CN111991397A - Flupentixol melitracen microsphere and preparation method thereof - Google Patents
Flupentixol melitracen microsphere and preparation method thereof Download PDFInfo
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- CN111991397A CN111991397A CN202011091871.0A CN202011091871A CN111991397A CN 111991397 A CN111991397 A CN 111991397A CN 202011091871 A CN202011091871 A CN 202011091871A CN 111991397 A CN111991397 A CN 111991397A
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- Prior art keywords
- flupentixol
- melitracen
- hydrochloride
- drug
- preparation
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Links
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- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
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- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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Abstract
The invention relates to the technical field of medicines, and particularly relates to flupentixol melitracen microspheres and a preparation method thereof. The flupentixol and melitracen microsphere comprises flupentixol hydrochloride, melitracen hydrochloride and a polyester material, and has the advantages of no organic solvent, simple preparation process, high drug loading, remarkable slow release effect and capability of being used for long-acting injection.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to flupentixol melitracen microspheres and a preparation method thereof.
Background
Flupentixol-melitracen (Flupentixol-melitracen) contains Flupentixol and melitracen as two components. Flupentixol acts as an antipsychotic by antagonizing dopamine D2 receptors in the brain. Melitracen is a tricyclic antidepressant drug, and has the functions of antagonizing reserpine, resisting catalepsy and enhancing epinephrine and NA. The combination of flupentixol and melitracen can improve the content of various neurotransmitters such as synaptic cleft DA, NV and 5-HT in brain, thereby regulating the function of the central nervous system, and is suitable for neurasthenia, chronic fatigue syndrome, depression or anxiety neurosis, cardiac or gastrointestinal neurosis, autonomic nervous dysfunction and various depression anxiety states; also useful for neuropathic headache, migraine, tension headache, trigeminal neuralgia, sciatica, certain types of intractable pain and chronic pain conditions.
At present, various documents disclose flupentixol and melitracen compound preparation and a preparation method thereof.
Chinese patent application CN101912397A discloses a flupentixol and melitracen tablet containing cyclodextrin, hydrogenated vegetable oil, lactose, starch, hydroxypropyl cellulose, microcrystalline cellulose and other excipients, wherein in one embodiment, a flupentixol premix is mixed with beta-cyclodextrin, lactose monohydrate, corn starch, and hydroxypropyl cellulose, purified water is added for wet granulation to obtain flupentixol granules, and then melitracen, corn starch, lactose monohydrate, and hydroxypropyl cellulose are mixed, purified water is added for wet granulation to obtain melitracen granules, and the flupentixol granules and melitracen granules are combined, mixed with microcrystalline cellulose, croscarmellose sodium, talc powder, hydroxypropyl cellulose, hydrogenated vegetable oil, and magnesium stearate, and tabletted. The process adopts beta cyclodextrin as a stabilizer, the dosage is large, and the tablet is easy to absorb moisture.
Chinese patent application CN105663062A discloses a flupentixol melitracen pharmaceutical composition and a preparation method thereof, and a flupentixol melitracen tablet prepared from the composition. In the flupentixol and melitracen pharmaceutical composition, flupentixol and melitracen are uniformly mixed according to the following method: the melitracen was added to flupentixol homogeneously in portions under counter jet milling for mixing. The operation method is simple, the cost is low, the uniformity of the flupentixol and melitracen medicinal composition can be obviously improved, and the dissolution rates of the flupentixol and the melitracen are also obviously improved. However, the jet milling has large energy consumption and unstable yield, the process controllability and reproducibility are difficult to ensure, the irritation of flupentixol hydrochloride and melitracen hydrochloride is strong, dust flies in the production process, and the operation feasibility is poor.
The flupentixol hydrochloride is the hydrochloride form of the atypical antipsychotic flupentixol, is a thioxanthine derivative, has strong dopamine receptor blocking effect, and has anxiolytic and antidepressant effects in small dose. The melitracen hydrochloride is a tricyclic biphasic antidepressant, and has an excitation characteristic when being applied at a low dose. The finished products prepared by the patent application are all short-acting preparations and need to be taken every day, and in the actual application process, clinicians reflect that patients suffering from depression often deny their own diseases, and the compliance of taking medicine is poor. Therefore, the development of long-acting antidepressant preparations capable of realizing sustained release of the drug is imperative.
Sustained release of the drug can be achieved in a number of ways, including: repeated oral administration, repeated topical (transdermal) administration, repeated pulmonary administration, and long-acting injections. Long acting injections have many natural advantages over other delivery systems, firstly a prolonged duration of action. Repeated administration can cause peak-valley phenomenon, and the long-acting injection slowly releases the drug, so that the blood concentration is kept between the minimum treatment concentration and the safety threshold, thereby being beneficial to reducing the toxic and side effects of the drug and prolonging the action time of the drug. Secondly, the long-acting injection can reduce the administration times and improve the compliance of patients.
A wide variety of delivery systems are used to design long acting injections, including oily solutions and suspensions, aqueous suspensions, in situ gels, microspheres, liposomes, and the like. The microspheres are solid spherical particles with a particle size within the range of 1000 μm. They consist of natural or synthetic polymers in which drugs or other biologically active substances are entrapped or encapsulated. Microspheres have their own advantages over other sustained and controlled release drug delivery systems, such as: (1) the release rate and the release duration of the drug can be adjusted by changing materials and preparation processes; (2) compared with other drug controlled release systems such as liposomes, the stability of the microspheres is better.
However, the microsphere preparation process is complex: the emulsification-solvent evaporation method generally requires the use of an organic solvent and an aqueous solution containing the emulsifier to prepare a single emulsion or a multiple emulsion, stirring and volatilizing to remove the organic solvent, washing off the emulsifier in the process of collecting microspheres, and finally carrying out vacuum drying or freeze drying to obtain the final product. The spray drying method needs a large amount of organic solvent, and has higher requirement on equipment explosion prevention. When preparing a microsphere loaded with different drugs, due to differences in drug properties (such as solubility, particle size, crystal form and drug-polymer interaction), a series of experiments are repeated to optimize the formulation in order to increase drug loading and achieve the desired drug release.
Therefore, it is very necessary to develop flupentixol melitracen microspheres and a preparation method thereof, which can solve the above technical problems.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide flupentixol melitracen microspheres which do not contain organic solvents, have simple preparation process, high drug loading and obvious slow-release effect and can be used for long-acting injection and a preparation method thereof.
The invention is realized by the following technical scheme:
a flupentixol melitracen microsphere comprises flupentixol hydrochloride, melitracen hydrochloride and a polyester material.
Preferably, the mass ratio of the flupentixol hydrochloride to the melitracen hydrochloride is 1: 15-25.
More preferably, the mass ratio of flupentixol hydrochloride to melitracen hydrochloride is 1: 20.
Preferably, the mass ratio of the melitracen hydrochloride to the polyester material is 1: 0.8-1.2.
More preferably, the mass ratio of the melitracen hydrochloride to the polyester material is 1: 1.
Preferably, the polyester material is one or more of polylactide, polyglycolide, and polylactide-glycolide copolymers.
The invention also relates to a preparation process of the flupentixol melitracen microsphere, which comprises the following steps: mixing the polyester material, the melitracen hydrochloride and the flupentixol hydrochloride, carrying out hot melting extrusion, cooling and crushing to obtain the finished product.
Preferably, the temperature of the hot melt extrusion is 115-150 ℃.
Preferably, said hot-melt extrusion gives a cylindrical intermediate with a diameter of 2 to 4 mm.
Preferably, the crushed mesh number is 70-200 meshes.
More preferably, the preparation process comprises the following steps: the polyester material, the melitracen hydrochloride and the flupentixol hydrochloride are uniformly mixed according to a proportion, and are subjected to hot melting extrusion at 115-150 ℃, cooling and cutting to obtain a cylindrical intermediate with the diameter of 2-4mm, and the cylindrical intermediate is crushed to 70-200 meshes to obtain the finished product.
The invention also relates to a preparation process of the flupentixol melitracen microsphere, which comprises the following steps: mixing the polyester material and the melitracen hydrochloride, carrying out hot melting extrusion, cooling, crushing, and adding flupentixol hydrochloride to obtain the finished product.
Preferably, the temperature of the hot melt extrusion is 115-150 ℃.
Preferably, said hot-melt extrusion gives a cylindrical intermediate with a diameter of 2 to 4 mm.
Preferably, the crushed mesh number is 70-200 meshes.
Preferably, the flupentixol hydrochloride is crushed, sieved by a 190-mesh sieve of 170-.
More preferably, the preparation process comprises the following steps: mixing the polyester material and melitracen hydrochloride, carrying out hot melting extrusion at the temperature of 115-200 ℃, cooling and cutting to obtain a cylindrical intermediate with the diameter of 2-4mm, crushing to 70-200 meshes, and adding 170-190 meshes of flupentixol hydrochloride to obtain the flupentixol hydrochloride.
The invention also relates to a pharmaceutical preparation which comprises the flupentixol melitracen microsphere or the flupentixol melitracen microsphere prepared by the preparation method.
Preferably, the pharmaceutical formulation is an injectable formulation.
Preferably, the pharmaceutical formulation further comprises pharmaceutically acceptable excipients.
More preferably, the pharmaceutically acceptable excipients include one or more of osmotic pressure regulators, pH regulators, solubilizers, antioxidants, bacteriostats, emulsifiers, and suspending agents.
Preferably, the preparation for injection is one of injection, sterile powder for injection and concentrated solution for injection, and can be used for intramuscular injection, intravenous drip and the like.
The invention has the beneficial effects that:
the invention adopts the polyester material, the melitracen hydrochloride and the flupentixol hydrochloride to prepare the flupentixol melitracen microsphere, thereby effectively improving the drug loading rate and the slow release effect.
The invention adopts the hot-melt extrusion technology to prepare the cylindrical small rod containing the melitracen hydrochloride, the flupentixol hydrochloride and the polyester material, and the drug-carrying microspheres are obtained after crushing, compared with the single emulsion method, the drug-carrying amount of the drug is obviously improved; compared with spray drying method, the method avoids the burst effect of the medicine. The drug-loaded microspheres prepared by the invention meet the requirement of long-acting release for two weeks in an in vitro release medium, and no organic solvent is needed in the preparation process, thereby avoiding the generation of three wastes.
The preparation method is simple in preparation process, strong in operability and beneficial to industrial production.
Drawings
FIG. 1 is a release curve diagram of flupentixol hydrochloride in each example of preparing drug-loaded microspheres by spray drying method.
Fig. 2 is a release curve diagram of melitracen hydrochloride in each example of preparation of drug-loaded microspheres by spray drying method.
FIG. 3 is a release curve diagram of flupentixol hydrochloride in each example of preparing drug-loaded microspheres by hot-melt extrusion.
Fig. 4 is a release curve diagram of melitracen hydrochloride in each example of preparation of drug-loaded microspheres by a hot-melt extrusion method.
FIG. 5 is a scanning electron microscope image of each example of preparing drug-loaded microspheres by spray drying method (upper left: example 5, upper right: example 6, lower left: example 7, and lower right: example 8).
FIG. 6 is a scanning electron microscope image of each example of the preparation of drug-loaded microspheres by hot-melt extrusion (top left: example 9, top right: example 10, bottom left: example 11, and bottom right: example 12).
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
1.1 preparation of microspheres by Single emulsion Process
Dissolving a certain amount of main drug and polylactide in dichloromethane to obtain an oil phase, injecting the oil phase into an external aqueous phase polyvinyl alcohol solution which is stirred at a high speed (7000rpm), volatilizing for 4 hours, centrifuging, removing the external aqueous phase, freeze-drying to obtain drug-loaded microspheres, and measuring the drug-loaded capacity of the drug-loaded microspheres, wherein the specific table is shown in table 1.
Table 1 single emulsion method for preparing drug-loaded microspheres formula information and drug-loading amount of each example
As shown in Table 1, the drug-loaded microspheres containing only one main drug prepared by the single emulsion method have extremely low drug loading rate, even 0, and the preparation is unsuccessful. The drug-loaded microspheres containing two main drugs (the mass ratio of flupentixol hydrochloride to melitracen hydrochloride is 1:20) are prepared by the same method as the example 3, and the preparation is not successful.
1.2 spray drying method for preparing drug-loaded microspheres
Dissolving a certain amount of melitracen hydrochloride and polylactide in dichloromethane to obtain a solution A, spray-drying (air inlet temperature: 45.0 ℃, blower frequency: 10.0Hz and atomization pressure: 0.2MPa) to obtain drug-loaded particles, and then adding flupentixol hydrochloride and the drug-loaded particles to mix to obtain the drug-loaded microspheres. The drug-loaded amount of two main drugs in the drug-loaded microspheres is measured as shown in table 2, a small amount of the drug-loaded microspheres are put into a dialysis bag, a release medium (phosphate buffer solution) with the pH value of 7.4 is added, the mass-to-volume ratio of the drug-loaded microspheres to the release medium is 0.625mg/ml, the drug-loaded microspheres and the release medium are placed into a constant-temperature culture oscillator (37 +/-0.5 ℃, 50rpm) for incubation, and the drug-loaded microspheres are taken out at a preset time point to measure the drug release degree, which is specifically shown in table 3-table 4 and fig.. Characterization data for drug-loaded microspheres are shown in figure 5.
Table 2 spray drying method for preparing drug-loaded microspheres, prescription information and drug-loading amount of each example
Table 3 spray drying method for preparation of drug-loaded microparticles each example flupentixol hydrochloride release
TABLE 4 spray drying preparation of drug loaded microparticles the release rate of melitracen hydrochloride of each example
1.3 preparation of drug-loaded microspheres by hot-melt extrusion method
Examples 9-12 Hot melt extrusion Using a Pharma 11 hot melt extruder, available from Thermo Fisher Scientific.
1.3.1 Add flupentixol hydrochloride before Hot melt extrusion: mixing polylactide, melitracen hydrochloride and flupentixol hydrochloride, feeding, carrying out hot melt extrusion, cooling, cutting into sections, preparing a long cylindrical (diameter is 3mm) intermediate, and crushing to 130 meshes to obtain the drug-loaded microspheres.
1.3.2 hot melt extrusion of flupentixol hydrochloride followed by addition of: mixing polylactide and melitracen hydrochloride, feeding the mixture, performing hot melt extrusion, cooling and cutting the mixture into sections to prepare a long cylindrical (with the diameter of 3mm) intermediate, crushing the intermediate into 130 meshes to obtain drug-loaded particles, and adding flupentixol hydrochloride to the drug-loaded particles for mixing to obtain the drug-loaded microspheres.
1.3.3 the contents of the two main drugs of the drug-loaded microsphere are measured, as shown in Table 5. And a small amount of the microspheres is put into a dialysis bag, a release medium (phosphate buffer solution) with the pH value of 7.4 is added, the mass-to-volume ratio of the drug-loaded microspheres to the release medium is 0.625mg/ml, the dialysis bag is placed in a constant temperature culture shaker (37 +/-0.5 ℃ and 50rpm) for incubation, and the microspheres are taken out at a preset time point to measure the drug release degree, which is specifically shown in table 6-table 7 and fig. 3-fig. 4. Characterization data for drug-loaded microspheres are shown in figure 6.
Table 5 preparation of drug-loaded microspheres by hot melt extrusion method prescription information and drug-loading amount of each example
TABLE 6 preparation of drug-loaded microparticles by Hot melt extrusion method for the Release degree of flupentixol hydrochloride of each example
TABLE 7 preparation of drug-loaded microparticles by Hot melt extrusion method the release rate of melitracen hydrochloride in each example
The above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.
Claims (10)
1. A flupentixol melitracen microsphere is characterized by comprising flupentixol hydrochloride, melitracen hydrochloride and a polyester material.
2. Flupentixol and melitracen hydrochloride microspheres according to claim 1, characterized in that the mass ratio of flupentixol hydrochloride to melitracen hydrochloride is 1:15-25, preferably 1: 20; the mass ratio of the melitracen hydrochloride to the polyester material is 1:0.8-1.2, and preferably 1: 1.
3. Flupentixol melitracen microspheres according to claim 2, wherein the polyester material is one or more of polylactide, polyglycolide and polylactide-glycolide copolymers.
4. A process for the preparation of flupentixol melitracen microspheres as claimed in any one of claims 1 to 3, characterized in that it comprises the following steps: mixing the polyester material, the melitracen hydrochloride and the flupentixol hydrochloride, carrying out hot melting extrusion, cooling and crushing to obtain the finished product.
5. The process according to claim 4, wherein the temperature of the hot-melt extrusion is 115-150 ℃.
6. A process for the preparation of flupentixol melitracen microspheres as claimed in any one of claims 1 to 3, characterized in that it comprises the following steps: and uniformly mixing the polyester material and the melitracen hydrochloride according to a proportion, carrying out hot melting extrusion, cooling, crushing, and adding flupentixol hydrochloride to obtain the compound.
7. The process according to claim 6, wherein the temperature of the hot-melt extrusion is 115-150 ℃.
8. The process according to claim 6, wherein the hot-melt extrusion gives a cylindrical intermediate having a diameter of 2 to 4mm, and the crushed mesh size is 70 to 200 mesh.
9. A pharmaceutical preparation comprising the flupentixol melitracen microspheres according to any one of claims 1 to 3 or the flupentixol melitracen microspheres prepared by the preparation method according to any one of claims 4 to 8.
10. The pharmaceutical formulation of claim 9, wherein the pharmaceutical formulation is an injectable formulation.
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| US5871778A (en) * | 1992-11-17 | 1999-02-16 | Yoshitomi Pharmaceutical Industries, Ltd. | Sustained release microsphere preparation containing antipsychotic drug |
| US20130217673A1 (en) * | 2012-02-22 | 2013-08-22 | Warsaw Orthopedic, Inc | Mixed monoamine reuptake inhibitor in a biodegradable polymer carrier |
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| US20190160182A1 (en) * | 2016-06-09 | 2019-05-30 | Yang Der TIEN | Nanodroplet compositions for the efficient delivery of anti-cancer agents |
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| US5871778A (en) * | 1992-11-17 | 1999-02-16 | Yoshitomi Pharmaceutical Industries, Ltd. | Sustained release microsphere preparation containing antipsychotic drug |
| US20130217673A1 (en) * | 2012-02-22 | 2013-08-22 | Warsaw Orthopedic, Inc | Mixed monoamine reuptake inhibitor in a biodegradable polymer carrier |
| CN105663062A (en) * | 2016-02-17 | 2016-06-15 | 南京卓泰医药科技有限公司 | Flupentixol and melitracen medicine composition and preparation method thereof |
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