CN112263546A - Zopiclone suspension nanometer preparation administrated through nasal cavity and preparation method thereof - Google Patents
Zopiclone suspension nanometer preparation administrated through nasal cavity and preparation method thereof Download PDFInfo
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- GBBSUAFBMRNDJC-MRXNPFEDSA-N (5R)-zopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-MRXNPFEDSA-N 0.000 title claims abstract description 149
- 229960000820 zopiclone Drugs 0.000 title claims abstract description 149
- 238000002360 preparation method Methods 0.000 title claims abstract description 70
- 239000000725 suspension Substances 0.000 title claims abstract description 39
- 210000003928 nasal cavity Anatomy 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 49
- 239000006070 nanosuspension Substances 0.000 claims abstract description 27
- 239000000843 powder Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000004108 freeze drying Methods 0.000 claims abstract description 15
- 239000000523 sample Substances 0.000 claims abstract description 6
- 238000001556 precipitation Methods 0.000 claims abstract description 5
- 239000003381 stabilizer Substances 0.000 claims description 56
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 239000007788 liquid Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000002994 raw material Substances 0.000 claims description 15
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- 238000005507 spraying Methods 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 11
- 229920001992 poloxamer 407 Polymers 0.000 claims description 10
- 229940044476 poloxamer 407 Drugs 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
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- 238000005303 weighing Methods 0.000 claims description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
- 239000002563 ionic surfactant Substances 0.000 claims description 3
- 229920001983 poloxamer Polymers 0.000 claims description 3
- 229960000502 poloxamer Drugs 0.000 claims description 3
- 229920000136 polysorbate Polymers 0.000 claims description 3
- 238000001132 ultrasonic dispersion Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims 1
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- 230000001186 cumulative effect Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 3
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- 229960001412 pentobarbital Drugs 0.000 description 2
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- 230000028527 righting reflex Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
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- 239000003929 acidic solution Substances 0.000 description 1
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- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
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- 230000003340 mental effect Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 238000007709 nanocrystallization Methods 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000196 olfactory nerve Anatomy 0.000 description 1
- 210000002475 olfactory pathway Anatomy 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- CYXKNKQEMFBLER-UHFFFAOYSA-N perhexiline Chemical compound C1CCCNC1CC(C1CCCCC1)C1CCCCC1 CYXKNKQEMFBLER-UHFFFAOYSA-N 0.000 description 1
- 229960000989 perhexiline Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 230000003860 sleep quality Effects 0.000 description 1
- 230000036578 sleeping time Effects 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
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- 238000005550 wet granulation Methods 0.000 description 1
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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
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- 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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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Abstract
The invention discloses a zopiclone suspension nanometer preparation administrated through a nasal cavity and a preparation method thereof. The zopiclone suspension nano preparation consists of zopiclone and a dispersing agent, an initial nano suspension is obtained by combining an ultrasonic spray-precipitation method, probe ultrasonic is carried out by an ultrasonic cell disruption instrument, and freeze drying is carried out, so that the zopiclone suspension nano freeze-dried powder is obtained. The zopiclone suspension nanometer preparation provided by the invention is simple in component, good in stability, good in particle size and drug loading capacity, and capable of improving the in-vitro release degree of the hydrophobic drug zopiclone. The zopiclone nano preparation prepared by the invention can enable the medicine to bypass blood brain barriers and directly reach a central nervous system after nasal administration, and has high bioavailability and quick response.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a preparation method of a novel medicament nano-dosage form, and particularly relates to a preparation method of a nasal administration zopiclone nano-preparation and physicochemical representation thereof, wherein the nasal administration is used for achieving the purpose of quick response.
Background
Zopiclone (Zopiclone) is a non-benzodiazepine sedative hypnotic drug acting on GABA in central nervous systemANeurotransmitter receptors can obviously prolong the sleep time, improve the sleep quality and reduce the number of awakenings at night. Compared with widely used benzodiazepine drugs, zopiclone has stronger effect and is not easy to have side effects such as next morning residue, drug accumulation, drug dependence and the like. Because of definite curative effect, small side effect and low addiction, the benzodiazepine medicines are gradually replaced to become the mainstream medicines for treating insomnia.
To ensure the stabilization of the brain environment, the blood-brain barrier selectively prevents foreign substances from entering the brain tissue from the blood. It has been shown that an olfactory pathway exists between the nasal cavity and the brain through which drugs can reach the central nervous system by bypassing the blood-brain barrier (Kumar M, Misra A, Babbar A K, et al. Intra mental nanoscale captured brain targeting drug delivery system of risperidone [ J ]. International Journal of pharmaceuticals, 2008,358(1-2): 285-). For the medicines acting on the central nervous system, such as zopiclone, the nasal administration preparation can be developed to quickly take effect, and the use is convenient. After the medicine enters the nasal cavity, part of the medicine can be absorbed into blood through the sniffing mucous membrane of the breathing part and enters the brain tissue through blood circulation; another part can enter the central nervous system directly via the olfactory nerve. Compared with oral administration, the nasal administration can also avoid liver first pass effect. Therefore, the nasal administration can not only shorten the onset time of the medicine, but also improve the concentration of the medicine in the central nervous system and increase the bioavailability of the medicine.
Most of the zopiclone sold in the market is an oral tablet, and few other dosage forms are reported. Zopiclone is practically insoluble in water, affecting the drug efficacy. The Chinese patent publication CN102106825A discloses a preparation method of a zopiclone solid preparation, which is characterized in that zopiclone is dissolved in an acidic solution and then mixed with an alkalizer and auxiliary materials for wet granulation, so that the defects of serious pollution and large loss of the traditional mechanical crushing method are avoided, and the prepared zopiclone preparation has better dissolution rate.
The nanosuspension technology is one of the leading technologies for solving the problem of poor solubility of drugs at present, and substances such as appropriate surfactants are usually adopted as stabilizers to uniformly disperse nanoscale drug particles into colloidal dispersions, and common preparation methods include a precipitation method, a medium grinding method, a high-pressure homogenization method and the like. The nanometer suspension has simple components, good safety and high drug content, and can effectively increase the dissolution rate of insoluble drugs. The nanometer medicinal preparation has controlled release, improved therapeutic effect, and reduced adverse side effects. For example, the invention patent publication CN110711176A discloses a sinetipin nanosuspension and a preparation method thereof, wherein the sinetipin nanosuspension prepared by subjecting a target drug sinetipin and a stabilizer to nanocrystallization treatment such as a medium grinding method, a high-pressure homogenization method or a high-pressure homogenization-ultrasonic method has the characteristics of high dissolution rate and high bioavailability. The Chinese patent publication CN111419900A discloses an improved nano suspension freeze-dried preparation based on perhexiline and a preparation method thereof, which improves the dissolution rate of insoluble components in the medicine and remarkably increases the in vitro simulated cumulative release rate.
Disclosure of Invention
The invention aims to overcome the problems that the existing zopiclone medicines are all oral tablets, are difficult to quickly reach and act on a central nervous system, and have low intracerebral medicine concentration, low medicine utilization degree and the like due to liver first pass effect and blood brain barrier.
Another objective of the present invention is to provide a method for preparing zopiclone nano-preparation, aiming at the problem of poor water solubility of zopiclone.
In order to achieve the purpose, the invention adopts the following technical scheme: each 3000 weight parts of the zopiclone suspension nanometer preparation comprises 1-6 parts of zopiclone raw material medicine, 1-3 parts of a stabilizer and the balance of water.
Furthermore, every 3000 weight parts of the preparation preferably comprises 2-3 parts of zopiclone, 1-3 parts of a stabilizer and the balance of water.
Wherein the stabilizer is water-soluble nonionic surfactant such as poloxamer, tween and other series surfactants, and ionic surfactant such as sodium dodecyl sulfate or mixture thereof.
The preferable stabilizer is water-soluble nonionic surfactant such as poloxamer, tween and other series surfactants. More preferred stabilizer is poloxamer 407, tween 80 or a mixture of two.
The preparation method of the zopiclone suspension nanometer preparation administrated through the nasal cavity adopts the combination of an ultrasonic spraying method and a precipitation method, and comprises the following steps of:
(1) weighing a stabilizer in an amount required by a formula, adding pure water, and performing ultrasonic treatment to completely dissolve the stabilizer to obtain a stabilizer solution;
(2) weighing zopiclone raw material medicine, and dissolving the zopiclone raw material medicine in a proper organic solvent to obtain an organic zopiclone solution;
(3) ultrasonically atomizing the zopiclone organic solution obtained in the step (2) under the driving of nitrogen by using an ultrasonic sprayer, spraying the organic solution into the stabilizer solution obtained in the step (1), and keeping continuously stirring to obtain a zopiclone suspension;
(4) further ultrasonically dispersing the zopiclone suspension obtained in the step (3) by using an ultrasonic cell disruptor and reducing the particle size to obtain a suspension, namely, a zopiclone nano suspension;
(5) freeze-drying the zopiclone nano suspension obtained in the step (4) to obtain zopiclone nano freeze-dried powder;
(6) and (3) fully dispersing the zopiclone nano freeze-dried powder obtained in the step (5) into pure water according to the requirement of the net content of the final preparation medicament, and performing ultrasonic dispersion to obtain a zopiclone suspension nano preparation capable of being administrated through a nasal cavity.
In the step (2), the organic solvent is one or a mixture of acetone, N-N dimethylformamide, dimethyl sulfoxide and methanol. The preferred organic solvent is N-N dimethylformamide.
In the step (3), the volume of the stabilizer solution is 10-50 times that of the organic solution.
In the step (3), the nitrogen pressure for pushing the zopiclone solution is 0.01-0.1Mpa, the liquid inlet speed of the zopiclone organic solution is 4-5mL/h, and the ultrasonic power is 8.5-9.5W.
In the step (4), the ultrasonic power of the probe used by the cell disruption instrument is 250-.
In the step (5), the freeze-drying conditions are known freeze-drying conditions, such as temperature of-55 ℃, vacuum degree of 15Pa and freeze-drying time of 48 h.
Has the advantages that: the zopiclone nano preparation disclosed by the invention only consists of the original zopiclone and the stabilizer, has simple components and greatly improves the safety of the medicine. The zopiclone nanometer preparation obviously increases the dissolution speed of the insoluble medicine zopiclone, and the cumulative dissolution rate in 1 hour can reach more than 80 percent. The particle size and the drug-loading rate of the zopiclone nano preparation can be effectively adjusted by changing the proportion of the zopiclone and the stabilizer, and the drug-loading rate can reach 50%. The zopiclone nanometer suspension is frozen and dried into solid powder, so that particle agglomeration caused by long-term placement of the suspension can be avoided, the particle size is increased, and the zopiclone freeze-dried powder has good redispersibility. Can be used as nasal drop for direct administration after redissolution, or used as preparation intermediate, and mixed with other medicinal adjuvants to make into other preparations such as spray. The preparation method disclosed by the invention is simple, convenient and quick to operate, low in cost, safe and nontoxic, and good in process controllability, and the obtained preparation is simple in component, and has the characteristics of high dissolution speed, good stability, high drug content and the like.
Drawings
FIG. 1 is a schematic diagram of the combined ultrasonic spray-precipitation method for preparing nanoparticles;
FIG. 2 is the particle size distribution of zopiclone nanosuspension lyophilized powder after reconstitution;
figure 3 is a transmission electron micrograph of zopiclone nanosuspension;
figure 4 is a release profile of zopiclone nanosuspension and zopiclone drug substance in 0.1mol HCl solution;
FIG. 5 is statistics of the sleep latency of the experimental animal mice;
FIG. 6 is the statistics of sleep time of experimental mice.
Detailed description of the preferred embodiments
In order to make the technical principles and advantages of the present invention more apparent, the present invention is further described in detail below with reference to specific embodiments and the accompanying drawings. In the examples, the zopiclone drug substance and the other reagents used are commercially available.
Example 1: preparation of zopiclone nano preparation
The preparation process schematic diagram of zopiclone nanosuspension is shown in the attached figure 1, and the specific steps are as follows:
50mg of poloxamer 407 is weighed as a stabilizer, 150mL of pure water is added, and the mixture is subjected to ultrasonic treatment for 20 minutes to be completely dissolved to obtain a stabilizer solution. 100mg of zopiclone raw material medicine is weighed and dissolved in 15mL of N, N-dimethylformamide. And (2) spraying the zopiclone solution into the stabilizer solution in the form of atomized liquid under the push of nitrogen by using an ultrasonic sprayer, continuously stirring, wherein the nitrogen pressure is 0.01MPa, the liquid inlet speed is 4.8mL/h, the ultrasonic power is 9W, and further ultrasonically dispersing the crude zopiclone suspension by using an ultrasonic cell disruptor after all the zopiclone solution is sprayed for 15 times, wherein the ultrasonic power is 300W, and the ultrasonic time is 2s and 5 s. Then, the zopiclone nano suspension is pre-frozen for 12 hours at the temperature of minus 80 ℃, and then transferred to a freeze dryer for freeze drying at the temperature of minus 55 ℃ and the vacuum degree of 15Pa for 48 hours to obtain freeze-dried powder. The obtained lyophilized powder has particle size of about 121nm after reconstitution, as shown in figure 2. The drug loading was 64.1%. Taking a proper amount of freeze-dried powder to disperse in pure water to obtain zopiclone nano suspension; and (4) dripping the suspension on a copper net, and forming a thin and uniform sample particle layer after natural air drying. This sample was characterized using TEM and the results are shown in figure 3, with the zopiclone nanoparticles being of uniform spherical structure.
In vitro Release behavior Studies
The in vitro release degree of the physical mixture of the zopiclone raw material medicament and poloxamer 407 and the prepared zopiclone nano suspension freeze-dried powder is measured by adopting a dynamic membrane dialysis method, and the specific method comprises the following steps:
0.1mol/L HCl solution was used as the release medium. Appropriate amount of zopiclone nano freeze-dried powder and physical mixture (the contents of the two drugs and the dispersant are the same) are filled in a dialysis bag (MW8000) which is processed in advance, put in a beaker containing 100mL of release medium and immediately put in a constant temperature oscillator at 37 ℃ and 50 r/min. 3mL were sampled at the predetermined sampling time points (5min, 10min, 20min, 30min, 60min, 90min, 2h, 3h, 4h) and supplemented with an equal amount of fresh medium. The absorbance at 304nm is measured by ultraviolet spectrophotometry, and the cumulative release rate is calculated according to the absorbance result and a previously measured standard curve. The obtained result is shown in figure 4, compared with the original medicine, the zopiclone nano preparation has faster in-vitro release speed, and the cumulative release degree in 1 hour can reach more than 80%.
Animal experiments with zopiclone nano-formulations
(1) Direct sleep experiment
18 ICR mice with the weight of 20 +/-2 g are randomly divided into three groups (blank group, gastric lavage group and nasal group), the nasal group is used for re-dissolving the zopiclone nano freeze-dried powder into the suspension by nasal drip at the dose of 10mg/kg, the gastric lavage group is used for re-dissolving the zopiclone nano freeze-dried powder into the suspension by gastric lavage at the same dose, and the blank group is used for nasal administration of physiological saline with the same volume. After a period of administration, the mice develop sleep. The period from the administration to the occurrence of sleep is the sleep latency. The mice in each group were compared for differences in sleep latency. The results are shown in fig. 5, the sleep latency was greatly reduced in the transnasal and gavage groups compared to the blank group, and the average sleep latency was shorter in the transnasal group than in the gavage group. The zopiclone nano preparation has high-efficiency hypnotic effect, and the nano preparation can take effect more quickly by means of nasal administration.
(2) Experiment for prolonging sleep time of sodium pentobarbital
18 ICR mice with the weight of 20 +/-2 g are randomly divided into three groups (blank group, gastric lavage group and nasal group), the nasal group is used for re-dissolving the zopiclone nano freeze-dried powder into the suspension by nasal drip at the dose of 10mg/kg, the gastric lavage group is used for re-dissolving the zopiclone nano freeze-dried powder into the suspension by gastric lavage at the same dose, and the blank group is used for nasal administration of physiological saline with the same volume. 50mg/kg sodium pentobarbital is injected intraperitoneally 60 minutes after administration. After a period of injection of pentobarbital sodium, the mouse righting reflex disappeared. The time from disappearance of righting reflex to recovery is the sleep time of the animals, and the difference between the sleep time of each administration group and the sleep time of the control group is compared. The results are shown in FIG. 6. Compared with a control group, the sleeping time of the mice in the transnasal group and the gavage group is increased, which shows that the zopiclone nano preparation has the effective sedative and hypnotic effects.
Example 2: preparation of zopiclone nano preparation
Example 2 compared to example 1, only the ratio of stabilizer to zopiclone was changed, specifically described as:
100mg of poloxamer 407 is weighed as a stabilizer, 150mL of pure water is added, and the mixture is subjected to ultrasonic treatment for 20 minutes to be completely dissolved to obtain a stabilizer solution. 100mg of zopiclone raw material medicine is weighed and dissolved in 15mL of N-N dimethylformamide. And (2) spraying the zopiclone solution into the stabilizer solution in the form of atomized liquid under the push of nitrogen by using an ultrasonic sprayer, continuously stirring, wherein the nitrogen pressure is 0.01MPa, the liquid inlet speed is 4.8mL/h, the ultrasonic power is 9W, and further ultrasonically dispersing the crude zopiclone suspension by using an ultrasonic cell disruptor after all the zopiclone solution is sprayed for 15 times, wherein the ultrasonic power is 300W, and the ultrasonic time is 2s and 5 s. Then, the zopiclone nano suspension is pre-frozen for 12 hours at the temperature of minus 80 ℃, and then transferred to a freeze dryer for freeze drying at the temperature of minus 55 ℃ and the vacuum degree of 15Pa for 48 hours to obtain freeze-dried powder.
Example 3: preparation of zopiclone nano preparation
Example 3 compared to example 1, only the kind of stabilizer was changed, specifically described as:
50mg of Tween 80 and a stabilizer are weighed, 150mL of pure water is added, and ultrasonic treatment is carried out for 20 minutes to completely dissolve the Tween 80 and the stabilizer to obtain a stabilizer solution. 100mg of zopiclone raw material medicine is weighed and dissolved in 15mL of N-N dimethylformamide. And (2) spraying the zopiclone solution into the stabilizer solution in the form of atomized liquid under the push of nitrogen by using an ultrasonic sprayer, continuously stirring, wherein the nitrogen pressure is 0.01MPa, the liquid inlet speed is 4.8mL/h, the ultrasonic power is 9W, and further ultrasonically dispersing the crude zopiclone suspension by using an ultrasonic cell disruptor after all the zopiclone solution is sprayed for 15 times, wherein the ultrasonic power is 300W, and the ultrasonic time is 2s and 5 s. Then, the zopiclone nano suspension is pre-frozen for 12 hours at the temperature of minus 80 ℃, and then transferred to a freeze dryer for freeze drying at the temperature of minus 55 ℃ and the vacuum degree of 15Pa for 48 hours to obtain freeze-dried powder.
Example 4: preparation of zopiclone nano preparation
Compared with the embodiment 1, the embodiment 4 only changes the kind and the parts of the stabilizer, and the concrete description is as follows:
100mg of sodium dodecyl sulfate and a stabilizer are weighed, 150mL of pure water is added, and the mixture is subjected to ultrasonic treatment for 20 minutes to be completely dissolved to obtain a stabilizer solution. 100mg of zopiclone raw material medicine is weighed and dissolved in 15mL of N-N dimethylformamide. And (2) spraying the zopiclone solution into the stabilizer solution in the form of atomized liquid under the push of nitrogen by using an ultrasonic sprayer, continuously stirring, wherein the nitrogen pressure is 0.01MPa, the liquid inlet speed is 4.8mL/h, the ultrasonic power is 9W, and further ultrasonically dispersing the crude zopiclone suspension by using an ultrasonic cell disruptor after all the zopiclone solution is sprayed for 15 times, wherein the ultrasonic power is 300W, and the ultrasonic time is 2s and 5 s. Then, the zopiclone nano suspension is pre-frozen for 12 hours at the temperature of minus 80 ℃, and then transferred to a freeze dryer for freeze drying at the temperature of minus 55 ℃ and the vacuum degree of 15Pa for 48 hours to obtain freeze-dried powder.
Example 5: preparation of zopiclone nano preparation
Example 5 compared with example 1, only the kind of organic solvent is changed, specifically described as:
50mg of poloxamer 407 is weighed as a stabilizer, 150mL of pure water is added, and the mixture is subjected to ultrasonic treatment for 20 minutes to be completely dissolved to obtain a stabilizer solution. 100mg of zopiclone raw material drug was weighed and dissolved in 15mL of acetone. And (2) spraying the zopiclone solution into the stabilizer solution in the form of atomized liquid under the push of nitrogen by using an ultrasonic sprayer, continuously stirring, wherein the nitrogen pressure is 0.01MPa, the liquid inlet speed is 4.8mL/h, the ultrasonic power is 9W, and further ultrasonically dispersing the crude zopiclone suspension by using an ultrasonic cell disruptor after all the zopiclone solution is sprayed for 15 times, wherein the ultrasonic power is 300W, and the ultrasonic time is 2s and 5 s. Then, the zopiclone nano suspension is pre-frozen for 12 hours at the temperature of minus 80 ℃, and then transferred to a freeze dryer for freeze drying at the temperature of minus 55 ℃ and the vacuum degree of 15Pa for 48 hours to obtain freeze-dried powder.
Example 6: preparation of zopiclone nano preparation
Example 6 compared with example 1, only the liquid inlet speed and the ultrasonic power of the ultrasonic sprayer are changed, and the specific description is as follows:
50mg of poloxamer 407 is weighed as a stabilizer, 150mL of pure water is added, and the mixture is subjected to ultrasonic treatment for 20 minutes to be completely dissolved to obtain a stabilizer solution. 100mg of zopiclone raw material medicine is weighed and dissolved in 15mL of N-N dimethylformamide. And (2) spraying the zopiclone solution into the stabilizer solution in the form of atomized liquid under the push of nitrogen by using an ultrasonic sprayer, continuously stirring, wherein the nitrogen pressure is 0.01MPa, the liquid inlet speed is 4mL/h, and the ultrasonic power is 9.5W, further ultrasonically dispersing the crude zopiclone suspension by using an ultrasonic cell crusher after all the zopiclone solution is sprayed, wherein the ultrasonic power is 300W, and the ultrasonic is stopped for 5s after 2s, and ultrasonically treating for 15 times. Then, the zopiclone nano suspension is pre-frozen for 12 hours at the temperature of minus 80 ℃, and then transferred to a freeze dryer for freeze drying at the temperature of minus 55 ℃ and the vacuum degree of 15Pa for 48 hours to obtain freeze-dried powder.
Example 7: preparation of zopiclone nano preparation
Example 7 compared with example 1, only the number of times of the ultrasonic wave of the probe is changed, which is specifically described as follows:
the preparation process of zopiclone nanosuspension is schematically shown in figure 1. 50mg of poloxamer 407 is weighed as a stabilizer, 150mL of pure water is added, and the mixture is subjected to ultrasonic treatment for 20 minutes to be completely dissolved to obtain a stabilizer solution. 100mg of zopiclone raw material medicine is weighed and dissolved in 15mL of N-N dimethylformamide. And (2) spraying the zopiclone solution into the stabilizer solution in the form of atomized liquid under the push of nitrogen by using an ultrasonic sprayer, continuously stirring, wherein the nitrogen pressure is 0.01MPa, the liquid inlet speed is 4.8mL/h, the ultrasonic power is 9W, and further ultrasonically dispersing the crude zopiclone suspension by using an ultrasonic cell disruptor after all the zopiclone solution is sprayed for 30 times, wherein the ultrasonic power is 300W, and the ultrasonic time is 2s and 5 s. Then, the zopiclone nano suspension is pre-frozen for 12 hours at the temperature of minus 80 ℃, and then transferred to a freeze dryer for freeze drying at the temperature of minus 55 ℃ and the vacuum degree of 15Pa for 48 hours to obtain freeze-dried powder.
Example 8: preparation of zopiclone nano preparation
Example 8 compared to example 1, only the ratio of stabilizer solution to organic zopiclone solution was changed, specifically described as:
the preparation process of zopiclone nanosuspension is schematically shown in figure 1. 50mg of poloxamer 407 is weighed as a stabilizer, 150mL of pure water is added, and the mixture is subjected to ultrasonic treatment for 20 minutes to be completely dissolved to obtain a stabilizer solution. 100mg of zopiclone raw material medicine is weighed and dissolved in 10mL of N-N dimethylformamide. And (2) spraying the zopiclone solution into the stabilizer solution in the form of atomized liquid under the push of nitrogen by using an ultrasonic sprayer, continuously stirring, wherein the nitrogen pressure is 0.01MPa, the liquid inlet speed is 4.8mL/h, the ultrasonic power is 9W, and further ultrasonically dispersing the crude zopiclone suspension by using an ultrasonic cell disruptor after all the zopiclone solution is sprayed for 15 times, wherein the ultrasonic power is 300W, and the ultrasonic time is 2s and 5 s. Then, the zopiclone nano suspension is pre-frozen for 12 hours at the temperature of minus 80 ℃, and then transferred to a freeze dryer for freeze drying at the temperature of minus 55 ℃ and the vacuum degree of 15Pa for 48 hours to obtain freeze-dried powder.
Example 9: preparation of zopiclone nano preparation
Example 9 compared to example 1, only the parts of zopiclone and the ratio of the stabilizer solution to the organic zopiclone solution were changed, specifically described as follows:
the preparation process of zopiclone nanosuspension is schematically shown in figure 1. 50mg of poloxamer 407 is weighed as a stabilizer, 150mL of pure water is added, and the mixture is subjected to ultrasonic treatment for 20 minutes to be completely dissolved to obtain a stabilizer solution. 50mg of zopiclone raw material medicine is weighed and dissolved in 20mL of N-N dimethylformamide. And (2) spraying the zopiclone solution into the stabilizer solution in the form of atomized liquid under the push of nitrogen by using an ultrasonic sprayer, continuously stirring, wherein the nitrogen pressure is 0.01MPa, the liquid inlet speed is 4.8mL/h, the ultrasonic power is 9W, and further ultrasonically dispersing the crude zopiclone suspension by using an ultrasonic cell disruptor after all the zopiclone solution is sprayed for 15 times, wherein the ultrasonic power is 300W, and the ultrasonic time is 2s and 5 s. Then, the zopiclone nano suspension is pre-frozen for 12 hours at the temperature of minus 80 ℃, and then transferred to a freeze dryer for freeze drying at the temperature of minus 55 ℃ and the vacuum degree of 15Pa for 48 hours to obtain freeze-dried powder.
Claims (10)
1. A zopiclone suspension nanometer preparation administrated through a nasal cavity is characterized in that each 3000 weight parts of the preparation comprises 1-6 parts of zopiclone, 1-3 parts of a stabilizer and the balance of water.
2. The zopiclone suspension nano-preparation for nasal administration according to claim 1, wherein the preparation comprises 2 to 3 parts of zopiclone, 1 to 3 parts of stabilizer and the balance of water by weight of 3000 parts of the preparation.
3. The NanoTab suspension for nasal administration according to claim 1, wherein said stabilizer is selected from the group consisting of water-soluble nonionic surfactants and ionic surfactants.
4. The zopiclone suspension nanoformulation for nasal administration of claim 1, wherein the water-soluble non-ionic surfactant is selected from the group consisting of poloxamer and tween and the ionic surfactant is sodium lauryl sulfate.
5. The zopiclone suspension nanoformulation for nasal administration according to claim 1, wherein the stabilizer is one or a mixture of poloxamer 407 and tween 80.
6. A method of making a NanoTaulation of zopiclone suspension for nasal administration according to any of claims 1-5, using a combination of ultrasonic spraying and precipitation, comprising the steps of:
(1) weighing the stabilizer with the formula ratio, adding pure water, and dissolving to obtain a stabilizer solution;
(2) weighing zopiclone raw material medicine according to the formula ratio, and dissolving the zopiclone raw material medicine in an organic solvent to obtain an organic zopiclone solution;
(3) ultrasonically atomizing the zopiclone organic solution obtained in the step (2), spraying the organic solution into the stabilizer solution obtained in the step (1), and keeping continuously stirring to obtain a zopiclone suspension;
(4) ultrasonically dispersing the zopiclone suspension obtained in the step (3) by using an ultrasonic cell disruption instrument to obtain a suspension, namely, a zopiclone nano suspension;
(5) freeze-drying the zopiclone nano suspension obtained in the step (4) to obtain zopiclone nano freeze-dried powder;
(6) and (3) fully dispersing the zopiclone nano freeze-dried powder obtained in the step (5) into pure water according to the requirement of the net content of the final preparation medicament, and performing ultrasonic dispersion to obtain a zopiclone suspension nano preparation capable of being administrated through a nasal cavity.
7. The method according to claim 6, wherein in the step (2), the organic solvent is one or more selected from acetone, N-N dimethylformamide, dimethyl sulfoxide and methanol.
8. The method according to claim 6, wherein in the step (3), the volume of the stabilizer solution is 10 to 50 times that of the organic zopiclone solution.
9. The preparation method according to claim 6, wherein in the step (3), the organic zopiclone solution obtained in the step (2) is ultrasonically atomized and sprayed into the stabilizer solution obtained in the step (1) under the driving of nitrogen by using an ultrasonic sprayer, wherein the nitrogen pressure for driving the zopiclone solution is 0.01-0.1MPa, the liquid inlet speed of the organic zopiclone solution is 4-5mL/h, and the ultrasonic power is 8.5-9.5W.
10. The preparation method according to claim 6, wherein in the step (4), the ultrasonic power of the probe used by the cell disruptor is 250-350W, and the ultrasonic is suspended for 1-5s every 1-5s for 15-30 times.
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CN103169649A (en) * | 2013-04-11 | 2013-06-26 | 中国人民解放军总医院 | Temperature and ion dual-sensitive in-situ gel nasal cavity drug delivery system |
CN109803663A (en) * | 2016-06-03 | 2019-05-24 | 马特恩制药股份公司 | Nasal medicine composition with porous excipient |
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