Patent Application
20240293420
The present application claims the right of the priority of the prior application No. 202110651136.9 submitted to China National Intellectual Property Administration on Jun. 10, 2021, titled “PHARMACEUTICAL COMPOSITION, PREPARATION, AND PREPARATION METHOD THEREFOR AND USE THEREOF”. The contents of the prior application are incorporated herein by reference in its entirety.
The present disclosure relates to the field of pharmaceutical compositions, and specifically relates to a pharmaceutical composition, a preparation, and a preparation method therefor and a use thereof.
ATP receptors are classified into two main families, P2Y- and P2X-purinergic receptors, based on their molecular structure, transduction mechanism, and pharmacological properties. P2X-purinergic receptors are a family of ATP-gated cation channels and several subtypes have been cloned, including: six homomeric receptors, P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7; and three heteromeric receptors, P2X2/3, P2X4/6, and P2X1/5. It has been found that P2X3 receptors are specifically expressed in the primary afferent nerve fibers of “hollow viscera”, such as lower urinary tract and respiratory tract.
Cough is the main symptom of respiratory diseases, and 70% to 80% of patients in respiratory clinics have cough symptoms. With the increasing prevalence of COPD, IPF, etc., and cough as the main symptom of most respiratory diseases, the demand is also increasing. As a defensive nerve reflex of the body, cough is beneficial to clear respiratory secretions and harmful factors, but frequent and severe cough will seriously affect the work, life, and social activities of patients.
There are not many varieties of P2X3 antagonists specifically developed for cough indications, and the current project with rapid progress is Roche's AF-219 project, which shows good efficacy on refractory cough in the latest completed phase II clinical trial, but with serious dysgeusia problem.
At present, there is no drug on the market that inhibits P2X3 pathway for the treatment of many conditions including chronic cough. Therefore, the development of new drugs that can inhibit the activity of P2X3 is of positive significance for the treatment of diseases.
The present disclosure provides a pharmaceutical composition, comprising an active ingredient and a pharmaceutically acceptable excipient; the active ingredient comprises a compound of formula A:
the excipient is selected from one, two or more of the following excipients including, but not limited to, a diluent, a disintegrant, an adhesive, a glidant, and a lubricant.
According to technical solutions of the present disclosure, the compound of formula A is selected from one, two or more of a crystal form I, a crystal form III, and a crystal form V.
According to technical solutions of the present disclosure, the crystal form I has characteristic peaks at 8.56°±0.20°, 12.48°±0.20°, and 22.13°±0.20° in an X-ray powder diffraction expressed at a 2θ angle using Cu-Kα radiation.
Further, the crystal form I has characteristic peaks at 8.56°±0.20°, 12.48°±0.20°, 22.13°±0.20°, 13.53°±0.20°, 14.25°±0.20°, 25.18°±0.20°, and 26.07°±0.20° in an X-ray powder diffraction expressed at a 2θ angle using Cu-Kα radiation.
Further, the crystal form I has characteristic peaks at 8.56°±0.20°, 12.48°±0.20°, 22.13°±0.20°, 13.53°±0.20°, 14.25°±0.20°, 25.18°±0.20°, 26.07°±0.20°, 22.32°±0.20°, 23.23°±0.20°, and 23.42°±0.20° in an X-ray powder diffraction expressed at a 2θ angle using Cu-Kα radiation.
Preferably, the crystal form I has an XRPD pattern substantially as shown in
Preferably, the crystal form I has a differential scanning calorimetry pattern with an endothermic peak at about 152° C. and a melting enthalpy of about 44±2 J/g.
Preferably, the crystal form I has a thermogravimetric analysis pattern and a differential scanning calorimetry pattern substantially as shown in
Preferably, the crystal form I has a polarizing microscope pattern substantially as shown in
According to technical solutions of the present disclosure, the crystal form III has characteristic peaks at 12.91°±0.20°, 16.77°±0.20°, 19.27°±0.20°, and 22.80°±0.20° in an X-ray powder diffraction expressed at a 2θ angle using Cu-Kα radiation.
Further, the crystal form III has characteristic peaks at 12.91°±0.20°, 16.77°±0.20°, 19.27°±0.20°, 22.80°±0.20°, 13.75°±0.20°, 14.46°±0.20°, and 20.86°±0.20° in an X-ray powder diffraction expressed at a 2θ angle using Cu-Kα radiation.
Further, the crystal form III has characteristic peaks at 12.91°±0.20°, 16.77°±0.20°, 19.27°±0.20°, 22.80°±0.20°, 13.75°±0.20°, 14.46°±0.20°, 20.86°±0.20°, 21.08°±0.20°, 23.75°±0.20°, and 24.05°±0.20° in an X-ray powder diffraction expressed at a 2θ angle using Cu-Kα radiation.
Preferably, the crystal form III has an XRPD pattern substantially as shown in
Preferably, the crystal form III contains 0.4 equivalents of water.
Preferably, the crystal form III has a thermogravimetric analysis pattern with a weight loss gradient of about 1.5% in the range of room temperature to 100° C.
Preferably, the crystal form III has a differential scanning calorimetry pattern with a first endothermic peak showing removal of 0.4 water.
Preferably, the thermogravimetric analysis pattern and differential scanning calorimetry pattern of the crystal form III are substantially as shown in
Preferably, the crystal form III has a polarizing microscope pattern substantially as shown in
According to technical solutions of the present disclosure, the crystal form V has characteristic peaks at 8.38°±0.20°, 9.15°±0.20°, 13.52°±0.20°, and 18.44°±0.20° in an X-ray powder diffraction expressed at a 2θ angle using Cu-Kα radiation.
Further, the crystal form V has characteristic peaks at 8.38°±0.20°, 9.15°±0.20°, 13.52°±0.20°, 18.44°±0.20°, 16.26°±0.20°, 16.89°±0.20°, and 17.86°±0.20° in an X-ray powder diffraction expressed at a 2θ angle using Cu-Kα radiation.
Further, the crystal form V has characteristic peaks at 8.38°±0.20°, 9.15°±0.20°, 13.52°±0.20°, 18.44°±0.20°, 16.26°±0.20°, 16.89°±0.20°, 17.86°±0.20°, 22.35°±0.20°, 23.56°±0.20°, and 24.74°±0.20° in an X-ray powder diffraction expressed at a 2θ angle using Cu-Kα radiation.
Preferably, the crystal form V has an XRPD pattern substantially as shown in
Preferably, the crystal form V has a differential scanning calorimetry pattern with an endothermic peak at about 166° C. and a melting enthalpy of about 70±2 J/g.
Preferably, the crystal form V has a thermogravimetric analysis pattern and a differential scanning calorimetry pattern substantially as shown in
Preferably, the crystal form V has a polarizing microscope pattern substantially as shown in
According to technical solutions of the present disclosure, the compound of formula A has a particle size of 1 to 40 μm, for example 1.5 to 35 μm.
According to technical solutions of the present disclosure, the compound of formula A has a D10 particle size of 1 to 5 μm, for example 1.5 to 4 μm, exemplarily 2 μm, 2.21 μm, 2.5 μm, and 3 μm.
Further, the compound of formula A has a D50 particle size of 6 to 15 μm, for example 8 to 12 μm, exemplarily 9 μm, 10.2 μm, 11 μm, and 11.5 μm.
Further, the compound of formula A has a D90 particle size of 20 to 40 μm, for example 25 to 35 μm, exemplarily 27 μm, 29.1 μm, and 30 μm.
According to technical solutions of the present disclosure, the compound of formula A has a loose density (bulk density) of 0.2 to 0.3 g/mL, for example 0.22 to 0.28 g/mL, exemplarily 0.23 g/mL, 0.24 g/mL, 0.25 g/mL, 0.26 g/mL, 0.27 g/mL, and 0.29 g/mL.
According to technical solutions of the present disclosure, the compound of formula A has a tap density (bulk density) of 0.32 to 0.5 g/mL, for example 0.35 to 0.45 g/mL, exemplarily 0.33 g/mL, 0.36 g/mL, 0.38 g/mL, 0.40 g/mL, 0.42 g/mL, 0.44 g/mL, and 0.48 g/mL.
The pharmaceutically acceptable excipient is preferably an excipient which is chemically non-reactive with or inert to the active ingredient.
According to technical solutions of the present disclosure, the diluent can be selected from one, two or more of the following substances: lactose, microcrystalline cellulose, sucrose, glucose, mannitol, sorbitol, calcium sulfate, calcium gluconate, calcium hydrogen phosphate, calcium phosphate, calcium carbonate, calcium bicarbonate, starch, carboxymethyl starch, pregelatinized starch, etc., for example lactose and/or microcrystalline cellulose; and further, the lactose is lactose monohydrate.
For example, the diluent comprises a first diluent and a second diluent. The first diluent and the second diluent are different, and independently selected from one of the above diluents. Preferably, the first diluent is microcrystalline cellulose, and the second diluent is lactose monohydrate.
According to technical solutions of the present disclosure, the disintegrant can be selected from one, two or more of the following substances: croscarmellose sodium, pregelatinized starch, microcrystalline cellulose, alginic acid, lignocellulose, sodium carboxymethyl starch, guar gum, cross-linked polyvinylpyrrolidone, etc., for example croscarmellose sodium.
According to technical solutions of the present disclosure, the adhesive can be selected from one, two or more of the following substances: hydroxypropyl cellulose, gelatin, dextrin, maltodextrin, sucrose, gum arabic, polyvinylpyrrolidone, methyl cellulose, carboxymethyl cellulose, ethyl cellulose, polyvinyl alcohol, polyethylene glycol, and hydroxypropyl methyl cellulose, etc., for example hydroxypropyl cellulose; and further, the adhesive can be low-substituted hydroxypropyl cellulose or high-substituted hydroxypropyl cellulose.
According to technical solutions of the present disclosure, the glidant can be selected from one, two or more of the following substances: colloidal silica, silica, talc, calcium silicate, magnesium silicate, and calcium hydrogen phosphate, etc., for example colloidal silica.
According to technical solutions of the present disclosure, the lubricant can be selected from one, two or more of the following substances: magnesium stearate, calcium stearate, zinc stearate, talc, glycerol monostearate, polyethylene glycol (e.g. polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000), sodium benzoate, adipic acid, fumaric acid, boric acid, sodium chloride, sodium oleate, triacetin, polyoxyethylene monostearate, sucrose monolaurate, sodium chloride, sodium lauryl sulfate, and magnesium lauryl sulfate, etc., for example magnesium stearate, calcium stearate, and/or zinc stearate.
According to technical solutions of the present disclosure, the excipient may further comprise a corrigent. For example, the corrigent can be selected from one, two or more of the following substances: stevia, fructose, glucose, fructose syrup, honey, aspartame, protein sugar, xylitol, mannitol, lactose, sorbitol, flavor, and maltitol, etc.
According to one embodiment of the present disclosure, the diluent is lactose monohydrate and microcrystalline cellulose, the disintegrant is croscarmellose sodium, the adhesive is hydroxypropyl cellulose, the glidant is colloidal silica, and the lubricant is magnesium stearate.
According to technical solutions of the present disclosure, the pharmaceutical composition comprises the following components: the compound of formula A, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica, and magnesium stearate.
In the pharmaceutical composition described herein, the content of each component can be selected as desired, for example, the content of the compound of formula A can be present in the pharmaceutical composition in a therapeutically effective amount.
According to technical solutions of the present disclosure, the pharmaceutical composition comprises 10 to 40 parts, for example 15 to 35 parts, exemplarily 12 parts, 18 parts, 20 parts, 23 parts, 25 parts, 27 parts, 30 parts, 32 parts, and 38 parts by weight of the compound of formula A.
According to technical solutions of the present disclosure, the pharmaceutical composition comprises 50 to 80 parts, for example 55 to 75 parts, exemplarily 52 parts, 58 parts, 60 parts, 63 parts, 65 parts, 70 parts, 72 parts, and 78 parts by weight of the diluent. Further, the first diluent and the second diluent have a weight ratio of (10 to 25):(40 to 55), for example (15 to 20):(40 to 55), exemplarily 17.4:49.6.
According to technical solutions of the present disclosure, the pharmaceutical composition comprises 0.5 to 6 parts, for example 1 to 5 parts, exemplarily 0.75 parts, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, and 5.5 parts by weight of the disintegrant.
According to technical solutions of the present disclosure, the pharmaceutical composition comprises 0.5 to 6 parts, for example 1 to 5 parts, exemplarily 0.75 parts, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, and 5.5 parts by weight of the adhesive.
According to technical solutions of the present disclosure, the pharmaceutical composition comprises 0.1 to 3 parts, for example 0.3 to 2 parts, exemplarily 0.5 parts, 1 part, 1.2 parts, 1.5 parts, and 2.5 parts by weight of the glidant.
According to technical solutions of the present disclosure, the pharmaceutical composition comprises 0.1 to 3 parts, for example 0.3 to 2 parts, exemplarily 0.5 parts, 1 part, 1.2 parts, 1.5 parts, and 2.5 parts by weight of the lubricant.
The sum of parts by weight of each component in the pharmaceutical composition is 100 parts.
According to technical solutions of the present disclosure, the pharmaceutical composition comprises the following components by weight: 10 to 40 parts of compound of formula A, a total of 50 to 80 parts of lactose monohydrate and microcrystalline cellulose, 0.5 to 6 parts of croscarmellose sodium, 0.5 to 6 parts of hydroxypropyl cellulose, 0.1 to 3 parts of colloidal silica, and 0.1 to 3 parts of magnesium stearate;
According to exemplary embodiments of the present disclosure, the pharmaceutical composition comprises the following components by weight: 25 mg of compound of formula A, 49.6 mg of lactose monohydrate, 17.4 mg of microcrystalline cellulose, 3.0 mg of croscarmellose sodium, 3.0 mg of hydroxypropyl cellulose, 1.0 mg of colloidal silica, and 1.0 mg of magnesium stearate;
According to exemplary embodiments of the present disclosure, the pharmaceutical composition comprises the following components by weight: 100 mg of compound of formula A, 198.4 mg of lactose monohydrate, 69.6 mg of microcrystalline cellulose, 12.0 mg of croscarmellose sodium, 12.0 mg of hydroxypropyl cellulose, 4.0 mg of colloidal silica, and 4.0 mg of magnesium stearate.
According to embodiments of the present disclosure, the pharmaceutical composition is in a solid form, such as a powdered solid form.
According to embodiments of the present disclosure, the pharmaceutical composition may be prepared in a dosage form suitable for administration.
The present disclosure also provides a pharmaceutical preparation, such as a solid preparation, comprising the pharmaceutical composition. Exemplarily, the solid preparation may be a tablet, a capsule, or a granule.
According to exemplary embodiments of the present disclosure, the tablet is a coated tablet, comprising a tablet core and a coating layer. Preferably, the tablet core comprises the pharmaceutical composition.
According to exemplary embodiments of the present disclosure, there is no particular limitation on the composition of the coating layer, which may be prepared, for example, by using a commercially available known gastric-soluble film coating premix, or according to known methods. For example, the coating layer further comprises one, two or more selected from polyvinyl alcohol, polyethylene glycol, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylic resin VI, polyvinylpyrrolidone, propylene glycol, castor oil, silicone oil, triglyceride, talc, titanium dioxide, and coloring agent. Film coating materials may also be purchased commercially, such as Opadry gastric-soluble coating series and “EASPRAY™” gastric-soluble coating series.
According to one technical solution of the present disclosure, the tablet core of the coated tablet comprises the following components by weight: 10 to 40 parts of compound of formula A, a total of 50 to 80 parts of lactose monohydrate and microcrystalline cellulose, 0.5 to 6 parts of croscarmellose sodium, 0.5 to 6 parts of hydroxypropyl cellulose, 0.1 to 3 parts of colloidal silica, and 0.1 to 3 parts of magnesium stearate;
Exemplarily, the tablet core of the coated tablet comprises the following components: 25 mg of compound of formula A, 49.6 mg of lactose monohydrate, 17.4 mg of microcrystalline cellulose, 3.0 mg of croscarmellose sodium, 3.0 mg of hydroxypropyl cellulose, 1.0 mg of colloidal silica, and 1.0 mg of magnesium stearate;
Exemplarily, the tablet core of the coated tablet comprises the following components: 100 mg of compound of formula A, 198.4 mg of lactose monohydrate, 69.6 mg of microcrystalline cellulose, 12.0 mg of croscarmellose sodium, 12.0 mg of hydroxypropyl cellulose, 4.0 mg of colloidal silica, and 4.0 mg of magnesium stearate;
The present disclosure further provides a method for preparing the pharmaceutical composition, comprising mixing the components comprised therein. Preferably, a prescribed amount of the compound of formula A, the glidant and the first diluent are first sieved (e.g., through a 60 mesh sieve), and then mixed with other components.
The present disclosure also provides a method for preparing the tablet, comprising compressing the pharmaceutical composition into a tablet, for example by a wet granulation tabletting method, and optionally with or without coating.
Preferably, the wet granulation tabletting method comprises: wet granulating the pharmaceutical composition except the lubricant, pelletizing, drying, and pelletizing again to obtain a dry granule; mixing the dry granule with the lubricant, and tabletting.
According to embodiments of the present disclosure, in the drying step of the wet granulation tabletting method, the weight loss on drying of the material is controlled at 1.5% to 2.5%. Preferably, in the drying step, when the weight loss on drying of the material is between 1.0% and 2.5%, an inlet air temperature is turned off to stop drying. Preferably, in the drying step, the equipment used is a fluidized bed.
According to embodiments of the present disclosure, in the wet granulating step, the stirring speed is 200 to 400 rpm, preferably 250.0 rpm; the cutting speed is 1000.00 to 2000.00 rpm, preferably 1500.0 rpm; the granulation time is 30 seconds to 2 minutes, preferably 60 seconds.
Further, the wet granulating comprises: mixing the compound of formula A, the glidant (e.g., colloidal silica), the diluent (e.g., microcrystalline cellulose and lactose monohydrate), and the disintegrant (e.g., croscarmellose sodium), spraying an adhesive solution (e.g., hydroxypropyl cellulose) into the mixture, and granulating after the adhesive solution is sprayed, optionally with or without water replenishing;
Preferably, the preparation of the mixture comprises:
The present disclosure also provides a method for storing the pharmaceutical composition or the preparation, comprising storing the pharmaceutical composition or the preparation in the dark. Further, storage conditions further comprise dry storage.
The present disclosure also provides a use of the pharmaceutical composition in the manufacture of a P2X3 inhibitor.
In the use, the P2X3 inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample to provide a comparison, or prepared as a kit according to conventional methods in the art to provide rapid detection of the inhibitory effect of P2X3.
The present disclosure also provides a use of the pharmaceutical composition in the manufacture of a pharmaceutical preparation, such as a solid preparation, further such as tablets, especially in the manufacture of a tablet by a direct tabletting method.
According to technical solutions of the present disclosure, the pharmaceutical preparation is a drug for preventing, curing, treating, or alleviating a disease in animals that is at least partially mediated by P2X3 or related to P2X3 activity; or, the drug is used for the treatment of pain, pruritus, endometriosis, urinary tract disease, or respiratory disease.
In some embodiments, the disease comprises pain; and the pain includes, but is not limited to: inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine, or cluster headache.
In some embodiments, the disease comprises a urinary tract disease; the urinary tract disease includes urinary incontinence, overactive bladder, dysuria, cystitis, prostatitis, prostatodynia, and benign prostatic hyperplasia;
In some embodiments, the disease comprises a respiratory disease including, but not limited to, a respiratory disorder including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, acute cough, or chronic cough.
The chronic cough is a cough that lasts for more than eight weeks and causes serious adverse social, psychological, and physical effects.
In some embodiments, the disease comprises a respiratory disease including acute cough or chronic cough. The cough is an acute cough or a chronic cough, and the cough is associated with a disease, disorder, or condition selected from chronic obstructive pulmonary disease, asthma, tuberculosis, bronchitis, bronchiectasis, suppurative lung disease, respiratory malignancy, hypersensitivity, cystic fibrosis, pulmonary fibrosis, respiratory inflammation, emphysema, pneumonia, lung cancer, neoplasia of the lung, sore throat, common cold, influenza, respiratory infection, bronchoconstriction, sarcoidosis, viral or bacterial infection of the upper airway, angiotensin converting enzyme (ACE) inhibitor therapy, smoker's cough, chronic dry cough without phlegm, neoplastic cough, cough due to gastroesophageal reflux, and inhalation of irritants, smoke, fog, dust, or air pollution.
In some embodiments, the pruritus is associated with an inflammatory skin disease, an infectious skin disease, an autoimmune skin disease, or a pregnancy-related skin disease.
In some embodiments, the pruritus is associated with an inflammatory skin disease selected from atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis, xerotic dermatitis, dysplastic dermatitis, lichen planus, lichen sclerosus, polymorphic eruption psoriasis, Graves disease, mucoid degeneration, mastocytosis, and urticaria.
In some embodiments, the pruritus is associated with an infectious skin disease selected from fungal disease, bacterial and viral infections, scabies, podiatry, insect bites, and folliculitis.
In some embodiments, the pruritus is associated with an autoimmune skin disease selected from dermatitis herpetiformis (Duhring's disease), bullous pemphigoid, genetic skin disease, Darier's disease, and Hailey-Hailey disease.
In some embodiments, the pruritus is associated with a pregnancy-related skin disease selected from polymorphic eruption of pregnancy (PEP), atopic eruption of pregnancy, pemphigoid gestationis, neoplasia, and cutaneous T-cell lymphoma.
In some embodiments, the pruritus is associated with prurigo nodularis.
In some embodiments, the pruritus is associated with renal disease or a process for the treatment of renal disease.
In some embodiments, the pruritus is associated with chronic renal disease.
In some embodiments, the pruritus is associated with a process for the treatment of renal disease, wherein the process for the treatment of renal disease is selected from hemodialysis and peritoneal dialysis.
In some embodiments, the pruritus is associated with a medical procedure or treatment.
In some embodiments, the pruritus is associated with medical treatment with a drug selected from opioids, antimalarial drugs, anticancer therapies, and epidermal growth factor receptor inhibitors.
In some embodiments, the disease mediated by P2X3 or related to P2X3 activity is endometriosis. Symptoms related to the endometriosis are selected from dysmenorrhea, dyspareunia, dysuria, and schizophrenia.
The present disclosure also provides a use of the pharmaceutical composition or preparation in the treatment and/or prevention of a disease.
The present disclosure also provides a use of the pharmaceutical composition or preparation for preventing, curing, treating, or alleviating a disease in animals (e.g., humans) that is at least partially mediated by P2X3 or related to P2X3 activity. The disease includes, but is not limited to, respiratory disease, cough, chronic cough, idiopathic pulmonary fibrosis, chronic pulmonary obstruction, asthma, pain, urinary incontinence, autoimmune disease, overactive bladder, dysuria, inflammation, Alzheimer's disease, Parkinson's disease, sleep disorder, epilepsy, mental illness, arthritis, neurodegeneration, traumatic brain injury, myocardial infarction, rheumatoid arthritis, stroke, thrombosis, atherosclerosis, colon syndrome, inflammatory bowel disease, digestive tract disease; gastrointestinal dysfunction, respiratory failure, sexual dysfunction, cardiovascular system disease, heart failure, hypertension, urinary incontinence, cystitis, arthritis, endometriosis, blood disease, musculoskeletal and connective tissue developmental disorder, and systemic disorder.
In some embodiments, the disease comprises pain; and the pain includes, but is not limited to: inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine, or cluster headache.
In some embodiments, the disease comprises a urinary tract disease.
In some embodiments, the disease comprises a respiratory disease including, but not limited to, a respiratory disorder including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or chronic cough.
The chronic cough is a cough that lasts for more than eight weeks and causes serious adverse social, psychological, and physical effects.
In some embodiments, the disease comprises pruritus associated with an inflammatory skin disease, an infectious skin disease, an autoimmune skin disease, or a pregnancy-related skin disease.
In some embodiments, the pruritus is associated with an inflammatory skin disease selected from atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis, xerotic dermatitis, dysplastic dermatitis, lichen planus, lichen sclerosus, polymorphic eruption psoriasis, Graves disease, mucoid degeneration, mastocytosis, and urticaria.
In some embodiments, the pruritus is associated with an infectious skin disease selected from fungal disease, bacterial and viral infections, scabies, podiatry, insect bites, and folliculitis.
In some embodiments, the pruritus is associated with an autoimmune skin disease selected from dermatitis herpetiformis (Duhring's disease), bullous pemphigoid, genetic skin disease, Darier's disease, and Hailey-Hailey disease.
In some embodiments, the pruritus is associated with a pregnancy-related skin disease selected from polymorphic eruption of pregnancy (PEP), atopic eruption of pregnancy, pemphigoid gestationis, neoplasia, and cutaneous T-cell lymphoma.
In some embodiments, the pruritus is associated with prurigo nodularis.
In some embodiments, the pruritus is associated with renal disease or a process for the treatment of renal disease.
In some embodiments, the pruritus is associated with chronic renal disease.
In some embodiments, the pruritus is associated with a process for the treatment of renal disease, wherein the process for the treatment of renal disease is selected from hemodialysis and peritoneal dialysis.
In some embodiments, the pruritus is associated with a medical procedure or treatment.
In some embodiments, the pruritus is associated with medical treatment with a drug selected from opioids, antimalarial drugs, anticancer therapies, and epidermal growth factor receptor inhibitors.
In some embodiments, the disease mediated by P2X3 or related to P2X3 activity is endometriosis. Symptoms related to the endometriosis are selected from dysmenorrhea, dyspareunia, dysuria, and schizophrenia.
The present disclosure also provides a method for treating or preventing a disease by administering a prophylactically and/or therapeutically effective amount of the pharmaceutical composition or preparation to a patient.
By administering the pharmaceutical composition, the side effects of dysgeusia associated with the treatment are reduced.
Various terms and phrases used in the present disclosure have general meanings known to those skilled in the art. Even so, these terms and phrases are expected to be described and explained in greater detail herein. If any of the terms and phrases referred to are inconsistent with the known meanings, the meanings expressed in the present disclosure shall prevail.
A polymorph of the compound of formula A in the present disclosure includes crystal forms of non-solvate (anhydrate) and solvate of the compound of formula A.
The polymorph of the compound of formula A in the present disclosure has have characteristic peaks in X-ray powder diffraction expressed at 2θ angles, wherein “±0.20” is the allowable measurement error range.
The polymorph of the compound of formula A in the present disclosure can be used in combination with other active ingredients, provided that it does not produce other adverse effects, such as allergic reactions.
As used herein, the term “composition” is meant to include a product containing a specified amount of each of the specified ingredients, as well as any product derived directly or indirectly from a combination of the specified amount of each of the specified ingredients.
Those skilled in the art can prepare the polymorph of the compound of formula A in the present disclosure into a suitable pharmaceutical composition using a known pharmaceutical carrier. The pharmaceutical composition may be specially formulated for oral administration, for parenteral injection, or for rectal administration in solid or liquid form. The pharmaceutical composition may be formulated into a variety of dosage forms for ease of administration, such as oral preparations (e.g., tablets, capsules, solutions, or suspensions); and injectable preparations (e.g., injectable solutions or suspensions, or injectable dry powders that can be used immediately after adding a drug solvent before injection).
As used herein, the term “therapeutically and/or prophylactically effective amount” refers to the amount of a drug or pharmaceutical preparation that elicits a biological or medical response in a tissue, system, animal, or human sought by a researcher, veterinarian, physician, or other person.
When used for therapeutic and/or prophylactic purposes as described above, the total daily dose of the compound of formula A (including its crystal form) and the pharmaceutical composition in the present disclosure must be determined by the attending physician within the scope of reliable medical judgment. For any specific patient, the specific therapeutically effective dose level depends on a variety of factors, including a disorder being treated and the severity of the disorder; activity of a specific compound used; a specific composition used; age, weight, general health status, sex and diet of the patient; administration time, administration route and excretion rate of the specific compound used; duration of treatment; drugs used in combination or simultaneously with the specific compounds used; and similar factors known in the medical field. For example, it is a common practice in the art to start with a dose of the compound below the level required to obtain the desired therapeutic effect and gradually increase the dose until the desired effect is obtained.
The pharmaceutical compositions and preparations of the present disclosure have good safety and/or stability, as well as high P2X3 antagonistic activity with less impact on the taste. It has been found that crystal form I, crystal form III, and crystal form IV of the active ingredient in the pharmaceutical composition of the present disclosure have good solid-state properties, wherein crystal form III has good physicochemical properties, and physical and chemical stability; crystal form III has a better PK advantage compared with crystal form I and crystal form IV, and there is no significant difference between the solubility of crystal form III in biological media and that of crystal form I and crystal form V; the crystal form III is less likely to cause risk of crystal transformation during storage and production, and it is easy to prepare, suitable for industrialized scale-up production, especially in the development of solid preparations, which is conducive to maintaining the stability, effectiveness, safety, and quality controllability of API during the preparation process, and has a better prospect of medicinal use.
The technical solutions of the present disclosure will be further described in detail below in conjunction with specific examples. It should be understood that the following examples are only used to illustrate and explain the present disclosure, and should not be construed as a limitation on the scope of protection of the present disclosure. All techniques realized based on the above contents of the present disclosure are within the scope of protection intended by the present disclosure.
Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.
The solid obtained in the experiment was tested and analyzed for crystal form using PANalytical Empyrean equipped with a PIXcel1D detector. The instrument parameters are as follows: scanning range: 3 to 400 (2θ); step size: 0.013° (2θ); tube voltage: 45 KV; tube current: 40 mA.
The crystal form III (batch number: A10230-047P1) sample was tested and analyzed by VH-XRPD, and this part of the work was completed by WuXi AppTec-STAPharmaceutical. The instrument parameters are as follows:
The humidity change program settings are as follows:
Samples were subjected to thermogravimetric analysis using Discovery TGA 55 (TA Instruments, US). 2 to 3 mg of the sample was placed in a pre-tared open aluminum tray, automatically weighed in a TGA heating furnace, and then heated to 250° C. at a heating rate of 10° C./min under dry N2 atmosphere.
Solid samples were subjected to DSC analysis using TA Instrument Differential Scanning Calorimeter Q200 and Discovery DSC 250. The sample was weighed to record the value, and then placed in the sample chamber. The sample was heated from 25° C. to different endpoint temperatures at a rate of 10° C./min.
A small amount of powder sample was taken and placed on a slide, added dropwise with a small amount of silicone oil to be better dispersed, covered with a coverslip, and then placed on the stage of Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN). The morphology of the sample was observed at an appropriate magnification and photographed.
The water vapor adsorption/desorption data of the samples were collected on an adsorption instrument manufactured by ProUmid GmbH & Co. KG, Germany. Conventionally, about 100 mg of sample was taken and placed in a tared sample tray. The weight change of the sample during the humidity change was recorded by the instrument software. The anhydrous crystal forms I and V were tested according to the following parameters.
The crystal form III was tested with an initial humidity of 50% (ambient humidity), and the specific test parameters are shown in the table below:
1H-NMR was performed on AVANCE III HD 300 equipped with a SampleXpress 60 auto sampler.
The instrument used for liquid chromatography analysis was Agilent HPLC 1260 series, and the analytical method is shown in the table below.
To a 100 mL round-bottom flask were sequentially added tert-butyl (S)-2-ethynylmorpholine-4-carboxylate (3.1 g, 1.0 eq, intermediate 1-4), 4-bromo-2,6-difluorobenzaldehyde (2.76 g, 1.0 eq, compound 172-1), 4-chloropyridin-2-amine (1.61 g, 1.0 eq, compound 172-2), CuCl (0.37 g, 0.3 eq), Cu(OTf)2 (1.36 g, 0.3 eq), and isopropanol (50 mL). The reaction mixture was replaced with nitrogen for three times, heated in an oil bath at 80° C. overnight, and raw material compound 172-2 disappeared, as detected by TLC. The reaction mixture was evaporated to dryness by rotary evaporation to remove isopropanol, and extracted with EA and ammonia water sequentially. The EA phase was washed with saturated brine and citric acid sequentially, dried over anhydrous sodium sulfate, evaporated to dryness by rotary evaporation, and purified by column chromatography to obtain intermediate 172-3 (3.0 g, purity: 78%) as a white solid. LC-MS: [M+H]+=542.2.
Intermediate 172-3 (2.67 g) was dissolved in dichloromethane (24 mL), and then dioxane hydrochloride (24 mL) was added thereto. The reaction mixture was stirred at room temperature for 1.0 hour, and the reaction was completed, as detected by LC-MS. The reaction mixture was evaporated to dryness by rotary evaporation, added with water (15 mL) and dichloromethane (15 mL), and extracted to obtain an aqueous phase, which was added with sodium bicarbonate aqueous solution to adjust the pH to alkalescence (pH=8 to 9). The phases were separated to obtain a dichloromethane phase, and the aqueous phase was extracted with dichloromethane (10 mL×2). The dichloromethane phases were combined, washed with saturated brine, and evaporated to dryness by rotary evaporation to obtain intermediate 172-4 (1.70 g, purity: 88.6%) as a white solid. LC-MS: [M+H]+=442.1.
Intermediate 172-4 (1.4 g, 1.0 eq) was dissolved in dichloromethane (10 mL), then triethylamine (480 mg, 1.5 eq) was added thereto, and methyl chloroacetate (388 mg, 1.3 eq) was added dropwise thereto. The reaction mixture was reacted for 1.0 hour, and a product was generated, as shown by LC-MS. After the reaction was completed, the reaction mixture was added with water (10 mL) and stirred for 30 minutes. The phases were separated to obtain a dichloromethane phase, and the aqueous phase was extracted with dichloromethane (10 mL×2). The dichloromethane phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness by rotary evaporation, and purified by column chromatography to obtain intermediate 172-5 (1.01 g, purity: 93.02%) as a white solid. LC-MS: [M+H]+=499.8.
Intermediate 172-5 (0.73 g, 1.0 eq) was dissolved in dioxane (4 mL), and BnSH (0.24 g, 1.3 eq), Pd2(dba)3 (0.04 g, 0.03 eq), Xantphos (0.04 g, 0.05 eq), and DIEA (0.60 g, 3.0 eq) were added thereto. The reaction mixture was replaced with nitrogen for three times, and reacted overnight at 80° C. The raw material completely disappeared, as monitored by LC-MS. To the reaction mixture were added dichloromethane (10 mL) and water (10 mL). The phases were separated to obtain a dichloromethane phase, and the aqueous phase was extracted with dichloromethane (10 mL×2). The dichloromethane phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness by rotary evaporation, and purified by column chromatography to obtain intermediate 172-6 (0.82 g, purity: 91.53%) as a white solid. LC-MS: [M+H]=544.2.
To a reaction flask was added intermediate 172-6 (510 mg), and acetonitrile (3 mL) was added to dissolve it. The reaction mixture was then added with glacial acetic acid (281 mg, 5.0 eq), and added dropwise with SO2Cl2 (506 mg, 4.0 eq) under an ice bath. The reaction mixture was reacted at 0° C. for 1 hour. The raw material disappeared, and intermediate 172-7 was generated, as shown by LC-MS. The reaction mixture was directly used in the next step without treatment.
To the above reaction mixture was added dropwise ammonia water (2 mL) diluted with acetonitrile (1 mL) at 0° C., and reaction mixture was reacted at room temperature for 0.5 hours. The raw material completely disappeared, and a target product was generated, as shown by LC-MS. The reaction mixture was extracted twice with water and ethyl acetate, washed with brine solution, dried over anhydrous sodium sulfate, concentrated, and purified by C18 chromatography column (water/acetonitrile, RRt=22.5 min). Compound A in an amorphous state (compound A is the compound of formula A) (185 mg, purity: 99.74%) was obtained as a white solid. LC-MS: [M+H]=501.1.
1H NMR (400 MHz, DMSO-d6) δ=8.11 (d, J=7.4, 1H), 7.29 (d, J=1.6, 1H), 7.22 (s, 2H), 7.14 (d, J=6.6, 2H), 6.60 (dd, J=7.4, 2.1, 1H), 3.33 (d, J=12.8, 1H), 3.13 (d, J=11.3, 2H), 3.07 (s, 3H), 2.97 (d, J=7.8, 1H), 2.77-2.69 (m, 1H), 2.69-2.61 (m, 1H), 2.53 (dd, J=15.5, 8.3, 1H).
A total of 11.1 g of compound A was obtained with reference to the preparation of the compound of formula A, and 20 mL of acetone was added thereto. The reaction mixture was refluxed at 65° C. (under nitrogen atmosphere) for 2.0 hours, directly evaporated to dryness by rotary evaporation to remove acetone, and dried in vacuum at 40° C. for 12 hours. There was about 1% acetone residue, as shown by NMR. The reaction mixture was again dried in vacuum at 80° C. for 12 hours, and there was still acetone residue, as shown by NMR. 5.3 g of the residue was taken and again dried in vacuum at 80° C. for 12 hours, and there was still acetone residue, as shown by NMR, and the resulting product was added with acetonitrile (16 mL). The reaction mixture was refluxed at 85° C. (under nitrogen atmosphere) for 2.0 hours, directly evaporated to dryness by rotary evaporation to remove acetonitrile, and then dried in vacuum at 80° C. for 12 hours. The product was qualified without residual solvent, as shown by NMR, and put in storage for 5.2 g. The product has a purity of 99.29% as a white powder.
The PLM and XRPD results showed that the raw material is an irregular crystal of 10 to 50 μm with an average crystallinity and an amorphous state. As shown in
Compound A was dissolved in a certain amount of THF, and concentrated to dryness under reduced pressure to obtain an amorphous sample. The XRPD characterization is as shown in
The XRPD pattern of crystal form I expressed at 2θ angles is as shown in
The XRPD pattern of crystal form II expressed at 2θ angles is as shown in
The crystal form I product slurry was slurried in 50 to 95% water/acetone (V/V) to obtain crystal form IV
The XRPD pattern of crystal form IV expressed at 2θ angles is substantially as shown in
The XRPD pattern of crystal form V expressed at 2θ angles is as shown in
Crystal form VI was obtained by slurrying crystal form I or crystal form V at 60° C. in a mixed solvent of water/acetone with a water content of 10% (volume ratio) at 60° C.
The XRPD pattern of crystal form VI expressed at 2θ angles is as shown in
The XRPD of crystal form VII expressed at 2θ angles is substantially as shown in
Crystal form III was used as a seed crystal, and water was added dropwise to a saturated solution of 50% THF/water at 40° C. as an anti-solvent to obtain an oil substance. The mixture was cooled to room temperature, and then continued to slurry to obtain crystal form VIII (wet filter cake).
The XRPD pattern of crystal form VIII expressed at 2θ angles is substantially as shown in
Crystal form III was slurried in a saturated solution of 50% DMSO/water at 40° C. to obtain crystal form IX.
In TGA pattern of the crystal form IX, there is a weight loss of 18.23% in the temperature range of RT to 160° C. In DSC pattern of the crystal form IX, there is a corresponding endothermic peak corresponding to the TGA weight loss on the DSC pattern, and the TGA and DSC patterns are as shown in
The following table shows data about the positions of the diffraction peaks in the XRPD patterns of nine different crystal forms of the present disclosure whose relative intensity is greater than 10% and whose relative peak intensity ranks among the top ten.
In order to further develop a form of the compound of formula A of the present disclosure suitable for pharmaceutical preparation, a total of nine different crystal forms were obtained through screening experiments, including two anhydrous crystal forms (crystal form I and crystal form V), three hydrates (crystal form III, crystal form IV, and crystal form VI), and four solvates (crystal form II, crystal form VIII, and crystal form IX). Specific characterization data and performance comparisons are summarized in Table B below. After comparative analysis, it is found that crystal forms I, III, and V have good solid-state properties compared to the other crystal forms and will be subsequently tested for stability and solubility in biological media, respectively.
Crystal form I can be obtained by the preparation method in Example 3. It was found that crystal form I absorbed moisture under high humidity environment and was transformed into crystal form IV as a hydrate, but transformed into the initial crystal form I after being dried in a vacuum oven at 30° C. (
Crystal form III was obtained by the preparation method in Example 5. The experimental results (
Crystal form IV is a hygroscopic product of crystal form I under high humidity environment, and can be obtained by slurrying crystal form I or crystal form V in a mixed solvent of water/acetone with a water content of 50% to 95%. Crystal form IV was only stable under high humidity environment, and was transformed into crystal form I as an anhydrous crystal form after vacuum drying and dehydration (
Crystal form V is an anhydrous crystal form, which was obtained only by slurrying the first batch of raw materials in water at 60° C. or by suspending and slurrying crystal forms I and V in equal proportions at 60° C., but neither of the preparations could be subsequently repeated.
Crystal form VI was obtained by slurrying crystal form I or crystal form V at 60° C. in a mixed solvent of water/acetone with a water content of 10% (volume ratio) at 60° C. As shown in
Crystal form VIII is a hydrate, but the hydrate is unstable. After dehydration (vacuum drying at 40° C. for 3 hours), crystal form VIII was transformed into crystal form I (
The physical and chemical stability of crystal forms I, III, and V at 60° C. (closed) and 40° C./75% RH (open) for 7 days were investigated respectively. As shown in Table C and
Crystal form III was used as a target crystal form for the next step of development, and the stability of crystal form III was further confirmed. The physical and chemical stability of crystal form III at 60° C. (closed) and 40° C./75% RH (open) for 3 months were investigated. As shown in Table D and
The results of solubility tests of crystal forms I, III, and V in biological media of SGF, FaSSIF, and FeSSF are as shown in Table E and
As shown in
The results of the above tests show that crystal form III has good physicochemical properties, and physical and chemical stability, and that there is no significant difference between the solubility of crystal form III in biological media and that of crystal form I and crystal form V. Since crystal form I is easy to transform into crystal form IV when RH >40%, there is a risk of crystal transformation during storage and production, and crystal form V is not easy to prepare and is not suitable for scale-up production, crystal form III is more preferred in the present disclosure, which is suitable for preparation development.
To reaction kettle A was added DMSO (4 V) under nitrogen atmosphere, and the stirring was started. API was added thereto, and the reaction kettle was rinsed with DMSO (0.8 V). The temperature was adjusted to 25±5° C., and the reaction mixture was stirred for at least 0.5 hours.
To reaction kettle B was added purified water (20 V) through a microporous filter, and the temperature was adjusted to 40±5° C. To reaction kettle B was added dropwise DMSO solution in reaction kettle A through a microporous filter for at least 2 hours, and the microporous filter was rinsed with DMSO (0.2 V). The reaction mixture was stirred for at least 4 hours, and a sample was collected for XRPD analysis with a standard of being consistent with the XRPD pattern of the control (crystal form III). If it did not meet the standard, the temperature was controlled at 40±5° C. The reaction mixture was stirred for at least another 4 hours, and a sample was collected for XRPD analysis until it met the standard. The reaction mixture was cooled to 25±5° C. and stirred for at least 2 hours. The reaction mixture was centrifuged with a 300 mesh filter cloth bag, and the filter cake was rinsed with purified water (2 V) and collected. To reaction kettle B was added purified water (10 V) through a microporous filter under nitrogen atmosphere, and the stirring was started. The above wet filter cake was added thereto, and the temperature was controlled at 25±5° C. The reaction mixture was stirred for at least 0.5 hours, centrifuged with a 300 mesh filter cloth bag, and the filter cake was rinsed with purified water (5 V) and collected.
The filter cake was dried in a vacuum oven at 45±5° C. for at least 4 hours, and a sample was collected for GC with a standard of DMSO ≤0.5000%. If it did not meet the standard, a sample was collected for GC analysis at least every 2 hours until it met the standard. A sample was collected for KF with a standard of 2.0% to 3.0%. If KF was higher than 3.0%, the reaction mixture was dried at 45±5° C. for at least 1 hour, and a sample was collected for KF until it met the standard. If KF was lower than 2.0%, wet nitrogen stream was blown into the oven for at least 0.5 hours, and a sample was collected for KF until it met the standard.
The basic information of the prepared multiple batches of products is summarized in Table F:
In specific preparation formulation and preparation process, the crystal form is often prone to crystal transformation, which leads to changes in drug properties, compatibility, etc., which in turn has an impact on the stability, effectiveness, safety, quality controllability, etc. of the preparation. Therefore, it is necessary to further study the stability performance of crystal form III in the preparation of the present disclosure.
The running procedure of the test is as shown in
The results showed that the adsorption and desorption curves of crystal form III almost completely overlapped, indicating that crystal form III did not form a hydrate or formed a non-stoichiometric hydrate during the moisture absorption process. Combined with the low dehydration temperature in the aforementioned TGA pattern (
The absorption curve in
Based on the test results of Example 13, the stability of crystal form III during a cycle of moisture desorption-absorption of 40% RH-0% RH-40% RH at 25° C. was investigated in order to confirm the control strategy of crystal form III.
The results showed (see Table G): during the cycle of moisture desorption-absorption of 40% RH-0% RH-40% RH at 25° C., it was found that crystal form III was completely dehydrated at 0% RH and transformed into a new crystal form, anhydrous crystal form X, which could be reversibly transformed into crystal form III. Combined with the completely consistent characteristics of the DVS adsorption-desorption curve of crystal form III, it is determined that crystal form III is a non-stoichiometric hydrate.
In the range of 50% RH to 200 RH, there is a slight difference at the position of about 12.9° (2θ) under different humidity conditions. However, the crystal form patterns (see
The present disclosure preferred crystal forms I, III, and V of the compound in the above examples for pharmacokinetic experiments in Beagles, and the relevant experiments are as follows:
Animal: 9 Beagles, male, divided into three groups with 3 in each group, weight ranging from 10 to 13 kg (source & certificate number: Beijing Marshall Biotechnology Co., Ltd., No. 1103182011000161)
Administration mode and dosage: PO: 10 mg/kg
Preparation: 0.5% CMC-Na was used as the solvent, and 400 mg of each of the three different crystal forms of compound A were weighed and added to the corresponding 79 mL of solvent, respectively. The mixture was subjected to ultrasonication for 20 minutes, added with a stirrer, and mixed thoroughly for 3 hours (the storage period from compound preparation to animal administration at room temperature was less than 6 hours). After the drug solution became a homogeneous and fine suspension, which was observed by the naked eye, the solvent was gradually added until the specified volume reached the target concentration. The preparation was stirred for 10 minutes at room temperature before administration, and stirred continuously during administration.
Time points for sampling: the time points for blood sampling in the PO group were 0.167, 0.5, 1, 2, 4, 6, 8, and 24 hours.
Animals in the PO group were fasted overnight except for free access to water before administration, and resumed food supply 4 hours after administration.
After Beagles in the two groups were administered, blood was collected from Beagles by jugular vein puncture according to the time points for sampling. About 1.0 mL of blood was collected at each time point and transferred to an anticoagulant EP tube (containing 10 μL of EDTA-K2, 375 mg/mL). The tube was gently inverted three times, stored in an ice box (no more than 30 minutes), and centrifuged at 3200 g for 10 minutes at 4° C. The plasma was transferred to an ultra-low temperature refrigerator and stored until detection.
Sample pretreatment process: 40 μL of sample was taken, and 160 μL of acetonitrile solution containing 0.1% FA and 200 ng/mL of mixed standard solution was added to precipitate the protein. The mixture was vortexed and mixed well, and the sample was centrifuged in a 4° C. centrifuge at 13000 pm for 10 minutes. 100 μL of the supernatant was transferred to another 96 deep well plate, then 100 μL of methanol:water (1:3, v:v) solution containing 0.1% FA was added thereto, and the mixture was shaken and mixed for 10 minutes.
The data would be analyzed using WinNonlin (version 5.2.1 Pharsight, Mountain View, CA) through a non-compartmental model to obtain PK parameters (selecting Cmax, Tmax, AUClast, T1/2, and other parameters according to different routes of administration). The results are shown in the table below.
Lactose monohydrate was mixed with croscarmellose sodium in a low-density polyethylene bag for 1 minute, and the mixture was sieved through a 40 mesh sieve as mixture 2.
Magnesium stearate was sieved once through the same 40 mesh sieve, and placed in another pharmaceutical low-density polyethylene bag.
100 mg coated tablets were packed into 75 mL oral solid pharmaceutical high-density polyethylene (HDPE) bottles with a packaging specification of 30 tablets/bottle. A bottle label was put on each bottle.
In order to investigate the impact of the preparation process of the preparation on the crystal form, samples were taken at different stages during the preparation process of the coated tablets according to Example 17.3 and analyzed. The analysis results are shown in Table I. The summarized results of the XRPD patterns of the products at each time point for sampling are shown in
The investigation results are shown in Table J. The XRPD results of the crystal form of the coated tablet, API, and the blank excipient are shown in
25 mg and 100 mg tablet cores and coated tablets were investigated for their stability. The results of related substances are shown in Table K-1 and Table K-2. The results of dissolution detection are shown in Table K-3 and Table K-4. The results of crystal form stability are shown in
Remarks: Under the conditions of 25° C./92.5% RH/open/30 days, the coated tablets were mildewed, so they were not detected.
It can be seen from the above results that for 25 mg tablet core, there was no significant change in the related substances after being placed under the conditions of 60° C./open, 25° C./92.5% RH/open, 40° C./75% RH/closed, and light/closed for 10 days, while there was a significant increase in the related substances after being placed under the conditions of light/open for 10 days and 20 days, compared with the result that there was no significant change in the related substances of coated tablets, indicating that the coating can effectively avoid the impact of light on the product.
For 25 mg and 100 mg coated tablets, there was no significant change in the related substances after being placed under the conditions of 60° C./open and 40° C./75% RH/closed for 30 days; there was no significant change in the related substances after being placed under the conditions of light/open for 20 days and light/closed for 10 days; and there was no significant change in the related substances after being placed under the conditions of 25° C./92.5% RH/open for 10 days (mildew occurred after being placed for 30 days, not detected). The above results of the stability of the related substances indicate that the coated tablet has good stability.
From the above results, it can be seen that there was no significant change in the dissolution rate of 100 mg tablet core after being placed under the conditions of 60° C./open, 40° C./75% RH/closed, 25° C./92.5% RH/open, and light/open for 10 days. There was no significant change in the dissolution rate of 25 mg and 100 mg coated tablets after being placed under the conditions of 60° C./open and 40° C./75% RH/closed for 30 days; and there was no significant change in the dissolution rate of 100 mg coated tablet after being placed under the conditions of 25° C./92.5% RH/open and light/open for 10 days. The above data indicate that the product has good dissolution stability.
From the the results of the crystal stability investigation of the 100 mg tablet core and coated tablet as shown in
It has been experimentally demonstrated that the pharmaceutical compositions and preparations of the present disclosure have good safety and/or stability, as well as high P2X3 antagonistic activity with less impact on the taste.
The embodiments of the present disclosure have been described above. However, the present disclosure is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present disclosure shall be included in the scope of protection of the present disclosure.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202110651136.9 | Jun 2021 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2022/098223 | 6/10/2022 | WO |
