CN109984999A - A kind of pharmaceutical composition and its preparation method and application - Google Patents
A kind of pharmaceutical composition and its preparation method and application Download PDFInfo
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- CN109984999A CN109984999A CN201910349031.0A CN201910349031A CN109984999A CN 109984999 A CN109984999 A CN 109984999A CN 201910349031 A CN201910349031 A CN 201910349031A CN 109984999 A CN109984999 A CN 109984999A
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- pharmaceutical composition
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- composition according
- cithrol
- insoluble
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- -1 Sorbitan ester Chemical class 0.000 claims abstract description 24
- 229960004372 aripiprazole Drugs 0.000 claims abstract description 17
- 238000002347 injection Methods 0.000 claims abstract description 15
- 239000007924 injection Substances 0.000 claims abstract description 15
- 239000000164 antipsychotic agent Substances 0.000 claims abstract description 13
- 239000008135 aqueous vehicle Substances 0.000 claims abstract description 12
- 229940005529 antipsychotics Drugs 0.000 claims abstract description 9
- 239000002245 particle Substances 0.000 claims abstract description 9
- 229940102213 injectable suspension Drugs 0.000 claims abstract description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 10
- 239000003002 pH adjusting agent Substances 0.000 claims description 10
- 239000011780 sodium chloride Substances 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 8
- 239000012530 fluid Substances 0.000 claims description 7
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 5
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 5
- 229930195729 fatty acid Natural products 0.000 claims description 5
- 239000000194 fatty acid Substances 0.000 claims description 5
- 150000004665 fatty acids Chemical class 0.000 claims description 5
- 201000000980 schizophrenia Diseases 0.000 claims description 5
- 230000000561 anti-psychotic effect Effects 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 4
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 2
- 229940100242 glycol stearate Drugs 0.000 claims description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims 1
- 229940070765 laurate Drugs 0.000 claims 1
- 238000005303 weighing Methods 0.000 claims 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 abstract description 9
- 229940002612 prodrug Drugs 0.000 abstract description 4
- 239000000651 prodrug Substances 0.000 abstract description 4
- 239000000725 suspension Substances 0.000 abstract description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 12
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical class CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 12
- 239000002075 main ingredient Substances 0.000 description 11
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 11
- 239000008215 water for injection Substances 0.000 description 11
- 206010018910 Haemolysis Diseases 0.000 description 8
- 230000008588 hemolysis Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 229960001340 histamine Drugs 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 5
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000002427 irreversible effect Effects 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 208000020925 Bipolar disease Diseases 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- DDINXHAORAAYAD-UHFFFAOYSA-N aripiprazole lauroxil Chemical compound C1=C2N(COC(=O)CCCCCCCCCCC)C(=O)CCC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC(Cl)=C1Cl DDINXHAORAAYAD-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 108010050939 thrombocytin Proteins 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 229960003798 aripiprazole lauroxil Drugs 0.000 description 1
- 229940075231 aristada Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 208000025307 bipolar depression Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000000879 optical micrograph Methods 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000011164 primary particle Substances 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Dermatology (AREA)
- Psychiatry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dispersion Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a kind of pharmaceutical compositions, including following components: water-insoluble antipsychotics；Cithrol；Sorbitan ester and aqueous vehicles；What described pharmaceutical composition was formed is aqueous, injectable suspension.The water-insoluble antipsychotics is Aripiprazole prodrug --- lauroyl Aripiprazole, selection suitable particle diameter and the pharmaceutical composition of specific prescription proportion preparation prepare the good, release with stability and meet the requirements and especially have the clinic mixed suspension injection of good safety, have high application value.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of pharmaceutical composition and its preparation method and application.
Background technique
Aripiprazole (Aripiprazole), chemical name are as follows: 7- { 4- [4- (2,3- dichlorophenyl) -1- piperazinyl] fourth
Oxygroup } -3 4- dihydro -2- (lH)-Kui quinoline ketone, molecular formula C23H27N3O2Cl2, molecular weight 448.4, chemical structural formula are as follows:
Aripiprazole is dopamine D 2 partial agonist, thrombocytin 5-HT1AReceptor stimulating agent and thrombocytin 5-HT2AReceptor
Antagonist.As useful antipsychotic drug in schizophrenia, bipolar disorders, depression and the treatment of other CNS diseases
Object.
Lauroyl Aripiprazole (Aripiprazole lauroxil) is the prodrug of Aripiprazole, is situated between in vivo through enzyme
It leads catalyzing hydrolysis and forms N- methylol Aripiprazole, be then hydrolyzed into Aripiprazole, and then play antipsychotic effect.Love
The granted listing of lauroyl Aripiprazole long-acting injection of Er Lan Alkermes company research and development, trade name Aristada.The medicine
Object is release injectable suspension, monthly injects long-acting treatment atypical psychotropic division disease drug primary or that injection in every 6 weeks is primary,
For adult schizoid treatment.But other slow-release injected auxiliary materials used above-mentioned and in the prior art can be made
At adverse reactions such as haemolysis.Therefore, the safety and validity for improving Aripiprazole prodrug sustained release injection, are urgently to be resolved
Problem.
Summary of the invention
The present invention is intended to provide the controlled-release preparation composite of a kind of Aripiprazole and its prodrug, to solve the above problems.
The first aspect of the present invention provides a kind of pharmaceutical composition, which is characterized in that including following components:
(d) water-insoluble antipsychotics；
(e) cithrol；
(f) sorbitan fatty esters；
(c) aqueous vehicles；
What described pharmaceutical composition was formed is aqueous, injectable suspension.
Further alternative, the water-insoluble antipsychotics accounts for 10~30wt% in described pharmaceutical composition；
Preferably, content is 15~28wt%；
Further alternative, the cithrol accounts for 0.05~1wt% in described pharmaceutical composition；It is preferred that
, content is 0.1%~0.3wt%；
It is further alternative, the sorbitan fatty esters account in described pharmaceutical composition 0.05~
1wt%；Preferably, content is 0.3%~0.5wt%；
Further, the cithrol and the mass ratio of sorbitan fatty esters be 1:1~
1:4；Preferably, mass ratio 1:3.8；
Further, the sum of the cithrol and sorbitan fatty esters mass content account for institute
State 0.15~2wt% in pharmaceutical composition；
Further alternative, it is 68~89% that the aqueous vehicles, which account for the mass fraction in described pharmaceutical composition,；
Further, the water-insoluble antipsychotic drug is lauroyl Aripiprazole, and structural formula is as follows:
Further, in the cithrol, the fatty acid includes 12 to 22 carbon atoms, the poly- second
Glycol average molecular weight range 400 to 8000；Preferably, the cithrol is polyethylene glycol stearate
(Kolliphor)；
Further, in the sorbitan fatty esters, the fatty acid includes 10 to 20 carbon atoms；It is preferred that
, the sorbitan fatty esters are sorbitan laurate esters (SPAN 20)；
Further, the aqueous vehicles include water for injection, sodium chloride and pH adjusting agent；
Further, the pH adjusting agent is disodium hydrogen phosphate and/or sodium dihydrogen phosphate；
Further, the partial size of the water-insoluble antipsychotics is D10: 2 μm~10 μm, and D50: 10 μm~30
μm, and D90: 65 μm of <；Another aspect of the present invention is to provide the preparation method of any composition as above, which is characterized in that packet
Include following steps:
S1: cithrol and sorbitan fatty esters are weighed by said ratio, appropriate volume is added
Water for injection makes it dissolve, and is prepared into auxiliary material mixed liquor；
S2: sodium chloride and pH adjusting agent are weighed by said ratio, is prepared into aqueous vehicles；
S3: after aqueous vehicles described in auxiliary material mixed liquor described in S1 and S2 are sufficiently mixed, then appropriate particle size is added
Water-insoluble antipsychotics prepare medical fluid, then with homogenizer be sufficiently mixed medical fluid to get.
Another convenience, the present invention also provides described in any item pharmaceutical compositions as above to treat antipsychotic drugs in preparation
In purposes.
Further, the treatment antipsychotic drugs are the drugs for treating schizophrenia or schizophrenia sample disease.
Detailed description of the invention
Fig. 1 is the experiment of different-grain diameter product vitro release
Fig. 2A indicates that original grinds the partial size of reference preparation
What Fig. 2 B was indicated is the product cut size of 1 preparation of embodiment
Beneficial effect
The used new non-ionic surfactants cithrol of the present invention, has the advantage that compared with tween
Class nonionic surface active agent is safer, no hemolytic, no skin, eye irritation improve Drug safety；
And solubilising power is more brilliant, can linearly increase, can be dropped with the increase of concentration to the solubilising power of different dewatering medicaments
Low solubilizer dosage increases drug safety；In addition, the surfactant viscosity is relatively slow, it can be achieved that high concentration with concentration increase
When low injection pain, to increase patient's compliance.
Specific embodiment
The present invention is further explained in the light of specific embodiments, to help the contents of the present invention are understood.
1. the explanation of auxiliary material used in is as shown in table 1:
Table 1
2. bulk pharmaceutical chemicals size controlling
For the redispersibility and stability for guaranteeing product, need to control main ingredient partial size.Conventional particle size control method
Mainly have and 1) recrystallizes, 2) air-flow crushing, 3) ball mill grinding.
By taking lauroyl Aripiprazole as an example, it is suspended prepared by main ingredient and excipient after being handled using different air-flow crushing conditions
Type injection release in vitro situation is shown in Fig. 1, and rate of release increases with air-flow crushing pressure increase, but reaches master after certain pressure
Powder diameter no longer significantly reduces, and also no longer with pressure increase is crushed significant changes occur for rate of release.It can be seen that in this hair
In the range of bright selected partial size (65 μm of D10:2~10 μm, D50:10~30 μm and D90 <), the present invention is prepared mixed
Outstanding note type penetrates agent energy sustained release, is able to satisfy clinical demand, realizes long-term effectiveness.
Additionally, it is preferred that preparation prepared by main ingredient partial size and original, which grind reference preparation optical microphotograph sem observation result, sees Fig. 2 (packet
Include Fig. 2A and Fig. 2 B) it is found that Fig. 2A expression is that original grinds reference preparation, what Fig. 2 B was indicated is the preparation of embodiment 1.Embodiment 1
Form is similar under both preparation and former triturates microscope, is irregular crystal, moiety aggregation；The two particle size range also phase
Seemingly.
3. the pharmaceutical composition of Examples 1 to 5 preparation
According to above-mentioned primary particle size the selection result, following all examples and comparative example all use the main ingredient of above-mentioned partial size into
Row preparation.
3.1 prescription proportion is as shown in table 1:
Table 1
3.2 preparation method
Embodiment 1-6 the preparation method is as follows:
S1: it is weighed by said ratioHS-15 and span 20, appropriate volume water for injection, which is added, keeps its molten
Solution, is prepared into auxiliary material mixed liquor；S2: sodium chloride and pH adjusting agent disodium hydrogen phosphate and biphosphate are weighed by said ratio
Sodium is prepared into aqueous vehicles；S3: after aqueous vehicles described in auxiliary material mixed liquor described in S1 and S2 are sufficiently mixed, then
Addition appropriate particle size main ingredient prepare medical fluid, then with the abundant medical fluid of homogenizer to get.
3.3 experimental results: can form suspension emulsion, and no oily precipitating can be suspended for a long time without irreversible heavy
Drop.
4. the preparation of comparative example 1~3
4.1 comparative examples 1
Prescription:
The preparation method is as follows:
Span 20 and Tween 80 are weighed by above-mentioned prescription proportion, appropriate volume water for injection is added and makes it dissolve, then weighs
Water for injection is mended to enough after completely dissolution, injection medium is made by recipe quantity sodium chloride and pH adjusting agent.By appropriate particle size
Main ingredient be added in the injection Vehicle of preparation, main ingredient is mixed with medium using homogenizer.
Experimental result: solution occurs muddy after span 20 and Tween 80 mixing, can not carry out subsequent preparation, illustrate span 20
And Tween 80 compatibility is bad.
4.2 comparative examples 2
Prescription:
| Supplementary material (g) | Dosage |
| Lauroyl Aripiprazole | 27.56 |
| Polysorbas20 | 0.10 |
| Span 20 | 0.38 |
| Sodium chloride | 0.60 |
| Disodium hydrogen phosphate | 0.05 |
| Sodium dihydrogen phosphate | 0.05 |
| Water for injection | To 100g |
The preparation method is as follows:
Span 20 and polysorbas20 are weighed by above-mentioned prescription proportion, appropriate volume water for injection is added and makes it dissolve, then weighs
Water for injection is mended to enough after completely dissolution, injection medium is made by recipe quantity sodium chloride and pH adjusting agent.By appropriate particle size
Main ingredient be added in the injection Vehicle of preparation, main ingredient is mixed with medium using homogenizer.
Experimental result: can form suspension emulsion after span 20 and polysorbas20 mixing, no oily precipitating occurs after 60 days
Irreversible sedimentation, stability is bad, therefore no longer carries out follow-up study.
4.3 comparative examples 3
Prescription:
| Supplementary material (g) | Dosage |
| Lauroyl Aripiprazole | 27.56 |
| Polysorbas20 | 0.15 |
| Span 20 | 0.38 |
| Sodium chloride | 0.60 |
| Disodium hydrogen phosphate | 0.05 |
| Sodium dihydrogen phosphate | 0.05 |
| Water for injection | To 100g |
The preparation method is as follows:
Span 20 and polysorbas20 are weighed by above-mentioned prescription proportion, appropriate volume water for injection is added and makes it dissolve, then weighs
Water for injection is mended to enough after completely dissolution, injection medium is made by recipe quantity sodium chloride and pH adjusting agent.By appropriate particle size
Main ingredient be added in the injection Vehicle of preparation, main ingredient is mixed with medium using homogenizer.
Experimental result: can form suspension emulsion after span 20 and polysorbas20 mixing, no oily precipitating can be suspended for a long time
Without irreversible sedimentation.
Conclusion: by the comparing result of embodiment 1,2 and comparative example 1~3 it is found that the surface that the embodiment of the present invention 1 uses is lived
Property agent amount it is minimum, but the medical fluid prepared is more stable, there is better safety, and the preparation of comparative example 2 is unstable,
Therefore no longer carry out follow-up study.
5. effect test --- viscosity
Method: injection viscosity is measured using viscosimeter
As a result: in this experiment, the viscosity of embodiment 1 and embodiment 2 is respectively less than comparative example 3, and high viscosity solution can pierce
Swash vascular system, cause injection pain, patient's compliance is reduced, it follows that the drug that the prescription that the present invention uses is prepared
Composition has better patient's compliance.
6. effect test --- hemolysis in vitro test
Method: observation method carries out hemolytic test by visual observation
Experiment condition:
Experimental result:
| Time (h) | Negative control | Positive control | Embodiment 1 | Embodiment 2 | Comparative example 3 |
| 0.25 | - | + | - | - | - |
| 0.5 | - | ++ | - | - | - |
| 0.75 | - | ++ | - | - | - |
| 1 | - | ++ | - | - | - |
| 2 | - | ++ | - | - | - |
| 4 | - | ++ | - | - | + |
| 6 | - | ++ | - | - | + |
Note: ++ indicate complete hemolysis ,+indicate part haemolysis ,-indicate do not occur haemolysis
As a result: over time, in off-test haemolysis does not occur for negative control and embodiment 1,2,
Positive control generates obvious haemolysis, and comparative example 3 occurs slight hemolysis phenomenon in off-test, illustrates that the present invention uses
The pharmaceutical composition that prescription is prepared has better safety.
7. effect test --- serum histamine levels
Method: the content of enzyme-linked immunization (ELASA method) measurement guinea pig serum histamine is used
As a result: embodiment 1,2 and comparative example 3 will lead to guinea pig serum histamine levels and increase, caused by embodiment 1,2
Serum histamine levels elevation amplitude is below comparative example 3, and wherein solubilizer level used in embodiment 1 is minimum, caused blood
Clear histamine levels elevation amplitude is also minimum, and serum histamine levels fall back rate is most fast.The prescription for illustrating that the present invention uses is prepared
Pharmaceutical composition have better safety.
Claims (14)
1. a kind of pharmaceutical composition, which is characterized in that including following components:
(a) water-insoluble antipsychotics；
(b) cithrol；
(c) sorbitan fatty esters；
(d) aqueous vehicles；
What described pharmaceutical composition was formed is aqueous, injectable suspension.
2. pharmaceutical composition according to claim 1, which is characterized in that the water-insoluble antipsychotics accounts for described
The mass fraction of pharmaceutical composition is 10~30%.
3. pharmaceutical composition according to claim 1, which is characterized in that the cithrol accounts for the drug
Mass fraction in composition is 0.05~1%.
4. pharmaceutical composition according to claim 1, which is characterized in that the sorbitan fatty esters account for described
Mass fraction in pharmaceutical composition is 0.05~1%.
5. pharmaceutical composition according to claim 3 or 4, which is characterized in that the cithrol and fat
The mass ratio of sour sorbitan ester is 1:1~1:4.
6. pharmaceutical composition according to any one of claims 1 to 4, which is characterized in that the water-insoluble antipsychotic
Medicine is lauroyl Aripiprazole, and structural formula is as follows:
7. pharmaceutical composition according to any one of claims 1 to 4, which is characterized in that the cithrol
In, the fatty acid includes 12 to 22 carbon atoms, the polyethylene glycol average molecular weight range 400 to 8000；Preferably, institute
Stating cithrol is polyethylene glycol stearate.
8. pharmaceutical composition according to any one of claims 1 to 4, which is characterized in that the fatty acid sorbitan
In alcohol ester, the fatty acid includes 10 to 20 carbon atoms；Preferably, the sorbitan fatty esters are anhydrosorbitol
Sugar alcohol laurate.
9. pharmaceutical composition according to any one of claims 1 to 4, which is characterized in that the aqueous vehicles include note
It penetrates with water, sodium chloride and pH adjusting agent.
10. pharmaceutical composition according to claim 9, which is characterized in that the pH adjusting agent be disodium hydrogen phosphate and/or
Sodium dihydrogen phosphate.
11. according to claim 1~4,10 described in any item pharmaceutical compositions, which is characterized in that the anti-essence of water-insoluble
The partial size of refreshing medicine is D10: 2 μm~10 μm, and D50: 10 μm~30 μm, and D90: 65 μm of <.
12. such as the preparation method of any one of claim 1~11 described pharmaceutical composition, which comprises the following steps:
S1: weighing cithrol and sorbitan fatty esters by said ratio, and appropriate volume injection is added
It is made it dissolve with water, is prepared into auxiliary material mixed liquor；
S2: sodium chloride and pH adjusting agent are weighed by said ratio, is prepared into aqueous vehicles；
S3: after aqueous vehicles described in auxiliary material mixed liquor described in S1 and S2 are sufficiently mixed, then the water of appropriate particle size is added
Insoluble antipsychotics prepares medical fluid, then with homogenizer be sufficiently mixed medical fluid to get.
13. purposes of the pharmaceutical composition as claimed in any one of claims 1 to 11 in preparation treatment antipsychotic drugs.
14. purposes according to claim 13, which is characterized in that the treatment antipsychotic drugs are treatment schizophrenia
Or the drug of schizophrenia sample disease.
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