WO2023227106A1 - 一种核苷类衍生化合物的药物组合物及其制备方法和用途 - Google Patents
一种核苷类衍生化合物的药物组合物及其制备方法和用途 Download PDFInfo
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- 229940050410 gluconate Drugs 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N glycerol 1-phosphate Chemical class OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
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- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical group OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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Definitions
- the present invention relates to the field of pharmaceutical preparations, and in particular to a pharmaceutical composition of a nucleoside derivative compound and its preparation method and use.
- the new coronavirus is an enveloped single-stranded RNA virus belonging to the genus ⁇ -coronavirus. Similar to SARS and MERS, the SARS-CoV-2 genome encodes non-structural proteins: 3C-like protease (3-chymotrypsin-like protease, 3CLpro), papain-like protease (PLpro), helicase and RNA-dependent RNA polymerase (RdRp); structural proteins: such as spike glycoprotein and accessory proteins.
- the surface spike glycoprotein of the new coronavirus binds to the angiotensin-converting enzyme (ACE2) receptor on the surface of human cells to infect human respiratory epithelial cells.
- ACE2 angiotensin-converting enzyme
- the viral RNA 5' end open reading frame (ORF1a/b) will encode polyproteins (pp1a and pp1ab), which are required for viral replication. Enzyme processing and maturation play an important role. pp1a and pp1ab can be cleaved by papain-like protease (PLpro) and 3C-like protease (3CLpro) to produce non-structural proteins, including RNA-dependent RNA polymerase and helicase, etc., which play a key role in the transcription and replication of the new coronavirus. role.
- PLpro papain-like protease
- 3CLpro 3C-like protease
- Remdesivir is a methylcarbamate monophosphate prodrug of an adenosine analogue, originally developed by Gilead as an anti-Ebola virus drug. Remdesivir, as an RdRp inhibitor, has shown activity against the new coronavirus at the cellular level. However, clinical trials have shown that Remdesivir does not significantly reduce mortality in humans. And because the clinical dosage is close to the safe dosage, some obvious side effects have to attract attention.
- the present invention provides a pharmaceutical composition and its preparation method and use.
- a pharmaceutical composition is provided.
- a pharmaceutical composition comprising compound SHEN26 or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients,
- the pharmaceutically acceptable excipients may include at least one selected from the group consisting of diluents, disintegrants, binders, lubricants and glidants.
- the pharmaceutically acceptable excipients include diluents, disintegrants, binders and lubricants.
- the diluent may include at least one selected from the group consisting of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and mannitol; preferably, the diluent is microcrystalline cellulose.
- the disintegrant may include at least one selected from the group consisting of croscarmellose sodium, crospovidone XL-10, sodium carboxymethylcellulose, low-substituted hydroxypropylcellulose, and pregelatinized starch. ; Preferably, the disintegrant is croscarmellose sodium.
- the binder may include at least one selected from the group consisting of hydroxypropylcellulose, povidone K30, hypromellose, and starch; preferably, the binder is hydroxypropylcellulose.
- the lubricant may include at least one selected from magnesium stearate, sodium stearyl fumarate, stearic acid, and talc; preferably, the lubricant is magnesium stearate.
- the composition may also include an external lubricant.
- the glidant may include selected from colloidal silica.
- the content of the compound SHEN26 may be 15wt%-70wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the compound SHEN26 is 15wt%, 20wt%, 25wt%, 30wt%, 35wt%, 40wt%, 45wt%, 50wt%, 51wt%, 52wt %, 53wt%, 54wt%, 55wt%, 56wt%, 57wt%, 58wt%, 59wt%, 60wt%, 65wt% or 70wt%. In some embodiments, the content of compound SHEN26 is 50wt%-60wt% based on the total mass of the pharmaceutical composition.
- the content of the diluent may be 20wt%-70wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the diluent is 20wt%, 25wt%, 30wt%, 31wt%, 32wt%, 33wt%, 34wt%, 35wt%, 36wt%, 37wt %, 38wt%, 39wt%, 40wt%, 45wt%, 50wt%, 55wt%, 60wt%, 65wt% or 70wt%. In some embodiments, the content of the diluent is 30wt%-40wt% based on the total mass of the pharmaceutical composition.
- the content of the disintegrant may be 1 wt%-10 wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the disintegrant is 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt% or 10wt%. In some embodiments, the content of the disintegrant is 2wt%-4wt% based on the total mass of the pharmaceutical composition.
- the content of the binder may be 1 to 10 wt%. In some embodiments, based on the total mass of the pharmaceutical composition, the content of the binder is 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt% or 10wt%. In some embodiments, the content of the binder is 4wt%-6wt% based on the total mass of the pharmaceutical composition.
- the content of the lubricant may be 0.1wt%-5wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the lubricant is 0.1wt%, 0.1wt%, 0.2wt%, 0.3wt%, 0.4wt%, 0.5wt%, 0.6wt%, 0.7wt%, 0.8wt%, 0.9wt% or 1wt%. In some embodiments, the content of the lubricant is 0.5wt%-1wt% based on the total mass of the pharmaceutical composition.
- the content of the external lubricant may be 0.5wt%-5wt%. In some embodiments, the content of the external lubricant is 0.5wt%, 1.0wt%, 1.5wt%, 2.0wt%, 3.0wt%, 4.0wt% or 5wt% based on the total mass of the pharmaceutical composition. In some embodiments, the content of the external lubricant is 0.5wt%-1.5wt% based on the total mass of the pharmaceutical composition.
- the pharmaceutically acceptable excipients include diluents, disintegrants, binders, lubricants, and external lubricants, and the diluents are microcrystalline cellulose; the disintegrants are cross-linked Bicarmellose sodium, the binder is hydroxypropyl cellulose, the lubricant is magnesium stearate, the content of the compound SHEN26 is 50wt%-60wt% based on the total mass of the pharmaceutical composition.
- the content of the diluent is 30wt%-40wt%
- the content of the disintegrant is 2wt%-4wt%
- the content of the binder is 4wt%-6wt%
- the content of the lubricant is 0.5 wt%-1wt%
- the content of the external lubricant is 0.5wt%-1.5wt%.
- the pharmaceutically acceptable excipients include diluents, disintegrants, binders, lubricants, and external lubricants, and the diluents are microcrystalline cellulose; the disintegrants are cross-linked Bicarmellose sodium, the binder is hydroxypropyl cellulose, the lubricant is magnesium stearate, calculated based on the total mass of the pharmaceutical composition, the content of the compound SHEN26 is 55.56wt%, so The content of the diluent is 34.94wt%, the content of the disintegrant is 3wt%, the content of the binder is 5wt%, the content of the lubricant is 0.5wt%, the content of the external lubricant is is 1wt%.
- the dosage form of the composition may be an oral solid preparation.
- the oral solid preparation may include tablets, granules or capsules.
- the specification of the pharmaceutical composition may be 10 mg-500 mg.
- the pharmaceutical composition has a strength of 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg or 200 mg.
- a second aspect provides a use of the aforementioned pharmaceutical composition.
- a pharmaceutical composition according to the first aspect is prepared for preventing, alleviating or treating coronavirus infection, or the replication or propagation of homologous variant viruses and the resulting cytopathic effects. uses in products.
- the infection may include fever, cough, sore throat, pneumonia, acute respiratory infection, severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis or septic shock.
- the pharmaceutical composition described in the first aspect is used in the preparation of products for detecting coronavirus or homologous variant viruses thereof.
- the coronavirus may include: MHV-A59, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2, mouse hepatitis virus, feline infectious peritonitis virus, canine coronavirus, bovine coronavirus, avian infectious bronchitis virus or porcine coronavirus, preferably, the SARS-CoV-2 includes a mutant strain or an unmutated strain of SARS-CoV-2; more preferably, the SARS-CoV-2 The mutant strains of SARS-CoV-2 include SARS-CoV-2 mutant strain B.1, SARS-CoV-2 mutant strain B.1.351, SARS-CoV-2 mutant strain B.1.617.2, SARS-CoV-2 Mutant strain C.37, SARS-CoV-2 mutant strain P.1 family tree, SARS-CoV-2 mutant strain B.1.525, SARS-CoV-2 mutant strain
- the pharmaceutical composition may be suitable for humans or animals; and/or the animals include bovines, equines, ovines, porcines, canines, felines, rodents, primates Animal, bird animal or fish animal.
- a method for preparing the aforementioned pharmaceutical composition is provided.
- a method for preparing the pharmaceutical composition described in the first aspect includes: mixing compound SHEN26 and pharmaceutically acceptable excipients, dry granulation, adding an external lubricant, and mixing , tableting or capsule filling or bagging to obtain the composition.
- a method for preparing the pharmaceutical composition described in the first aspect includes: mixing compound SHEN26 and pharmaceutically acceptable excipients, wet granulation, grinding, drying, dry grinding, adding An external lubricant is added, mixed, tableted or capsule filled or bagged to obtain the composition.
- a method for preparing the pharmaceutical composition described in the first aspect includes: grinding or pulverizing the compound SHEN26 and mixing it with pharmaceutically acceptable excipients, dry granulation, and adding additional ingredients Lubricant, mixing, tableting or capsule filling or bagging to obtain the composition.
- a method for preparing the pharmaceutical composition described in the first aspect includes: grinding or pulverizing compound SHEN26 and mixing it with pharmaceutically acceptable excipients, wet granulation, grinding, and drying, Dry grinding, adding external lubricant, mixing, pressing Tablets or capsules are filled or bagged to obtain the composition.
- the present invention preferably adopts dry granulation to prepare the aforementioned pharmaceutical composition. Compared with the direct mixing process, the use of dry granulation is beneficial to avoid the risk of material stratification and avoid the problem of uneven mixing.
- a certain embodiment of the present invention has at least one of the following beneficial technical effects:
- the pharmaceutical composition provided by the present invention has the advantages of high dissolution, fast release rate, good compatibility of raw materials and excipients, good stability, and high bioavailability.
- auxiliary materials provided by the present invention is beneficial to improving the dissolution, release rate, compatibility and stability of raw materials and auxiliary materials of the obtained pharmaceutical composition (stability includes properties, content, related substances, moisture content, dissolution rate , release rate, etc.), and is conducive to improving the material properties during the preparation process of pharmaceutical compositions.
- Adopting the prescription ratio of the SHEN26 compound and/or the prescription ratio of each excipient provided by the present invention is beneficial to improving the dissolution, release rate, raw material compatibility and stability of the obtained pharmaceutical composition (stability includes properties , content, related substances, humidified weight, dissolution, release rate, etc.), and is conducive to improving the material properties (viscosity, material formability, particle hardness) during the preparation process of the pharmaceutical composition.
- room temperature means ambient temperature, which can be 10°C-40°C, or 20°C-30°C; in some embodiments, it is 22°C-28°C; in some embodiments, it is 24°C-24°C. 26°C; in some embodiments, 25°C.
- the term "specification" refers to the weight of the active ingredient in a unit of preparation (single tablet or single capsule).
- the 50 mg specification in the present invention refers to a single tablet or single capsule containing 50 mg of compound SHEN26.
- D90 refers to the particle size corresponding to the cumulative particle size distribution number of a sample reaching 90%. Its physical meaning is that 90% of particles have a particle size smaller than it. For example, "D90 is not greater than 100 ⁇ m” means "90% of particles are not greater than 100 ⁇ m.”
- D10 refers to the particle size corresponding to when the cumulative particle size distribution number of a sample reaches 10%;
- D50 refers to the particle size corresponding to the cumulative particle size distribution number of a sample reaches 50%.
- open refers to placing the drug or preparation in an open container without capping and sealing, leaving the capsule in contact with the external environment.
- closed means that after placing the drug or preparation in the container, the lid is closed and sealed with aluminum foil to isolate the capsule from the outside environment.
- “Pharmaceutically acceptable salts” used in the present invention refer to organic salts and inorganic salts of the compounds of the present invention.
- Pharmaceutically acceptable salts are well known in the art, as documented in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
- Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods recorded in books and literature, such as ion exchange method these salts.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glyceryl phosphate Salt, gluconate, hemisulfate, enanthate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactosurate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, brown Palmitate, pamate, pectate, persulfate, 3-phenylpropionate, pic
- Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4 alkyl)4 salts.
- the present invention also contemplates the formation of quaternary ammonium salts of any compound containing an N group.
- Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
- Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and others.
- Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations that counter counter ion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1- C8 sulfonates and aromatic sulfonates.
- optional means that the subsequently described event or circumstance may, but need not, occur.
- optional surfactant means that the surfactant may or may not be present.
- external lubricant refers to substances added after granulation to reduce the friction between the granulated particles, prevent the raw materials and excipients from sticking to the surface of the punch, or reduce the friction between the tablet and the die hole wall.
- weight percent or “percent by weight”, “wt%” or “w/w%” is defined as the weight of an individual component in a composition divided by the total weight of all components of the composition and multiplied by 100.
- treatment refers to a clinical intervention intended to alter the natural course of a disease in the individual being treated. Desired therapeutic effects include, but are not limited to, preventing the emergence or recurrence of disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, ameliorating or alleviating the disease state, and alleviating or improving prognosis.
- “Pharmaceutically acceptable” means: within the scope of adequate medical judgment, suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions and similar reactions, and is reasonably reasonable Benefit/risk ratio of a substance or compound.
- references to the terms “one embodiment,” “some embodiments,” “an example,” “specific examples,” or “some examples” or the like means that specific features are described in connection with the embodiment or example. , structures, materials or features are included in at least one embodiment or example of the invention. In this specification, the schematic expressions of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the specific features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine different embodiments or examples and features of different embodiments or examples described in this specification unless they are inconsistent with each other.
- compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, compositions are prepared by uniformly and thoroughly bringing into association the active compound with liquid carriers, finely divided solid carriers, or both.
- the reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
- Dissolution test Compare the direct mixing process recipe with the dry granulation process recipe. The dissolution results are shown in Table 5.
- Preparation method pulverize compound SHEN26 and mix with internal auxiliary materials, dry granulation, add external auxiliary materials, mix, and fill capsules to obtain capsules of compound SHEN26.
- Preparation method pulverize compound SHEN26 and mix with pharmaceutically acceptable excipients, dry granulate, add external lubricant, mix, and fill capsules to obtain compound SHEN26 capsules.
- Dissolution test Take the compound SHEN26 capsules obtained in Example 3 and detect the dissolution respectively. The results are shown in Table 10.
- Preparation method Compound SHEN26 is crushed and sieved (passed through a 40-mesh sieve and a 60-mesh sieve respectively), mixed with pharmaceutically acceptable excipients, dry granulated, added with external lubricant, mixed, and filled into capsules to obtain the compound SHEN26. capsule.
- Dissolution test Take the compound SHEN26 capsules obtained in Example 4 and detect the dissolution respectively. The results are shown in Table 13.
- the final formulation of dry granulation has relatively good fluidity, and the particle size D90 of the raw material drug is in the range of 195.440 ⁇ m–327.667 ⁇ m, which will not affect the dissolution behavior of the product.
- the raw materials were crushed and passed through a 60-mesh sieve for process inspection.
- Preparation method Grind or pulverize compound SHEN26 and mix with pharmaceutically acceptable excipients, dry granulate, add external lubricant, mix, and fill capsules to obtain compound SHEN26 capsules.
- Dissolution testing Take the compound SHEN26 capsules obtained in Example 5 and detect the dissolution respectively. The results are shown in Table 15.
- Excipients with moderate dosage such as cross-linked carboxymethyl Sodium cellulose
- main drug: disintegrant 1:1
- the smaller amount of excipients such as magnesium stearate
- main drug: lubricant 5:1. See Table 16 for the manufacturer information of raw and auxiliary materials and the ratio of raw and auxiliary materials in the compatibility test.
- Placement conditions Place the sample in high temperature (60°C), high humidity (25°C/90% ⁇ 5%RH), acceleration (40°C/75% ⁇ 5%RH), light (visible light 4500Lux ⁇ 500Lux, near ultraviolet light Under the experimental conditions of 85 ⁇ w/cm 2 ), samples were taken for inspection on the 0th day, the 10th day, and the 30th day. Detect appearance, humidified weight, content and related substances.
- gelatin hollow capsule 3# is opaque and rich in yellow components, except for the pigment, the rest are the same as the gelatin hollow capsule 4# and 0# opaque white hollow capsules, which are gelatin and titanium dioxide, so this experiment only examines the gelatin hollow capsule Capsule 3# has an opaque and rich yellow capsule shell.
- Table 17 Packaging information (bottled)
- Table 18 Packaging information (double aluminum packaging)
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Abstract
本发明提供一种核苷类衍生化合物的药物组合物及其制备方法和用途,属于药物领域。所述药物组合物包括化合物SHEN26和药学上可接受的辅料。所述药学上可接受的辅料包括选自稀释剂、崩解剂、粘合剂、润滑剂和助流剂中的至少一种。所述药物组合物具有溶出度高、原辅料相容性好、稳定性好、生物利用度高等优点。
Description
本发明涉及药物制剂领域,具体涉及一种核苷类衍生化合物的药物组合物及其制备方法和用途。
新冠病毒是一种具有包膜的单链RNA病毒,为β属冠状病毒。与SARS和MERS类似,SARS-CoV-2基因组编码非结构蛋白:3C样蛋白酶(3-chymotrypsin-like protease,3CLpro)、木瓜蛋白酶样蛋白酶(papain-likeprotease,PLpro)、解旋酶(helicase)和RNA依赖RNA聚合酶(RNA-dependent RNA polymerase,RdRp);结构蛋白:如棘突糖蛋白(spike glycoprotein)和附属蛋白(accessory proteins)。新冠病毒的表面棘突糖蛋白与人体细胞表面血管紧张素转换酶(ACE2)受体的结合从而感染人的呼吸道上皮细胞。病毒在进入宿主细胞后解体,将核衣壳和病毒RNA释放到细胞质中,病毒RNA 5′末端开放阅读框(ORF1a/b)将编码多聚蛋白质(pp1a和pp1ab),它们对病毒复制所需酶的加工、成熟起重要作用。pp1a和pp1ab可被木瓜蛋白酶样蛋白酶(PLpro)和3C样蛋白酶(3CLpro)裂解,产生非结构蛋白,包括RNA依赖性RNA聚合酶和解螺旋酶等,它们对于新冠病毒的转录和复制的起着关键的作用。目前,冠状病毒识别受体的表面棘突糖蛋白、参与复制及转录过程的重要蛋白3CLpro、PLpro与RdRp是四个十分具有抗病毒药物研发吸引力的靶点。
关于新冠疫苗的研发,12月2日,英国首先批准了辉瑞和BioNTech新冠疫苗的紧急使用权。一方面此款疫苗的普遍使用效果还未得知,另一方严格的低温保存要求对其广泛使用带来了极大的不便。
关于新冠药物研发,目前瑞德西韦是美国FDA唯一批准的新冠用药。瑞德西韦(Remdesivir)是一个腺苷类似物的单磷酸氨甲酯前药,起初为吉利德公司开发的抗埃博拉病毒药物。瑞德西韦作为RdRp抑制剂,在细胞层面表现出了抗新冠病毒的活性,但经临床试验表明,瑞德西韦在人体上并没有显著的降低死亡率。且由于临床使用剂量已接近安全剂量,一些明显的副作用不得不引起关注。
因此,仍需要有一种安全性好,稳定性好,生物利用度好的治疗新冠病毒的药物。
发明内容
为解决上述问题,本发明提供一种药物组合物及其制备方法和用途。
第一方面,提供一种药物组合物。
一种药物组合物,其包括化合物SHEN26或其药学上可接受的盐,和药学上可接受的辅料,
所述药学上可接受的辅料可以包括选自稀释剂、崩解剂、粘合剂、润滑剂和助流剂中的至少一种。在一些实施例中,所述药学上可接受的辅料包括稀释剂、崩解剂、粘合剂和润滑剂。
所述稀释剂可以包括选自微晶纤维素、无水磷酸氢钙、甘露醇中的至少一种;优选地,所述稀释剂为微晶纤维素。
所述崩解剂可以包括选自交联羧甲基纤维素钠、交联聚维酮XL-10、羧甲基纤维素钠、低取代羟丙纤维素、预胶化淀粉中的至少一种;优选地,所述崩解剂为交联羧甲基纤维素钠。
所述粘合剂可以包括选自羟丙纤维素、聚维酮K30、羟丙甲纤维素、淀粉中的至少一种;优选地,所述粘合剂为羟丙纤维素。
所述润滑剂可以包括选自硬脂酸镁、硬脂富马酸钠、硬脂酸、滑石粉中的至少一种;优选地,所述润滑剂为硬脂酸镁。
所述组合物还可以包括外加润滑剂。所述助流剂可以包括选自胶态二氧化硅。
以药物组合物的总质量计算,所述化合物SHEN26的含量可以为15wt%-70wt%。在一些实施例中,以药物组合物的总质量计算,所述化合物SHEN26的含量为15wt%、20wt%、25wt%、30wt%、35wt%、40wt%、45wt%、50wt%、51wt%、52wt%、53wt%、54wt%、55wt%、56wt%、57wt%、58wt%、59wt%、60wt%、65wt%或70wt%。在一些实施例中,以药物组合物的总质量计算,所述化合物SHEN26的含量为50wt%-60wt%。
以药物组合物的总质量计算,所述稀释剂的含量可以为20wt%-70wt%。在一些实施例中,以药物组合物的总质量计算,所述稀释剂的含量为20wt%、25wt%、30wt%、31wt%、32wt%、33wt%、34wt%、35wt%、36wt%、37wt%、38wt%、39wt%、40wt%、45wt%、50wt%、55wt%、60wt%、65wt%或70wt%。在一些实施例中,以药物组合物的总质量计算,所述稀释剂的含量为30wt%-40wt%。
以药物组合物的总质量计算,所述崩解剂的含量可以为1wt%-10wt%。在一些实施例中,以药物组合物的总质量计算,所述崩解剂的含量为1wt%、2wt%、3wt%、4wt%、5wt%、6wt%、7wt%、8wt%、9wt%或10wt%。在一些实施例中,以药物组合物的总质量计算,所述崩解剂的含量为2wt%-4wt%。
以药物组合物的总质量计算,所述粘合剂的含量可以为1wt%-10wt%。在一些实施例中,以药物组合物的总质量计算,所述粘合剂的含量为1wt%、2wt%、3wt%、4wt%、5wt%、6wt%、7wt%、8wt%、9wt%或10wt%。在一些实施例中,以药物组合物的总质量计算,所述粘合剂的含量为4wt%-6wt%。
以药物组合物的总质量计算,所述润滑剂的含量可以为0.1wt%-5wt%。在一些实施例中,以药物组合物的总质量计算,所述润滑剂的含量为0.1wt%、0.1wt%、0.2wt%、0.3wt%、0.4wt%、0.5wt%、0.6wt%、0.7wt%、0.8wt%、0.9wt%或1wt%。在一些实施例中,以药物组合物的总质量计算,所述润滑剂的含量为0.5wt%-1wt%。
以药物组合物的总质量计算,所述外加润滑剂的含量可以为0.5wt%-5wt%。在一些实施例中,以药物组合物的总质量计算,所述外加润滑剂的含量为0.5wt%、1.0wt%、1.5wt%、2.0wt%、3.0wt%、4.0wt%或5wt%。在一些实施例中,以药物组合物的总质量计算,所述外加润滑剂的含量为0.5wt%-1.5wt%。
在一些实施例中,所述药学上可接受的辅料包括稀释剂、崩解剂、粘合剂、润滑剂和外加润滑剂,所述稀释剂为微晶纤维素;所述崩解剂为交联羧甲基纤维素钠,所述粘合剂为羟丙纤维素,所述润滑剂为硬脂酸镁,以药物组合物的总质量计算,所述化合物SHEN26的含量为50wt%-60wt%,所述稀释剂的含量为30wt%-40wt%,所述崩解剂的含量为2wt%-4wt%,所述粘合剂的含量为4wt%-6wt%,所述润滑剂的含量为0.5wt%-1wt%,所述外加润滑剂的含量为0.5wt%-1.5wt%。
在一些实施例中,所述药学上可接受的辅料包括稀释剂、崩解剂、粘合剂、润滑剂和外加润滑剂,所述稀释剂为微晶纤维素;所述崩解剂为交联羧甲基纤维素钠,所述粘合剂为羟丙纤维素,所述润滑剂为硬脂酸镁,以药物组合物的总质量计算,所述化合物SHEN26的含量为55.56wt%,所述稀释剂的含量为34.94wt%,所述崩解剂的含量为3wt%,所述粘合剂的含量为5wt%,所述润滑剂的含量为0.5wt%,所述外加润滑剂的含量为1wt%。
所述组合物的剂型可以为口服固体制剂。
所述口服固体制剂可以包括选自片剂、颗粒剂或者胶囊剂。
所述药物组合物的规格可以为10mg-500mg。在一些实施例中,所述药物组合物的规格为10mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、75mg、100mg、125mg、150mg或者200mg。
第二方面,提供一种前述药物组合物的用途。
在本发明的一些实施方式中,一种第一方面所述药物组合物在制备用于预防、缓解或治疗冠状病毒感染,或其同源变异病毒的复制或繁殖及其所产生的细胞病变效应的产品中的用途。
所述感染可以包括发热、咳嗽、咽痛、肺炎、急性呼吸道感染、严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症或脓毒性休克。
在本发明的一些实施方式中,一种第一方面所述药物组合物在制备用于检测冠状病毒或其同源变异病毒的产品中的用途。
所述冠状病毒可以包括:MHV-A59、HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1、SARS-CoV,MERS-CoV、SARS-CoV-2、小鼠肝炎病毒、猫传染性腹膜炎病毒、犬冠状病毒、牛冠状病毒、禽传染性支气管炎病毒或猪冠状病毒,优选地,所述SARS-CoV-2包括SARS-CoV-2的突变株或未突变株;更优选地,所述SARS-CoV-2的突变株包括SARS-CoV-2突变株B.1、SARS-CoV-2突变株B.1.351、SARS-CoV-2突变株B.1.617.2、SARS-CoV-2突变株C.37、SARS-CoV-2突变株P.1族谱、SARS-CoV-2突变株B.1.525、SARS-CoV-2突变株B.1.427或SARS-CoV-2突变株B.1.429。
所述药物组合物可以适用于人或动物;和/或所述动物包括牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物、鸟类动物或鱼类动物。
第三方面,提供一种前述药物组合物的制备方法。
在本发明的一些优选的实施方式中,一种第一方面所述药物组合物的制备方法,其包括:将化合物SHEN26和药学上可接受的辅料混合,干法制粒,加入外加润滑剂,混合,压片或胶囊填充或装袋,得到所述组合物。
在本发明的一些实施方式中,一种第一方面所述药物组合物的制备方法,其包括:将化合物SHEN26和药学上可接受的辅料混合,湿法制粒,研磨,干燥,干磨,加入外加润滑剂,混合,压片或胶囊填充或装袋,得到所述组合物。
在本发明的一些优选的实施方式中,一种第一方面所述药物组合物的制备方法,其包括:将化合物SHEN26研磨或粉碎后和药学上可接受的辅料混合,干法制粒,加入外加润滑剂,混合,压片或胶囊填充或装袋,得到所述组合物。
在本发明的一些实施方式中,一种第一方面所述药物组合物的制备方法,其包括:将化合物SHEN26研磨或粉碎后和药学上可接受的辅料混合,湿法制粒,研磨,干燥,干磨,加入外加润滑剂,混合,压
片或胶囊填充或装袋,得到所述组合物。
本发明优选采用干法制粒制备前述药物组合物,相比直接混合工艺,采用干法制粒有利于避免出现物料分层风险,避免出现混合不均匀的问题。
相比现有技术,本发明的某一个实施例至少具有包括以下有益技术效果中的一种:
(1)本发明所提供的所述药物组合物具有溶出度高、释放速度快、原辅料相容性好、稳定性好、生物利用度高等优点。
(2)采用本发明所提供的辅料,有利于提高所得药物组合物的溶出度、释放速度、原辅料相容性和稳定性(稳定性包括性状、含量、有关物质、增湿重、溶出度、释放速度等的稳定性),并且有利于改善药物组合物制备过程中的物料性状。
(3)采用本发明所提供的SHEN26化合物的处方比例和/或各辅料的处方比例,有利于提高所得药物组合物的溶出度、释放速度、原辅料相容性和稳定性(稳定性包括性状、含量、有关物质、增湿重、溶出度、释放速度等的稳定性),并且有利于改善药物组合物制备过程中的物料性状(粘性、物料成型性、颗粒硬度)。
术语定义:
本发明中,“室温”表示环境温度,可以为10℃-40℃,可以为20℃-30℃;在一些实施例中,为22℃-28℃;在一些实施例中,为24℃-26℃;在一些实施例中,为25℃。
术语“规格”是指一个单位的制剂(单片或单颗胶囊)中活性成分的重量,例如本发明中的50mg规格是指单片或单颗胶囊中含50mg化合物SHEN26。
术语“D90”是指一个样品的累计粒度分布数达到90%时所对应的粒径。它的物理意义是粒径小于它的的颗粒占90%,例如“D90不大于100μm”表示“不大于100μm的颗粒占90%”。D10指一个样品的累计粒度分布数达到10%时所对应的粒径;D50是指一个样品的累计粒度分布数达到50%时所对应的粒径。
术语“开口”是指将药物或制剂置于敞口容器中,未进行旋盖及封口,使胶囊与外界环境接触。
术语“闭口”是指将药物或制剂置于容器后,将盖子盖好,并使用铝箔封口,使胶囊与外界环境隔绝。
在本发明的上文中,无论是否使用“大约”或“约”等字眼,所有在此公开了的数字均为近似值。基于公开的数字,每一个数字的数值有可能会出现±10%以下的差异或者本领域人员认为的合理的差异,如±1%、±2%、±3%、±4%或±5%的差异。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的,如文献:S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括,但并不限于,与氨基基团反应形成的无机酸盐有盐酸盐,氢溴酸盐,磷酸盐,硫酸盐,高氯酸盐,和有机酸盐如乙酸盐,草酸盐,马来酸盐,酒石酸盐,柠檬酸盐,琥珀酸盐,丙二酸盐,或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐,藻酸盐,抗坏血酸盐,天冬氨酸盐,苯磺酸盐,苯甲酸盐,重硫酸盐,硼酸盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,环戊基丙酸盐,二葡萄糖酸盐,十二烷基硫酸盐,乙磺酸盐,甲酸盐,反丁烯二酸盐,葡庚糖酸盐,甘油磷酸盐,葡萄糖酸盐,半硫酸盐,庚酸盐,己酸盐,氢碘酸盐,2-羟基-乙磺酸盐,乳糖醛酸盐,乳酸盐,月桂酸盐,月桂基硫酸盐,苹果酸盐,丙二酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,油酸盐,棕
榈酸盐,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,特戊酸盐,丙酸盐,硬脂酸盐,硫氰酸盐,对甲苯磺酸盐,十一酸盐,戊酸盐,等等。通过适当的碱得到的盐包括碱金属,碱土金属,铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠,锂,钾,钙,镁,等等。药学上可接受的盐进一步包括适当的、无毒的铵,季铵盐和抗平衡离子形成的胺阳离子,如卤化物,氢氧化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C1-C8磺酸化物和芳香磺酸化物。
术语“任选”、“任选的”或“任选地”是指随后描述的事件或情形可以但不一定出现。例如,“任选的表面活性剂”是指表面活性剂可以存在或可以不存在。
术语“外加润滑剂”表示在制粒后加入的为降低制粒所得颗粒之间摩擦力、防止原辅料粘着冲头表面或降低药片与冲模孔壁之间摩擦力的物质。
术语“重量百分比”或“以重量计的百分比”、“wt%”或“w/w%”定义为组合物中单个组分的重量除以组合物所有组分的总重量然后乘以100。
术语“和/或”应理解为意指可选项中的任一项或可选项中的任意两项或多项的组合。
在本文中,术语“治疗”指意欲改变正在接受治疗的个体中疾病之天然过程的临床介入。想要的治疗效果包括但不限于防止疾病出现或复发、减轻症状、减小疾病的任何直接或间接病理学后果、防止转移、降低病情进展速率、改善或缓和疾病状态,以及缓解或改善预后。
“药学上可接受的”意为:在充分的医学判断范围内,适于与人和低等动物组织接触而不存在不适宜的毒性、刺激性、过敏反应及类似反应、而且具有相当的合理获益/风险比率的物质或化合物。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
在本申请中,“组合物”可以方便地表现为单位剂量形式并且可以通过制药领域中熟知的方法的任何一种进行制备。所有的方法包括使活性成分与构成一种或多种附属成分的载体相结合的步骤。通常,通过均匀并充分地使活性化合物与液体载体、细碎固体载体或这两者相结合,制备组合物。
本发明中,“化合物SHEN26”、“SHEN26”和“SHEN26化合物”均表示同一含义。
为了使本领域的技术人员更好地理解本发明的技术方案,下面进一步披露一些非限制实施例以对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。
“#0”表示0号胶囊壳。“#4”表示4号胶囊壳。“API”表示原料药,以下具体实施例中是指化合物SHEN26。“rpm”表示转速单位“转每分钟”。
溶出测定方法
除另有说明外,本品制剂研究中所使用的溶出测定方法见表1。
表1.溶出方法
实施例1:制备工艺考察
(1)直接混合工艺
处方:见表2。
操作:将SHEN26化合物与微晶纤维素102、甘露醇100SD、交联羧甲基纤维素钠和硬脂酸镁LIGAMED MF-2-V直接混合,得到混粉,填充胶囊,得到SHEN26化合物胶囊。
粉体学特性检测:检测SHEN26化合物原料粉体学特性及将SHEN26化合物和其他辅料直接混合后混粉的粉体学特性,结果见表3。
表2:直接混合工艺处方组成
表3:API及处方粉体学特性结果
结果分析:由以上数据可知,原料药具有相对较好的流动性,与辅料直接混合后卡尔指数进一步降低,且API粒径较大,在生产过程中存在分层风险,因此进一步考察干法制粒工艺。
(2)干法制粒工艺
处方:见表4。
操作:将化合物SHEN26与内加辅料混合,干法制粒,加入外加辅料,混合,填充胶囊,得到所述化合物SHEN26胶囊。
表4:处方组成
溶出检测:将直接混合工艺处方与干法制粒工艺处方进行对比,溶出结果见表5。
表5:溶出结果
结果分析:由以上数据可知,两个工艺的胶囊的溶出均符合要求,但直接混合灌装胶囊后溶出30min
后达到较高的含量,表明直接混合工艺可能存在分层风险,因此最终确定干法制粒工艺进行处方开发。
实施例2:粘合剂用量考察
处方:见表6A、表6B和表6C。
表6A:处方组成
表6B:处方组成
表6C:处方组成
制备方法:将化合物SHEN26粉碎后和内加辅料混合,干法制粒,加入外加辅料,混合,填充胶囊,得到所述化合物SHEN26胶囊。
现象观察:在干法制粒过程中,观察物料粘性、成型性和颗粒硬度,结果如表7所示。
表7:干法制粒现象
结果分析:由以上干法制粒现象可知,处方37167-032A-1和37167-032B-1干法制粒过程中带状物成型性较差;当粘合剂羟丙纤维素EXF用量为3%时,处方37167-032A-2和37167-032B-2带状物成型性差,颗粒较软;调整粘合剂羟丙纤维素EXF用量为5%后,处方37167-032A和37167-032B虽然有轻微粘辊现象,但带状物成型性较好,颗粒硬度适中,因此选用5%羟丙纤维素EXF的作为粘合剂。
实施例3:填充剂种类考察
处方:见表8。
表8:处方组成
制备方法:将化合物SHEN26粉碎后和药学上可接受的辅料混合,干法制粒,加入外加润滑剂,混合,填充胶囊,得到所述化合物SHEN26胶囊。
现象观察:在干法制粒过程中,观察物料粘性、成型性和颗粒硬度,结果如表9所示。
溶出检测:取实施例3所得化合物SHEN26胶囊,分别检测溶出度,结果如表10所示。
表9:干法制粒现象
表10:溶出度结果
结果分析:由以上干法制粒现象可知,当微晶纤维素102:甘露醇100SD比例为2:1时,37167-023A和37167-023B处方在干法制粒过程中出现轻微粘辊轮现象,带状物成型性较好,颗粒硬度适中;当去掉填充剂甘露醇后,37167-036A/B处方在干法制粒过程中未出现粘辊轮现象,带状物成型性较好,颗粒硬度适中,且溶出度满足要求,因此确定选用微晶纤维素102作为填充剂。
实施例4:原料药粒径考察
处方:见表11。
表11:处方组成
制备方法:将化合物SHEN26粉碎后过筛(分别过40目筛和60目筛),和药学上可接受的辅料混合,干法制粒,加入外加润滑剂,混合,填充胶囊,得到所述化合物SHEN26胶囊。
现象观察:在干法制粒后,检查粉体学特性,结果如表12所示。
溶出检测:取实施例4所得化合物SHEN26胶囊,分别检测溶出度,结果如表13所示。
表12:干法制粒处方粉体学特性结果
表13:溶出度结果
由以上结果可知,干法制粒最终处方具有相对较好的流动性,且原料药粒径D90在195.440μm–327.667μm范围内,不会对产品的溶出行为产生影响。考虑到原料药大粒径对工艺的影响,故将原料药进行粉碎过60目筛处理后进行工艺考察。
实施例5:化合物SHEN26胶囊的制备
处方:见表14。
表14:SHEN26胶囊单位剂量产品组成
备注:*明胶空心胶囊,4#不透明白色(帽色号:44.801,体色号:44.801)及0#不透明白色(帽色号:44.801,体色号:44.801)-CN,US成分为钛白粉和明胶。N/A:不适用。
制备方法:将化合物SHEN26研磨或粉碎后和药学上可接受的辅料混合,干法制粒,加入外加润滑剂,混合,填充胶囊,得到所述化合物SHEN26胶囊。
溶出度检测:取实施例5所得化合物SHEN26胶囊,分别检测溶出度,结果如表15所示。
表15:溶出度结果
结果分析:采用本发明所提供的处方和制备工艺所得化合物SHEN26胶囊溶出释放快速且完全。
实施例6:原辅料相容性
操作:选用口服固体制剂常用辅料与SHEN26原料药以不同比例混合,放置于不同条件下,分别于不同时间点取出后以外观、增湿重、含量及有关物质为指标,判断原料药与辅料的相容性。原辅料比例根据《化学药物制剂研究基本技术指导原则》和制剂规格,设定用量较大的辅料均按照主药:稀释剂=1:5的比例混合,用量适中的辅料(如交联羧甲基纤维素钠)按照主药:崩解剂=1:1的比例混合,用量较小的辅料(如硬脂酸镁),按照主药:润滑剂=5:1的比例混合。相容性实验原辅料生产厂家信息及原辅料比例见表16。
放置条件:将样品放置于高温(60℃)、高湿(25℃/90%±5%RH)、加速(40℃/75%±5%RH)、光照(可见光4500Lux±500Lux,近紫外光85μw/cm2)的实验条件下,在0天,第10天,第30天取样考察。检测外观、增湿重、含量及有关物质。
表16:原辅料相容性考察
备注:由于明胶空心胶囊3#不透明富黄色组分,除色素外,其余与明胶空心胶囊4#及0#不透明白色空心胶囊组分相同,均为明胶与钛白粉,故本实验仅考察明胶空心胶囊3#不透明富黄色胶囊壳。
结果:上述辅料与SHEN26相容性良好,在各放置条件下30天,外观、增湿重、含量及有关物质均无显著性变化。
实施例7:稳定性考察
操作:取实施例5所得批号为37167-054A和37167-054B的化合物SHEN26胶囊,按表17和表18所述包装进行包装,然后分别于光照(开口)、40℃/75%RH(开口)、40℃/75%RH(闭口)条件放置0天、10天和30天,并检测溶出度和有关物质,结果如表19和表20所示。
表17:包装信息(瓶装)
表18:包装信息(双铝包装)
表19:稳定性结果-溶出度
表20:稳定性结果-有关物质
结果分析:
由以上溶出数据可知:瓶装或双铝包装的50mg规格和200mg规格胶囊在光照(开口)、40℃/75%RH(开口)、40℃/75%RH(闭口)条件放置30天后,溶出度和有关物质均无明显变化,本发明所提供的的化合物SHEN26胶囊具有良好的稳定性。
本发明的方法已经通过较佳实施例进行了描述,相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明内。
Claims (15)
- 一种药物组合物,其包括化合物SHEN26或其药学上可接受的盐,和药学上可接受的辅料,
- 根据权利要求1所述的药物组合物,所述药学上可接受的辅料包括选自稀释剂、崩解剂、粘合剂、润滑剂和助流剂中的至少一种;任选地,所述药学上可接受的辅料包括稀释剂、崩解剂、粘合剂和润滑剂。
- 根据权利要求2所述的药物组合物,所述稀释剂包括选自微晶纤维素、无水磷酸氢钙、甘露醇中的至少一种;优选地,所述稀释剂为微晶纤维素;和/或所述崩解剂包括选自交联羧甲基纤维素钠、交联聚维酮XL-10、羧甲基纤维素钠、低取代羟丙纤维素、预胶化淀粉中的至少一种;优选地,所述崩解剂为交联羧甲基纤维素钠;和/或所述粘合剂包括选自羟丙纤维素、聚维酮K30、羟丙甲纤维素、淀粉中的至少一种;优选地,所述粘合剂为羟丙纤维素;和/或所述润滑剂包括选自硬脂酸镁、硬脂富马酸钠、硬脂酸、滑石粉中的至少一种;优选地,所述润滑剂为硬脂酸镁;和/或所述助流剂包括选自胶态二氧化硅。
- 根据权利要求1-3任一项所述的药物组合物,所述药物组合物还包括外加润滑剂。
- 根据权利要求2-4任一项所述的药物组合物,以药物组合物的总质量计算,所述化合物SHEN26的含量为15wt%-70wt%或者50wt%-60wt%;和/或以药物组合物的总质量计算,所述稀释剂的含量为20wt%-70wt%或者30wt%-40wt%;和/或以药物组合物的总质量计算,所述崩解剂的含量为1wt%-10wt%或者2wt%-4wt%;和/或以药物组合物的总质量计算,所述粘合剂的含量为1wt%-10wt%或者4wt%-6wt%;和/或以药物组合物的总质量计算,所述润滑剂的含量为0.1wt%-5wt%或者0.5wt%-1wt%;和/或以药物组合物的总质量计算,所述外加润滑剂的含量为0.5wt%-5wt%或者0.5wt%-1.5wt%。
- 根据权利要求1-5任一项所述的药物组合物,所述药学上可接受的辅料包括稀释剂、崩解剂、粘合剂、润滑剂或外加润滑剂,所述稀释剂为微晶纤维素;所述崩解剂为交联羧甲基纤维素钠,所述粘合剂为羟丙纤维素,所述润滑剂为硬脂酸镁,以药物组合物的总质量计算,所述化合物SHEN26的含量为50wt%-60wt%,所述稀释剂的含量为30wt%-40wt%,所述崩解剂的含量为2wt%-4wt%,所述粘合剂的含量为4wt%-6wt%,所述润滑剂的含量为0.5wt%-1wt%,所述外加润滑剂的含量为0.5wt%-1.5wt%。
- 根据权利要求1-6任一项所述的药物组合物,所述组合物的剂型为口服固体制剂。
- 根据权利要求7所述的药物组合物,所述口服固体制剂包括选自片剂、颗粒剂或者胶囊剂。
- 根据权利要求1-8任一项所述的药物组合物,所述药物组合物的规格为10mg-500mg,或者50mg或200mg。
- 一种权利要求1-9任一项所述药物组合物在制备用于预防、缓解或治疗冠状病毒感染,或其同源变异病毒的复制或繁殖及其所产生的细胞病变效应的产品中的用途。
- 根据权利要求10所述的用途,所述感染包括发热、咳嗽、咽痛、肺炎、急性呼吸道感染、严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症或脓毒性休克。
- 一种权利要求1-9任一项所述药物组合物在制备用于检测冠状病毒或其同源变异病毒的产品中的用途。
- 根据权利要求10-12任一项所述的用途,所述冠状病毒包括:MHV-A59、HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1、SARS-CoV,MERS-CoV、SARS-CoV-2、小鼠肝炎病毒、猫传染性腹膜炎病毒、犬冠状病毒、牛冠状病毒、禽传染性支气管炎病毒或猪冠状病毒,优选地,所述SARS-CoV-2包括SARS-CoV-2的突变株或未突变株;更优选地,所述SARS-CoV-2的突变株包括SARS-CoV-2突变株B.1、SARS-CoV-2突变株B.1.351、SARS-CoV-2突变株B.1.617.2、SARS-CoV-2突变株C.37、SARS-CoV-2突变株P.1族谱、SARS-CoV-2突变株B.1.525、SARS-CoV-2突变株B.1.427或SARS-CoV-2突变株B.1.429。
- 根据权利要求10-13任一项所述的用途,其特征在于,所述药物组合物适用于人或动物;和/或所述动物包括牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物、鸟类动物或鱼类动物。
- 一种权利要求1-9任一项所述药物组合物的制备方法,其包括:将化合物SHEN26和药学上可接受的辅料混合,干法制粒,加入外加润滑剂,混合,压片或胶囊填充或装袋,得到所述组合物;或者将化合物SHEN26和药学上可接受的辅料混合,湿法制粒,研磨,干燥,干磨,加入外加润滑剂,混合,压片或胶囊填充或装袋,得到所述组合物;或者将化合物SHEN26研磨或粉碎后和药学上可接受的辅料混合,干法制粒,加入外加润滑剂,混合,压片或胶囊填充或装袋,得到所述组合物;或者将化合物SHEN26研磨或粉碎后和药学上可接受的辅料混合,湿法制粒,研磨,干燥,干磨,加入外加润滑剂,混合,压片或胶囊填充或装袋,得到所述组合物。
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US20220081462A1 (en) * | 2020-08-27 | 2022-03-17 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
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US20220081462A1 (en) * | 2020-08-27 | 2022-03-17 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
CN113735862A (zh) * | 2020-12-30 | 2021-12-03 | 南方科技大学 | 一种治疗病毒感染的核苷类化合物及其用途 |
CN113185519A (zh) * | 2021-04-23 | 2021-07-30 | 苏州富德兆丰生化科技有限公司 | 一种核苷类化合物及其在治疗猫传染性腹膜炎中的应用 |
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