meaning as used in the art of patent law.

[0111] As used herein, the phrase "at least one" in relation to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers may optionally be present, whether related or unrelated to those specifically identified elements.

[0112] Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B", or equivalently, "at least one of A and / or B") may refer, in one embodiment, to at least one A, optionally including more than one A, without the presence of B (and optionally including elements other than B); in another embodiment, to at least one B, optionally including more than one B, without the presence of A (and optionally including elements other than A); in yet another embodiment, to at least one A, optionally including more than one A, and at least one B, optionally including more than one B (and optionally including other elements); and so on.

[0113] As used herein, all transitional phrases such as "includes," "including," "carrying," "having," "containing," "involving," "holding," etc. should be construed as open ended, meaning including but not limited to.

[0114] As stated in the U.S. Patent Office Manual of Patent Examining Procedure, only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively.

[0115] As used herein, "subject" or "patient" refers to any mammal (e.g., a human), such as a mammal that may be susceptible to a disease or condition, such as tumorigenesis or cancer. Examples include humans, non-human primates, cattle, horses, pigs, sheep, goats, dogs, cats, or rodents, such as mice, rats, hamsters, or guinea pigs. In various embodiments, a subject refers to a subject that has been or will be the subject of treatment, observation, or experiment. For example, a subject can be a subject diagnosed with cancer or otherwise known to have cancer, or a subject selected for treatment, observation, or experiment based on a known cancer in the subject.

[0116] As used herein, "treating" refers to the improvement of a disease or condition or at least one sign or symptom thereof. "Treatment" may refer to reducing the progression of a disease or condition, as determined by, for example, stabilization of at least one sign or symptom or a decrease in the rate of progression of at least one sign or symptom. In another embodiment, "treating" refers to delaying the onset of a disease or condition.

[0117] As used herein, "preventing" or "prevention" refers to reducing the risk of acquiring or having signs or symptoms of a given disease or condition, ie, prophylactic treatment.

[0118] As used herein, the phrase "therapeutically effective amount" refers to an amount of a compound, material, or composition comprising a compound of the present teachings that is effective to produce a desired therapeutic effect. Thus, a therapeutically effective amount treats or prevents a disease or condition, such as ameliorating at least one sign or symptom of a condition. In various embodiments, the disease or condition is cancer.

[0119] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH2 is attached through a carbon atom (C).

[0120] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "optionally substituted aryl" encompasses "aryl" and "substituted aryl" as defined herein. One of ordinary skill in the art will understand that for any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible, and / or inherently unstable.

[0121] All numerical ranges herein include all numerical values ​​and ranges of all numerical values ​​within the numerical ranges. As non-limiting examples, (C1-C6) alkyl also includes any one of C1, C2, C3, C4, C5, C6, (C1-C2), (C1-C3), (C1-C4), (C1-C5), (C2-C3), (C2-C4), (C2-C5), (C2-C6), (C3-C4), (C3-C5), (C3-C6), (C4-C5), (C4-C6) and (C5-C6) alkyl.

[0122] In addition, although the numerical ranges and parameters setting forth the broad scope of the present disclosure are approximate as described above, the numerical values ​​set forth in the Examples section are reported as precisely as possible. However, it should be understood that such numerical values ​​inherently contain certain errors caused by the measuring equipment and / or measuring techniques.

[0123] List of abbreviations and terms 1 H-NMR: Proton Nuclear Magnetic Resonance Spectroscopy ADME: absorption, distribution, metabolism and excretion AE: adverse event AUC 0-24 : Area under the concentration-time curve from 0 to 24 hours after administration BBB: blood-brain barrier C max : Maximum plasma concentration cGMP: cyclic guanosine monophosphate DMSO: dimethyl sulfoxide DSFC: Dorsal Skin Fold Cell F cells: blood cells that have fetal hemoglobin FIH: First time in humans FTIR: Fourier Transform Infrared Spectroscopy GC: Gas chromatography HBB: hemoglobin subunit beta HbF: Fetal hemoglobin HBG: gamma-globin gene HbS: sickle hemoglobin hERG: human ether-à-go-go related gene HPLC: High Performance Liquid Chromatography HU: Hydroxyurea IC: Inhibitory concentration IC 50 : Half minimum inhibitory concentration ICAM-1: intercellular adhesion molecule-1 ICH: International Conference on Harmonization ICP-MS: Inductively Coupled Plasma Mass Spectrometry IV: Intravenous MAD: multiple ascending dose MTD: Maximum tolerated dose NO: Nitric Oxide NOAEL: no observed adverse effect level PD: Pharmacodynamics PDE9: Phosphodiester-9 PEG: polyethylene glycol PIC: Powder in capsule PK: Pharmacokinetics PKG: protein kinase G RBC: Red blood cells RH: Relative humidity SCD: sickle cell disease SD: Standard deviation SEM: standard error of the mean sGC: soluble guanylate cyclase t ½ :half life TK: Toxicokinetics T max : Maximum concentration time VOC: vaso-occlusive crisis WBC: White blood cells w / w%: weight / weight percentage Example It should be understood that the following examples are intended to illustrate rather than limit the present disclosure. Various other examples and modifications of the foregoing description and examples will be apparent to those skilled in the art upon reading the present disclosure without departing from the spirit and scope of the present disclosure, and it is intended that all such examples or modifications are included within the scope of the appended claims. All publications and patents cited herein are incorporated herein by reference in their entirety.

[0124] Example 1. Synthesis and preparation of compound 1 Compound 1 is an enantiomer of 6-[4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one disclosed in WO 2013 / 053690. Compound 1 can be prepared by chiral selective purification of 6-[4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one prepared according to the method disclosed in WO 2013 / 053690 (the contents of which are incorporated herein by reference in their entirety). Compound 1 can also be prepared using the method disclosed in WO 2017 / 005786 (the contents of which are incorporated herein by reference in their entirety).

[0125] Compound 1 The Compound 1 API product used in ongoing clinical development is an immediate release tablet. Coating can be used to ensure consistency in appearance across tablet strengths and placebo.

[0126] Early clinical studies were conducted with Compound 1 drug substance filled directly into opaque white gelatin capsules (powder in capsules, PIC) without excipients or processing aids. Tablet forms of drug products blended with excipients have been developed for oral administration as this allows for scale-up of the manufacturing process and ensures content consistency. These tablets were tested for purity, potency, dissolution, total aerobic microbial counts, and defined limits for total yeast and mold counts. In addition, specified microorganisms were tested.

[0127] Each tablet contains 20 mg, 50 mg, 100 mg or 200 mg of Compound 1 API (API monohydrate) or placebo. Representative tablet compositions are shown in Table 1 below.

[0128] Table 1. Compound 1 50 mg coated tablets

[0129] Purified water is removed during processing.

[0130] All tablets were formulated so that the target weight of the core tablet was 400 mg and the target weight of the coated tablet was 440 mg. To this end, the amounts of Compound 1 and microcrystalline cellulose were adjusted accordingly. The amounts of all other excipients remained unchanged.

[0131] Description of the manufacturing process and process controls The manufacture of coated tablets follows the general procedures for blending, tableting and coating.

[0132] Roller compaction of drugs: The compound 1 API was first processed by roller compaction to obtain a more uniform intermediate suitable for further blending and processing. A defined amount of API was passed through a roller compactor at a roller speed of 200-300 PSI and 4.0 RPM. The rolled material was passed through a 20 mesh screen to obtain a uniform particle size. The compressed and screened API was stored in a double-lined polyethylene bag, awaiting tablet manufacturing.

[0133] Blending of API and excipients by roller compaction: A defined amount of roller compacted API was mixed with defined excipients (excluding coating solution) using a 16 qt. V-shell blender. Blending was performed in such a way that not less than 300 revolutions of the blender were completed within a defined period of time. Samples were taken from multiple locations in the V-shell blender to verify blend uniformity.

[0134] The blended material was stored in suitable HDPE containers in double lined polyethylene bags until further processing.

[0135] Tableting: Tablet manufacturing was performed in a gravity-feed tablet press with 11 mm upper and lower flat tablet punches. The tablet press was adjusted to meet the predetermined specifications for tablet weight, hardness, thickness, friability, and disintegration, as defined below. All cores were screened through a metal detector and dusted before film coating.

[0136] Film coating: A uniform coating mixture was prepared by mixing a defined amount of Opadry II White in purified water and mixing the suspension for not less than 45 minutes. The tablets were loaded onto the pan coating equipment and preheated to 43°C before starting the coating operation. The preheated tablets were then coated in a 15-inch coating pan rotating at 10-15 RPM. The spray rate of the coating suspension was controlled at 10 g / min and the inlet air temperature was maintained at 40-60°C.

[0137] Tablets were sampled and weighed at defined time intervals to determine if the desired target weight gain (10%) was met. Once coating was complete, the coated tablets were cooled to ≤ 30°C.

[0138] Bulk Packaging: The coated tablets were sampled for release testing and then transferred to HDPE containers double lined with double lined polyethylene bags.

[0139] Clinical Packaging: Tablets for clinical trials were packaged, including inkjet marking of each container with a batch number to ensure identification. Thirty-three (33) tablets were filled into each 60 cc round white HDPE bottle by manual counting. This count was verified by another individual prior to filling each bottle. After filling, each bottle was manually closed with a 33 mm white polypropylene child-resistant cap and induction sealed.

[0140] Example 2. Development of 300 mg tablets Development activities for the 300 mg tablets showed that the addition of hydroxypropyl cellulose (HPC-SSL-SFP) and increasing percentage levels of microcrystalline cellulose (Avicel PH200) resulted in acceptable results for increased tablet hardness and reduced loss during friability testing. However, the addition of HPC increased the mean disintegration time from less than one minute to approximately 37 minutes. Multiple percentage levels of HPC-SSL-SPF were evaluated in the 300 mg tablet formulation. The formulations evaluated are shown in Table 2 below.

[0141] Table 2. Optimization of the percentage level of HPC-SSL-SPF used in the formulation.

[0142]

[0143] Multiple formulations of different percentage levels of hydroxypropyl cellulose (HPC-SSL-SFP) were evaluated to determine a formulation that produced acceptable results. Table 3 below shows the formulation used to develop the 300 mg film-coated tablets.

[0144] Table 3. Formulation of 300 mg film-coated tablets

[0145] Blending / Granulation: Excipients used for development were recorded for a batch size of 2,380 tablets. Compound 1 drug substance was roller compacted. Compound 1 and all excipients were screened through a 20 mesh handheld sieve in the following order: 1) Compound 1 drug substance; 2) pregelatinized starch (Starch 1500); 3) colloidal silicon dioxide (Cab-O-Sil); and 4) microcrystalline cellulose (Avicel PH200).

[0146] Once the target weight is reached, a hardness profile (tablet hardness vs. disintegration time) is established and samples are collected. Each sample is used to perform tablet physical testing including weight, hardness, thickness, disintegration and friability.

[0147] Process Guide: Tablet thickness range: 4.65-4.85 mm.

[0148] Tablet hardness target: 10 kP.

[0149] Friability (USP Friability): Not more than 0.3%, no capping.

[0150] Disintegration (as per USP): All tablets disintegrated completely in not more than 15 minutes.

[0151] Coating: Tablets from the development batch were coated under target conditions to evaluate the ability of the core to withstand pan coating. Before loading the tablets into the coating pan, the pan was sprayed with Opadry II, 85F18422, White and allowed to dry. The operator monitored the spraying and drying process to ensure that no coating peeling occurred. This formed a thin layer of coating to prevent tablet defects such as scratches caused by the coating pan. The tablets were coated with Opadry II, 85F18422, White to 4.8% weight gain.

[0152] Results and Discussion: The goal of the development activities was to develop a formulation for Compound 1 tablets that contained an optimal percentage level of hydroxypropyl cellulose (HPC-SSL-SFP) that produced acceptable results. The formulation used was designed to produce tablets with acceptable hardness, thickness, friability, and disintegration results. Tablets from each formulation were tested for hardness, thickness, friability, and disintegration. Target results: (1) Thickness: 4.50-4.80 mm, (2) Friability: ≤0.3% loss, (3) Disintegration: ≤15 minutes, and (4) Hardness of approximately 10 kPa. Friability, disintegration, and hardness were tested in accordance with USP compounding standards (the United States Pharmacopeia and the United States National Pharmaceutical Codex are recognized standards in testing).

[0153] Feasibility batches with 0.5% HPC: The first formulation evaluated contained 0.5% hydroxypropyl cellulose (HPC-SSL-SFP) and is shown in Table 4 below.

[0154] Table 4. Formulation of Compound 1 300 mg Tablets (0.5% HPC)

[0155] Tablets were prepared with a target fill weight of 420.0 mg and a thickness range of 4.50 mm - 4.80 mm.

[0156] To test the disintegration time, the tablets were continuously immersed in water until 6 tablets were completely disintegrated. The results are shown in Table 5 below.

[0157] Table 5. Disintegration time

[0158] The goal was to have all tablets completely disintegrate in 15 minutes or less. Based on the data in Table 5, all tablets completely disintegrated in less than 15 minutes, meeting the target time. Using a target fill weight of 420.0 mg, the remaining tablet blend was compressed.

[0159] Another physical test performed was friability. Friability examines the tendency of tablets to break, crumble or crack after tablet compression. The acceptance criteria for the batch is a percentage loss of 0.3% or less. The data collected during friability is shown in Table 6 below.

[0160] Table 6. Fragility

[0161] The 0.5% hydroxypropyl cellulose (HPC-SSL-SFP) percentage level produced results that met the acceptance criteria provided in the batch record.

[0162] Feasible batch with 1.5% HPC Tablets were compressed using a formulation containing 1.5% hydroxypropyl cellulose (HPC-SSL-SFP) and these tablets were physically tested to see if they also produced acceptable results. The formulation is shown in Table 7 below.

[0163] Table 7. Formulation of Compound 1, 300 mg tablet (1.5% HPC)

[0164] The tablets were continuously immersed in water until the three tablets were completely disintegrated. The results are shown in Table 8.

[0165] Table 8. Disintegration time

[0166] The disintegration times all exceeded the acceptance criteria of 15 minutes, indicating a disintegration result failure. The increase in disintegration time was due to the increase in the level of hydroxypropyl cellulose (HPC-SSL-SPF). It can be noted that the loss of friability was less than 0.3%.

[0167] After physical testing was completed, the tablets were film coated to a weight gain of approximately 4.8% w / w. After comparing the results of the physical testing performed on each formulation, it was determined that Compound 1, 300 mg tablets (0.5% HPC) produced acceptable results for tablets.

[0168] Example 3. Compound 1 reduces leukocyte adhesion and activation Polymorphic mononuclear cells (PMNs), particularly neutrophils, play a key role in the pathogenesis of sickle cell disease (SCD), and activated neutrophils have been shown to be more adherent to each other, platelets, and vascular endothelium. Recently, a variety of drugs targeting leukocytes that bind to endothelial cells have been developed in clinical studies in patients. Compound 1 was able to increase the expression of fetal hemoglobin in patient-derived cells and in a mouse model of SCD, and to reduce vascular occlusion in a mouse model of SCD. In this example, the ability of Compound 1 to reduce the adhesive properties of neutrophils from SCD patients and to reduce sE-selectin (sE-Sel) and PMN activation markers in a mouse model of SCD was investigated.

[0169] Endothelial E-selectin (E-Sel) slows leukocyte rolling, followed by fixed adhesion and transmigration of activated leukocytes. Plasma levels of sE-Sel, generated by enzymatic cleavage of the extracellular domain of E-Sel, are elevated in SCD patients, likely mediated by its interaction with leukocytes. In the Townes mouse model, plasma sE-Sel was 144% higher (139 mg / ml) than levels seen in control mice (57 mg / ml). This was significantly reduced in Townes mice treated with compound 1, where plasma sE-Sel levels were only 61% higher (92 mg / ml) than in control mice.

[0170] Compound 1 was found to reduce circulating levels of PMNs in the SCD model, but not in long-term studies of healthy animals. This appeared to be accompanied by a compound 1-mediated reduction in disease-specific cellular activation, including a 67% reduction in myeloid-derived myeloperoxidase (MPO) levels and a 26% reduction in neutrophil-derived arginase levels in the lung ( Figure 1). Using a previously described in vitro adhesion assay simulating blood flow, in which activated endothelial cells HMEC-1 are located on the inner surface of the microchannel, whole blood samples perfused from patients with SS (the most common form of sickle cell) showed neutrophil aggregation and binding to the endothelial monolayer. This was quantified by real-time monitoring of green fluorescent patches in the microchannel, as neutrophils were labeled with a specific AlexaFluor® 488-conjugated antibody prior to the perfusion step. Untreated patient neutrophils showed a significant amount of adhesion to activated HMEC-1. When added to the blood samples prior to the perfusion step, compound 1 significantly reduced adhesion in a dose-dependent manner. The inhibitory effect began as early as 15 minutes of incubation, with the strongest inhibition of adhesion observed after 30 minutes of incubation with 30 μM compound 1. Under these conditions, adhesion was reduced by an average of 54% (p = 0.03) ( Figure 2 Mechanistically, without intending to be bound by any theory, compound 1 may target the fixation and adhesion step of neutrophils because it reduces the expression levels of key neutrophil integrins, including CD11a and CD11b. Taken together, these data suggest that compound 1 acts to reduce PBMC-mediated pathology in SCD by targeting aberrant neutrophil adhesion independent of their circulating cell count.

[0171] Example 4. Phase 2a Randomized Double-blind Placebo-treated Adult Patients with Sickle Cell Anemia (SCA) Control Research Purpose: Primary objective: To evaluate the safety and tolerability of compound 1 in adult patients with sickle cell anemia (SCA) who were hydroxyurea (HU) naive and in adult SCA patients who were receiving stable doses of HU, defined as homozygous sickle hemoglobin (HbSS) or sickle β 0 Thalassemia.

[0172] Secondary objectives: Characterize the pharmacokinetic (PK) profile of Compound 1 in adult patients with SCA who do not receive a stable dose of HU; Characterize the PK profile of HU in adult patients with SCA before and after receiving Compound 1 to determine if there are clinically relevant PK interactions.

[0173] Exploratory objectives: To evaluate the pharmacodynamic (PD) effects of Compound 1 in adult patients with SCA who received or did not receive stable HU; to evaluate the potential efficacy of Compound 1 on SCA-related clinical outcome measures in adult patients with SCA who received or did not receive stable HU.

[0174] method: This is a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, PK and exploratory PD and clinical outcomes of the phosphodiesterase 9 (PDE9) inhibitor compound 1, administered once daily for 16 to 24 weeks in 2 SCA patient populations: those who have not received HU (population A) and those who are currently receiving a stable dose of HU according to standard of care (population B). Up to approximately 36 patients were included in population A and 18 patients were included in population B.

[0175] Population A: After a screening period of up to 4 weeks, eligible patients in Population A (i.e., patients who did not receive HU) received Compound 1 or placebo for a total of 24 weeks. On Day 1, patients were randomized in a 1:1:1 ratio to receive 30 mg, 50 mg, 100 mg of Compound 1 or placebo orally daily for the first 12 weeks; during the second 12 weeks (Weeks 13-24), the dose of each patient could be doubled (i.e., from 50 mg to 100 mg; from 100 mg to 200 mg; or placebo). (Note that because all dose levels of placebo and Compound 1 were identical in appearance, dose escalation did not affect the blinding of the study drug). All available clinical data were reviewed approximately every 2 weeks throughout the study, and dose escalation was performed on an individual patient basis at Day 85 only after approval based on the review of each patient's individual clinical safety data.

[0176] Population B: Following up to 4 weeks of screening, eligible patients in Population B (i.e., patients receiving stable HU) entered a run-in period and had blood samples drawn to characterize the PK profile of the patient's prescribed dose of HU in the absence of Compound 1 (e.g., characterize the patient's baseline HU PK profile). Two complete baseline HU PK profiles were determined (blood samples were drawn within 10 hours at least 48 hours apart).

[0177] Compound 1 dosing in Population B was not initiated until at least 4 weeks of safety data from the 6 patients in Population A had been reviewed and it was determined that it was safe and appropriate to initiate dosing in Population B. Following approval to initiate dosing in Population B, once baseline HU PK blood draws were completed, patients were randomized in a 2:1 ratio on Day 1 to receive oral compound 130 mg, 50 mg, or placebo for 16 weeks. During the first 4 weeks (Weeks 1-4), patients received study drug according to randomized treatment assignment; during the next 12 weeks (Weeks 5-16), each patient's dose could be doubled (e.g., from 50 mg to 100 mg; or placebo). As with Population A, dose escalation on Day 29 was performed only after approval based on each patient's individual clinical safety data.

[0178] Study design rationale: This is the first study in a patient population (patients with SCA) and therefore aims to examine the safety, tolerability and PK of Compound 1 across a dose range as well as potential PD effects and clinical efficacy in adult patients with SCA. Considering the possibility that Compound 1, if approved, could be administered as a single agent or co-administered with HU, the effects of Compound 1 were evaluated in SCA patients who had not received HU or any other treatment known to modulate HbF levels (Population A), as well as in a population currently receiving a stable dose of HU (Population B).

[0179] Available nonclinical and healthy volunteer clinical data suggest that Compound 1 is safe and well tolerated at once-daily doses of 30, 50, 100, and 200 mg, and that potential clinically beneficial PD effects may be observed when administered at doses of at least 100 mg for at least 24 weeks. Therefore, Population A was designed to explore the PD dose response in patients, as well as the tolerability of the 200 mg dose level in sickle cell patients who tolerated the 100 mg dose well.

[0180] Results from Population B were intended to provide information about compound 1 when administered concomitantly with HU, both of which increase HbF levels through an alternative biochemical pathway that increases intracellular cGMP. Because there were no clinical data to support the concomitant administration of compound 1 with HU, patients in Population B were initiated on compound 1 at the lower dose used in Population A (30 mg or 50 mg) and titrated to 100 mg only after the 50 mg dose had been safe and tolerated for 4 weeks. In addition, although available nonclinical data did not suggest that concomitant administration of HU with compound 1 increased exposure to compound 1, dosing in Population B was not initiated until 4 weeks of safety data were available from 2 patients in Population A, each of whom received 30 mg or 50 mg (the starting dose in Population B) and 100 mg (2 times the starting dose) and placebo.

[0181] Diagnosis and main inclusion criteria: Inclusion criteria: Each patient must meet all of the following criteria to participate in the study: 1. Male or female aged ≥18 years or ≤50 years. 2. Confirmed diagnosis of SCA (HbSS or sickle-β0 thalassemia). Note that the diagnosis of SCA must be confirmed by electrophoresis, HPLC and / or genotyping if it is not already on file in the patient record. 3. Use of HU: For patients in population A: have not received HU within 90 days before screening and do not intend to take HU in the next 6 months. For patients in population B: have received HU for at least 6 months before screening, have been on a stable dose for at least 60 days, and do not intend to change dose level, dose regimen, or discontinue HU in the next 6 months. 4. Female patients must not be pregnant and have no intention of becoming pregnant. Male patients must not intend to get their partner pregnant.

[0182] Exclusion criteria: Patients who met any of the following criteria were excluded from the study: 1. Total Hb > 11.0 g / dL or < 6 g / dL at screening. 2. Reticulocyte count < 100 x 109 / L. 3. Hospitalization > 3 times (at least 24 hours) for vaso-occlusive crisis (VOC) (including acute chest syndrome (ACS) and priapism) in the previous year. 4. Receiving chronic outpatient opioid therapy (equivalent to ≥ 10 mg oral morphine per day) for any reason other than avascular necrosis (AVN). Note: Chronic therapy is defined as continuous daily opioid use for ≥ 8 weeks. 5. Transfused or donated blood or any blood products within 60 days of Day 1 or on a chronic transfusion regimen. 6. Positive for human immunodeficiency virus (HIV), hepatitis C (HCV) antibodies (unless the patient has successfully completed medical therapy to cure / clear HCV), and hepatitis B surface antigen (HBsAg). 7. For female patients of childbearing potential, positive serum human chorionic gonadotropin (hCG) test on Day 1 (screening) or positive urine hCG test. 8. Estimated glomerular filtration rate (eGFR) <50 mL / min, as calculated by the formula based on the Modification of Diet in Renal Disease (MDRD) study using creatinine, age, sex, and race. 9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN). 10. Body mass index (BMI) <17.5 or >35 kg / m2; total body weight <50 kg. 11. Use of PDE5 inhibitors (including but not limited to sildenafil, tadalafil, vardenafil) within 7 days before the first dose of study drug, or planned use at any time during the study. 12. History of drug or alcohol abuse as judged by the investigator within the past 1 year, or positive alcohol (alcoholometer) test (screening or Day 1). 13. Cancer that has not been completely remitted for at least five years. Patients with squamous cell or basal cell carcinoma of the skin, localized cervical cancer, or localized prostate cancer may be eligible provided that the condition is, in the opinion of the investigator, adequately diagnosed and determined to be clinically resolvable and that the patient's participation in the study does not pose a safety concern. 14. A history of clinically significant allergic or hypersensitivity reaction to any drug used in the study or to any component of the study drug formulation, as determined by the investigator. 15. On the ECG, the corrected QT interval, Fridericia formula (QTcF) is > 450 ms in males and > 470 ms in females, or clinically significant abnormalities are determined by the investigator. 16. A history of major surgery within 4 weeks of Day 1, or minor surgery within 2 weeks of Day 1. 17. Any influenza-like syndrome or other respiratory infection within 2 weeks of Day 1, or vaccination with a live attenuated virus within 4 weeks of Day 1. 18. Participation in a study of an investigational drug or device within 30 days prior to Day 1.19. Use within 30 days prior to Day 1 or plan to use during the study any medication or substance known to strongly inhibit or induce cytochrome P450 enzymes (CYPs), including but not limited to cimetidine, cyclosporine, erythromycin, omeprazole, rifampin, ritonavir, and St. John's wort. If there is any question as to whether a substance is permitted, please review the product label (if applicable) and consult the sponsor. 20. Consumption of grapefruit, grapefruit juice, or grapefruit products within 24 hours prior to Day 1, or plan to consume grapefruit products during the study. 21. Any CYP3A sensitive substrates (except opioids) used within 30 days before Day 1 or planned to be used during the study, including but not limited to alfentanil, avanafil, budesonide, buspirone, conivaptan, darifenacin, darunavir, dasatinib, dronedarone, ebastine, eletriptan, eplerenone, everolimus, felodipine, ibrutinib, indinavir, lomitapide, lurasidone, maraviroc, midazolam, naloxone, nisoldipine, quetiapine, saquinavir, sirolimus, tacrolimus, ticagrelor, tipranavir, tolvaptan, and triazolam. 22. Use of any drug or substance known to be a significant substrate or inhibitor of P-glycoprotein (P-gp) within 30 days prior to Day 1 or planned during the study, including but not limited to cyclosporine, lovastatin, propranolol, quinidine, and simvastatin. If there is any question as to whether the use of a substance is permitted, please review the product label (if applicable) and consult the sponsor. 23. Other prior or ongoing medical conditions, physical examination findings, or laboratory abnormalities that, in the opinion of the investigator, may adversely affect the patient's safety, make it impossible to complete the course of treatment or follow-up, or impair the evaluation of study outcomes.

[0183] Study product, dosage and route of administration: Compound 1 is provided as 50, 100 or 200 mg white tablets and is administered orally with food. The different doses of Compound 1 in tablet form are visually identical.

[0184] Reference treatment, dosage and administration: The placebo consisted of a tablet containing a matrix without Compound 1 and had the same appearance as the Compound 1 tablet. The placebo was administered orally with food.

[0185] Duration of treatment: For Population A, the total duration of the study was approximately 32 weeks, including a screening period of up to 4 weeks, a treatment period of 24 weeks, and a 4-week follow-up assessment after the last dose of study drug.

[0186] For Population B, the total duration of the study was approximately 32 weeks, including a screening period of up to 4 weeks, a run-in period of approximately 8 weeks, a treatment period of 16 weeks, and a 4-week follow-up assessment after the last dose of study drug.

[0187] end: Unless otherwise stated, the endpoints for Population A and Population B were the same.

[0188] Primary endpoints: Safety and tolerability of Compound 1 as measured by: incidence and severity of adverse events (AEs) and serious adverse events (SAEs); changes from baseline in 12-lead electrocardiogram (ECG) parameters, clinical laboratory tests (chemistry, hematology, coagulation, urine), and vital signs; and physical examination results.

[0189] Secondary endpoints: Plasma PK profile of Compound 1 after oral administration to adult patients with SCA (Population A and B); Plasma PK profile of HU before and after oral administration of Compound 1 to adult patients with SCA (Population B only).

[0190] Exploratory endpoints: Compound 1 PD measured by the following (additional exploratory biomarkers may also be tested): total hemoglobin (Hb) level; HbF value (%); %F cell percentage; hemolytic index of red blood cells (unconjugated bilirubin, reticulocyte count, lactase dehydrogenase and haptoglobin levels); soluble E-selectin (sE-Sel), soluble P-selectin (sP-Sel) and soluble intercellular adhesion molecule 1 (sICAM-1); high-sensitivity C-reactive protein (hs-CRP). Clinical outcomes of Compound 1 measured by pain-related measures (frequency, severity and duration of pain; impact of pain / fatigue on work / school and daily living activities; need / use of analgesics; SCA-related events requiring professional medical or health care, including events requiring hospitalization or treatment, such as blood transfusion), and physical, social and emotional impact of SCA measured by the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me).

[0191] In addition, a separate blood sample is collected to confirm the diagnosis by electrophoresis, high-performance liquid chromatography (HPLC), and / or DNA sequencing (as needed) and for possible pharmacogenomic analysis of genes that can influence treatment response, including but not limited to α-globin and BCL11A.

Claims

1. An oral pharmaceutical composition comprising: (i) about 100 mg to about 300 mg of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one (Compound 1) or a pharmaceutically acceptable salt, solvate or polymorph thereof; (ii) a filler selected from about 4% to about 6% by weight of pregelatinized starch and / or about 15% to about 50% by weight of microcrystalline cellulose; and (iii) a processing aid selected from about 1% to about 2.5% by weight of colloidal silicon dioxide and / or about 0.5% to about 1.5% by weight of magnesium stearate, wherein the pharmaceutical composition is in the form of a solid tablet suitable for administration to a patient.

2. The pharmaceutical composition of claim 1, having a friability of no more than about 0.3% weight loss, and a disintegration time of less than about 15 minutes, as determined by USP friability and USP disintegration tests.

3. The pharmaceutical composition of claim 1, having at least one of a friability of no more than about 0.3% weight loss or a disintegration time of less than about 15 minutes as determined by USP friability and USP disintegration tests.

4. The pharmaceutical composition according to any one of the preceding claims, further comprising hydroxypropyl cellulose (HPC).

5. The pharmaceutical composition of claim 4, wherein the hydroxypropyl cellulose (HPC) is present in an amount of about 0.4% to about 0.5% by weight.

6. The pharmaceutical composition of claim 4, wherein the hydroxypropyl cellulose (HPC) is present in an amount of about 0.5% by weight.

7. The pharmaceutical composition according to any one of claims 1 to 6, having a hardness of about 10 kPa and / or a thickness of about 4.50 to about 4.80 mm.

8. The pharmaceutical composition of any one of claims 1 to 7, comprising about 100 mg, 200 mg or about 300 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or polymorph thereof.

9. The pharmaceutical composition of claim 8, comprising about 300 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or polymorph thereof.

10. The pharmaceutical composition according to any one of claims 1 to 9, comprising about 5% by weight of pregelatinized starch.

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