CN115177594B - Acetinib pharmaceutical preparation and preparation method thereof - Google Patents
Acetinib pharmaceutical preparation and preparation method thereof Download PDFInfo
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- CN115177594B CN115177594B CN202210786731.8A CN202210786731A CN115177594B CN 115177594 B CN115177594 B CN 115177594B CN 202210786731 A CN202210786731 A CN 202210786731A CN 115177594 B CN115177594 B CN 115177594B
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- acitinib
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- acytinib
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- pharmaceutical formulation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to an acitinib pharmaceutical preparation, which comprises acitinib, a stabilizer, a filler and a solubilizer. The acitinib medicinal preparation has the advantages of good quality, high stability, good dissolution rate, simple preparation method and controllable quality.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to an acitinib pharmaceutical preparation and a preparation method thereof.
Background
Acxitinib (Axitinib) is a multi-target tyrosine kinase inhibitor developed by Pfizer company, can inhibit vascular endothelial growth factor receptors VEGFR1, VEGFR2, VEGFR3, platelet derived growth factor receptor and c-KIT, is used for other systems to treat ineffective advanced renal cancer, and is approved by FDA for marketing on day 1 and 27 of 2012. The currently marketed product of acitinib is a tablet.
Acetinib is white powder, has a melting point of 218.4 ℃, is slightly soluble in polyethylene glycol 400, is slightly soluble in methanol or ethanol, is extremely slightly soluble in acetonitrile, is almost insoluble in water, has a solubility of 0.8mg/ml in a hydrochloric acid solution of pH1.2 at 20 ℃, and has a solubility of 0.2 mug/ml in a phosphate buffer solution of pH6.8, and is a typical pH dependent drug. Meanwhile, the acytinib is unstable to light and is easy to degrade in the presence of heat or water, so that related substances of the preparation are increased. The wet granulation tabletting method has the advantages that the preparation process is complex, the time consumption is long, the steps of heating, adding water and the like exist at the same time, and the factors lead the acitinib to be easily degraded in the wet granulation process, so that related substances are increased, and the clinical use safety is affected. The currently marketed acitinib tablets are prepared by a dry granulation tabletting method. The acytinib has extremely low solubility, belongs to insoluble medicines, and is easy to have the problem of unqualified dissolution rate when being pressed into full powder. The prior art has a plurality of ways aiming at the problem of the dissolubility of the acitinib, for example, the Chinese patent application CN107890462A improves the dissolution rate through formula adjustment and main medicine granularity control; the D90 of the Acetinib raw powder in the Chinese patent application CN107961224A is in the range of 15-25 mu m, and meanwhile, a solubilizer is needed to be added, so that the dissolution rate is improved, and the used solubilizer brings certain side effects; the Chinese patent application CN106913547A dissolves the acitinib in glacial acetic acid, mesoporous silicon dioxide is added, the composite of the acitinib and the silicon dioxide is prepared in alkaline solution of sodium hydroxide, and then the composite is mixed with filler, disintegrating agent and the like, and the mixture is granulated, tabletted and the like, and although the medicine is dissolved out rapidly, the technology is complex, and the production cost is increased. Chinese patent CN105769785B discloses an acitinib tablet directly pressed from powder and a preparation method thereof, the particle size of raw material of acitinib is controlled to be less than or equal to 30 μm, preferably, D90 is less than or equal to 12 μm, and the particle size of diluent is also strictly required, and the preparation process is more complex; adding the acitinib into an alcohol hydrochloride solution, and uniformly stirring to obtain a mixed solution in Chinese patent application CN 112999176A; pharmaceutically acceptable auxiliary materials are uniformly mixed, added into an alcaine alcohol solution containing the acitinib, stirred, granulated, dried, then added with a lubricant, mixed and tableted, the same process is complex, and meanwhile, the problems of equipment corrosion and high operation risk degree of hydrochloric acid are required. In summary, in order to solve the problems of the solubility and stability of the acitinib, the prior art has limitations. The inventor obtains the prescription of the drug preparation of the acitinib and the preparation method thereof in the process of researching a large amount of the acitinib for a long time, the process is simple, the dosage of auxiliary materials is small, and the prepared acitinib preparation has extremely high quality and stability, and the safety of medication is increased; meanwhile, compared with the prior art, the water-soluble polyurethane has excellent solubility and is obviously superior to the prior art.
Disclosure of Invention
The invention provides a stable and good-solubility acitinib pharmaceutical preparation and a preparation method thereof, and the technical scheme is as follows:
an acitinib pharmaceutical formulation comprising: acetinib, stabilizers, fillers and solubilizers.
As a preferred embodiment, the filler is mannitol.
As a preferred embodiment, the solubilizing agent is nicotinamide.
As a preferred embodiment, the stabilizer is sodium tartrate.
As a preferred embodiment, the mass fraction of the stabilizer in the acitinib pharmaceutical preparation is 10% -13%.
As a preferred embodiment, the mass fraction of the filler in the acitinib pharmaceutical preparation is 50% -55%.
As a preferred embodiment, the mass fraction of the solubilizer in the acitinib pharmaceutical formulation is 29% to 39.5%.
As a preferred embodiment, the formulation is a tablet containing 1 to 5 micrograms of axitinib per tablet.
As a preferred embodiment, the preparation is a tablet, and each tablet contains 23 micrograms of stabilizer, 105 micrograms of filler and 65 micrograms of solubilizer.
The invention also provides a preparation method of the acitinib pharmaceutical preparation, which comprises the following steps:
(1) Sequentially sieving the acytinib, the stabilizer, the filler and the solubilizer which are dried at 60 ℃ in advance through a 80-mesh sieve;
(2) And (3) fully mixing the raw materials and the auxiliary materials, measuring the content, determining the weight according to the specification, tabletting by a machine, checking and packaging to obtain the finished product.
The formulation adopted by the prescription of the invention can ensure that the dissolution rate of the drug preparation of the acitinib is at an excellent level, simultaneously remarkably improves the stability of the acitinib, and simultaneously meets the requirements of the dissolution rate and the stability of the acitinib preparation.
The specific embodiment is as follows:
for a better understanding of the present invention, the following examples are further illustrative of the present invention, but the contents of the present invention are not limited to the following examples only.
EXAMPLE 1 comparison of the dissolution of Acxitinib with different amounts of nicotinamide and sodium tartrate
The preparation with different proportions is prepared according to the following preparation method:
(1) Sieving the acytinib, mannitol, nicotinamide and sodium tartrate which are dried at 60 ℃ in advance with a 80-mesh sieve;
(2) And (3) fully mixing the raw materials and the auxiliary materials, measuring the content, determining the weight according to the specification, tabletting by a machine, checking and packaging to obtain the finished product.
The dissolution of the tablets was determined at 37℃using 900ml of 0.01M hydrochloric acid solution as dissolution medium and a paddle method at a rotational speed of 50 rpm after 30 minutes.
Formulation formulations and dissolution results are shown in table 1 below, wherein the formulation formulations in each set of examples were ultimately formulated into 1000 tablets.
TABLE 1 comparative test results of the amount of nicotinamide and sodium tartrate
Prescription of prescription | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
Acetinib (g) | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
Mannitol (g) | 105 | 105 | 105 | 105 | 105 | 105 | 105 | 105 |
Nicotinamide (g) | —— | —— | 65 | 65 | 60 | 65 | 68 | 62 |
Sodium tartrate (g) | —— | 23 | —— | 23 | 23 | 20 | 25 | 20 |
Dissolution (%) | 20.1 | 20.4 | 21.2 | 99.8 | 90.3 | 91.2 | 92.0 | 92.4 |
Example 2
Prescription:
acetinib: 1g of
Mannitol: 105g
Nicotinamide: 65g
Sodium tartrate 23g
And (3) manufacturing: 1000 tablets
The preparation method of the acitinib pharmaceutical preparation comprises the following steps:
(1) Sieving the acytinib, mannitol, nicotinamide and sodium tartrate which are dried at 60 ℃ in advance with a 80-mesh sieve;
(2) And (3) fully mixing the raw materials and the auxiliary materials, measuring the content, determining the weight according to the specification, tabletting by a machine, checking and packaging to obtain the finished product.
Example 3 preparation of Acxitinib pharmaceutical formulation
Prescription:
acetinib: 10g
Mannitol: 1050g
Nicotinamide: 650g
Sodium tartrate 230g
And (3) manufacturing: 10000 tablets
The preparation method of the acitinib pharmaceutical preparation comprises the following steps:
(1) Sieving the acytinib, mannitol, nicotinamide and sodium tartrate which are dried at 60 ℃ in advance with a 80-mesh sieve;
(2) And (3) fully mixing the raw materials and the auxiliary materials, measuring the content, determining the weight according to the specification, tabletting by a machine, checking and packaging to obtain the finished product.
Example 4 preparation of Acxitinib pharmaceutical formulation
Prescription:
acetinib: 50g
Mannitol: 1050g
Nicotinamide: 650g
Sodium tartrate 230g
And (3) manufacturing: 10000 tablets
The preparation method of the acitinib pharmaceutical preparation comprises the following steps:
(1) Sieving the acytinib, mannitol, nicotinamide and sodium tartrate which are dried at 60 ℃ in advance with a 80-mesh sieve;
(2) And (3) fully mixing the raw materials and the auxiliary materials, measuring the content, determining the weight according to the specification, tabletting by a machine, checking and packaging to obtain the finished product.
The present invention provides the following test and comparative results:
sample 1: acxitinib pharmaceutical preparation prepared by prescription 4 of example 1 of the invention
Sample 2: acetinib pharmaceutical preparation prepared in example 2 of the present invention
Sample 3: commercially available acitinib tablet
Samples 1-2 were subjected to dissolution tests under different conditions:
(1) Dissolution of the tablets was measured at 37℃with 900ml of 0.01M hydrochloric acid solution as dissolution medium, at a rotation speed of 50 rpm by the paddle method, after 30 minutes, and the result was found to be 2:
TABLE 2 dissolution test results
Sample of | Dissolution (%) |
1 | 99.7 |
2 | 99.6 |
(2) 900ml of acetate buffer with pH4.5 was used as dissolution medium, the dissolution rate was measured after 10 minutes at 75 revolutions per minute by paddle method, see 3:
TABLE 3 dissolution test results
Sample of | Dissolution (%) |
1 | 99.8 |
2 | 99.7 |
(3) 900ml of phosphate buffer solution (pH 4.0) is taken as a dissolution medium, the rotation speed is 50 revolutions per minute, the operation is carried out according to law, when the operation is carried out for 10min, a proper amount of solution is respectively taken, filtration is carried out, 10ml of primary filtrate is discarded, and the subsequent filtrate is taken as a sample solution; and taking a proper amount of the acitinib reference substance, precisely weighing, adding acetonitrile for dissolving and quantitatively diluting to prepare a solution with the concentration of about 5.50 mug in each 1ml serving as the reference substance solution. Precisely measuring 20 μl of each of the sample solution and the reference solution, respectively injecting into a liquid chromatograph, and recording the chromatograms. ) Octadecylsilane chemically bonded silica is used as a filler for chromatographic conditions and system applicability tests; the mobile phase was 0.02mol/L monoammonium phosphate solution-acetonitrile (70:30), the flow rate was 1.5ml/min, the detection wavelength was 260nm, and the results are shown in Table 4:
TABLE 4 dissolution test results
Sample of | Dissolution (%) |
1 | 99.9 |
2 | 99.8 |
The results of accelerated stability studies (40 ℃ + -2 ℃ C., 75% + -5% RH) for samples 1-3 are shown in Table 5. ( The dissolution test conditions were: at 37deg.C, 900ml of 0.01M hydrochloric acid solution is used as dissolution medium, and measured at rotation speed of 50 rpm by paddle method after 30 min )
TABLE 5 Acetinib accelerated test results
As can be seen from the results in tables 2 to 5, the preparation method provided by the invention has the advantages of simple process, good stability of the prepared acitinib pharmaceutical preparation, and good dissolution rate compared with the prior art. Similar results were obtained by performing the same test on the pharmaceutical formulations of acitinib prepared in other examples of the present invention.
While the invention has been described with respect to the preferred embodiments, it will be understood that the invention is not limited thereto, but is capable of modification and variation without departing from the spirit of the invention, as will be apparent to those skilled in the art.
Claims (6)
1. An acitinib pharmaceutical formulation, comprising: acytinib, stabilizer, filler and solubilizer; the solubilizer is nicotinamide, and the mass fraction of the solubilizer in the acitinib pharmaceutical preparation is 29% -39.5%; the stabilizer is sodium tartrate, and the mass fraction of the stabilizer in the acitinib pharmaceutical preparation is 10% -13%.
2. The pharmaceutical formulation of acytinib according to claim 1, wherein the filler is mannitol.
3. The acitinib pharmaceutical formulation according to claim 1, wherein the filler is present in the acitinib pharmaceutical formulation in a mass fraction of 50-55%.
4. The pharmaceutical formulation of acytinib according to claim 1, characterized in that it is a tablet containing 1-5 micrograms of acytinib per tablet.
5. The pharmaceutical formulation of acytinib according to claim 1, characterized in that it is a tablet containing 23 micrograms of stabilizer, 105 micrograms of filler and 65 micrograms of solubilizer per tablet.
6. A process for the preparation of a pharmaceutical formulation of acitinib according to any one of claims 1 to 5, comprising the steps of:
(1) Sequentially sieving the acytinib, the stabilizer, the filler and the solubilizer which are dried at 60 ℃ in advance through a 80-mesh sieve;
(2) And (3) fully mixing the raw materials and the auxiliary materials, measuring the content, determining the weight according to the specification, tabletting by a machine, checking and packaging to obtain the finished product.
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Citations (6)
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WO1997027750A1 (en) * | 1996-02-01 | 1997-08-07 | Anthea Enterprises Incorporated | Aqueous caffeine dosage forms |
CN1575798A (en) * | 2003-07-23 | 2005-02-09 | 复旦大学 | Rapid disintegration and rapid dissolution tablet containing kakonein |
WO2006011159A2 (en) * | 2004-06-21 | 2006-02-02 | Torrent Pharmaceuticals Limited | Stabilized pharmaceutical composition containing rabeprazole sodium with improved bioavailability |
WO2008001115A2 (en) * | 2006-06-29 | 2008-01-03 | Astex Therapeutics Limited | Pharmaceutical combinations of 1-cyclopropyl-3- [3- (5-m0rphoolin-4-ylmethyl-1h-benzoimidazol-2-yl) -lh-1-pyrazol- 4-yl] -urea |
CN107961224A (en) * | 2017-12-06 | 2018-04-27 | 齐鲁制药(海南)有限公司 | A kind of pazopanib piece and preparation method thereof |
WO2019071123A1 (en) * | 2017-10-06 | 2019-04-11 | Tesaro, Inc. | Combination therapies and uses thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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DE19818044A1 (en) * | 1998-04-22 | 1999-10-28 | Klinge Co Chem Pharm Fab | Reducing side effects or neutralizing action of carcinostatic or immunosuppressive agents, especially pyridine derivatives, using vitamin PP compounds, e.g. nicotinamide |
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- 2022-07-04 CN CN202210786731.8A patent/CN115177594B/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1997027750A1 (en) * | 1996-02-01 | 1997-08-07 | Anthea Enterprises Incorporated | Aqueous caffeine dosage forms |
CN1575798A (en) * | 2003-07-23 | 2005-02-09 | 复旦大学 | Rapid disintegration and rapid dissolution tablet containing kakonein |
WO2006011159A2 (en) * | 2004-06-21 | 2006-02-02 | Torrent Pharmaceuticals Limited | Stabilized pharmaceutical composition containing rabeprazole sodium with improved bioavailability |
WO2008001115A2 (en) * | 2006-06-29 | 2008-01-03 | Astex Therapeutics Limited | Pharmaceutical combinations of 1-cyclopropyl-3- [3- (5-m0rphoolin-4-ylmethyl-1h-benzoimidazol-2-yl) -lh-1-pyrazol- 4-yl] -urea |
WO2019071123A1 (en) * | 2017-10-06 | 2019-04-11 | Tesaro, Inc. | Combination therapies and uses thereof |
CN107961224A (en) * | 2017-12-06 | 2018-04-27 | 齐鲁制药(海南)有限公司 | A kind of pazopanib piece and preparation method thereof |
Non-Patent Citations (1)
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A green liquid chromatography method for rapid determination of ergosterol in edible fungi based on matrix solid-phase dispersion extraction and a core-shell column;Zhengming Qian et al.;Anal Methods;第12卷;第3337-3343页 * |
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