CN113368032A - Pharmaceutical composition, oral solid preparation and preparation method and application thereof - Google Patents
Pharmaceutical composition, oral solid preparation and preparation method and application thereof Download PDFInfo
- Publication number
- CN113368032A CN113368032A CN202010719897.9A CN202010719897A CN113368032A CN 113368032 A CN113368032 A CN 113368032A CN 202010719897 A CN202010719897 A CN 202010719897A CN 113368032 A CN113368032 A CN 113368032A
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- pharmaceutical composition
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- tablet
- oral solid
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Images
Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- Health & Medical Sciences (AREA)
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Abstract
Provides a pharmaceutical composition, an oral solid preparation containing the pharmaceutical composition, a preparation method and application thereof. The pharmaceutical composition comprises a therapeutically effective amount of a 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component, a filler, a disintegrant, a binder, and a lubricant. The pharmaceutical composition has good compatibility, excellent dissolution rate and processability and excellent oral absorption bioavailability.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a pharmaceutical composition, an oral solid preparation, and a preparation method and application thereof.
Background
Uric acid is a product of purine metabolism in humans. Uric acid is excreted in the human body as a final product of purine metabolism, usually through the intestine and kidneys, where renal excretion is the main route of uric acid excretion in the human body. Disorders associated with abnormal uric acid levels include hyperuricemia, gout, and the like. Hyperuricemia is a condition in which the metabolism of purine substances in the human body is disturbed, so that the synthesis or the excretion of uric acid in the human body is increased or reduced, and the uric acid level in the blood is abnormally high. Gouty arthritis refers to the painful inflammation caused by the excessive reaction (sensitivity) of the immune system of the body due to the deposition of uric acid in the joints, cartilage and kidneys in the form of monosodium salt when the concentration of uric acid in the blood of a human body exceeds 7 mg/dL.
The onset of hyperuricemia and gout disease has been in a markedly elevated state in europe and america, japan, china, southeast asia, and oceania. The increased incidence of hyperuricemia and gout is attributed to increased dietary changes, alcohol consumption and related diseases such as metabolic syndrome, renal insufficiency, and hypertension.
At present, the therapeutic drugs for hyperuricemia and gout mainly include 1) drugs that inhibit the production of uric acid, such as xanthine oxidase inhibitors allopurinol and febuxostat; 2) uricosuric drugs such as probenecid and benzbromarone; 3) inflammation inhibitors such as colchicine and the like. The medicines have certain defects in treatment, poor curative effect, large side effect and high cost, and are the main bottleneck of clinical application. It has been reported that levels of serum uric acid do not meet the desired therapeutic targets (< 6mg/dL) in 40% to 70% of patients receiving standard course therapy. Many currently available treatments for gout or hyperuricemia are associated with a variety of deleterious side effects, for example, xanthine oxidase inhibitors such as allopurinol are associated with allergic vasculitis, schwann-johnson syndrome, exfoliative dermatitis, anemia, and hepatic insufficiency. Uricosuric agents such as probenecid, bucolone and benzbromarone have side effects such as gastrointestinal disorders, urinary tract stones and fulminant liver failure in patients with specific constitutions.
The first URAT1 inhibitor zurampic (leinurad) was approved by the FDA in the united states at 12 months 2015 at a 200mg dose for treatment of hyperuricemia and gouty arthritis in combination with a xanthine oxidase inhibitor XOI (e.g., Febuxostat, etc.), but the additive effects of the combination were not very significant compared to the xanthine oxidase inhibitor alone. The Zurampic 400mg dose was not approved due to significant toxic side effects at high doses (incidence of kidney-related adverse events, particularly kidney stones).
Therefore, there is an urgent need to develop a novel pharmaceutical formulation or preparation for treating gout and hyperuricemia that can be marketed to meet the needs of patients with hyperuricemia and gout.
Disclosure of Invention
In view of the above problems, the present inventors have conducted further intensive studies based on a novel highly selective tyrosine kinase inhibitor, and finally developed an oral pharmaceutical formulation having good compatibility, excellent dissolution and processability, and excellent oral absorption bioavailability, and a preparation process and use thereof, thereby completing the present invention.
Therefore, it is an object of the present invention to provide a pharmaceutical composition, an oral solid preparation, a method for preparing the same, and use thereof, which have good compatibility, excellent dissolution rate and processability, and excellent oral absorption bioavailability.
In order to achieve the above objects, one aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothien-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropionic acid component, a filler, a disintegrant, a binder, and a lubricant.
The pharmaceutical composition according to the present invention further comprises one or more disintegrants selected from dry starch, sodium carboxymethyl starch, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium.
The pharmaceutical composition according to the present invention further comprises one or more fillers selected from the group consisting of starch, mannitol, microcrystalline cellulose, lactose, pregelatinized starch, and inorganic salts.
Further, the binder is selected from one or more of starch slurry, sugar powder, syrup, hypromellose, povidone, hydroxypropyl cellulose, methyl cellulose and ethyl cellulose, and sodium carboxymethyl cellulose.
Further, the lubricant is selected from one or more of magnesium stearate, silicon dioxide, talcum powder, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate and sodium stearyl fumarate.
The pharmaceutical composition according to the present invention further comprises 0.5 to 90 parts by weight of a 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothien-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component, 5 to 92 parts by weight of a filler, 0.5 to 30 parts by weight of a disintegrant, 0.5 to 20 parts by weight of a binder, and 0.1 to 10 parts by weight of a lubricant, based on 100 parts by weight of the total weight of the pharmaceutical composition.
The pharmaceutical composition according to the invention, further, the 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothien-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component is micronized particles having a particle size distribution with D10 of 0.5-1 μm, D50 of 1-2 μm and D90 of 2-3 μm.
According to another aspect of the present invention, there is provided an oral solid preparation comprising the pharmaceutical composition of any one of the above.
The oral solid preparation according to the present invention further has a dosage form selected from one of granules, tablets, capsules and powders.
The oral solid preparation according to the present invention, further, the tablet is one selected from the group consisting of a dispersible tablet, a chewable tablet, a soluble tablet, a sustained release tablet, a controlled release tablet, an orally disintegrating tablet, a gastric soluble tablet and an enteric coated tablet.
According to a further aspect of the present invention, there is provided a method for preparing the oral solid preparation described in any one of the above, comprising the steps of:
premixing a 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothien-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component, a partial disintegrant, a filler and a binder to obtain a premix;
wet granulating the premix to obtain wet granules;
drying the wet pellets to obtain dry granules;
dry-mixing the dry granules with a lubricant and the remainder of the disintegrant to obtain a dry blend; and
processing said dry blend into said oral solid dosage form.
The process according to the invention, further comprising, after the premixing step and before the wet granulation step, a step of sieving the premix; and/or, the process further comprises, after the wet granulation step and before the drying step, the step of sieving the wet granulate; and/or, the method further comprises the step of sieving the dry granules after the drying step and before the dry mixing step.
The method according to the invention further comprises, before the premixing step, the steps of: micronization treatment is carried out on the 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazole-3-yl) thio) -2-methylpropanoic acid component in advance.
Further, according to the method of the present invention, the oral solid preparation is a tablet, and the step of processing the dry blend into the oral solid preparation comprises: tabletting said dry blend to obtain said tablet.
According to another aspect of the present invention there is provided the use of a pharmaceutical composition as defined in any one of the above or an oral solid formulation as defined in any one of the above for the treatment of hyperuricemia or gout.
Advantageous effects
The pharmaceutical composition and the oral solid preparation containing the same obtained according to the present invention have good compatibility, excellent dissolution and processability, and excellent oral absorption bioavailability. The obtained oral pharmaceutical formulation or preparation has very significant inhibitory effect on URAT1, and can be used for treating hyperuricemia and gout.
Drawings
Fig. 1 shows the dissolution property profiles of the oral tablets manufactured in examples 1 to 4.
Fig. 2 shows the dissolution property profiles of the oral tablets manufactured in examples 5 to 8.
Detailed Description
The pharmaceutical composition according to the invention comprises a therapeutically effective amount of 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid, a filler, a disintegrant, a binder and a lubricant. When the pharmaceutical composition comprises the above components, it has good compatibility.
According to the invention, 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazole-3-yl) thio) -2-methylpropanoic Acid (API) is a novel high-selectivity tyrosine kinase inhibitor jointly developed by the company and Nanjing Mingde new drug development company, and in-vitro experiments show that the inhibitor is mediated by uric acid transporter URAT114The C-UA intake has obvious inhibiting effect, the inhibiting effect on URAT1 is about 177 times that of a reference compound Leinurad, and the inhibiting effect is more obvious. The API component is a white powder, may be prepared according to the method described in W02017202291a1, and typically has a particle size distribution with D10 of 2-4 μm, D50 of 11-17 μm and D90 of 22-45 μm. With respect to the amount of the API component in the pharmaceutical composition, it is sufficient that the pharmaceutical composition comprises a therapeutically effective amount of the API component. As an example, the amount may generally range from 0.5 parts by weight to 90 parts by weight, preferably from 1 part by weight to 60 parts by weight, more preferably from 1 part by weight to 50 parts by weight, most preferably from 1 part by weight to 35 parts by weight, based on 100 parts by weight of the total weight of the pharmaceutical composition.
According to the present invention, the pharmaceutical composition has significantly higher dissolution when the API component powder is micronized to have a particle size distribution with a D10 of 0.5-1 μm, a D50 of 1-2 μm and a D90 of 2-3 μm, especially at lower ratios of the API component to the pharmaceutical composition.
The filler used according to the present invention serves to increase the weight and volume of the tablet to facilitate tablet formation or sub-dosage. The filler may be selected from one or more of starch, mannitol, microcrystalline cellulose, lactose, pregelatinized starch, inorganic salts. Examples of the inorganic salts may include calcium hydrogen phosphate. In view of the moldability of the drug product, microcrystalline cellulose, lactose, pregelatinized starch, and calcium hydrogen phosphate are preferable, and microcrystalline cellulose and lactose are most preferable. As an example, the amount of the filler in the pharmaceutical composition may be generally 5 parts by weight to 92 parts by weight, preferably 10 parts by weight to 90 parts by weight, more preferably 20 parts by weight to 90 parts by weight, and most preferably 40 parts by weight to 90 parts by weight, based on 100 parts by weight of the total weight of the pharmaceutical composition.
In order to bind the bulk drug powders used according to the present invention together, a binder is added to the formulation. The binder may be selected from one or more of starch slurry, sugar powder and syrup, hypromellose, povidone, hydroxypropyl cellulose, methyl cellulose and ethyl cellulose, sodium carboxymethyl cellulose. Hypromellose is preferred. As an example, the amount of the binder in the pharmaceutical composition may be generally 0.5 to 20 parts by weight, preferably 0.5 to 15 parts by weight, more preferably 1 to 10 parts by weight, and most preferably 1 to 5 parts by weight, based on 100 parts by weight of the total weight of the pharmaceutical composition.
The disintegrant used according to the invention ensures that the tablets disintegrate rapidly into fine particles in the gastrointestinal fluids. The disintegrant can be selected from one or more of dry starch, sodium carboxymethyl starch, hydroxypropyl starch, low-substituted hydroxypropyl cellulose (such as hydroxypropyl cellulose with the average substitution mole number of 0.1-0.4 of hydroxypropyl groups on each glucose monomer), crospovidone and croscarmellose sodium. Since crospovidone can rapidly exhibit high capillary activity and excellent hydration ability, hardly has a tendency to gel, has excellent disintegration effect and good re-processability, it is preferable to use crospovidone as a disintegrant in the present invention. As for the amount of the disintegrant in the pharmaceutical composition, it may be generally 0.5 to 30 parts by weight, preferably 0.5 to 20 parts by weight, more preferably 1 to 15 parts by weight, most preferably 1 to 10 parts by weight, based on 100 parts by weight of the total weight of the pharmaceutical composition, as an example.
The lubricant used according to the present invention is used to increase the flowability of the granules or powder, reduce the friction between the granules or powder and the forming processing equipment (such as a die) to facilitate the pushing of the pharmaceutical composition out of the die hole, make the dosage of the formed drug accurate, smooth and beautiful, ensure uniform stress distribution during processing, prevent cracking and the like, reduce weight difference and ensure smooth processing operation. The lubricant may be selected from silicon dioxide, magnesium stearate, talc, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, sodium stearyl fumarate, and the like. Silicon dioxide and magnesium stearate are preferred in view of flowability. As an example, the amount of the lubricant in the pharmaceutical composition may be generally 0.1 to 10 parts by weight, preferably 0.25 to 8 parts by weight, more preferably 0.25 to 5 parts by weight, and most preferably 0.25 to 3 parts by weight, based on 100 parts by weight of the total weight of the pharmaceutical composition.
In addition to the above components, the pharmaceutical composition may also contain other components, such as flavoring agents, coloring agents, sustained-release agents, controlled-release agents, flavoring agents, dispersing agents, and the like. The amount of the above components is not limited as long as the compatibility, processability and dissolution property of the final drug product are not affected.
The pharmaceutical composition according to the present invention may be prepared into various oral solid preparations such as granules, tablets, capsules or powders. The tablet can be one selected from dispersible tablet, chewable tablet, soluble tablet, sustained release tablet, controlled release tablet, orally disintegrating tablet, gastric soluble tablet, and enteric coated tablet.
According to the present invention, the oral solid preparation may be a plain tablet or a coated tablet. When the oral solid preparation is a coated tablet, the amount of the coating layer may be 0.2 parts by weight to 7 parts by weight, preferably 0.5 parts by weight to 5 parts by weight, more preferably 1 part by weight to 4 parts by weight, based on 100 parts by weight of the total weight of the plain tablet.
According to the present invention, there is also provided a method for preparing the above oral solid preparation, comprising the steps of: premixing a 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothien-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component, a partial disintegrant, a filler and a binder to obtain a premix; wet granulating the premix to obtain wet granules; drying the wet pellets to obtain dry granules; dry-mixing the dry granules with a lubricant and the remainder of the disintegrant to obtain a dry blend; and processing said dry blend into said oral solid dosage form.
In the process according to the invention, 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothien-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropionic acid, a partial disintegrant (e.g., 20-80 wt%, 30-70 wt%, 40-60 wt%, or 50 wt%), a filler and a binder may be premixed to give a premix. Premixing may be performed using a mixer.
In the process according to the invention, 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothien-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropionic acid can be prepared beforehand and can also be subjected to a micronization treatment further before premixing. The micronization treatment may be carried out using a pulverizer, a grinder, a jet mill, or the like. The pulverizing or milling time may be from about 2 minutes to 30 minutes.
The process according to the invention may further comprise, after the pre-mixing step and before the wet granulation step, a step of sieving said pre-mixture. This step may be performed using a 60 mesh screen.
In the process according to the invention, the premix may be subjected to wet granulation to obtain wet granules. The above steps may be performed using a wet granulator. Wet granulation is performed by adding a solvent such as distilled water, ethanol. The solvent may also serve as a binding agent. The mixing time may be about 1min-30min, the mixer stirring speed may be about 300-.
In the process according to the invention, the wet pellets may be dried to obtain dry granules. The above steps may be performed using a dryer. The drying temperature may be about 40-70 ℃ and the drying time may be such that the final solvent content is less than 3% by weight, e.g., about 10-60 minutes.
The process according to the invention may also comprise, after the wet granulation step and before the drying step, a step of sieving the wet granulate. This step can be performed using a 14 mesh screen.
In the process according to the invention, the dry granules may be dry-mixed with the lubricant and the remainder of the disintegrant to give a dry blend. The above steps may be performed using a mixer. The mixing time may be about 1min to 30 min.
The method further comprises the step of sieving the dry granules after the drying step and before the dry mixing step. This step may be performed using an 18 mesh screen.
According to the present invention, the dry blend may be further processed into an oral solid formulation. In one or more embodiments, when the oral solid formulation is a tablet, the dry blend may be compressed to obtain the tablet. This step can be performed using a tablet press. In one or more other embodiments, when the oral solid formulation is a granule, the dry blend may be dispensed to obtain the granule. In one or more further embodiments, when the oral solid formulation is a capsule, the dry blend can be loaded into a capsule shell to provide the capsule.
According to the invention, the method may further comprise the steps of: coating treatment is performed using a coating agent to obtain coated tablets. Examples of the coating agent may include opadry coating solution. The above steps may be performed using a coating machine.
The oral administration or oral solid preparation of the pharmaceutical composition has remarkable inhibitory effect on URAT1, and can be used for treating hyperuricemia and gout.
Hereinafter, the present invention will be specifically described by some examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the present invention in any way.
Examples
(1) Compatibility of Components
First, compatibility between the components was examined according to the following method. Mixing the API component with other components according to the proportion in the table 1, and then placing according to the conditions in the table 2; sampling and measuring at specified time points, and inspecting the change of appearance, content and related substances. Analysis was performed by HPLC.
TABLE 1 API mixing ratio Table with other Components
TABLE 2 compatibility test conditions
1 test item X includes: appearance, content and related substances, 0day samples were stored at-20 ℃.
Total illuminance of 1.2 × 106Irradiating with Lux hr visible light, and applying near ultraviolet of 200w hr/m2And (4) performing conditional irradiation.
The mixture has no obvious change in properties by 5 days and 10 days, and is white powder, and the related substances and content investigation results are shown in tables 3-1 and 3-2 respectively.
TABLE 3-1 compatibility test results
TABLE 3-2 compatibility test results
The changes of total impurities and contents of the API compound are analyzed through appearance observation and HPLC, and the results show that the appearance of the API compound positive control and the mixture of the API compound and other components has no obvious change under high-temperature, high-humidity and illumination environments, the contents and the impurities are not obviously increased, and the API compound and other components have good compatibility.
(2) Dissolution rate
The dissolution profile of the drug was examined over 60min using the paddle method at 50rpm with phosphate buffer pH6.8 as dissolution medium maintained at 37. + -. 0.5 ℃.
(3) Workability
The processability of the drug was evaluated by whether the appearance of the drug was smooth during processing, whether sticking occurred, and whether the tablet had an appropriate hardness (measured using a durometer).
Example 1
Weighing 2.5 parts by weight of a 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component, 59 parts by weight of microcrystalline cellulose PH101, 29 parts by weight of lactose, 2.5 parts by weight of crospovidone and 3 parts by weight of hydroxypropyl methylcellulose, premixing and sieving by a 60-mesh sieve.
And (2) transferring the premix into a P1/6 type high-shear wet granulator, slowly adding pure water for granulation, adding the pure water through a peristaltic pump within 4-5 min, continuing stirring for 1min after the pure water is added, and sieving the mixture through a 14-mesh sieve after wet granulation (granulation parameters: stirring speed 370 rpm, and shearing speed 1000 rpm).
Drying with a TG200 boiling dryer. And transferring the wet granules into a dryer for drying. The inlet air temperature was set at 50 ℃. The moisture at the end of drying does not exceed 3%. Drying, sieving with 18 mesh sieve, and grading.
The dried dry granules, 0.5 parts by weight of colloidal silicon dioxide, 1 part by weight of magnesium stearate and 2.5 parts by weight of crospovidone were mixed in a mixing tank using a universal mixer (T2F). The mixing speed was 47 rpm and the mixing time was 3 minutes.
Tableting was performed using a DP30A tableting machine to obtain plain tablets.
Opadry 85a680001 white coating powder was slowly added with stirring to obtain a coating agent having a solid content of about 12.0 wt%. Coating the plain tablets with coating agent in BGB-5F type high efficiency coating machine (air inlet temperature (60 deg.C), controlling speed of feeding pump, temperature of tablet bed of-40 deg.C, atomizing pressure of 1.2bar, and fan pressure of 1.2bar) to obtain coated tablets. The coating weight gain is about 2 wt% to 3 wt%.
Example 2
Coated tablets were prepared in the same manner as in the example except that the 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothien-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component (D10: 3.30 μm, D50: 16.58 μm; D90: 52.04 μm) was pulverized for about 15 minutes using a jet mill in advance before premixing. Micronized 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothien-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropionic acid has a particle size distribution with a D10 of 0.63 μm, a D50 of 1.29 μm and a D90 of 2.89 μm, as measured by a neopatake laser granulometer.
Example 3
20 parts by weight of 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid, 35.2 parts by weight of microcrystalline cellulose PH101, 17.6 parts by weight of lactose 200, 2 parts by weight of crospovidone, and 2.4 parts by weight of hydroxypropyl methylcellulose are weighed, premixed and sieved through a 60-mesh screen.
And (2) transferring the premix into a P1/6 type high-shear wet granulator, slowly adding pure water for granulation, adding the pure water through a peristaltic pump within 4-5 min, continuing stirring for 1min after the pure water is added, and sieving the mixture through a 14-mesh sieve after wet granulation (granulation parameters: stirring speed 370 rpm, and shearing speed 1000 rpm).
Drying with a TG200 boiling dryer. And transferring the wet granules into a dryer for drying. The inlet air temperature was set at 50 ℃. The moisture at the end of drying does not exceed 3%. Drying, sieving with 18 mesh sieve, and grading.
The dried dry granules, 0.4 parts by weight of colloidal silicon dioxide, 0.4 parts by weight of magnesium stearate and 2 parts by weight of crospovidone were mixed in a mixing tank using a universal mixer (T2F). The mixing speed was 47 rpm and the mixing time was 3 minutes.
Tableting was performed using a DP30A tableting machine to obtain plain tablets.
Opadry 85a680001 white coating powder was slowly added with stirring to obtain a coating agent having a solid content of about 12.0 wt%. Coating the plain tablets with coating agent in BGB-5F type high efficiency coating machine (air inlet temperature (60 deg.C), controlling speed of feeding pump, temperature of tablet bed of-40 deg.C, atomizing pressure of 1.2bar, and fan pressure of 1.2bar) to obtain coated tablets. The coating weight gain is about 2 wt% to 3 wt%.
Example 4
20 parts by weight of a 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component, 40.5 parts by weight of pregelatinized starch, 30 parts by weight of mannitol, 2.5 parts by weight of crospovidone and 3 parts by weight of hydroxypropyl methylcellulose are weighed, premixed and sieved by a 60-mesh screen.
And (2) transferring the premix into a P1/6 type high-shear wet granulator, slowly adding pure water for granulation, adding the pure water through a peristaltic pump within 4-5 min, continuing stirring for 1min after the pure water is added, and sieving the mixture through a 14-mesh sieve after wet granulation (granulation parameters: stirring speed 370 rpm, and shearing speed 1000 rpm).
Drying with a TG200 boiling dryer. And transferring the wet granules into a dryer for drying. The inlet air temperature was set at 50 ℃. The moisture at the end of drying does not exceed 3%. Drying, sieving with 18 mesh sieve, and grading.
The dried dry granules, 0.5 parts by weight of colloidal silicon dioxide, 1 part by weight of magnesium stearate and 2.5 parts by weight of crospovidone were mixed in a mixing tank using a universal mixer (T2F). The mixing speed was 47 rpm and the mixing time was 3 minutes.
Tableting was performed using a DP30A tableting machine to obtain plain tablets.
Opadry 85a680001 white coating powder was slowly added with stirring to obtain a coating agent having a solid content of about 12.0 wt%. Coating the plain tablets with coating agent in BGB-5F type high efficiency coating machine (air inlet temperature (60 deg.C), controlling speed of feeding pump, temperature of tablet bed of-40 deg.C, atomizing pressure of 1.2bar, and fan pressure of 1.2bar) to obtain coated tablets. The coating weight gain is about 2 wt% to 3 wt%.
Example 5
20 parts by weight of a 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component, 40.5 parts by weight of pregelatinized starch, 30 parts by weight of mannitol, 2.5 parts by weight of crospovidone and 3 parts by weight of hydroxypropyl methylcellulose are weighed, premixed and sieved by a 60-mesh screen.
And (2) transferring the premix into a P1/6 type high-shear wet granulator, slowly adding pure water for granulation, adding the pure water through a peristaltic pump within 4-5 min, continuing stirring for 1min after the pure water is added, and sieving the mixture through a 14-mesh sieve after wet granulation (granulation parameters: stirring speed 370 rpm, and shearing speed 1000 rpm).
Drying with a TG200 boiling dryer. And transferring the wet granules into a dryer for drying. The inlet air temperature was set at 50 ℃. The moisture at the end of drying does not exceed 3%. Drying, sieving with 18 mesh sieve, and grading.
The dried dry granules, 0.5 parts by weight of colloidal silicon dioxide, 1 part by weight of magnesium stearate and 2.5 parts by weight of crospovidone were mixed in a mixing tank using a universal mixer (T2F). The mixing speed was 47 rpm and the mixing time was 3 minutes.
Tableting was performed using a DP30A tableting machine to obtain plain tablets.
Opadry 85a680001 white coating powder was slowly added with stirring to obtain a coating agent having a solid content of about 12.0 wt%. Coating the plain tablets with coating agent in BGB-5F type high efficiency coating machine (air inlet temperature (60 deg.C), controlling speed of feeding pump, temperature of tablet bed of-40 deg.C, atomizing pressure of 1.2bar, and fan pressure of 1.2bar) to obtain coated tablets. The coating weight gain is about 2 wt% to 3 wt%.
Example 6
25 parts by weight of a 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component, 74 parts by weight of microcrystalline cellulose, 36.75 parts by weight of lactose 200, 3.75 parts by weight of sodium carboxymethyl starch and 4.5 parts by weight of hydroxypropyl methylcellulose are weighed, premixed and sieved by a 60-mesh screen.
And (2) transferring the premix into a P1/6 type high-shear wet granulator, slowly adding pure water for granulation, adding the pure water through a peristaltic pump within 4-5 min, continuing stirring for 1min after the pure water is added, and sieving the mixture through a 14-mesh sieve after wet granulation (granulation parameters: stirring speed 370 rpm, and shearing speed 1000 rpm).
Drying with a TG200 boiling dryer. And transferring the wet granules into a dryer for drying. The inlet air temperature was set at 50 ℃. The moisture at the end of drying does not exceed 3%. Drying, sieving with 18 mesh sieve, and grading.
The dried dry granules, 0.75 parts by weight of colloidal silicon dioxide, 1.5 parts by weight of magnesium stearate and 3.75 parts by weight of sodium carboxymethyl starch were put in a mixing tank and mixed using a universal mixer (T2F). The mixing speed was 47 rpm and the mixing time was 3 minutes.
Tableting was performed using a DP30A tableting machine to obtain plain tablets.
Opadry 85a680001 white coating powder was slowly added with stirring to obtain a coating agent having a solid content of about 12.0 wt%. Coating the plain tablets with coating agent in BGB-5F type high efficiency coating machine (air inlet temperature (60 deg.C), controlling speed of feeding pump, temperature of tablet bed of-40 deg.C, atomizing pressure of 1.2bar, and fan pressure of 1.2bar) to obtain coated tablets. The coating weight gain is about 2 wt% to 3 wt%.
Example 7
25 parts by weight of a 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component, 74 parts by weight of microcrystalline cellulose, 36.75 parts by weight of lactose 200, 3.75 parts by weight of crospovidone and 4.5 parts by weight of hydroxypropyl methylcellulose are weighed, premixed and sieved by a 60-mesh screen.
And (2) transferring the premix into a P1/6 type high-shear wet granulator, slowly adding pure water for granulation, adding the pure water through a peristaltic pump within 4-5 min, continuing stirring for 1min after the pure water is added, and sieving the mixture through a 14-mesh sieve after wet granulation (granulation parameters: stirring speed 370 rpm, and shearing speed 1000 rpm).
Drying with a TG200 boiling dryer. And transferring the wet granules into a dryer for drying. The inlet air temperature was set at 50 ℃. The moisture at the end of drying does not exceed 3%. Drying, sieving with 18 mesh sieve, and grading.
The dried dry granules, 0.75 parts by weight of colloidal silicon dioxide, 1.5 parts by weight of magnesium stearate and 3.75 parts by weight of crospovidone were mixed in a mixing tank using an universal mixer (T2F). The mixing speed was 47 rpm and the mixing time was 3 minutes.
Tableting was performed using a DP30A tableting machine to obtain plain tablets.
Opadry 85a680001 white coating powder was slowly added with stirring to obtain a coating agent having a solid content of about 12.0 wt%. Coating the plain tablets with coating agent in BGB-5F type high efficiency coating machine (air inlet temperature (60 deg.C), controlling speed of feeding pump, temperature of tablet bed of-40 deg.C, atomizing pressure of 1.2bar, and fan pressure of 1.2bar) to obtain coated tablets. The coating weight gain is about 2 wt% to 3 wt%.
Example 8
Weighing 2.5 parts by weight of a 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component, 28 parts by weight of microcrystalline cellulose, 15 parts by weight of lactose, 1.25 parts by weight of crospovidone and 1.5 parts by weight of hydroxypropyl methylcellulose, premixing and sieving by a 60-mesh sieve.
And (2) transferring the premix into a P1/6 type high-shear wet granulator, slowly adding pure water for granulation, adding the pure water through a peristaltic pump within 4-5 min, continuing stirring for 1min after the pure water is added, and sieving the mixture through a 14-mesh sieve after wet granulation (granulation parameters: stirring speed 370 rpm, and shearing speed 1000 rpm).
Drying with a TG200 boiling dryer. And transferring the wet granules into a dryer for drying. The inlet air temperature was set at 50 ℃. The moisture at the end of drying does not exceed 3%. Drying, sieving with 18 mesh sieve, and grading.
The dried dry granules, 0.25 parts by weight of colloidal silicon dioxide, 0.25 parts by weight of magnesium stearate and 1.25 parts by weight of crospovidone were mixed in a mixing tank using a universal mixer (T2F). The mixing speed was 47 rpm and the mixing time was 3 minutes.
Tableting was performed using a DP30A tableting machine to obtain plain tablets.
Opadry 85a680001 white coating powder was slowly added with stirring to obtain a coating agent having a solid content of about 12.0 wt%. Coating the plain tablets with coating agent in BGB-5F type high efficiency coating machine (air inlet temperature (60 deg.C), controlling speed of feeding pump, temperature of tablet bed of-40 deg.C, atomizing pressure of 1.2bar, and fan pressure of 1.2bar) to obtain coated tablets. The coating weight gain is about 2 wt% to 3 wt%.
The processability results of the oral tablets manufactured in examples 1 to 8 are shown in table 4.
TABLE 4
As shown in table 4, the oral tablets manufactured in examples 1 to 8 were smooth, had good hardness (hardness between 4 and 9 Kp), and did not suffer from a sticking phenomenon during processing, thus having excellent processability.
As shown in fig. 1, the oral tablets manufactured in examples 1 to 4 were rapidly dissolved within 5 minutes, the dissolution rate was not lower than 94% within 30 minutes, and the dissolution rate was substantially stable after 30 minutes. In addition, comparing example 2 with example 1, it can be found that the dissolution rate of example 2 is improved by about 18% compared with that of example 1, and therefore, the dissolution rate of the drug can be remarkably improved by the micronized 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropionic acid component.
As shown in fig. 2, the oral tablets manufactured in examples 5 to 8 were rapidly dissolved within 5 minutes, the dissolution rate was not lower than 81% within 30 minutes, and the dissolution rate was substantially stable after 30 minutes.
The above-mentioned FIGS. 1-2 show that the oral tablets produced in the examples have excellent dissolution properties.
In addition, the tablets manufactured in examples 4 and 7 were selected for the bioavailability test of dogs. One tablet was administered to each dog,the dose administered was 2.5 mg/kg. The blood concentration was measured 24 hours after the administration. The results show that for the tablet of example 4, CmaxWas 2122nM, AUC0-inf5025nM h, AUCO-last 4016nM h, Tmax0.875h, and T1/2Is 9.93 h; for the tablets of example 7, Cmax1605nM, AUC0-inf5760nM · h, AUCO-last 5375nM · h, TmaxIs 0.750h, and T1/2The time is 3.49 h. The bioavailability of the tablets of examples 4 and 7 was 44.0% and 47.1%, respectively, indicating that the drug of the present invention has excellent oral absorption bioavailability.
The above-described embodiments are merely illustrative of the present invention and are not intended to limit the present invention. It will be appreciated by those skilled in the art that modifications and variations to the embodiments of the present invention are within the scope of the present invention without departing from the spirit and scope of the invention. And the scope of the invention should be determined from the appended claims.
Claims (15)
1. A pharmaceutical composition comprising a therapeutically effective amount of a 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothien-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component, a filler, a disintegrant, a binder, and a lubricant.
2. The pharmaceutical composition according to claim 1, wherein the disintegrant is selected from one or more of dry starch, sodium carboxymethyl starch, hydroxypropyl starch, low substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium.
3. The pharmaceutical composition according to claim 1, wherein the filler is selected from one or more of starch, mannitol, microcrystalline cellulose, lactose, pregelatinized starch, inorganic salts.
4. The pharmaceutical composition of claim 1, wherein the binder is selected from one or more of starch slurry, sugar powder, syrup, hypromellose, povidone, hydroxypropyl cellulose, methyl cellulose and ethyl cellulose, and sodium carboxymethyl cellulose.
5. The pharmaceutical composition of claim 1, wherein the lubricant is selected from one or more of magnesium stearate, silicon dioxide, talc, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, and sodium stearyl fumarate.
6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition comprises 0.5 to 90 parts by weight of the 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropionic acid component, 5 to 92 parts by weight of the filler, 0.5 to 30 parts by weight of the disintegrant, 0.5 to 20 parts by weight of the binder and 0.1 to 10 parts by weight of the lubricant, based on 100 parts by weight of the total weight of the pharmaceutical composition.
7. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that the 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothien-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropionic acid component is micronized particles having a particle size distribution with D10 of 0.5-1 μm, D50 of 1-2 μm and D90 of 2-3 μm.
8. An oral solid formulation comprising the pharmaceutical composition according to any one of claims 1 to 7.
9. The oral solid preparation according to claim 8, wherein the dosage form of the oral solid preparation is selected from one of granules, tablets, capsules and powders.
10. The oral solid preparation according to claim 8, wherein the tablet is one selected from the group consisting of a dispersible tablet, a chewable tablet, a soluble tablet, a sustained release tablet, a controlled release tablet, an orally disintegrating tablet, a gastric soluble tablet and an enteric coated tablet.
11. A process for preparing the oral solid formulation of any one of claims 8 to 10, characterized in that it comprises the steps of:
premixing a 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothien-1-yl) -1, 2, 4-triazol-3-yl) thio) -2-methylpropanoic acid component, a partial disintegrant, a filler and a binder to obtain a premix;
wet granulating the premix to obtain wet granules;
drying the wet pellets to obtain dry granules;
dry-mixing the dry granules with a lubricant and the remainder of the disintegrant to obtain a dry blend; and
processing said dry blend into said oral solid dosage form.
12. The method according to claim 11, further comprising the step of sieving the premix after the premixing step and before the wet granulation step; and/or, the process further comprises, after the wet granulation step and before the drying step, the step of sieving the wet granulate; and/or, the method further comprises the step of sieving the dry granules after the drying step and before the dry mixing step.
13. The method according to claim 11 or 12, further comprising, before the premixing step, the steps of: micronization treatment is carried out on the 2- ((5-bromo-4- (3-cyclopropyl-5, 5-difluoro-4, 5, 6, 7-tetrahydrobenzothiophen-1-yl) -1, 2, 4-triazole-3-yl) thio) -2-methylpropanoic acid component in advance.
14. The method of claim 11 or 12, wherein the oral solid formulation is a tablet and the step of processing the dry blend into the oral solid formulation comprises: tabletting said dry blend to obtain said tablet.
15. Use of the pharmaceutical composition according to any one of claims 1 to 7 or the oral solid formulation according to any one of claims 8 to 10 for the treatment of hyperuricemia or gout.
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