CN115590835B - Preparation method of lurasidone - Google Patents
Preparation method of lurasidone Download PDFInfo
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- CN115590835B CN115590835B CN202211307584.8A CN202211307584A CN115590835B CN 115590835 B CN115590835 B CN 115590835B CN 202211307584 A CN202211307584 A CN 202211307584A CN 115590835 B CN115590835 B CN 115590835B
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- lurasidone
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- loaded pellets
- polysorbate
- microcrystalline cellulose
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- PQXKDMSYBGKCJA-CVTJIBDQSA-N lurasidone Chemical compound C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 PQXKDMSYBGKCJA-CVTJIBDQSA-N 0.000 title claims abstract description 94
- 229960001432 lurasidone Drugs 0.000 title claims abstract description 91
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 77
- 229940079593 drug Drugs 0.000 claims abstract description 67
- 239000008188 pellet Substances 0.000 claims abstract description 30
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims abstract description 24
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 24
- 229940068968 polysorbate 80 Drugs 0.000 claims abstract description 24
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 24
- 239000000203 mixture Substances 0.000 claims abstract description 20
- 239000002245 particle Substances 0.000 claims abstract description 20
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims abstract description 18
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 14
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 14
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 14
- 239000008187 granular material Substances 0.000 claims abstract description 9
- 239000002775 capsule Substances 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 239000011248 coating agent Substances 0.000 claims abstract description 7
- 238000000576 coating method Methods 0.000 claims abstract description 7
- 238000001125 extrusion Methods 0.000 claims abstract description 5
- 238000011049 filling Methods 0.000 claims abstract description 4
- 238000007873 sieving Methods 0.000 claims abstract description 4
- 230000004580 weight loss Effects 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 abstract description 23
- 238000007254 oxidation reaction Methods 0.000 abstract description 23
- 239000004480 active ingredient Substances 0.000 abstract description 6
- 238000004090 dissolution Methods 0.000 description 23
- 239000007787 solid Substances 0.000 description 20
- 238000010521 absorption reaction Methods 0.000 description 11
- 238000009472 formulation Methods 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000012535 impurity Substances 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002978 peroxides Chemical class 0.000 description 4
- 229920000136 polysorbate Polymers 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 239000012876 carrier material Substances 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- -1 fatty acid esters Chemical class 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 229940036674 latuda Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002736 nonionic surfactant Substances 0.000 description 3
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 229940126701 oral medication Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229950008882 polysorbate Drugs 0.000 description 2
- 238000009790 rate-determining step (RDS) Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000006701 autoxidation reaction Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 229960002863 lurasidone hydrochloride Drugs 0.000 description 1
- NEKCRUIRPWNMLK-SCIYSFAVSA-N lurasidone hydrochloride Chemical compound Cl.C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 NEKCRUIRPWNMLK-SCIYSFAVSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940057847 polyethylene glycol 600 Drugs 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/501—Inorganic compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The preparation method disclosed by the application comprises the following steps: dissolving lurasidone micropowder with particle diameter smaller than 10 micrometers in polysorbate 80 and polyethylene glycol 6000 to obtain a medicinal solution; mixing microcrystalline cellulose and amorphous mesoporous silica particles to obtain a dry mixture; mixing and granulating the drug solution with the dry mixture in a high shear wet granulator to obtain granules: putting the granules into an extrusion spheronizing machine for extrusion and spheronizing, and sieving with a 1.0mm screen to obtain drug-loaded pellets, wherein the drug-loaded pellets take microcrystalline cellulose as a carrier for adsorbing drug solution and amorphous mesoporous silica particles as a coating for wrapping the carrier; and (3) drying the drug-loaded pellets until the drying weight loss is lower than 2.5%, and filling the drug-loaded pellets into capsules. The lurasidone is prepared into drug-loaded pellets, so that the lurasidone has acceptable fluidity, compressibility, better solubility and oxidation resistance, and the stability of the lurasidone and the solubility of the drug active ingredients are improved.
Description
Technical Field
The application relates to the technical field of medicinal preparations, in particular to a preparation method of lurasidone.
Background
Lurasidone (lurasidone) belongs to the fourth class of drugs of BCS, which has the following three problems:
the first problem is: the solubility is low. It is well known that the active ingredient in solid dosage forms must be dissolved out to be absorbed by the gastrointestinal tract. The absorption rate of a poorly water-soluble pharmaceutical active ingredient in an oral solid preparation is determined by its dissolution rate in the liquid at the absorption site, i.e., the dissolution rate is often a decisive factor for drug absorption. Lurasidone has low solubility and low biological membrane permeability, is poor in solubility and unstable in dissolution curve, so that the dissolution rate of the drug is very low, especially under the condition of higher pH value. The solubility of lurasidone is also related to the pH of the solution, with the highest lurasidone solubility at lower pH values, and then decreasing with increasing pH. The saturated solubilities of lurasidone at different pH values are shown in table 1.
TABLE 1
It is well known that the solubility of a drug has an effect on the dissolution of the drug. The dissolution rate of the medicine in vitro can indicate the absorption condition of the medicine in a human body to a certain extent. The inventors used commercially available lurasidone hydrochloride tablet Latuda as a reference formulation, which was similar to the original formulation. The present inventors prepared a self-grinding tablet by a conventional method, following the materials and amounts of the reference formulation, and used the self-grinding tablet as comparative example 1. The materials and amounts of the reference formulation and the raw formulation are set forth in Table 2. The comparative example 1 and the reference preparation were subjected to lurasidone in vitro dissolution experiments in different dissolution media (pH 1.2 to 6.8), and the experimental results are shown in table 3.
TABLE 2
TABLE 3 Table 3
As can be seen from table 3, the dissolution of lurasidone as an active ingredient in the tablet of comparative example 1 was similar to that of the reference formulation, and the dissolution rate was decreased from pH 4.2 and gradually decreased with an increase in pH; at a pH of 6.8, the release rate of lurasidone was only 1%. Furthermore, it can be seen that the dissolution of lurasidone decreases significantly from pH 5.0 to pH 6.8.
The second problem is: the fluidity is poor. The flow characteristics of lurasidone are shown in table 4.
TABLE 4 Table 4
| API lot number | D020-210704KB |
| Repose angle (theta) | 48.7° |
| Bulk Density (g/mL) | 0.21 |
| Tap Density (g/mL) | 0.33 |
| Compressible index (%) | 36.36 |
| Hausmers Ratio (Hausmers Ratio) | 1.57 |
| Fluidity (repose angle) | Poor flowability |
| Fluidity (compressible index) | Very poor flowability |
| Fluidity (Haoshanbi) | Very poor flowability |
In order to increase the solubility of lurasidone, a lurasidone micropowder having a particle size d (0.9) of less than 10 μm is generally used. As can be seen from table 4, the bulk density of lurasidone was 0.21g/mL, indicating that it was very fluffy and micronised was susceptible to static electricity and thus showed tackiness. By measuring all indexes representing fluidity, such as angle of repose, compressibility index, hausner ratio, etc., it is shown that lurasidone has poor fluidity, which is due to the fact that the drug substance is micronized and has a particle size of less than 10 microns. Lurasidone micropowder with particle size d (0.9) below 10 μm has the characteristics of fluffiness, viscosity and low bulk density, but the flowability of the powder becomes a difficulty in preparing tablets, and conventional tablets are liable to cause problems of weight and content uniformity due to improper powder flow. Since the flowability of the drug substance is poor and 25% is contained in the tablet formulation, the flowability of the whole tablet is very important, which makes the content uniformity a difficult problem when preparing immediate release tablets using lurasidone.
The third problem is: is easy to oxidize. Lurasidone is very sensitive to oxidation. Lurasidone is reported to degrade to 11% under oxidation. At RRT 0.626 minutes, the impurity content was about 5.77% due to the presence of oxidation. The poor oxidation resistance of lurasidone also affects the absorption of active ingredients by the human body.
At present, pharmaceutical manufacturers have adopted various technologies to prepare lurasidone preparation products so as to enhance the dissolution curve and further improve the absorption efficiency of the water-insoluble solid drug lurasidone. These techniques include: drug micronization, solid dispersion, precipitation, lyophilization and microencapsulation, but there is no effective preparation method in the prior art that can solve the above three problems of lurasidone simultaneously.
Disclosure of Invention
The application aims to solve the technical problem of providing a preparation method of lurasidone aiming at the defects of the prior art. The preparation method of lurasidone prepares the lurasidone micro powder with the particle size smaller than 10 microns into a spherical drug-loaded pellet form, so that the lurasidone has acceptable fluidity, compressibility, better solubility and oxidation resistance, and the stability of the lurasidone and the solubility of the drug active ingredient are improved.
The technical scheme adopted for solving the technical problems is as follows: a method for preparing lurasidone, comprising the following steps:
1) Dissolving lurasidone micropowder with the particle size smaller than 10 microns in polysorbate 80 and polyethylene glycol 6000 to obtain a drug solution with the required concentration;
2) Mixing microcrystalline cellulose and amorphous mesoporous silica particles to obtain a dry mixture;
3) Mixing the drug solution obtained in the step 1) with the dry mixture obtained in the step 2) in a high shear wet granulator and granulating to obtain granules:
4) Extruding and rounding the granules obtained in the step 3) in an extrusion rounding machine, and sieving with a 1.0mm screen to obtain drug-loaded pellets, wherein the drug-loaded pellets take microcrystalline cellulose as a carrier for adsorbing drug solution and amorphous mesoporous silica particles as a coating for wrapping the carrier;
5) And (3) drying the drug-loaded pellets until the drying weight loss is lower than 2.5%, and filling the drug-loaded pellets into capsules.
The lurasidone is dissolved in polysorbate 80 and polyethylene glycol 6000 to obtain a drug solution, and the drug solution is wrapped by microcrystalline cellulose and amorphous mesoporous silicon dioxide particles to obtain a liquid-solid system. Although the drug-loaded pellets prepared by the application are spherical, the drug lurasidone in the pellets is kept in a dissolved liquid state (namely a wet state), and the low-solubility lurasidone in the wet state has higher availability, so that the dissolution of the drug can be enhanced. Another advantage of the liquid-solid system is that it is less costly to produce than conventional tablets. We use microcrystalline cellulose in particulate form in the present application, the preferred specification being Avicel pH200. Microcrystalline cellulose has sufficient absorption properties to facilitate absorption of the drug solution to obtain wet carrier material particles; the amorphous mesoporous silica particles have high adsorptivity, can cover wet carrier material particles, and adsorb excess liquid.
The application takes polysorbate 80 as a nonionic surfactant and polyethylene glycol 6000 as a cosolvent, and the lurasidone micropowder is dissolved into a drug solution, so that the solubility and the dissolution rate of the lurasidone micropowder are increased. Polysorbate 80 and polyethylene glycol 600 are non-volatile solvents that are inert, high boiling point, water miscible, low viscosity, and the like. It is known that polysorbate 80 and polyethylene glycol 6000, which contain a large amount of peroxide, are self-oxidized, and lurasidone is an easily oxidized drug which is very sensitive to oxidation, and therefore, those skilled in the art will not use polysorbate 80 and polyethylene glycol 6000 together with a drug having poor oxidation resistance such as lurasidone, because it affects the stability of the drug. However, the application breaks the convention, creatively dissolves lurasidone in polysorbate 80 and polyethylene glycol 6000, wraps and shields the medicine through a carrier and a coating, prepares lurasidone into medicine-carrying pellets, wherein the medicine-carrying pellets are liquid-solid particles which wrap medicine solution, can effectively avoid the oxidation of lurasidone, and prevent the lurasidone from being degraded due to the oxidation, thereby ensuring the oxidation resistance and stability of the medicine. Through detection, the lurasidone medicine prepared by the method can be stably stored for 6 months under the condition of 40 ℃/75% RH, and has good oxidation resistance and stability.
According to the application, the drug-loaded pellets are filled in the capsules, so that the fluidity of lurasidone can be improved, and in the dissolution process of liquid-solid particles filled in the capsules, after the disintegration process is finished, the drug solution loaded on the liquid-solid particles is uniformly dispersed in the whole dissolution medium due to the porosity of the carrier material, and the drug-loaded pellets of the liquid-solid system show stronger solubility and drug release capacity because more drug surfaces are exposed in the dissolution medium. This phenomenon does not occur extensively during the conventional dissolution of 40mg lurasidone tablet Latuda. Compared with other expensive commercial preparations, the lurasidone preparation method prepares lurasidone into a liquid-solid system pellet form with quick release, and has stronger in-vitro and in-vivo drug release effects on the water-insoluble drug lurasidone.
Preferably, the particle diameter of the amorphous mesoporous silica particles is 10-5000 nm.
Preferably, the weight ratio of the lurasidone micro powder to the polysorbate 80 is 1 (0.5-1).
Preferably, the weight ratio of polysorbate 80 to polyethylene glycol 6000 is 10:1.
Preferably, the weight ratio of the lurasidone micro powder to the microcrystalline cellulose is 1:2.
Preferably, hydroxypropyl methylcellulose is also added to the drug solution. Hydroxypropyl methylcellulose is the binder.
Preferably, sodium carboxymethyl starch is also added to the dry mixture. Sodium carboxymethyl starch is a disintegrant.
Compared with the prior art, the application has the following advantages: the preparation method of lurasidone prepares the lurasidone micropowder with the particle size smaller than 10 microns into a spherical drug-loaded pellet form, and can effectively improve the solubility and the fluidity of lurasidone. Compared with the like products sold in the market, the method not only meets the dissolution requirement specified in pharmacopoeia, but also generates the drug release rate obviously higher than that of the like products sold in the market. Because drug dissolution is the rate limiting step in the absorption of nonpolar molecular oral drugs, liquid-solid systems also exhibit greater advantages over their commercial counterparts in terms of in vivo absorption efficiency. In fact, in vitro controlled dissolution studies using the lurasidone liquid-solid system and commercial products have demonstrated the advantages of the liquid-solid system for in vitro drug release. In addition, the application breaks the convention, creatively dissolves lurasidone in polysorbate 80 and polyethylene glycol 6000, wraps and shields the medicine through a carrier and a coating, prepares lurasidone into medicine carrying pellets which are liquid-solid particles wrapping medicine solution, can effectively avoid oxidation of lurasidone, and prevents lurasidone from being degraded due to oxidation, thereby ensuring the stability of the medicine.
Detailed Description
The present application is described in further detail below with reference to examples.
The preparation methods of lurasidone in example 1 and example 2 each include the following steps:
1) Dissolving lurasidone micropowder with particle diameter smaller than 10 micrometers and hydroxypropyl methylcellulose in polysorbate 80 and polyethylene glycol 6000 to obtain a medicinal solution with required concentration;
2) Mixing microcrystalline cellulose Avicel pH200, carboxymethyl starch sodium and amorphous mesoporous silica particles with the particle size of 10-5000 nm to obtain a dry mixture;
3) Mixing the drug solution obtained in the step 1) with the dry mixture obtained in the step 2) in a high shear wet granulator and granulating to obtain granules:
4) Extruding and rounding the granules obtained in the step 3) in an extrusion rounding machine, and sieving with a 1.0mm screen to obtain drug-loaded pellets, wherein the drug-loaded pellets take microcrystalline cellulose as a carrier for adsorbing drug solution and amorphous mesoporous silica particles as a coating for wrapping the carrier;
5) And (3) drying the drug-loaded pellets until the drying weight loss is lower than 2.5%, and filling the drug-loaded pellets into capsules.
The liquid-solid system formulation in example 1 is shown in Table 5, and the liquid-solid system formulation in example 2 is shown in Table 6.
TABLE 5
TABLE 6
The material types and sources used in example 1 and example 2 were as follows:
polyethylene glycol 6000 and polysorbate 80: tweens 80) (Merck corporation;
microcrystalline cellulose Avicel PH 200: f.m.c.corp;
sodium carboxymethyl starch: edward Mendell co., inc;
amorphous mesoporous silica particles 244FP: w.Grace Co;
hydroxypropyl methylcellulose HPMC E5-LV: dow Chemical co.
A commercially available 40mg lurasidone tablet Latuda was used as a reference formulation. The elution results of the reference preparation and examples 1 and 2 are shown in Table 7.
TABLE 7
As can be seen from Table 7, compared with the similar products on the market, the dissolution condition of the liquid-solid system pellets prepared by the application not only meets the dissolution requirements specified by pharmacopoeia, but also generates a drug release rate obviously higher than that of the similar products on the market. Because drug dissolution is the rate limiting step in the absorption of nonpolar molecular oral drugs, liquid-solid systems may also exhibit greater advantages over their commercial counterparts in vivo. In fact, in vitro controlled dissolution studies using the lurasidone liquid-solid system and commercial products have demonstrated the advantages of the liquid-solid system for in vitro drug release. Because it is spherical granule, the fluidity is very good.
The application takes polysorbate 80 as a nonionic surfactant and polyethylene glycol 6000 as a cosolvent, and the lurasidone micropowder is dissolved into a drug solution, so that the solubility and the dissolution rate of the lurasidone micropowder are increased. Polysorbate (PS) is an amphiphilic nonionic surfactant consisting of fatty acid esters of Polyoxyethylene (POE) sorbitan. The commercial polysorbate 80 is a mixture of various chemical components and mainly contains sorbitan POE fatty acid ester. It is well known that polysorbates are susceptible to degradation by autoxidation and hydrolysis. Peroxide undergoes significant degradation under accelerated stability conditions (40 ℃/75% RH) while peroxide accumulates significantly. The chemical reactivity of polyethylene glycol 6000 is due to the presence of two terminal hydroxyl groups, which may be esterified or etherified. All polyethylene glycols are oxidative and auto-oxidize due to the activity of peroxide and byproduct formation. In addition, polyethylene glycol automatically oxidizes if exposed to temperatures of 40 ℃ and above for a long period of time. Lurasidone is very sensitive to oxidation, and Lurasidone is reported to degrade to 11% under oxidation. Table 8 is the degradation of lurasidone in the presence of oxygen, for example, at RRT 0.626 min, with an impurity content of about 5.77% due to the presence of oxidation. The data in table 8 indicate that lurasidone is sensitive to oxidation.
TABLE 8
| Oxidation time | Lurasidone content | Impurity content |
| Purity | 100.0％ | 89.7 |
| RRT≈0.626 | Undetected | 5.77 |
| *RRT≈0.775 | Undetected | 0.11 |
| RRT≈0.809 | Undetected | 1.08 |
| *RRT≈0.956 | Undetected | 0.48 |
| RRT≈1.166 | Undetected | 0.15 |
| RRT≈1.329 | Undetected | 0.21 |
Comparative example 2 was prepared in the same manner as in example 2, except that polysorbate 80 and polyethylene glycol 6000 were not added in comparative example 2. The stability comparison results of lurasidone of example 2 and lurasidone of comparative example 2 under accelerated stability conditions are shown in table 9.
TABLE 9
From the data in table 9, it was surprisingly found that in example 2, lurasidone was stable for 6 months at 40 ℃/75% rh at a weight ratio of lurasidone to polysorbate 80 of 1:1. In contrast, in example 1, the above effect was also achieved in the case of a weight ratio of lurasidone to polysorbate 80 of 1:0.5.
Comparative example 2 was free of polysorbate 80 and polyethylene glycol 6000, although this would affect oxidative degradation of the impurities, the impurity levels were still high due to the sensitivity of lurasidone to oxidation.
Therefore, although the self-oxidized polysorbate 80 and polyethylene glycol 6000 are used for dissolving the lurasidone, the lurasidone is prepared into the drug-carrying pellets by the carrier and the coating and shielding the drug, and the drug-carrying pellets are liquid-solid particles which wrap the drug solution, so that the oxidation of the lurasidone can be effectively avoided even under the condition that the weight ratio of the lurasidone to the polysorbate 80 is up to 1:1, the degradation of the lurasidone caused by the oxidation is prevented, and the oxidation resistance and the stability of the drug are ensured.
Claims (2)
1. A method for preparing a lurasidone capsule, which is characterized by comprising the following steps:
1) Dissolving lurasidone micropowder with the particle size smaller than 10 microns in polysorbate 80 and polyethylene glycol 6000 to obtain a drug solution with the required concentration;
2) Mixing microcrystalline cellulose and amorphous mesoporous silica particles to obtain a dry mixture;
3) Mixing the drug solution obtained in the step 1) with the dry mixture obtained in the step 2) in a high shear wet granulator and granulating to obtain granules:
4) Extruding and rounding the granules obtained in the step 3) in an extrusion rounding machine, and sieving with a 1.0mm screen to obtain drug-loaded pellets, wherein the drug-loaded pellets take microcrystalline cellulose as a carrier for adsorbing drug solution and amorphous mesoporous silica particles as a coating for wrapping the carrier;
5) Drying the drug-loaded pellets until the drying weight loss is lower than 2.5%, and filling the drug-loaded pellets into capsules;
the weight ratio of the lurasidone micro powder to the polysorbate 80 is 1 (0.5-1), the weight ratio of the polysorbate 80 to the polyethylene glycol 6000 is 10:1, the weight ratio of the lurasidone micro powder to the microcrystalline cellulose is 1:2, hydroxypropyl methylcellulose is also added into the drug solution, and sodium carboxymethyl starch is also added into the dry mixture.
2. The preparation method of the lurasidone capsule according to claim 1, wherein the particle size of the amorphous mesoporous silica particles is 10-5000 nm.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1213538A (en) * | 1997-10-06 | 1999-04-14 | 沈阳药科大学 | Method of preparing fast-releasing and slowly-releasing solid dispersion micropill in liquid phase |
| CN103751139A (en) * | 2013-12-31 | 2014-04-30 | 北京万全德众医药生物技术有限公司 | Lurasidone orally disintegrating tablet |
| CN104324380A (en) * | 2014-10-17 | 2015-02-04 | 华东理工大学 | Nano drug carrier, preparation method and application thereof |
| RU2585023C1 (en) * | 2014-12-18 | 2016-05-27 | Общество с ограниченной ответственностью "Нанолек" | Granulating method |
| CN111818911A (en) * | 2017-12-26 | 2020-10-23 | 广东东阳光药业有限公司 | Lurasidone solid dispersion and preparation method thereof |
| CN114533735A (en) * | 2020-11-19 | 2022-05-27 | 常州恒邦药业有限公司 | Lurasidone hydrochloride pharmaceutical composition and preparation method thereof |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1213538A (en) * | 1997-10-06 | 1999-04-14 | 沈阳药科大学 | Method of preparing fast-releasing and slowly-releasing solid dispersion micropill in liquid phase |
| CN103751139A (en) * | 2013-12-31 | 2014-04-30 | 北京万全德众医药生物技术有限公司 | Lurasidone orally disintegrating tablet |
| CN104324380A (en) * | 2014-10-17 | 2015-02-04 | 华东理工大学 | Nano drug carrier, preparation method and application thereof |
| RU2585023C1 (en) * | 2014-12-18 | 2016-05-27 | Общество с ограниченной ответственностью "Нанолек" | Granulating method |
| CN111818911A (en) * | 2017-12-26 | 2020-10-23 | 广东东阳光药业有限公司 | Lurasidone solid dispersion and preparation method thereof |
| CN114533735A (en) * | 2020-11-19 | 2022-05-27 | 常州恒邦药业有限公司 | Lurasidone hydrochloride pharmaceutical composition and preparation method thereof |
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