CN114533735A - Lurasidone hydrochloride pharmaceutical composition and preparation method thereof - Google Patents
Lurasidone hydrochloride pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN114533735A CN114533735A CN202111376047.4A CN202111376047A CN114533735A CN 114533735 A CN114533735 A CN 114533735A CN 202111376047 A CN202111376047 A CN 202111376047A CN 114533735 A CN114533735 A CN 114533735A
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- lurasidone hydrochloride
- nanocrystal
- tween
- agent
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- 229960002863 lurasidone hydrochloride Drugs 0.000 title claims abstract description 121
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 35
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Images
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Abstract
The invention relates to a lurasidone hydrochloride pharmaceutical composition and a preparation method thereof. The invention discloses a lurasidone hydrochloride pharmaceutical composition which comprises lurasidone hydrochloride and a stabilizer, wherein the lurasidone hydrochloride is in a nano-scale. The lurasidone hydrochloride pharmaceutical composition prepared by the invention can improve the solubility and bioavailability of the drug and reduce the influence of food effect. The preparation method provided by the invention is simple to operate, low in production cost and easy to realize industrial scale-up production.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a lurasidone hydrochloride pharmaceutical composition and a preparation method thereof.
Background
The chemical name of lurasidone hydrochloride is (3aR,4S,7R,7aS) -2- { (1R,2R) -2- [4- (1, 2-benzisothiazol-3-yl) piperazin-1-ylmethyl]Cyclohexylmethyl } hexahydro-4, 7-methylene-2H-isoindole-1, 3-dione hydrochloride, a novel second generation antipsychotic drug developed by Sumitomo pharmaceutical Co., Ltd. U.S. FDA approved lurasidone hydrochloride tablet at 10 months in 2010
Is marketed for treating schizophrenia. In 2013, month 06, FDA approved for the treatment of bipolar depression. 2014 03, approved for marketing in the european union for the treatment of schizophrenia. In 2019, in the 01 month, NMPA imported drug registration permission is obtained, and the NMPA imported drug registration permission is used for treating psychopath patients. Lurasidone hydrochloride is a bidirectional inhibitor of central dopamine receptor 2(D2) and 5-hydroxytryptamine 2(5-HT 2A).
The FDA's specification requires that lurasidone hydrochloride should be taken with at least 350 kcal of diet and have low bioavailability (9% -19%). Taken with food, the blood concentration (C)max) And the area under the drug-time curve (AUC) was 3 and 2 times that taken on an empty stomach. The positive effect of food on lurasidone bioavailability may be attributed to delayed gastric emptying and altered gastrointestinal pH. However, the requirement of taking medicine after meal is difficult for patients taking mental disease, so that a method for improving lurasi is developedKetone bioavailability and food effect reducing drugs are challenges to the formulation workers.
Lurasidone hydrochloride is a BCS II drug of a biological pharmaceutical system, and low solubility and dissolution rate are main reasons causing low oral bioavailability.
The drug nanocrystal technology refers to that micron-sized drug particles are dispersed or precipitated and crystallized through grinding, so that the particle size can be reduced to a nanometer level and stably exist under the action of a stabilizer. The techniques for preparing nanocrystals can be classified into top-down methods (e.g., high-pressure homogenization or media milling) and bottom-up methods (e.g., good solvent-antisolvent addition, supercritical fluid methods). The bottom-up method is a physical and chemical process, and the process of drug dissolution (solvent) precipitation is not suitable for commercial production. The solvent residue problem exists, the process control is difficult, and the cost is high. The top-down method adopts a mechanical grinding mode to grind the grain diameter of the medicine to a nanometer level, and is suitable for commercial production.
The oral administration advantages of the nanocrystalline medicament are as follows: the surface area of the insoluble drug is closely related to the biological degree, the reduction of the particle size can obviously increase the saturated solubility and the dissolution rate of the drug, and the drug can be quickly absorbed and quickly take effect, thereby obviously improving the bioavailability of the drug. The common preparation of the insoluble drug is greatly influenced by food when being orally taken, the solubility is increased due to the secretion of bile after eating, the concentration of the surfactant is increased, the physiological environment at the moment is favorable for improving the bioavailability, and on the contrary, the bioavailability is generally reduced under the fasting state, so that the oral absorption difference is large. The nano preparation can reduce the difference of oral absorption of the medicine in the stomach and intestine and obviously reduce the food effect.
Patent application CN109998991A discloses a lurasidone hydrochloride long-acting intramuscular injection nanometer suspension and a preparation method thereof, wherein lurasidone hydrochloride is prepared into the nanometer suspension for intramuscular injection by combining a high-speed dispersion method and a wet medium grinding method. However, the nano-suspension is a long-acting injection, is not an oral preparation, does not relate to contents such as solidification, redissolution and the like, has poor stability and is difficult to store for a long time.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a stable and effective lurasidone hydrochloride pharmaceutical composition and a preparation method thereof, so as to improve the solubility and bioavailability of the drug and reduce the influence of food effect.
In order to achieve the purpose, the invention adopts the technical scheme that:
the lurasidone hydrochloride pharmaceutical composition comprises lurasidone hydrochloride and a stabilizing agent, wherein the lurasidone hydrochloride is nanoscale, and preferably is a crystal.
In the invention, the initial particle size of the lurasidone hydrochloride is d90 < 300 mu m, d90 < 200 mu m, d90 < 160 mu m, d90 < 120 mu m, d90 < 80 mu m, d90 < 50 mu m, d90 < 20 mu m, d90 < 10 mu m or the combination of several particle size ranges. When the particle size is d90 < 10 μm, the grinding efficiency can be greatly improved.
In the invention, the stabilizer is selected from one or more of cellulose, high molecular polymer, surfactant and natural stabilizer; preferably, the cellulose is selected from one or more of methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl methylcellulose, the high molecular polymer is selected from one or more of polyoxyethylene polyoxypropylene block copolymer, povidone, polyvinyl alcohol polyoxyethylene castor oil and polyethylene glycol succinate, the surfactant is selected from one or more of sodium dodecyl benzene sulfonate, sibiramine, tween, span and sodium dodecyl sulfate, and the natural stabilizer is selected from one or more of sodium alginate, glucan, Arabic gum, mannitol, lecithin and chitosan; more preferably one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyoxyethylene polyoxypropylene block copolymer, povidone, mannitol, span and tween; further preferably selecting one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, tween and span; still further preferred is a combination of hypromellose and tween.
In the present invention, the weight percentages of the components, calculated as the total weight of the formulation, are calculated as the total weight of the formulation of the pharmaceutical composition without solvent.
In the invention, the weight percentage of the stabilizer is 10-80%, preferably 10-70%, more preferably 20-60% based on the total weight of the prescription; more preferably 40 to 60%.
In the present invention, the hypromellose is selected from a combination of hypromelloses of one or several viscosity ranges; the preferable viscosity range is 1 to 6500mPa.s, and the more preferable viscosity range is 1 to 4000 mPa.s; further preferably, the viscosity is 1-400 mPa.s; further preferably 3 to 50 mPa.s; most preferably hydroxypropyl methylcellulose with the viscosity range of 3-15 mPa.s.
The viscosity of the invention refers to the apparent viscosity of a 2% hypromellose aqueous solution at 20 ℃. Including commercially available hypromellose of various types, such as K100LVP, K4M, E4MP, E10, E3, E5, E6, E15, E50, K3, SL, SSL, EF, and ELF, which satisfy the conditions.
In the invention, tween is selected from one or more of tween 20, tween 21, tween 40, tween 60, tween 61, tween 80, tween 81 and tween 85; preferably tween 40, tween 60 and tween 80; more preferably tween 80.
In the invention, the stabilizer is a combination of hydroxypropyl methylcellulose and tween, and the weight percentage of the hydroxypropyl methylcellulose is 10-60%, preferably 20-55%, and more preferably 30-55% by weight based on the total weight of the formula; further preferably 40-55%, and the weight percentage of tween is 0-10%, preferably 0-5%, more preferably 0.1-3%.
In the invention, the lurasidone hydrochloride accounts for 20-90 wt%, preferably 30-90 wt%, more preferably 40-80 wt%, and even more preferably 40-60 wt% of the total weight of the formula.
In the present invention, the solvent is water, including ultrapure water, water for injection, distilled water or the like.
In the invention, the stabilizer can be prepared into a 0.1-15% concentration solution, preferably a 0.1-10% concentration solution, more preferably a 0.1-5% concentration solution, and then further prepared into a nanocrystal suspension with the active ingredient.
In the invention, the particle size of the lurasidone hydrochloride in the lurasidone hydrochloride nanocrystal suspension is d90 < 1000nm, d90 < 800nm, d90 < 600nm, d90 < 300nm, d90 < 200nm, d90 < 100nm, d90 < 50nm or the combination of several particle size ranges. The smaller the particle size, the higher the degree of increasing the saturated solubility and dissolution rate of the medicine, and the medicine can be quickly absorbed and take effect rapidly, thereby obviously improving the bioavailability of the medicine. The grinding efficiency and the energy consumption are integrated, and the particle size of the lurasidone hydrochloride nanocrystal suspension is better when the d90 is less than 300 nm.
The invention also provides a pharmaceutical composition of lurasidone hydrochloride, wherein a re-dispersing agent and a filling agent are added into the nano-crystal suspension to prepare a nano-crystal cured substance.
In the invention, the redispersing agent is sucrose, trehalose, mannitol, lactose, glucose, maltose, polyvidone, polyethylene glycol, dextran, albumin, ethylene glycol, glycerol, dimethyl sulfoxide, dimethylformamide, tween, L-serine, sodium glutamate, alanine, glycine, sarcosine, acetate, citrate, tartrate, phosphate, microcrystalline cellulose, starch, sodium chloride, benzoate and benzenesulfonate; preferably sucrose, trehalose; more preferably sucrose.
In the invention, the weight percentage of the secondary dispersant is 1-40%, or 1-30%, or 1-25%, or 1-20%, or 5-20%, or 10-25% of the total weight of the prescription.
In the invention, one or more of anhydrous alpha-lactose, monohydrate alpha-lactose, beta-lactose, corn starch, wheat starch, potato starch, pregelatinized starch, dextrin, microcrystalline cellulose, mannitol, sucrose, powdered sugar, erythrose, xylitol, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, calcium sulfate, magnesium oxide, aluminum hydroxide, microcrystalline cellulose pill core, sucrose pill core, starch pellet and tartaric acid pill core are used as fillers; preferably lactose, starch, mannitol; more preferably lactose.
In the invention, the weight percentage of lactose is 20-90%, or 30-90%, or 40-90%, or 30-80%, or 50-80%, or 60-70% based on the total weight of the prescription.
In order to ensure the nanocrystal particle size of a finished preparation product, the particle size of the lurasidone hydrochloride nanocrystal composition after solidification and granulation is redissolved is monitored, and after the lurasidone hydrochloride nanocrystal condensate is redissolved, the particle size of the lurasidone hydrochloride is d90 which is less than 1000nm, d90 which is less than 800nm, d90 which is less than 600nm, d90 which is less than 400nm, d90 which is less than 200nm or the combination of several particle size ranges; preferably, the particle size is d90 < 600 nm.
The invention also provides a lurasidone hydrochloride composition, which comprises the lurasidone hydrochloride nanocrystal cured substance and one or more pharmaceutically acceptable excipients.
In the invention, the pharmaceutically acceptable excipients are common auxiliary materials and comprise one or more of a diluent, a disintegrating agent and a lubricant.
In the invention, the diluent comprises one or more of lactose, starch, microcrystalline cellulose, mannitol, pregelatinized starch and sucrose; microcrystalline cellulose is preferred.
In the invention, the weight percentage of the diluent is 1-30%, preferably 1-20%, more preferably 1-15%, and further preferably 5-15% based on the total weight of the prescription.
In the invention, the disintegrant comprises one or more of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, modified starch, microcrystalline cellulose, sodium alginate, carboxymethyl starch or sodium carboxymethyl starch; croscarmellose sodium is preferred.
In the invention, the weight percentage of the disintegrating agent is 1-15%, preferably 1-10%, more preferably 1-5% based on the total weight of the prescription.
In the invention, the lubricant comprises one or more of talcum powder, superfine silica gel powder, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl behenate, sodium lauryl sulfate, polyethylene glycol or magnesium stearate; magnesium stearate is preferred.
In the invention, the weight percentage of the lubricant is 0-5%, preferably 0-3%, more preferably 0.1-2% based on the total weight of the prescription.
In the invention, each unit dose of the lurasidone hydrochloride pharmaceutical composition contains 1-500 mg, 5-400 mg, 5-300 mg, 5-200 mg, 5-150 mg, 5-120 mg, 10-100 mg or 20-80 mg of lurasidone hydrochloride; preferably, each unit dose of the oral solid preparation of the lurasidone hydrochloride nanocrystal contains 5-150 mg of active ingredients, and more preferably contains 20mg, 40mg, 60mg, 80mg or 120mg of lurasidone hydrochloride.
In one embodiment of the present invention, the pharmaceutical composition comprises the following components:
| components | Percentage of |
| |
20～90％ |
| |
10～80％ |
or ,
| components | Percentage of |
| |
30～90％ |
| |
10～70％ |
or ,
or ,
| components | Percentage of |
| |
40～80 |
| Hydroxypropyl methylcellulose | |
| 20～60％ |
or ,
| components | Percentage of |
| |
40～80 |
| Hydroxypropyl methylcellulose | |
| 30～55％ | |
| Twain (T) | 0～5％ |
or ,
| components | Percentage of |
| |
40～60 |
| Hydroxypropyl methylcellulose | |
| 40～55％ | |
| Twain (T) | 0.1～3％ |
In another embodiment of the present invention, the pharmaceutical composition comprises the following components:
| components | Percentage of |
| Nanocrystal suspensions | 1～40％ |
| Redispersant | 1～30 |
| Filler | |
| 40～90％ |
or ,
| components | Percentage of |
| Nanocrystal suspensions | 5～35％ |
| Re-dispersing agent | 1～25 |
| Filler | |
| 50～80％ |
or ,
| components | Percentage of |
| |
10～30％ |
| Re-dispersing agent | 5～25 |
| Filler | |
| 60～75％ |
or ,
| components | Percentage of |
| |
10～25 |
| Sucrose | |
| 10～25 | |
| Lactose | |
| 60～70％ |
In another embodiment of the present invention, the pharmaceutical composition comprises the following components:
| components | Percentage of |
| Nanocrystal cured |
60～95％ |
| Diluent | 1～30％ |
| Disintegrating agent | 1～15 |
| Lubricant agent | |
| 0～5％ |
or ,
| components | Percentage of |
| Nanocrystal cured product | 70～95％ |
| Diluent | 1～20％ |
| Disintegrating agent | 1～10 |
| Lubricant agent | |
| 0～3％ |
or ,
| components | Percentage of |
| Nanocrystal cured |
80～95％ |
| Diluent | 1～15％ |
| Disintegrating agent | 1～5 |
| Lubricant agent | |
| 0～3％ |
or ,
| components | Percentage of |
| Nanocrystal cured |
80～95％ |
| Microcrystalline cellulose | 1～15％ |
| Disintegrating agent | 1～5 |
| Lubricant agent | |
| 0～3％ |
or ,
| components | Percentage of |
| Nanocrystal cured |
80～95％ |
| Microcrystalline cellulose | 1～15％ |
| Croscarmellose sodium | 1～5 |
| Lubricant agent | |
| 0～3％ |
or ,
| components | Percentage of |
| Nanocrystal cured |
80～95％ |
| Microcrystalline cellulose | 1～15％ |
| Croscarmellose sodium | 1～5％ |
| Magnesium stearate | 0.1～2％ |
In another embodiment of the present invention, the pharmaceutical composition comprises the following components:
| components | Percentage of |
| Lurasidone hydrochloride | 1～25％ |
| Stabilizing agent | 1～25％ |
| Re-dispersing agent | 1～30 |
| Filler | |
| 40～80％ | |
| Diluent | 1～25％ |
| Disintegrating agent | 1～15 |
| Lubricant agent | |
| 0～5％ |
or ,
| components | Percentage of |
| Lurasidone hydrochloride | 1～20％ |
| Stabilizer | 1～20％ |
| Re-dispersing agent | 1～25％ |
| Filler | 45～75％ |
| Diluent | 1～20％ |
| Disintegrating agent | 1～10 |
| Lubricant agent | |
| 0～3％ |
or ,
| components | Percentage of |
| Lurasidone hydrochloride | 1～15％ |
| Stabilizer | 1～20％ |
| Re-dispersing agent | 1～25 |
| Filler | |
| 50～75％ | |
| Diluent | 1～15％ |
| Disintegrating agent | 1～6 |
| Lubricant agent | |
| 0～3％ |
or ,
| components | Percentage of |
| Lurasidone hydrochloride | 1～15％ |
| Stabilizer | 1～15％ |
| |
10～20 |
| Filler | |
| 50～65％ | |
| Diluent | 1～15％ |
| Disintegrating agent | 1～5％ |
| Lubricant agent | 0.1～2％ |
In another embodiment of the present invention, the pharmaceutical composition comprises the following components:
| components | Percentage of |
| Lurasidone hydrochloride | 1～15％ |
| Hydroxypropyl methylcellulose | 1～15％ |
| Twain (Tween) | 0～1 |
| Redispersant | |
| 10～20 | |
| Filler | |
| 50～65％ | |
| Diluent | 1～15％ |
| Disintegrating agent | 1～5 |
| Lubricant agent | |
| 0～2％ |
or ,
| components | Percentage of |
| Lurasidone hydrochloride | 1～15％ |
| Hydroxypropyl methylcellulose | 1～15％ |
| Twain (T) | 0～1 |
| Sucrose | |
| 10～20 | |
| Filler | |
| 50～65％ | |
| Diluent | 1～15％ |
| Disintegrating agent | 1～5 |
| Lubricant agent | |
| 0～2％ |
or ,
or ,
| components | Percentage of |
| Lurasidone hydrochloride | 1～15％ |
| Hydroxypropyl methylcellulose | 1～15％ |
| Twain (T) | 0～1 |
| Sucrose | |
| 10～20 | |
| Lactose | |
| 50～65％ | |
| Microcrystalline cellulose | 1～15％ |
| Disintegrating agent | 1～5 |
| Lubricant agent | |
| 0～2％ |
or ,
| components | Percentage of |
| Lurasidone hydrochloride | 1～15％ |
| Hydroxypropyl methylcellulose | 1～15％ |
| Twain (T) | 0～1 |
| Sucrose | |
| 10～20 | |
| Lactose | |
| 50～65％ | |
| Microcrystalline cellulose | 1～15％ |
| Croscarmellose sodium | 1～5 |
| Lubricant agent | |
| 0～2％ |
or ,
the invention also provides a preparation method of the lurasidone hydrochloride pharmaceutical composition, which is characterized by comprising the following steps:
(1) preparing lurasidone hydrochloride, a stabilizer and a solvent into a nanocrystal suspension;
(2) adding a secondary dispersing agent and a filling agent into the nanocrystal suspension for granulation to obtain a nanocrystal condensate;
(3) adding a diluent, a disintegrating agent and a lubricant into the nanocrystal condensate to prepare a nanocrystal composition;
(4) the nanocrystal composition is prepared into an oral solid preparation.
In the invention, the nanocrystal suspension can be prepared by one or more of a precipitation method, an emulsification method, a high-pressure homogenization method, a medium grinding method or a high-pressure micro-jet method, and the medium grinding method is preferred.
In the invention, a wet grinding process is adopted for preparing the lurasidone hydrochloride nanocrystal suspension, and the solvent is water.
In the invention, the preparation method specifically comprises the following steps:
step 1, uniformly mixing water, lurasidone hydrochloride and a stabilizer, adding the mixture into a ball mill, and carrying out wet grinding to obtain lurasidone hydrochloride nanocrystal suspension;
step 2, filtering the lurasidone hydrochloride nanocrystal suspension obtained in the step 1, adding a re-dispersing agent and a filling agent, and granulating to obtain a lurasidone hydrochloride nanocrystal condensate;
step 3, taking the condensate obtained in the step 2, and sequentially adding a diluent, a disintegrating agent and a lubricant to obtain the lurasidone hydrochloride nanocrystal composition;
and 4, taking the composition obtained in the step 3, and preparing the composition into an oral preparation.
In the invention, firstly, a stabilizer is dissolved in water to prepare a stabilizer aqueous solution, and lurasidone hydrochloride is added and fully stirred; and adding the obtained lurasidone hydrochloride suspension into a ball mill, and carrying out wet grinding to obtain the lurasidone hydrochloride nanocrystal suspension with the target particle size.
In the invention, the lurasidone hydrochloride serving as an active drug is added into a grinding cavity for grinding to prepare the lurasidone hydrochloride nanocrystal suspension. Too high or too low a proportion of active drug both affects the milling efficiency and the resulting nanocrystal particle size. Therefore, in the preparation process of the lurasidone hydrochloride nanocrystal suspension, the weight percentage of the lurasidone hydrochloride is preferably 40-80%.
In the invention, the lurasidone hydrochloride nanocrystal suspension is solidified and granulated, and the processes of fluidized bed granulation, spray drying or freeze drying can be selected, and the fluidized bed granulation is preferred.
In the invention, the pharmaceutical composition can be prepared into various dosage forms, and the pharmaceutical preparation is a tablet, a granule, a capsule, a nasal administration preparation or a transdermal preparation; according to the selection of medication compliance, oral solid preparations, including granules, capsules and tablets, are preferred.
In one embodiment of the present invention, the pharmaceutical composition can be directly prepared into granules.
In another embodiment of the present invention, the pharmaceutical composition may be further compressed and optionally coated to obtain lurasidone hydrochloride nanocrystal tablets.
In another embodiment of the invention, the composition can be filled into capsule shells to obtain lurasidone hydrochloride capsules.
In addition, the lurasidone hydrochloride pharmaceutical composition prepared by the invention can also be used for preparing a medicament for treating mental diseases, and the preferable mental diseases are schizophrenia.
The lurasidone hydrochloride pharmaceutical composition prepared by the invention has the following advantages:
(1) the invention has the advantages of less auxiliary materials, reduced cost and small influence on the particle size after redissolution;
(2) the medicine crystal prepared by the invention has small particle size and can better improve the bioavailability;
(3) the nano preparation prepared by the invention reduces the difference of oral absorption of the medicine in the stomach and intestine and obviously reduces the food effect;
(4) in addition, the preparation process is simple and is easy for industrial amplification production.
Drawings
FIG. 1 is a graph of dissolution test of the lurasidone hydrochloride pharmaceutical composition of example 3.
Detailed Description
The present invention will be described in further detail with reference to examples, but the present invention is not limited to the following examples. Those skilled in the art should also realize that such equivalent substitutions and alterations can be made without departing from the spirit and scope of the present invention.
Experiment I, screening of stabilizers
The invention adopts a ball mill to prepare the nano-crystal by a wet grinding technology, and a stabilizing agent is required to be added for further reducing the grain diameter. The experiment selects one or more than two stabilizer compositions of different types, and tests are carried out under the same ball mill parameters (the linear speed is 10m/s, the rotating speed of a peristaltic pump is 40rpm, and the grinding time is 4 hours) to determine the optimal composition type, so that the optimal condition is that the particle size of the lurasidone hydrochloride nanocrystal suspension is small. The particle size distribution is measured by a Malvern3000 laser particle sizer, D50 and D90 are selected as measurement parameters, the weight is 1:1, the score (S) is calculated according to the following formula, and the stabilizer with higher score is better in composition by taking the score as an index: score (S) ═ 1/D50+ 1/D90.
The experimental design was as follows:
TABLE 1 selection of stabilizer species
As can be seen from the data, when the formula 4 adopts the combination of hypromellose E5 and Tween 80 as the stabilizer, the particle size of the obtained lurasidone hydrochloride nanocrystal suspension is smaller.
Experiment II, screening of redispersing agent and filling agent
The lurasidone hydrochloride nanocrystal suspension prepared by the formula 4 in the stabilizer screening is solidified and granulated by adopting a fluidized bed granulation technology, and different redispersing agents and filling agents are selected for testing to determine the optimal composition type, so that the optimal lurasidone hydrochloride nanocrystal composition with small particle size is obtained. The particle size distribution is measured by a Malvern3000 laser particle sizer, D50 and D90 are selected as measurement parameters, the weight is 1:1, the score (S) is calculated according to the following formula, and the re-dispersing agent and the filling agent with higher scores are better when the score is used as an index: score (S) ═ 1/D50+ 1/D90.
The experimental design was as follows:
TABLE 2 Redispersant and composition Filler type Screen
As can be seen from the data, the redispersing agent in the formula 7 is sucrose, the filling agent is lactose, and the lurasidone hydrochloride nanocrystal suspension is solidified and granulated, so that the influence on the particle size after redissolution is small.
Example 1
Nanocrystal suspension preparation: dissolving stabilizer hypromellose E5 and Tween 80 in water to obtain stabilizer water solution, adding lurasidone hydrochloride, and stirring; adding the obtained lurasidone hydrochloride suspension into a ball mill, adding zirconia beads with the thickness of 0.3mm, starting a peristaltic pump at the rotating speed of 44rpm, grinding the mixture in a grinding cavity at the rotating speed of 10m/s, and grinding the mixture by a wet method for 4 hours to obtain the lurasidone hydrochloride nanocrystal suspension.
Preparing a nanocrystal condensate: filtering the lurasidone hydrochloride nanocrystal suspension prepared in the above steps by using a 300-mesh screen, adding a re-dispersing agent sucrose, uniformly stirring, and granulating by using a fluidized bed by using a filler lactose as a carrier to obtain a lurasidone hydrochloride nanocrystal condensate.
Nanocrystal composition: and taking the prepared nanocrystal condensate, sequentially adding diluent microcrystalline cellulose, disintegrant croscarmellose sodium and lubricant magnesium stearate, uniformly mixing, and further preparing into granules, capsules or tablets.
Example 2
Nanocrystal suspension preparation: dissolving stabilizer hypromellose E5 and Tween 80 in water to obtain stabilizer water solution, adding lurasidone hydrochloride, and stirring; adding the obtained lurasidone hydrochloride suspension into a ball mill, adding zirconia beads with the thickness of 0.3mm, starting a peristaltic pump at the rotating speed of 22rpm, grinding the mixture in a grinding cavity at the rotating speed of 10m/s, and grinding the mixture by a wet method for 4 hours to obtain the lurasidone hydrochloride nanocrystal suspension.
Nanocrystalline cured was prepared in a similar manner as described in example 1.
The nanocrystal compositions were prepared in a similar manner as described in example 1.
Example 3
Nanocrystal suspensions were prepared in a similar manner as described in example 2.
Nanocrystalline cured was prepared in a similar manner as described in example 1.
The nanocrystal composition was prepared in a similar manner as described in example 1.
Example 4
Nanocrystal suspension preparation: dissolving stabilizer hypromellose E5 and Tween 80 in water to obtain stabilizer water solution, adding lurasidone hydrochloride, and stirring; adding the obtained lurasidone hydrochloride suspension into a ball mill, adding zirconia beads with the thickness of 0.3mm, starting a peristaltic pump at the rotating speed of 22rpm, grinding the mixture in a grinding cavity at the rotating speed of 10m/s, and grinding the mixture by a wet method for 1 hour to obtain the lurasidone hydrochloride nanocrystal suspension.
Nanocrystalline cured was prepared in a similar manner as described in example 1.
The nanocrystal composition was prepared in a similar manner as described in example 1.
EXAMPLE III particle size measurement
About 1mL of the nanocrystal suspension or about 2g of the nanocrystal composition was placed in a sample cell and the particle size distribution was measured using a Malvern3000 laser particle sizer with D50 and D90 as the parameters. The results of the particle size determination for each example are shown in the following table:
the results show that the particle size D90 of the lurasidone hydrochloride nanocrystal suspension prepared in the example 3 is less than 300nm, and the particle size distribution is uniform; the extent of growth of the nanocrystal cured D90 was minimal.
Experimental example four, particle size stability study
The lurasidone hydrochloride nanocrystal suspension prepared in example 3 is refrigerated at 2-8 ℃, the solidified powder is placed at room temperature, samples of different batches are taken at 1,3, 7 and 14 days respectively, the particle size distribution is measured by a Malvern3000 laser particle sizer, and D50 and D90 are selected as measurement parameters. The results of the experiments are shown in the following table.
The result shows that the nanocrystal suspension can keep stable granularity within 7 days under the refrigeration condition of 2-8 ℃, and the granularity is increased in 14 days; the nano crystal condensate can keep stable granularity within 14 days at room temperature.
Fifth Experimental example dissolution test
Dissolution tests are carried out on different solid preparation granules, tablets and capsules prepared from the lurasidone hydrochloride nanocrystal composition in the embodiment 3, according to the four dissolution test methods in the China pharmacopoeia 2020 edition, a paddle method of 50rpm/min is adopted, acetic acid-sodium acetate buffer solution with the pH of 4.5 is selected as a dissolution medium, the volume is 900mL, and the temperature is kept at 37 +/-0.5 ℃. Commercial lurasi hydrochlorideKetone sheet
As a control, 10mL of the solution was taken out at 5, 10, 20, 30, 45 and 60 minutes, respectively, and the isothermal elution medium was replenished in equal amounts. And filtering the extracted dissolution liquid through a filter membrane of 0.45 mu m, discarding 8mL of the primary filtrate, collecting the subsequent filtrate, and measuring the content of the lurasidone hydrochloride by using a high performance liquid chromatography.
The determination method comprises the following steps: according to high performance liquid chromatography, Xselect CSH C18 column was used as column, and phosphate buffer (ph4.0) -acetonitrile 40: 60, the flow rate is 1.0 ml/min; the detection wavelength was 230 nm. The release results were as follows:
the result showed that the release rate of the granules obtained in example 3 at pH4.5 dissolution at 60min was 94%, while the release rate of the commercially available tablets was only 62%.
Experimental example six, stability study
The granules prepared in example 3 were packaged in a composite film bag (specification: 40mg) and stability was examined under accelerated conditions of 40 ℃/RH 75%.
The determination method comprises the following steps: according to high performance liquid chromatography, an Xbridge C18 chromatographic column is used as a chromatographic column, a (phosphate buffer (pH7.0) -acetonitrile 80:20) is used as a mobile phase A, acetonitrile is used as a mobile phase B, and the flow rate is 1.0 ml/min; the detection wavelength was 210 nm. The results of the measurements are shown in the following table:
example 3-granules of the invention were stored under accelerated conditions for 6 months with no significant change in the relevant substances and good stability.
Claims (10)
1. The lurasidone hydrochloride pharmaceutical composition is characterized by comprising lurasidone hydrochloride and a stabilizer, wherein the lurasidone hydrochloride is in a nano-scale, preferably a crystal;
preferably, the stabilizer is selected from one or more of cellulose, high molecular polymer, surfactant and natural stabilizer; preferably, the cellulose is selected from one or more of methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl methylcellulose, the high molecular polymer is selected from one or more of polyoxyethylene polyoxypropylene block copolymer, povidone, polyvinyl alcohol polyoxyethylene castor oil and polyethylene glycol succinate, the surfactant is selected from one or more of sodium dodecyl benzene sulfonate, sibiramine, tween, span and sodium dodecyl sulfate, and the natural stabilizer is selected from one or more of sodium alginate, glucan, Arabic gum, mannitol, lecithin and chitosan; more preferably one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyoxyethylene polyoxypropylene block copolymer, povidone, mannitol, span and tween; further preferably selecting one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, tween and span; still more preferably a combination of hypromellose and tween;
preferably, the weight percentage of the stabilizer is 10-80%, preferably 10-70%, and more preferably 20-60% based on the total weight of the formula; more preferably 40 to 60%.
2. The pharmaceutical composition according to claim 1, wherein hypromellose is selected from one or a combination of several viscosity ranges; the preferable viscosity range is 1-6500 mPa.s; more preferably, the viscosity range is 1-4000 mPa.s; further preferably, the viscosity is 1-400 mPa.s; further preferably 3 to 50 mPa.s; most preferably 3-15 mPa.s hydroxypropyl methylcellulose;
and/or the presence of a gas in the gas,
the tween is selected from one or more of tween 20, tween 21, tween 40, tween 60, tween 61, tween 80, tween 81 and tween 85; preferably tween 40, tween 60 and tween 80; more preferably tween 80;
and/or the presence of a gas in the gas,
the stabilizer is a combination of hydroxypropyl methylcellulose and tween, and the weight percentage of the hydroxypropyl methylcellulose is 10-60%, preferably 20-55%, and more preferably 30-55% by weight of the total weight of the formula; further preferably 40-55%, and the weight percentage of tween is 0-10%, preferably 0-5%, more preferably 0.1-3%;
and/or the presence of a gas in the gas,
based on the total weight of the formula, the weight percentage of the lurasidone hydrochloride is 20-90%, preferably 30-90%, more preferably 40-80%, and further preferably 40-60%;
preferably, a solvent is added to prepare a nanocrystal suspension, preferably the solvent is water;
preferably, the particle size of the lurasidone hydrochloride in the pharmaceutical composition is one or a combination of several particle size ranges of d90 < 1000nm, d90 < 800nm, d90 < 600nm, d90 < 300nm, d90 < 200nm, d90 < 100nm and d90 < 50 nm; preferably, the particle size is d90 < 300 nm.
3. A lurasidone hydrochloride pharmaceutical composition is characterized in that a re-dispersing agent and a filling agent are added into the pharmaceutical composition of any one of claims 1-2, and a nanocrystal cured substance is further prepared;
preferably, the redispersing agent is one or more of sucrose, trehalose, mannitol, lactose, glucose, maltose, microcrystalline cellulose, starch, povidone, polyethylene glycol, dextran, albumin, ethylene glycol, glycerol, dimethyl sulfoxide, dimethylformamide, tween, L-serine, sodium glutamate, alanine, glycine, sarcosine, acetate, citrate, tartrate, phosphate, sodium chloride, benzoate and benzenesulfonate; preferably sucrose and/or trehalose; more preferably sucrose; further preferably, the weight percentage of the secondary dispersant is 1-40%, preferably 1-30%, more preferably 1-25%, and further preferably 10-25% based on the total weight of the formula;
preferably, the filler is selected from one or more of anhydrous alpha-lactose, alpha-lactose monohydrate, beta-lactose, corn starch, wheat starch, potato starch, pregelatinized starch, dextrin, microcrystalline cellulose, mannitol, sucrose, powdered sugar, erythrose, xylitol, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, calcium sulfate, magnesium oxide, aluminum hydroxide, microcrystalline cellulose pellet cores, sucrose pellet cores, starch pellets, tartaric acid pellet cores; preferably lactose, starch, mannitol; more preferably lactose;
more preferably, the weight percentage of the filler is 20 to 90%, preferably 40 to 90%, more preferably 50 to 80%, and even more preferably 60 to 70% based on the total weight of the formula;
preferably, after the nanocrystal condensate is redissolved, the particle size of the lurasidone hydrochloride is d90 < 1000nm, d90 < 800nm, d90 < 600nm, d90 < 400nm, d90 < 200nm or the combination of several particle size ranges; preferably, the particle size is d90 < 600 nm.
4. A pharmaceutical composition of lurasidone hydrochloride comprising the nanocrystal cured product of claim 3 and one or more pharmaceutically acceptable excipients;
preferably, the pharmaceutically acceptable excipient comprises one or more of a diluent, a disintegrant and a lubricant;
preferably, the diluent comprises one or more of lactose, starch, microcrystalline cellulose, mannitol, pregelatinized starch and sucrose; preferably microcrystalline cellulose; more preferably, the weight percentage of the diluent is 1-30%, preferably 1-20%, more preferably 1-15%, and further preferably 5-15% based on the total weight of the prescription;
preferably, the disintegrant comprises one or more of crospovidone, croscarmellose sodium, low substituted hydroxypropyl cellulose, starch, modified starch, microcrystalline cellulose, sodium alginate, carboxymethyl starch or sodium carboxymethyl starch; preferably croscarmellose sodium; more preferably, the weight percentage of the disintegrating agent is 1-15%, preferably 1-10%, more preferably 1-5% based on the total weight of the prescription;
preferably, the lubricant comprises one or more of talcum powder, superfine silica powder, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl behenate, sodium lauryl sulfate, polyethylene glycol or magnesium stearate; preferably magnesium stearate; more preferably, the weight percentage of the lubricant is 0-5%, preferably 0-3%, more preferably 0.1-2% based on the total weight of the prescription;
preferably, each unit dose of the pharmaceutical composition contains 1-500 mg, 5-400 mg, 5-300 mg, 5-200 mg, 5-150 mg, 5-120 mg, 10-100 mg or 20-80 mg of lurasidone hydrochloride; preferably, the composition contains 5-150 mg of lurasidone hydrochloride; more preferably 20mg, 40mg, 60mg, 80mg or 120mg lurasidone hydrochloride.
5. The pharmaceutical composition according to any one of claims 1 to 2, comprising the following components:
or ,
or ,
or ,
or ,
or ,
6. The pharmaceutical composition of claim 3, comprising the following components:
or ,
or ,
or ,
7. The pharmaceutical composition of claim 4, comprising the following components:
or ,
or ,
or ,
or ,
or ,
preferably, the first and second electrodes are formed of a metal,
or ,
or ,
or ,
More preferably still, the first and second liquid crystal compositions are,
or ,
or ,
or ,
or ,
or ,
8. A preparation method of a lurasidone hydrochloride pharmaceutical composition is characterized by comprising the following steps:
(1) preparing lurasidone hydrochloride, a stabilizer and a solvent into a nanocrystal suspension;
(2) adding a secondary dispersing agent and a filling agent into the nanocrystal suspension for granulation to obtain a nanocrystal condensate;
(3) adding a diluent, a disintegrant and a lubricant into the nanocrystal condensate to prepare a nanocrystal composition;
(4) the nanocrystal composition is prepared into an oral solid preparation;
the step (1) adopts one or more of a precipitation method, an emulsification method, a high-pressure homogenization method, a medium grinding method or a high-pressure micro-jet method, and the medium grinding method is preferred.
9. The method of claim 8, comprising the steps of:
step 1, uniformly mixing water, lurasidone hydrochloride and a stabilizer, adding the mixture into a ball mill, and carrying out wet grinding to obtain a lurasidone hydrochloride nanocrystal suspension;
step 2, filtering the lurasidone hydrochloride nanocrystal suspension obtained in the step 1, adding a re-dispersing agent and a filling agent, and granulating to obtain a lurasidone hydrochloride nanocrystal condensate;
step 3, taking the condensate obtained in the step 2, and sequentially adding a diluent, a disintegrating agent and a lubricant to obtain the lurasidone hydrochloride nanocrystal composition;
step 4, preparing the composition obtained in the step 3 into an oral solid preparation;
preferably, the granulation mode is fluidized bed granulation, spray drying or freeze drying; preferably fluidized bed granulation;
preferably, the oral solid preparation is a tablet, capsule or granule.
10. Use of the lurasidone hydrochloride pharmaceutical composition according to any one of claims 1 to 7 in the preparation of a medicament for treating a psychiatric disease, preferably schizophrenia.
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| CN2020113033028 | 2020-11-19 | ||
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115590835A (en) * | 2022-10-25 | 2023-01-13 | 宁波高新区美诺华医药创新研究院有限公司（Cn） | Preparation method of lurasidone |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115590835A (en) * | 2022-10-25 | 2023-01-13 | 宁波高新区美诺华医药创新研究院有限公司（Cn） | Preparation method of lurasidone |
| CN115590835B (en) * | 2022-10-25 | 2023-12-05 | 宁波高新区美诺华医药创新研究院有限公司 | Preparation method of lurasidone |
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