CN115957189A - Ambrisentan preparation and preparation method thereof - Google Patents
Ambrisentan preparation and preparation method thereof Download PDFInfo
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Abstract
The invention provides an ambrisentan preparation and a preparation method thereof, and belongs to the field of pharmaceutical preparations. The invention adopts the solid dispersion technology to prepare the active ingredient and the carrier into the solid dispersion, is beneficial to the dissolution and absorption of the medicine, obviously improves the dissolution rate and the bioavailability of the ambrisentan preparation, is suitable for large-scale industrial production, and has wide application prospect.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to an ambrisentan preparation and a preparation method thereof.
Background
Pulmonary Arterial Hypertension (PAH) is called "cancer in cardiovascular disease", and the disease mechanism and clinical typing are complex and the causative factors are diverse. The early PAH is characterized in that the dysfunction of the pulmonary vascular endothelium causes vasoconstriction, thrombosis and cell hyperproliferation, and symptoms such as tachypnea, dizziness, chest distress, syncope, edema of lower limbs and the like can be clinically seen; as PAH progresses further, the right ventricle of the patient fails and even dies due to a significant increase in Pulmonary Vascular Resistance (PVR) and a sustained rise in Pulmonary Arterial Pressure (PAP).
According to the difference of pharmacological mechanism, the anti-PAH drugs mainly comprise phosphodiesterase-5 inhibitor, endothelial receptor antagonist, cyclic prostate receptor agonist, nuclear factor kappa B inhibitor and the like, and since 1995, with the successive marketing of some therapeutic drugs, the survival rate of patients is improved, and the prognosis is improved. Wherein, the endothelial receptor antagonist is used as a main therapeutic drug, expands pulmonary vessels by preventing the combination of endothelin-1 and endothelin receptors, and is mainly used for treating connective tissue disease related PAH (CTD-PAH), embolic PAH and the like.
Ambrisentan was first an endothelin receptor antagonist developed by BASF Pharma. The drug was approved by FDA at 6/15 of 2007 and CFDA at 19/10 of 2010 and was orally administered for the treatment of pulmonary hypertension. The chemical name of ambrisentan is (+) - (2S) -2- [ (4, 6-dimethylpyrimidin-2-yl) oxy ] -3-methoxy-3, 3-diphenyl propionic acid, and the structure of the ambrisentan is shown as the formula (I):
the medicine has the advantages of convenient administration, obvious curative effect, good safety and the like, but the problems of uneven content, low dissolution rate, large dissolution rate difference among batches and the like can occur in the actual production due to poor water solubility, and finally the slow absorption of the medicine in vivo can be caused, the bioavailability in vivo after oral administration is limited, and the safety, the effectiveness and the quality controllability of the medicine are further influenced.
For poorly soluble drugs, dissolution, which is the rate-limiting process, is often the most important factor affecting their bioavailability. Dissolution can be increased by increasing the drug saturation solubility by solid dispersion techniques. The solid dispersion is a dispersion system in which a drug is highly dispersed in a solid carrier material in a molecular, colloidal, microcrystalline or amorphous state. The carrier in the system inhibits the aggregation tendency of particles which are highly dispersed by a solid dispersion method, and the surface area is enlarged; in addition, the carrier can promote the dissolution of the medicine, so that the solid dispersion can greatly improve the solubility of the medicine, improve the dissolution rate of the medicine and promote the absorption and bioavailability of the medicine.
The ambrisentan solid dispersion and the preparation thereof are prepared through a large number of researches, and the in vitro dissolution rate, the accumulated dissolution rate and the in vivo bioavailability of active ingredients are effectively improved.
Disclosure of Invention
The invention aims to provide a solid dispersion for improving dissolution rate of ambrisentan and a preparation method thereof, a preparation containing the solid dispersion and a preparation method thereof, and the prepared ambrisentan preparation has improved dissolution rate and bioavailability and is more suitable for clinical application of medicines.
The purpose of the invention is realized by the following technical scheme:
the invention provides an ambrisentan solid dispersion, which comprises ambrisentan and a carrier;
the carrier is one or more of polyvinylpyrrolidone, copovidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate, and preferably one or more of polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, acrylic resin and hydroxypropyl methylcellulose acetate succinate;
the weight ratio of ambrisentan to carrier is 1;
the solid dispersion is prepared by a hot-melt extrusion method, a spray drying method, a grinding method, a melting method or a solvent method, and is preferably prepared by the hot-melt extrusion method or the spray drying method;
when the solid dispersion is prepared by adopting a hot-melt extrusion method, the method comprises the following steps:
(1) Uniformly mixing ambrisentan and a carrier;
(2) Adding the mixture obtained in the step (1) into a hot-melt extruder, and carrying out melting, extrusion and cooling to obtain a solid dispersion;
optionally, ambrisentan and carrier can be pretreated before mixing in step (1), for example, sieved by a 20-60 mesh sieve, preferably a 40 mesh sieve;
optionally, the solid dispersion obtained in step (2) may be further sieved, such as 60-100 mesh sieve, preferably 80 mesh sieve;
the hot melting temperature set by the hot melting extruder in the step (2) is 100-250 ℃, and preferably 150-200 ℃; the rotating speed of the screw is 10-50 rpm/min, preferably 30rpm/min;
when the solid dispersion is prepared by adopting a spray drying method, the method comprises the following steps:
(1) Dissolving ambrisentan and a carrier in an organic solvent;
(2) Carrying out spray drying on the solvent obtained in the step (1), and collecting a solid dispersion;
the organic solvent is one or more of dichloromethane, acetone, methanol, ethanol, isopropanol, tetrahydrofuran and ethyl acetate, and preferably ethanol;
wherein, the spray dryer used in the step (2) needs to set proper parameters, such as the air inlet temperature of 100 ℃, the air volume of 100 percent and the pump speed of 40rpm/min;
optionally, the solid dispersion obtained in step (2) may be further sieved, such as 60-100 mesh sieve, preferably 80 mesh sieve;
the invention also provides a pharmaceutical composition containing the ambrisentan solid dispersion, which can be tablets, capsules, powder, granules, syrup or other liquid preparations;
in the present invention, one or more pharmaceutical excipients may be optionally added during the preparation of the composition comprising the solid dispersion to improve the flowability and other physical properties of the solid dispersion;
for example, the pharmaceutical composition may include, but is not limited to, one or more of diluents, binders, disintegrants, lubricants;
the weight percentage of the ambrisentan dispersion is 5-60%, preferably 10-40% based on the total weight of the prescription;
the diluent can be one or more of lactose, starch, corn starch, pregelatinized starch, microcrystalline cellulose, mannitol, sucrose, calcium hydrogen phosphate and calcium dihydrogen phosphate, preferably one or more of lactose, pregelatinized starch and microcrystalline cellulose; based on the total weight of the prescription, the weight percentage of the diluent is 1 to 90 percent, preferably 10 to 80 percent;
the adhesive can be one or more of polyvinylpyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, starch syrup, potato starch, partially pregelatinized starch and gelatin, and preferably is one or more of polyvinylpyrrolidone, copovidone, hydroxypropyl cellulose and hydroxypropyl methylcellulose; the weight percentage of the adhesive is 1-15%, preferably 1-10% based on the total weight of the prescription;
the disintegrating agent can be one or more of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose, preferably one or more of crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose; based on the total weight of the prescription, the weight percentage of the disintegrating agent is 0.5 to 15 percent, preferably 1 to 10 percent;
the lubricant can be one or more of talcum powder, stearic acid, magnesium stearate, colloidal silicon dioxide, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl behenate, polyethylene glycol and sodium lauryl sulfate, and preferably one or more of talcum powder, magnesium stearate, colloidal silicon dioxide and sodium stearyl fumarate; the weight percentage of the lubricant is 0 to 5 percent, preferably 0 to 3 percent, based on the total weight of the prescription;
the invention also provides a preparation method of the ambrisentan pharmaceutical composition, which comprises the following steps:
(1) Preparing the solid dispersion and other auxiliary materials into particles or preparing direct-compression powder;
(2) Tabletting or capsule filling the granules or the direct-compression powder obtained in the step (1), and optionally coating when tabletting is selected;
wherein, when the granules are prepared in the step (1), optionally, the steps of adding a wetting agent, sieving, wetting, finishing, drying, sieving, drying, finishing and the like can also be included; the sieving is to sieve by 20-40 meshes, preferably 24 meshes; the wetting agent can be purified water and ethanol water solution, and preferably purified water;
the tabletting weight specification in step (2) is selected from various specifications, for example, it may be 60mg, 80mg, 100mg, 120mg, 200mg, 240mg, preferably 100mg, 120mg, 200mg; the capsule fill weight specification is chosen from a number of specifications, for example, 60mg, 80mg, 100mg, 120mg, 200mg, 240mg, preferably 100mg, 120mg, 200mg.
The invention adopts a solid dispersion technology, the ambrisentan is prepared into a solid dispersion and then is converted into an amorphous state, the dissolution and absorption of the medicine are facilitated, the dissolution rate and the bioavailability of the prepared ambrisentan preparation are obviously improved, the dissolution difference among batches is small, and the preparation method is suitable for large-scale industrial production of the ambrisentan preparation and has wide prospects.
Drawings
FIG. 1 comparison of XRD spectra of Ambrisentan (API), HPMC and ambrisentan solid dispersion of example 4
Detailed Description
To further illustrate the present invention, the present invention will be specifically described with reference to specific examples, but the scope of the present invention is not limited to the specific examples.
Example 1
Preparing a solid dispersion: the hot melting temperature of the Haake micro-mixing rheometer is set to be 150-200 ℃, and the rotating speed of a screw is set to be 30rpm/min. Uniformly mixing ambrisentan and hydroxypropyl methylcellulose acetate succinate by a 40-mesh screen, placing the mixture in a feeding hopper, extruding the material in a strip shape through a head die hole, cooling at room temperature, crushing, and sieving by a 80-mesh screen to obtain an ambrisentan solid dispersion for later use.
| Prescription composition | Type number | Single dose of mg/granule | In proportion% |
| Ambrisentan solid dispersion | / | 30.0 | 25 |
| Microcrystalline cellulose | PH 101 | 42.0 | 35 |
| Lactose | 200 mesh | 36.0 | 30.0 |
| Polyvinylpyrrolidone | K30 | 3.6 | 3.0 |
| Croscarmellose sodium | / | 7.2 | 6.0 |
| Stearic acid sodium fumarate | / | 0.6 | 0.5 |
| Colloidal silica | / | 0.6 | 0.5 |
| Total weight of | / | 120 | 100 |
Preparing particles: weighing the ambrisentan solid dispersoid, microcrystalline cellulose, lactose, polyvinylpyrrolidone and croscarmellose sodium according to the formula amount, uniformly mixing, adding a proper amount of purified water as a wetting agent to prepare a soft material, sieving by a 24-mesh sieve for wet granulation, drying in an oven at 60 +/-5 ℃, sieving by the 24-mesh sieve for dry granulation, adding sodium stearyl fumarate and colloidal silicon dioxide, and uniformly mixing for later use.
Capsule tankAssembling: filling the above granules with 3 # The weight of each capsule is 120mg.
Example 2
Preparing a solid dispersion: the hot melting temperature of the Haake micro-mixing rheometer is set to be 150-200 ℃, and the rotating speed of a screw is set to be 30rpm/min. Uniformly mixing ambrisentan and hydroxypropyl methylcellulose acetate succinate through a 40-mesh screen, placing the mixture into a charging hopper, extruding the material in a strip shape through a die hole of a machine head, cooling at room temperature, crushing, and then sieving through a 80-mesh screen to obtain an ambrisentan solid dispersion for later use.
| Prescription composition | Model number | Single dose of mg/granule | In proportion% |
| Ambrisentan solid dispersion | / | 40.0 | 33.3 |
| Microcrystalline cellulose | PH 101 | 32.0 | 26.7 |
| Lactose | 200 mesh | 36.0 | 30.0 |
| Polyvinylpyrrolidone | K30 | 3.6 | 3.0 |
| Croscarmellose sodium | / | 7.2 | 6.0 |
| Stearyl fumarate sodium salt | / | 0.6 | 0.5 |
| Colloidal silica | / | 0.6 | 0.5 |
| Total weight of | / | 120 | 100 |
Preparing particles: weighing the ambrisentan solid dispersoid, microcrystalline cellulose, lactose, polyvinylpyrrolidone and croscarmellose sodium according to the formula amount, uniformly mixing, adding a proper amount of purified water as a wetting agent, preparing a soft material, sieving by a 24-mesh sieve for wet granulation, drying in an oven at 60 +/-5 ℃, sieving by the 24-mesh sieve for dry granulation, adding sodium stearyl fumarate and colloidal silicon dioxide, and uniformly mixing for later use.
And (3) capsule filling: filling 3 the above granules # The weight of the content of each capsule is 120mg.
Example 3
Preparing a solid dispersion: the hot melting temperature of the Haake micro-mixing rheometer is set to be 150-200 ℃, and the rotating speed of a screw is set to be 30rpm/min. Uniformly mixing ambrisentan and hydroxypropyl methylcellulose acetate succinate through a 40-mesh screen, placing the mixture into a charging hopper, extruding the material in a strip shape through a die hole of a machine head, cooling at room temperature, crushing, and then sieving through a 80-mesh screen to obtain an ambrisentan solid dispersion for later use.
| Prescription composition | Type number | Single dose of mg/granule | In proportion% |
| Ambrisentan solid dispersion | / | 12.0 | 10.0 |
| Microcrystalline cellulose | PH 101 | 60.0 | 50.0 |
| Lactose | 200 mesh | 36.0 | 30.0 |
| Polyvinylpyrrolidone | K30 | 3.6 | 3.0 |
| Croscarmellose sodium | / | 7.2 | 6.0 |
| Stearic acid sodium fumarate | / | 0.6 | 0.5 |
| Colloidal silica | / | 0.6 | 0.5 |
| Total weight of | / | 120 | / |
Preparing particles: weighing the ambrisentan solid dispersoid, microcrystalline cellulose, lactose, polyvinylpyrrolidone and croscarmellose sodium according to the formula amount, uniformly mixing, adding a proper amount of purified water as a wetting agent, preparing a soft material, sieving by a 24-mesh sieve, carrying out wet granulation, drying in an oven at 60 +/-5 ℃, sieving by the 24-mesh sieve, carrying out dry granulation, adding sodium stearyl fumarate and colloidal silicon dioxide, and uniformly mixing for later use.
And (3) capsule filling: filling 3 the above granules # The weight of the content of each capsule is 120mg.
Example 4
Preparing a solid dispersion: weighing 10.0g of ambrisentan and 10.0g of hydroxypropyl methylcellulose, dissolving in 500g of ethanol, and stirring until the ambrisentan and the hydroxypropyl methylcellulose are completely dissolved for later use. A Swiss step qi Mini Spray Dryer B-290 small Spray Dryer is adopted, the air inlet temperature is set to be 100 ℃, the air volume is 100%, after the air inlet temperature reaches a set value, a peristaltic pump is started, the pump speed is set to be 40rpm/min, the ambrisentan solid dispersion is collected and obtained, and the ambrisentan solid dispersion is screened by a 80-mesh sieve for later use.
Preparing direct-pressing powder: weighing the ambrisentan solid dispersoid, microcrystalline cellulose, pregelatinized starch, copovidone and croscarmellose sodium according to the formula amount, uniformly mixing, adding talcum powder and magnesium stearate, and mixing for later use.
Tabletting: the powder was tabletted using a 6mm diameter punch with a dimple round shape, each tablet weighing 100mg.
Coating: preparing gastric-soluble coating solution with the concentration of 5-12%, putting the tablet core into a coating pan, starting a coating machine to preheat, controlling the air inlet temperature at 60 +/-10 ℃ and the tablet bed temperature at 40 +/-5 ℃, spraying the prepared film coating solution by a spray gun, and increasing the weight to 3-5%.
Example 5
Preparing a solid dispersion: weighing 10.0g of ambrisentan and 10.0g of hydroxypropyl cellulose, dissolving in 500g of ethanol, and stirring until the ambrisentan and the hydroxypropyl cellulose are completely dissolved for later use. A Swiss stephen Mini Spray Dryer B-290 small Spray Dryer is adopted, the air inlet temperature is set to be 100 ℃, the air volume is 100%, after the air inlet temperature reaches a set value, a peristaltic pump is started, the pump speed is set to be 40rpm/min, the ambrisentan solid dispersion is collected and obtained, and the ambrisentan solid dispersion is sieved by a 80-mesh sieve for later use.
| Prescription composition | Model number | Single dose of mg/tablet | In proportion% |
| Ambrisentan solid dispersion | / | 20.0 | 20.0 |
| Microcrystalline cellulose | PH101 | 40.0 | 40.0 |
| Pregelatinized starch | Starch1500 | 30.5 | 30.5 |
| Copovidone | VA64 | 4.0 | 4.0 |
| Croscarmellose sodium | / | 4.0 | 4.0 |
| Talcum powder | / | 0.5 | 0.5 |
| Magnesium stearate | / | 1.0 | 1.0 |
| Total weight of | / | 100 | 100 |
Preparing direct-pressing powder: weighing the ambrisentan solid dispersoid, microcrystalline cellulose, pregelatinized starch, copovidone and croscarmellose sodium according to the formula amount, uniformly mixing, adding talcum powder and magnesium stearate, and mixing for later use.
Tabletting: the powder was tabletted using a 6mm phi dimpled round punch, each tablet weighing 100mg.
Coating: preparing gastric-soluble coating solution with the concentration of 5-12%, putting the tablet core into a coating pan, starting a coating machine to preheat, controlling the air inlet temperature at 60 +/-10 ℃ and the tablet bed temperature at 40 +/-5 ℃, spraying the prepared film coating solution by a spray gun, and increasing the weight to 3-5%.
Example 6
Preparing a solid dispersion: weighing 10.0g of ambrisentan and 40.0g of hydroxypropyl methylcellulose, dissolving in 500g of ethanol, and stirring until the ambrisentan and the hydroxypropyl methylcellulose are completely dissolved for later use. A Swiss step qi Mini Spray Dryer B-290 small Spray Dryer is adopted, the air inlet temperature is set to be 100 ℃, the air volume is 100%, after the air inlet temperature reaches a set value, a peristaltic pump is started, the pump speed is set to be 40rpm/min, the ambrisentan solid dispersion is collected and obtained, and the ambrisentan solid dispersion is screened by a 80-mesh sieve for later use.
| Prescription composition | Model number | Single dose of mg/granule | In proportion% |
| Ambrisentan solid dispersion | / | 50.0 | 50.0 |
| Microcrystalline cellulose | PH 101 | 10.0 | 10.0 |
| Pregelatinized starch | Starch1500 | 30.5 | 30.5 |
| Copovidone | VA64 | 4.0 | 4.0 |
| Croscarmellose sodium | / | 4.0 | 4.0 |
| Talcum powder | / | 0.5 | 0.5 |
| Magnesium stearate | / | 1.0 | 1.0 |
| Total weight of | / | 100 | 100 |
Preparing direct-pressing powder: weighing the ambrisentan solid dispersoid, microcrystalline cellulose, pregelatinized starch, copovidone and croscarmellose sodium according to the formula amount, uniformly mixing, adding talcum powder and magnesium stearate, and mixing for later use.
Tabletting: the powder was tabletted using a 6mm diameter punch with a dimple round shape, each tablet weighing 100mg.
Coating: preparing gastric-soluble coating solution with the concentration of 5-12%, putting the tablet core into a coating pan, starting a coating machine to preheat, controlling the air inlet temperature at 60 +/-10 ℃ and the tablet bed temperature at 40 +/-5 ℃, spraying the prepared film coating solution by a spray gun, and increasing the weight to 3-5%.
Comparative example 1
| Prescription composition | Model number | Single dose of mg/tablet | In proportion% |
| Ambrisentan | / | 10.0 | 10.0 |
| Microcrystalline cellulose | PH 101 | 50.0 | 50.0 |
| Pregelatinized starch | Starch1500 | 30.5 | 30.5 |
| Co-polyvidone | VA64 | 4.0 | 4.0 |
| Croscarmellose sodium | / | 4.0 | 4.0 |
| Talcum powder | / | 0.5 | 0.5 |
| Magnesium stearate | / | 1.0 | 1.0 |
| Total weight of | / | 100 | 100 |
Preparing direct-pressing powder: weighing ambrisentan, microcrystalline cellulose, pregelatinized starch, copovidone and croscarmellose sodium according to the formula amount, uniformly mixing, adding talcum powder and magnesium stearate, and mixing for later use.
Tabletting: the powder was tabletted using a 6mm diameter punch with a dimple round shape, each tablet weighing 100mg.
Coating: preparing gastric-soluble coating liquid with the concentration of 5-12%, putting the tablet core into a coating pan, starting a coating machine to preheat, controlling the air inlet temperature at 60 +/-10 ℃ and the tablet bed temperature at 40 +/-5 ℃, spraying the prepared film coating liquid by a spray gun, and increasing the weight to 3-5%.
Test example 1: drug in vitro dissolution study
Dissolution tests were performed on the samples prepared in examples 1 to 6 and comparative example 1. Wherein the dissolution rate adopts the second method (paddle method) of 0931 dissolution rate and release rate determination method of the four-part general rule in the 2020 edition of Chinese pharmacopoeia, the dissolution medium is phosphate buffer solution with pH7.4, 900ml, rotation speed of 50rpm/min, and sampling time points are 5, 10, 15, 30, 45, and 60min.
Dissolution results were as follows:
as can be seen by comparing the dissolution data of examples 1-6 with that of comparative example 1, the solid dispersion preparation containing ambrisentan prepared by the hot-melt extrusion technology and the spray drying technology can effectively improve the in vitro dissolution rate and dissolution rate of the drug, thereby improving the bioavailability of the drug.
Among them, the dissolution results of examples 1, 2, 4 and 5 are excellent, and the dissolution results of examples 1 and 4 are excellent.
Test example 2: pharmacokinetic testing
Pharmacokinetic studies in rats were performed using the samples prepared in example 4 and comparative example 1.
12 male Wistar rats (220-260 g) were used and animals were randomly divided into two groups of 6 animals each. Rats were fasted overnight before the experiment, but allowed free access to water. The tablets prepared in example 4 and comparative example 1 were ground, diluted with water to a concentration of 1mg/ml (in terms of ambrisentan) and orally administered to rats at a dose of 10mg/kg body weight. Plasma was separated by centrifugation at 3000rpm for 10min at 0.5ml of retroantral venous plexus blood at 1, 2, 4,6, 8, 12 hours, treated with a small amount of acetonitrile and repeated centrifugation at 3000rpm for 10min. Appropriate amounts of plasma were mixed with the mobile phase and analyzed using high performance liquid chromatography. And pharmacokinetic parameters were calculated in a non-compartmental model using the software Kinetica (TM).
Pharmacokinetic parameters of drug peak concentration C in rats of example 4 and comparative example 1 were investigated max Time to peak T max Terminal elimination half-life t 1/2 The average residence time MRT and the area under the curve AUC of the drug time are shown in the table below.
| Pharmacokinetic parameters | Example 4 | Comparative example 1 |
| C max (μg/mL) | 7.14 | 3.57 |
| T max (h) | 2 | 2 |
| t 1/2 | 4.55 | 2.74 |
| MRT(h) | 8.43 | 5.19 |
| AUC 0→t (μg/mL*h) | 39.25 | 18.51 |
It can be seen that the sample containing the solid dispersion prepared in example 4 was rapidly absorbed, the blood concentration reached a maximum after 2 hours of administration, and the bioavailability calculated after 12 hours of administration was significantly higher than that of comparative example 1, indicating that the conversion of the poorly soluble drug into an amorphous form after preparing a solid dispersion was helpful for dissolution and absorption of the drug.
Claims (10)
1. An ambrisentan solid dispersion, which is characterized by comprising ambrisentan and a carrier;
optionally, the carrier is one or more of polyvinylpyrrolidone, copovidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate, and preferably one or more of polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, acrylic resin and hydroxypropyl methylcellulose acetate succinate.
2. An ambrisentan solid dispersion according to claim 1, characterized in that the weight ratio of ambrisentan to carrier is 1.
3. A method for preparing the ambrisentan solid dispersion according to any one of claims 1-2, characterized in that the ambrisentan solid dispersion is prepared by a hot-melt extrusion method, a spray drying method, a grinding method, a melting method or a solvent method, preferably by a hot-melt extrusion method or a spray drying method.
4. The method of claim 3, comprising the steps of:
(1) Uniformly mixing ambrisentan and a carrier;
(2) And (2) adding the mixture obtained in the step (1) into a hot-melt extruder, and carrying out melting, extrusion and cooling to obtain the solid dispersion.
5. The method of claim 3, comprising the steps of:
(1) Dissolving ambrisentan and a carrier in an organic solvent;
(2) And (2) carrying out spray drying on the solvent obtained in the step (1), collecting a solid dispersion, and optionally, further sieving.
6. The preparation method according to claim 5, wherein the organic solvent is one or more of dichloromethane, acetone, methanol, ethanol, isopropanol, tetrahydrofuran and ethyl acetate, preferably ethanol.
7. An ambrisentan pharmaceutical composition comprising the ambrisentan solid dispersion of any one of claims 1-2;
optionally, the dosage form of the ambrisentan pharmaceutical composition is tablets, capsules, powder, granules, syrup or other liquid preparations.
8. The ambrisentan pharmaceutical composition according to claim 7, further comprising a pharmaceutically acceptable excipient; the pharmaceutically acceptable auxiliary materials include but are not limited to one or more of diluents, binders, disintegrants and lubricants.
9. An ambrisentan pharmaceutical composition according to claim 8, characterized in that the weight percentage of the ambrisentan dispersion is 5-60%, preferably 10-40% by total weight of the prescription;
and/or the presence of a gas in the atmosphere,
the diluent is one or more of lactose, starch, corn starch, pregelatinized starch, microcrystalline cellulose, mannitol, sucrose, calcium hydrophosphate and monocalcium phosphate, and is preferably one or more of lactose, pregelatinized starch and microcrystalline cellulose; based on the total weight of the prescription, the weight percentage of the diluent is 1 to 90 percent, preferably 10 to 80 percent;
and/or the presence of a gas in the gas,
the adhesive is one or more of polyvinylpyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, starch syrup, potato starch, partially pregelatinized starch and gelatin, preferably one or more of polyvinylpyrrolidone, copovidone, hydroxypropyl cellulose and hydroxypropyl methylcellulose; the weight percentage of the adhesive is 1-15%, preferably 1-10% based on the total weight of the prescription;
and/or the presence of a gas in the gas,
the disintegrating agent is one or more of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose, preferably one or more of crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose; based on the total weight of the prescription, the weight percentage of the disintegrating agent is 0.5 to 15 percent, preferably 1 to 10 percent;
and/or
The lubricant is one or more of talcum powder, stearic acid, magnesium stearate, colloidal silicon dioxide, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl behenate, polyethylene glycol and sodium lauryl sulfate, and preferably one or more of talcum powder, magnesium stearate, colloidal silicon dioxide and sodium stearyl fumarate; the weight percentage of the lubricant is 0 to 5 percent, preferably 0 to 3 percent based on the total weight of the prescription.
10. A process for preparing an ambrisentan pharmaceutical composition according to any one of claims 7-9, comprising the steps of:
(1) Preparing the solid dispersion and other auxiliary materials into particles or preparing direct-pressure powder;
(2) Tabletting or encapsulating the granules or powder obtained in step (1), optionally including a coating step when tabletting is selected.
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| Country | Link |
|---|---|
| CN (1) | CN115957189A (en) |
-
2021
- 2021-10-08 CN CN202111171701.8A patent/CN115957189A/en active Pending
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