CN115006400A - Pharmaceutical composition containing piperazixil and preparation method thereof - Google Patents
Pharmaceutical composition containing piperazixil and preparation method thereof Download PDFInfo
- Publication number
- CN115006400A CN115006400A CN202110239862.XA CN202110239862A CN115006400A CN 115006400 A CN115006400 A CN 115006400A CN 202110239862 A CN202110239862 A CN 202110239862A CN 115006400 A CN115006400 A CN 115006400A
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- pharmaceutical composition
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- acceptable carrier
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Abstract
The invention relates to a drug combination containing piperazili and a preparation method thereof. Belongs to the technical field of pharmaceutical preparations. The preparation contains 3% -25% of water-soluble acid, the pharmaceutical composition adopts a wet granulation process, raw material medicines and partial auxiliary materials are granulated and then mixed with the water-soluble acid for tabletting, and the water-soluble acid in the preparation is selected from one or more of fumaric acid, citric acid, oxalic acid and vitamin C. The tablets prepared have a good dissolution behaviour in dissolution media with a higher pH value, such as phosphate buffer pH6.5, compared to tablets without water soluble acid.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, provides a quick-release pharmaceutical preparation, and particularly relates to a pharmaceutical composition containing piperazixil and a preparation method thereof.
Background
According to data of International Research center for Research on Cancer (IARC) under the World Health Organization (WHO), the age-normalized incidence of breast Cancer in the World in 2012 (43.1/10 ten thousand) ranks the first of female cancers, colorectal Cancer (14.3/10 ten thousand) far ahead of the second rank accounts for 35.3% of new tumors in women, and the death number accounts for 20.8% of all Cancer deaths in women. The newly published data of the cancer center in China also reveals that the breast cancer still can be the cancer species with the highest incidence rate in women in 2015, and is positioned at the 6 th position of the mortality ranking of all cancer species in women.
Surgical treatment is still one of the main treatment means of breast cancer, and there are various ways, and there is no uniform suggestion on the selection. Radiotherapy is the main component for treating breast cancer, is one of local treatment means, is less than surgical treatment, and is limited by factors such as the constitution of patients in anatomy. At present, chemotherapy becomes the most important treatment means after operation treatment, and with continuous and successful development of new chemotherapeutics, the treatment effect is obviously improved, the risk of postoperative recurrence and metastasis of early breast cancer is reduced, the 5-year survival rate of breast cancer patients is improved, the illness state of recurrent and metastatic breast cancer is relieved, and the survival quality of the patients is improved.
Cetrazuril is a CDK4/6 inhibitor, and can selectively inhibit cyclin-dependent kinases 4 and 6(CDK4/6), restore cell cycle control, and block tumor cell proliferation. The disease Progression Free Survival (PFS) was statistically significantly prolonged in the combined pipariril + letrozole treatment group (20.2 months vs 10.2 months, p ═ 0.0004) compared to the standard therapeutic drug letrozole (letrozole) treatment group.
In clinical trials, the adverse reaction of the thujaplicin can be effectively controlled. The marketing of the thuja occilier product has increased a more effective way to treat breast cancer patients.
Perubel Xili capsules sell for about $ 49.6 million worldwide in 2019, and have a promising market prospect, but the bioavailability of Perubel Xili capsules can be affected by the fed or fasted state of the patient, certain drugs used, such as Proton Pump Inhibitors (PPIs) or H2 receptor antagonists, and certain medical conditions, resulting in large variations in clinical efficacy between patients and the patient himself.
There is therefore a need to find pipbicilide formulations which are substantially pH-independent, without significant food effects or adverse interactions with PPIs, the first task to achieve this being to prepare formulations which have a better dissolution profile in dissolution media of different pH values in vitro, and which have good storage stability.
The invention patent CN107666914A discloses a method for preparing a drug preparation containing pimaride, which uses water-soluble acid succinic acid for improving the dissolution rate of the drug in a ph5.5 acetate buffer and a ph6.5 phosphate buffer. The inventor finds that when fumaric acid, citric acid, oxalic acid or vitamin C is used as water-soluble acid, a specific preparation process is adopted, the technical effect consistent with that of succinic acid can be achieved, and a better alternative scheme in the prior art is provided.
The piperazixil is a solubility pH-dependent drug, the bioavailability in a human body is related to the pH value of the gastrointestinal tract, and is influenced by an alkaline drug (such as a proton pump inhibitor drug) to be taken, in order to improve the situation, a water-soluble acid is added into a formula of the piperazixil tablet, but the piperazixil easily generates an addition product with the acid to influence the product stability, so that on one hand, a proper water-soluble acid is required to be found, the drug solubility can be improved, and a small amount of acid addition product can be generated in the product effective period, on the other hand, a proper preparation process is required to be developed, and the stability problem is further solved from the process aspect.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition which adopts fumaric acid, citric acid, oxalic acid and/or vitamin C as water-soluble acid and contains thujaplicin, and can be used as a good alternative technical scheme in the prior art. The medicinal preparation obtained by the invention has better dissolution curve in dissolution media with different pH values and has good storage stability.
The invention provides a drug composition containing piperazidine, which comprises 10 wt% to 35 wt% of piperazidine, 3 wt% to 25 wt% of water-soluble acid and a pharmaceutically acceptable carrier, wherein the water-soluble acid is selected from one or more of fumaric acid, citric acid, oxalic acid and vitamin C.
In some preferred embodiments, the pharmaceutically acceptable carrier comprises a diluent selected from the group consisting of: one or more of microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, xylitol, magnesium carbonate, calcium hydrogen phosphate and calcium phosphate, wherein the diluent comprises 10-80 wt% of the pharmaceutical composition.
In some preferred embodiments, the pharmaceutically acceptable carrier comprises a binder selected from the group consisting of: one or more of povidone, hypromellose, hydroxypropyl cellulose, methylcellulose, and sodium carboxymethylcellulose, the binder comprising 0 wt% to 5 wt% of the pharmaceutical composition.
In some preferred embodiments, the pharmaceutically acceptable carrier comprises a film-forming material selected from the group consisting of: one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene glycol, zein, acrylic resin and sodium carboxymethyl cellulose, wherein the film-forming material accounts for 0-10 wt% of the pharmaceutical composition.
The pharmaceutical composition of the present invention, in some preferred embodiments, the pharmaceutically acceptable carrier comprises a lubricant selected from the group consisting of: magnesium stearate, calcium stearate, zinc stearate and sodium stearyl fumarate, the lubricant comprises 0.5 wt% to 10 wt% of the pharmaceutical composition.
In some preferred embodiments, the pharmaceutically acceptable carrier comprises a glidant selected from silicon dioxide, and the glidant accounts for 0 wt% to 5 wt% of the pharmaceutical composition; the pharmaceutically acceptable carrier further comprises a disintegrant selected from the group consisting of: the pharmaceutical composition comprises crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose and carboxymethyl starch sodium, wherein the disintegrant accounts for 3-15 wt% of the pharmaceutical composition.
The preferred prescription of the drug composition containing the piperazixili comprises the following components:
the pharmaceutical compositions of the present invention, in some preferred embodiments, are in the form of tablets, such as single layer tablets or bilayer tablets.
In some preferred embodiments, the pharmaceutical composition of the present invention dissolves in a dissolution medium of 500ml of ph6.5 phosphate buffer at 37 ℃:
(a) not less than 30% pipabriside in 15 minutes; or
(b) Not less than 35% of piparixiline in 30 minutes; or
(c) Not less than 40% pipabriside in 45 minutes; or
(d) Any two or three of (a), (b) and (c) are satisfied simultaneously.
The pharmaceutical composition of the present invention, in some preferred embodiments, exhibits a total related substance amount of less than 0.5% of thujacil when stored for 3 months at 40 ℃ and 75% RH.
The invention also provides a preparation method of the drug composition containing the piperazili, which comprises the following steps:
(1) carrying out primary granulation on the piparicin and a pharmaceutically acceptable carrier by adopting high-shear wet granulation or fluidized bed one-step granulation;
(2) coating and drying the granules obtained in the step (1) by using an aqueous solution containing a film-forming material to obtain dry granules, wherein the film-forming material is selected from the following materials: one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene glycol, zein, acrylic resin and sodium carboxymethyl cellulose;
(3) and (3) uniformly mixing the dry granules obtained in the step (2) with an additional auxiliary material containing water-soluble acid, and tabletting to prepare the medicinal composition containing the piperazixil.
The piperazili raw material has strong adhesiveness, the content of main drugs in the prescription is high, the common wet granulation or dry granulation process has serious sticking phenomenon, and the industrialized mass production cannot be realized. Meanwhile, in order to solve the problem of stability, the process that the piperazixili raw material and partial auxiliary materials are firstly granulated and coated in granules and then mixed with water-soluble acid is adopted, the contact between the raw material and the water-soluble acid is reduced to the maximum extent on the premise of ensuring the dissolution rate of the product, and the preparation prepared by the method simultaneously meets the requirements of three aspects of dissolution rate, stability and production feasibility amplification.
Drawings
FIG. 1 is a graph showing the dissolution behavior of the products obtained in examples 1 to 5 in comparison with those on the market;
FIG. 2 is a graph showing the comparison between the dissolution behavior of the product obtained in comparative example 2 and that of a commercially available product.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that: the embodiments of the present invention are given for illustration only, and not for limitation, and the simple modifications of the present invention based on the technical solutions of the present invention belong to the protection scope of the present invention.
The invention is further illustrated by the following examples.
In the examples of the present invention, the term "commercially available product" means: the pai bai xili tablet marketed in the U.S. by Pfizer Inc, under the trade name IBRANCE.
Example 1: fluidized bed granulation/coating process for preparing tablets containing piparicin and citric acid
Batch production: 700 pieces of batch number: 200522-3
Note: removed during processing.
(1) One-step granulation and granule coating by a fluidized bed:
hydroxypropyl methylcellulose E5 with the prescription amount of 2.2 percent is added into purified water while stirring to prepare a solution with the concentration of 5 percent (w/w) for later use.
The weighed raw and auxiliary materials added in the fluidized bed are put into the fluidized bed, the air inlet temperature is 50-70 ℃, and the air inlet air quantity is 10-30m 3 Spraying HPMC solution into the granules at an atomizing pressure of 0.5-1.0 bar, controlling the temperature of the material to be 20-35 ℃ in the granulating process, drying the granules after spraying, sampling and measuring the moisture when the temperature of the material reaches 40-60 ℃, and controlling the moisture to be less than or equal to 2.0%.
(2) Dry granulation:
the dried granules were subjected to dry granulation by a U5 granulator, and sieved through a 1.5mm round sieve at 1000 rpm.
(3) Non-lubricated blend 1:
crushing citric acid by a crusher, sieving by a 30-mesh sieve, and taking the citric acid below the 30-mesh sieve for later use.
And (3) installing a hopper mixer according to requirements, placing other additional auxiliary materials except the magnesium stearate into the hopper mixer, mixing, setting the rotating speed to be 15rpm, and mixing for 5 min. Sieving the materials by a U5 granulator, wherein the sieve mesh is a round hole sieve with the aperture of 1.2mm, and the rotating speed is 500 +/-50 rpm.
(4) Non-lubricated blend 2:
and (3) adding the non-lubricated mixed material 1 and the dry-sized granules containing the medicine into a hopper mixer together for mixing, setting the mixing rotation speed to be 15rpm, mixing for 15min, and starting equipment for mixing.
(5) Total mixing:
and (3) sieving the magnesium stearate with a 40-mesh sieve, adding the sieved magnesium stearate into a hopper mixer, setting the mixing speed to be 15rpm, mixing for 5min, and starting equipment for mixing.
(6) Tabletting:
setting the tabletting speed of a tabletting machine to be 0.96-1.44 ten thousand tablets per hour, and controlling the hardness of the tablet core to be 10-15 kg.
(7) Coating:
preparing coating liquid, setting the air inlet temperature of a coating machine to be 50-70 ℃, and controlling the core temperature to be 40-55 ℃ in the coating process. The target weight is increased by 3 percent, and the weight increase control range is 2 to 4 percent.
Example 2: tablet containing pipabride and fumaric acid prepared by high-shear wet granulation combined with fluidized bed granule coating process
Batch production: 1200 pieces of batch number: 200224-3
Note: removed during processing.
(1) High shear wet granulation
Hydroxypropyl methylcellulose E3 with the prescription amount of 0.64% is added into purified water while stirring to prepare a solution with the concentration of 4% (w/w) for later use.
Placing the piperacillin, the internal microcrystalline cellulose PH102 and the internal crospovidone XL into a wet mixing granulator, setting a stirring speed of 150rpm and a cutter speed of 1000rpm, premixing for 5min, setting the stirring speed of 150rpm and the cutter speed of 1000rpm after premixing, adding the binder solution under stirring, and granulating for 5 min. After the completion of granulation, wet granulation was performed.
(2) Fluidized bed particle coating:
hydroxypropyl methylcellulose E3 with the prescription amount of 1.28% is added into purified water while stirring to prepare a solution with the concentration of 5% (w/w) for later use.
Setting the air inlet temperature to be 50-70 ℃ and the air inlet air quantity to be 10-30m 3 Spraying HPMC solution into the granules at an atomization pressure of 0.5-1.0 bar, controlling the temperature of the material to be 20-35 ℃ in the granulating process, drying after spraying, sampling when the temperature of the material reaches 40-60 ℃ to measure the moisture, and controlling the moisture to be less than or equal to 2.0%.
(3) Dry granulation: the dried granules were subjected to dry granulation by a U5 granulator, and sieved through a 1.5mm round sieve at 1000 rpm.
(4) Total mixing of the medicine-containing layer:
sieving magnesium stearate with 40 mesh sieve, adding into hopper mixer together with dried and granulated medicine-containing granules, setting mixing speed at 15rpm for 5min, and starting equipment for mixing.
(5) Non-lubrication mixing of an acid layer:
crushing fumaric acid by a crusher, sieving with a 30-mesh sieve, and taking the fumaric acid below the 30-mesh sieve for later use.
Adding all the auxiliary materials except the magnesium stearate in the acid layer into a hopper mixer for mixing, setting the mixing speed to be 15rpm, mixing for 15min, and starting the equipment for mixing.
(6) Total mixing of acid layers: and (3) sieving the magnesium stearate with a 40-mesh sieve, adding the sieved magnesium stearate into a hopper mixer, setting the mixing speed to be 15rpm, mixing for 5min, and starting equipment for mixing.
(7) Tabletting: and tabletting the medicine-containing layer and the acid layer material by a double-layer tablet, and controlling the hardness of the tablet core to be 10-15 kg.
(8) Coating:
preparing coating liquid, setting the air inlet temperature of a coating machine to be 50-70 ℃, and controlling the core temperature to be 40-55 ℃ in the coating process. The target weight is increased by 3 percent, and the weight increase control range is 2 to 4 percent.
Example 3: tablet containing pipbicillin and oxalic acid prepared by high-shear wet granulation combined with fluidized bed granule coating process
Batch production: 1000 lot numbers: 200323-4
Note: removed during processing.
(1) High shear wet granulation
Hydroxypropyl methylcellulose E3 with the prescription amount of 0.64% is added into purified water while stirring to prepare a solution with the concentration of 5% (w/w) for later use.
Placing the piperazixili, the internally added microcrystalline cellulose PH102 and the internally added crospovidone XL in a wet mixing granulator, setting the stirring speed to be 150rpm and the cutter speed to be 1000rpm, premixing for 5min, setting the stirring speed to be 150rpm and the cutter speed to be 1000rpm after premixing, adding the binder solution under stirring, and granulating for 5 min. After the completion of granulation, wet granulation was performed.
(2) Fluidized bed particle coating:
hydroxypropyl methylcellulose E3 with the prescription amount of 1.28% is added into purified water while stirring to prepare a solution with the concentration of 7% (w/w) for later use.
Setting the air inlet temperature to be 50-70 ℃ and the air inlet air quantity to be 10-30m 3 Spraying HPMC solution into the granules at an atomization pressure of 0.5-1.0 bar, controlling the temperature of the material to be 20-35 ℃ in the granulating process, drying after spraying, sampling when the temperature of the material reaches 40-60 ℃ to measure the moisture, and controlling the moisture to be less than or equal to 2.0%.
(3) Dry granulation: the dried granules were subjected to dry granulation by a U5 granulator, and sieved through a 1.5mm round sieve at 1000 rpm.
(4) Non-lubrication mixing of the medicine-containing layer:
adding the dried and granulated granules containing medicine and other medicinal layer containing medicine plus adjuvants except magnesium stearate into a hopper mixer, setting the mixing speed at 15rpm for 15min, and starting the equipment for mixing.
(5) Total mixing of the medicine-containing layer:
sieving magnesium stearate with 40 mesh sieve, adding into hopper mixer, setting mixing speed at 15rpm for 5min, and starting equipment for mixing.
(6) Non-lubrication mixing of an acid layer:
crushing oxalic acid by a crusher, sieving by a 30-mesh sieve, and taking oxalic acid below the 30-mesh sieve for later use.
Adding all the auxiliary materials except the magnesium stearate in the acid layer into a hopper mixer for mixing, setting the mixing speed to be 15rpm, mixing for 15min, and starting the equipment for mixing.
(7) Total mixing of acid layers: and (3) sieving the magnesium stearate with a 40-mesh sieve, adding the sieved magnesium stearate into a hopper mixer, setting the mixing speed to be 15rpm, mixing for 5min, and starting equipment for mixing.
(8) Tabletting: and tabletting the medicine-containing layer and the acid layer material by a double-layer tablet, and controlling the hardness of the tablet core to be 10-15 kg.
(9) Coating: preparing coating liquid, setting the air inlet temperature of a coating machine to be 50-70 ℃, and controlling the core temperature to be 40-55 ℃ in the coating process. The target weight is increased by 3 percent, and the weight increase control range is 2 to 4 percent.
Example 4: tablet containing piparicin and citric acid prepared by high-shear wet granulation combined with fluidized bed granule coating process
Batch production: 1000 lot numbers: 200309-2
Note: removed during processing.
(1) High shear wet granulation
Hydroxypropyl methylcellulose E5 with the prescription amount of 0.64% is added into purified water while stirring to prepare a solution with the concentration of 3.5% (w/w) for later use.
Placing the piperazixili, the internally added microcrystalline cellulose PH102 and the internally added crospovidone XL in a wet mixing granulator, setting the stirring speed to be 150rpm and the cutter speed to be 1000rpm, premixing for 5min, setting the stirring speed to be 150rpm and the cutter speed to be 1000rpm after premixing, adding the binder solution under stirring, and granulating for 5 min. After the completion of granulation, wet granulation was performed.
(2) Fluidized bed particle coating:
hydroxypropyl methylcellulose E5 with the prescription amount of 2.56% is added into purified water while stirring to prepare a solution with the concentration of 6% (w/w) for later use.
Adding the wet particles into a fluidized bed, setting the air inlet temperature to be 50-70 ℃ and the air inlet quantity to be 10-30m 3 Spraying HPMC solution into the granules at an atomization pressure of 0.5-1.0 bar, controlling the temperature of the material to be 20-35 ℃ in the granulating process, drying after spraying, sampling when the temperature of the material reaches 40-60 ℃ to measure the moisture, and controlling the moisture to be less than or equal to 2.0%.
(3) Dry granulation: the dried granules were subjected to dry granulation by a U5 granulator, which was sieved with a 1.5mm round sieve at 1000 rpm.
(4) Non-lubrication mixing:
crushing citric acid by a crusher, sieving by a 30-mesh sieve, and taking the citric acid below the 30-mesh sieve for later use.
Installing hopper mixer as required, placing the dry and whole granule containing medicine and the adjuvant except magnesium stearate in the hopper mixer, mixing, setting rotation speed at 15rpm, and mixing for 15 min.
(5) Total mixing: and (3) sieving the magnesium stearate with a 40-mesh sieve, adding the sieved magnesium stearate into a hopper mixer, setting the mixing speed to be 15rpm, mixing for 5min, and starting equipment for mixing.
(6) Tabletting: setting the tabletting speed of a tabletting machine to be 0.96-1.44 ten thousand tablets per hour, and controlling the hardness of the tablet core to be 10-15 kg.
(7) Coating film
Preparing coating liquid, setting the air inlet temperature of a coating machine to be 50-70 ℃, and controlling the core temperature to be 40-55 ℃ in the coating process. The target weight is increased by 3 percent, and the weight increase control range is 2 to 4 percent.
Example 5: fluidized bed one-step granulation and granule coating for preparing tablet containing piparicin and vitamin C
Batch production: 800 pieces of batch number: 200228
Note: removed during processing.
(1) One-step granulation and granule coating by a fluidized bed:
hydroxypropyl methylcellulose E5 with the prescription amount of 1.8% is added into purified water while stirring to prepare a solution with the concentration of 5% (w/w) for later use.
Placing the weighed internal addition part of raw and auxiliary materials into a fluidized bed, setting the air inlet temperature to be 50-70 ℃ and the air inlet air quantity to be 10-30m 3 Spraying HPMC solution into the granules at an atomization pressure of 0.5-1.0 bar, controlling the temperature of the material to be 20-35 ℃ in the granulating process, drying after spraying, sampling when the temperature of the material reaches 40-60 ℃ to measure the moisture, and controlling the moisture to be less than or equal to 2.0%.
(2) Dry granulation: the dried granules were subjected to dry granulation by a U5 granulator, and sieved through a 1.5mm round sieve at 1000 rpm.
(3) Non-lubrication mixing:
crushing the vitamin C by a crusher, sieving by a 30-mesh sieve, and taking the vitamin C below the 30-mesh sieve for later use.
Installing hopper mixer as required, placing the dry and whole granule containing medicine and the adjuvant except magnesium stearate in the hopper mixer, mixing, setting rotation speed at 15rpm, and mixing for 15 min.
(4) Total mixing: and (3) sieving the magnesium stearate with a 40-mesh sieve, adding the sieved magnesium stearate into a hopper mixer, setting the mixing speed to be 15rpm, mixing for 5min, and starting equipment for mixing.
(5) Tabletting: setting the tabletting speed of a tabletting machine to be 0.96-1.44 ten thousand tablets per hour, and controlling the hardness of the tablet core to be 10-15 kg.
(6) Coating: preparing coating liquid, setting the air inlet temperature of a coating machine to be 50-70 ℃, and controlling the core temperature to be 40-55 ℃ in the coating process. The target weight is increased by 3 percent, and the weight increase control range is 2 to 4 percent.
Comparative example 1: preparation of tablet containing piparicin and fumaric acid by high-shear wet granulation
Batch production: 500 pieces of batch number: 200411
Note: removed during processing.
(1) High shear wet granulation
Povidone K30 in the prescribed amount was added to purified water with stirring to prepare a solution with a concentration of 10% (w/w) for use.
Placing the piperacillin, the internal microcrystalline cellulose PH102 and the internal crospovidone XL into a wet mixing granulator, setting the stirring speed to be 250rpm and the cutter speed to be 1000rpm, premixing for 5min, setting the stirring speed to be 250rpm and the cutter speed to be 1000rpm after premixing, adding the binder solution under stirring, and granulating for 5 min. After completion of granulation, wet granulation was performed.
(2) Fluidized bed drying:
adding the wet particles into a fluidized bed, setting the air inlet temperature to be 50-70 ℃ and the air inlet air quantity to be 10-30m 3 And h, drying, sampling when the temperature of the material reaches 40-60 ℃, measuring the moisture, and controlling the moisture to be less than or equal to 2.0%.
(3) Dry granulation: the dried granules were subjected to dry granulation by a U5 granulator, which was sieved with a 1.5mm round sieve at 1000 rpm.
(4) Non-lubrication mixing:
crushing fumaric acid by a crusher, sieving with a 30-mesh sieve, and taking the fumaric acid below the 30-mesh sieve for later use.
A hopper mixer is arranged according to requirements, the medicine-containing particles after dry size stabilization and the auxiliary materials except the magnesium stearate are arranged in the hopper mixer for mixing, the rotating speed is set to be 15rpm, and the mixing is carried out for 15 min.
(5) Total mixing:
sieving magnesium stearate with 40 mesh sieve, adding into hopper mixer, setting mixing speed at 15rpm for 5min, and starting equipment for mixing.
(6) Tabletting: setting the tabletting speed of a tabletting machine to be 0.96-1.44 ten thousand tablets per hour, and controlling the hardness of the tablet core to be 10-15 kg.
(7) Coating: preparing coating liquid, setting the air inlet temperature of a coating machine to be 50-70 ℃, and controlling the core temperature to be 40-55 ℃ in the coating process. The target weight is increased by 3 percent, and the weight increase control range is 2 to 4 percent.
Comparative example 2: piparix tablet without water-soluble acid
Batch production: 500 pieces of batch number: 200522-6
Note: removed during processing.
(1) And (3) high-shear wet granulation:
hydroxypropyl methylcellulose E5 with the prescription amount of 0.64 percent is added into purified water while stirring to prepare a solution with the concentration of 3.5 percent (w/w) for standby.
Placing the piperacillin, the internal microcrystalline cellulose PH102 and the internal crospovidone XL into a wet mixing granulator, setting the stirring speed to be 250rpm and the cutter speed to be 1000rpm, premixing for 5min, setting the stirring speed to be 250rpm and the cutter speed to be 1000rpm after premixing, adding the binder solution under stirring, and granulating for 5 min. After the completion of granulation, wet granulation was performed.
(2) Fluidized bed particle coating:
hydroxypropyl methylcellulose E5 with the prescription amount of 1.28% is added into purified water while stirring to prepare a solution with the concentration of 5% (w/w) for later use.
Adding the wet particles into a fluidized bed, setting the air inlet temperature to be 50-70 ℃ and the air inlet quantity to be 10-30m 3 Spraying HPMC solution into the granules at an atomization pressure of 0.5-1.0 bar, controlling the temperature of the material to be 20-35 ℃ in the granulating process, drying after spraying, sampling when the temperature of the material reaches 40-60 ℃ to measure the moisture, and controlling the moisture to be less than or equal to 2.0%.
(3) Dry granulation: the dried granules were subjected to dry granulation by a U5 granulator, and sieved through a 1.5mm round sieve at 1000 rpm.
(4) Non-lubricated blend 1:
and (3) installing a hopper mixer as required, placing other additional auxiliary materials except the magnesium stearate into the hopper mixer, mixing, setting the rotating speed to be 15rpm, and mixing for 5 min. Sieving the materials by a U5 granulator, wherein the sieve mesh is a round hole sieve with the aperture of 1.2mm, and the rotating speed is 500 +/-50 rpm.
(5) Non-lubricated blend 2:
and (3) adding the non-lubricated mixed material 1 and the dry and whole granules containing the medicine into a hopper mixer for mixing, setting the mixing rotation speed to be 15rpm, mixing for 15min, and starting equipment for mixing.
(6) Total mixing: and (3) sieving the magnesium stearate with a 40-mesh sieve, adding the sieved magnesium stearate into a hopper mixer, setting the mixing speed to be 15rpm, mixing for 5min, and starting equipment for mixing.
(7) Tabletting: setting the tabletting speed of a tabletting machine to be 0.96-1.44 ten thousand tablets per hour, and controlling the hardness of the tablet core to be 10-15 kg.
(8) Coating: preparing coating liquid, setting the air inlet temperature of a coating machine to be 50-70 ℃, and controlling the core temperature to be 40-55 ℃ in the coating process. The target weight is increased by 3 percent, and the weight increase control range is 2 to 4 percent.
Examples of the experiments
(1) Dissolution determination
According to the dissolution and release determination method (second method of 0931 of the four-part general rules of the 2020 edition of Chinese pharmacopoeia).
Wherein the pibaixi reference substance is 99.7 percent of pibaixi, and is produced by Shandong Anhong pharmaceutical Co.
Dissolution conditions: using 500ml of pH6.5 buffer solution (0.68 g of potassium dihydrogen phosphate, 15.2ml of 0.1mol/L sodium hydroxide solution and diluted to 100ml with water) as dissolution medium, rotating at 50rpm, and taking 5ml of solution (automatic dissolution instrument, automatic sampling instrument for rinsing with volume not less than 5ml) and simultaneously supplementing 5ml of solution at 10, 15, 20, 30 and 45 minutes according to the method.
Test solution: precisely measuring 1ml of the dissolution liquid, placing in a 10ml measuring flask, diluting to scale with dissolution medium, and shaking.
Control solution: precisely weighing about 25mg of the pibesilide reference substance, placing the pibesilide reference substance in a 100ml measuring flask, dissolving and diluting the pibesilide reference substance to the scale by using a 0.1mol/L hydrochloric acid solution, shaking up, precisely weighing 5ml, placing the pibesilide reference substance in a 50ml measuring flask, diluting the pibesilide reference substance to the scale by using a dissolution medium, and shaking up to obtain the pibesilide.
System applicability requirements: the relative standard deviation of the control solution measured continuously should not exceed 2.0%.
The determination method comprises the following steps: taking the test solution and the reference solution, measuring absorbance at 288nm wavelength under ultraviolet-visible spectrophotometry (0401 in China pharmacopoeia 2020 edition), and calculating the dissolution amount of each tablet.
The comparative data of dissolution behavior from the articles of examples 1-5 to the commercial articles are shown in Table 1; the comparative data of dissolution behavior from the preparation in comparative example 2 with the commercial product are shown in table 2.
TABLE 1 comparison of dissolution behavior from the preparations of examples 1 to 5 with commercially available products
Table 2 dissolution behavior from the product in comparative example 2 was compared with a commercial product
(2) Stability of
The samples prepared in examples 1-4 and comparative example 1 are packaged by polyamide/aluminum/polyvinyl chloride cold stamping solid pharmaceutical composite hard sheets and pharmaceutical aluminum foils, and placed under the conditions of 40 ℃ +/-2 ℃ and 75% +/-5% relative humidity for 3 months, the substances related to the samples of examples 1-4 have no obvious change and accord with the standard regulation compared with 0 day, and the substances related to the sample of comparative example 1 have obvious increase compared with 0 day, and the data are shown in Table 3.
Table 3 samples of examples 1-4 and comparative example 1 accelerated 3 month stability data
Claims (10)
1. A pharmaceutical composition containing thujaplicin comprises 10 wt% to 35 wt% of thujaplicin, 3 wt% to 25 wt% of water-soluble acid and a pharmaceutically acceptable carrier, wherein the water-soluble acid is selected from one or more of fumaric acid, citric acid, oxalic acid and vitamin C.
2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable carrier comprises a diluent selected from the group consisting of: one or more of microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, xylitol, magnesium carbonate, calcium hydrogen phosphate and calcium phosphate, wherein the diluent comprises 10 wt% to 80 wt% of the pharmaceutical composition.
3. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable carrier comprises a binder selected from the group consisting of: one or more of povidone, hypromellose, hydroxypropyl cellulose, methylcellulose, and sodium carboxymethylcellulose, the binder comprising 0 wt% to 5 wt% of the pharmaceutical composition.
4. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable carrier comprises a film-forming material selected from the group consisting of: one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene glycol, zein, acrylic resin and sodium carboxymethylcellulose, wherein the film-forming material accounts for 0-10 wt% of the pharmaceutical composition.
5. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable carrier comprises a lubricant selected from the group consisting of: magnesium stearate, calcium stearate, zinc stearate and sodium stearyl fumarate, wherein the lubricant accounts for 0.5 to 10 wt% of the pharmaceutical composition.
6. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable carrier comprises a glidant selected from silicon dioxide, the glidant comprises 0 wt% to 5 wt% of the pharmaceutical composition; the pharmaceutically acceptable carrier further comprises a disintegrant selected from the group consisting of: crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose and sodium starch glycolate, wherein the disintegrant accounts for 3 to 15 wt% of the pharmaceutical composition.
7. The pharmaceutical composition according to claim 1, in the form of a tablet, preferably a single-layer tablet or a double-layer tablet.
8. The pharmaceutical composition according to any one of claims 1 to 7, wherein in a dissolution medium of 500ml of pH6.5 phosphate buffer at 37 ℃ the following are dissolved:
(a) not less than 30% pipabriside in 15 minutes; or
(b) Not less than 35% pipabriside in 30 minutes; or
(c) Not less than 40% pipabriside in 45 minutes; or
(d) Any two or three of (a), (b) and (c) are satisfied simultaneously.
9. The pharmaceutical composition according to any one of claims 1 to 7, which shows a total related substance amount of less than 0.5% of thujaplicin when stored for 3 months at 40 ℃ and 75% RH.
10. A process for the preparation of a pharmaceutical composition containing thuja cily according to claim 1, comprising the steps of:
(1) carrying out primary granulation on the piparicin and a pharmaceutically acceptable carrier by adopting high-shear wet granulation or fluidized bed one-step granulation;
(2) coating and drying the granules obtained in the step (1) by using an aqueous solution containing a film-forming material to obtain dry granules, wherein the film-forming material is selected from the following materials: one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene glycol, zein, acrylic resin and sodium carboxymethyl cellulose;
(3) and (3) uniformly mixing the dry granules obtained in the step (2) with an additional auxiliary material containing water-soluble acid, and tabletting to prepare the medicinal composition containing the piperazixil.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110239862.XA CN115006400A (en) | 2021-03-04 | 2021-03-04 | Pharmaceutical composition containing piperazixil and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110239862.XA CN115006400A (en) | 2021-03-04 | 2021-03-04 | Pharmaceutical composition containing piperazixil and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115006400A true CN115006400A (en) | 2022-09-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110239862.XA Pending CN115006400A (en) | 2021-03-04 | 2021-03-04 | Pharmaceutical composition containing piperazixil and preparation method thereof |
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| Country | Link |
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| CN (1) | CN115006400A (en) |
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2021
- 2021-03-04 CN CN202110239862.XA patent/CN115006400A/en active Pending
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