CN109984999B - Pharmaceutical composition and preparation method and application thereof - Google Patents
Pharmaceutical composition and preparation method and application thereof Download PDFInfo
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- CN109984999B CN109984999B CN201910349031.0A CN201910349031A CN109984999B CN 109984999 B CN109984999 B CN 109984999B CN 201910349031 A CN201910349031 A CN 201910349031A CN 109984999 B CN109984999 B CN 109984999B
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims description 18
- 239000003814 drug Substances 0.000 claims abstract description 33
- -1 fatty acid esters Chemical class 0.000 claims abstract description 25
- 229940079593 drug Drugs 0.000 claims abstract description 24
- 239000002245 particle Substances 0.000 claims abstract description 20
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 16
- 229960004372 aripiprazole Drugs 0.000 claims abstract description 16
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 16
- 230000000561 anti-psychotic effect Effects 0.000 claims abstract description 7
- 239000008135 aqueous vehicle Substances 0.000 claims abstract description 6
- 239000000164 antipsychotic agent Substances 0.000 claims abstract description 5
- 229940102213 injectable suspension Drugs 0.000 claims abstract description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 26
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 claims description 14
- 235000011067 sorbitan monolaureate Nutrition 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 13
- 239000008215 water for injection Substances 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 201000000980 schizophrenia Diseases 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- 239000012736 aqueous medium Substances 0.000 claims description 5
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical group [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 5
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 5
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 5
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 5
- 208000028017 Psychotic disease Diseases 0.000 claims description 4
- 208000020186 Schizophreniform disease Diseases 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims 4
- 229950006451 sorbitan laurate Drugs 0.000 claims 4
- BKVAAWMQOQLENB-UHFFFAOYSA-N 15-hydroxy stearic acid Chemical compound CCCC(O)CCCCCCCCCCCCCC(O)=O BKVAAWMQOQLENB-UHFFFAOYSA-N 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940124811 psychiatric drug Drugs 0.000 claims 1
- 235000014113 dietary fatty acids Nutrition 0.000 abstract description 20
- 229930195729 fatty acid Natural products 0.000 abstract description 20
- 239000000194 fatty acid Substances 0.000 abstract description 20
- 238000002347 injection Methods 0.000 abstract description 17
- 239000007924 injection Substances 0.000 abstract description 17
- 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 8
- 239000000725 suspension Substances 0.000 abstract description 7
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 abstract description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 12
- 206010018910 Haemolysis Diseases 0.000 description 6
- 229920001213 Polysorbate 20 Polymers 0.000 description 6
- 230000008588 hemolysis Effects 0.000 description 6
- 229960001340 histamine Drugs 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 6
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000002427 irreversible effect Effects 0.000 description 3
- 238000010902 jet-milling Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 208000020925 Bipolar disease Diseases 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
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- RDYWTOWUSVAZGN-UHFFFAOYSA-N 7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-1-(hydroxymethyl)-3,4-dihydroquinolin-2-one Chemical compound C1=C2N(CO)C(=O)CCC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC(Cl)=C1Cl RDYWTOWUSVAZGN-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- LWZFANDGMFTDAV-WYDSMHRWSA-N [2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical group CCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-WYDSMHRWSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 229960003798 aripiprazole lauroxil Drugs 0.000 description 1
- 229940075231 aristada Drugs 0.000 description 1
- 238000000498 ball milling Methods 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 208000025307 bipolar depression Diseases 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 229940100242 glycol stearate Drugs 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect 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
- 239000002075 main ingredient Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011164 primary particle Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000000007 visual effect Effects 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
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Dispersion Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a pharmaceutical composition comprising a water-insoluble antipsychotic agent; polyethylene glycol fatty acid esters; sorbitan esters and aqueous vehicles; the pharmaceutical composition forms an aqueous, injectable suspension. The water-insoluble antipsychotic drug is aripiprazole prodrug-lauroyl aripiprazole, and a pharmaceutical composition prepared by selecting a proper particle size and a specific prescription proportion is used for preparing a clinical suspension injection with good stability, a release rate meeting the requirement, and particularly good safety, and has extremely high application value.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a pharmaceutical composition, and a preparation method and application thereof.
Background
Aripiprazole (Aripiprazole), chemical name: 7- {4- [4- (2, 3-dichlorophenyl) -1-piperazinyl]Butoxy } -34-dihydro-2- (lH) -quininone with the molecular formula C23H27N3O2Cl2Molecular weight is 448.4, and chemical structural formula is:
the aripiprazole is dopamine D2 partial agonist, serotonin 5-HT1AReceptor agonists and serotonin 5-HT2AA receptor antagonist. As antipsychotics useful in the treatment of schizophrenia, bipolar disorder, depression and other CNS disorders.
Lauroyl Aripiprazole (Aripiprazole lauroxil) is a prodrug of Aripiprazole that undergoes enzyme-mediated catalytic hydrolysis in vivo to form N-hydroxymethyl Aripiprazole, which is subsequently hydrolyzed to Aripiprazole, thereby exerting an anti-schizophrenia effect. The lauroyl aripiprazole long-acting injection developed by the Ireland Alkermes company is approved on the market under the trade name Aristada. The medicine is slow release injection suspension, is a long-acting medicine for treating atypical schizophrenia, and is injected once every month or once every 6 weeks, and is used for treating adult schizophrenia. However, the above-mentioned and other excipients used in the sustained release injections in the prior art cause adverse reactions such as hemolysis. Therefore, the improvement of the safety and effectiveness of the aripiprazole prodrug sustained-release injection is a problem to be solved urgently.
Disclosure of Invention
The present invention aims to provide a sustained release formulation composition of aripiprazole and its prodrug to solve the above problems.
In a first aspect, the present invention provides a pharmaceutical composition, which is characterized by comprising the following components:
(d) a water-insoluble antipsychotic;
(e) polyethylene glycol fatty acid esters;
(f) sorbitan esters of fatty acids;
(c) an aqueous vehicle;
the pharmaceutical composition forms an aqueous, injectable suspension.
Further optionally, the water-insoluble antipsychotic drug comprises 10-30 wt% of the pharmaceutical composition; preferably, the content is 15-28 wt%;
further optionally, the polyethylene glycol fatty acid ester accounts for 0.05-1 wt% of the pharmaceutical composition; preferably, the content is 0.1 to 0.3 weight percent;
further optionally, the fatty acid sorbitan ester accounts for 0.05-1 wt% of the pharmaceutical composition; preferably, the content is 0.3 to 0.5 weight percent;
furthermore, the mass ratio of the polyethylene glycol fatty acid ester to the fatty acid sorbitan ester is 1: 1-1: 4; preferably, the mass ratio is 1: 3.8;
furthermore, the sum of the mass contents of the polyethylene glycol fatty acid ester and the fatty acid sorbitan ester accounts for 0.15-2 wt% of the pharmaceutical composition;
further optionally, the mass fraction of the aqueous vehicle in the pharmaceutical composition is 68-89%;
further, the water-insoluble antipsychotic is lauroyl aripiprazole, of the formula:
further, in the polyethylene glycol fatty acid ester, the fatty acid contains 12 to 22 carbon atoms, and the polyethylene glycol has an average molecular weight in the range of 400 to 8000; preferably, the polyethylene glycol fatty acid ester is polyethylene glycol stearate (Kolliphor);
further, in the sorbitan fatty acid ester, the fatty acid contains 10 to 20 carbon atoms; preferably, the fatty acid sorbitan ester is sorbitan laurate (SPAN 20);
further, the aqueous vehicle comprises water for injection, sodium chloride and a pH regulator;
further, the pH regulator is disodium hydrogen phosphate and/or sodium dihydrogen phosphate;
further, the particle size of the water-insoluble antipsychotic drug is D10: 2 μm to 10 μm, and D50: 10 μm to 30 μm, and D90: less than 65 μm; another aspect of the present invention is to provide a method for preparing the composition as described above, which comprises the following steps:
s1: weighing polyethylene glycol fatty acid ester and fatty acid sorbitan ester according to the proportion, adding a proper volume of water for injection to dissolve the polyethylene glycol fatty acid ester and the fatty acid sorbitan ester, and preparing an auxiliary material mixed solution;
s2: weighing sodium chloride and pH regulator according to the above ratio, and preparing into aqueous medium;
s3: and (3) fully mixing the auxiliary material mixed solution of the S1 and the aqueous vehicle of the S2, adding the water-insoluble antipsychotic drugs with proper particle size to prepare liquid medicine, and fully mixing the liquid medicine by using a homogenizer to obtain the antipsychotic drug.
The invention also provides application of the pharmaceutical composition in preparation of a medicament for treating psychosis.
Furthermore, the drug for treating the psychosis is a drug for treating schizophrenia or schizophreniform diseases.
Drawings
FIG. 1 is an in vitro release test of products with different particle sizes
FIG. 2A shows the particle size of the original ground reference preparation
FIG. 2B shows the particle size of the product of the formulation of example 1
Advantageous effects
The novel nonionic surfactant polyethylene glycol fatty acid ester adopted by the invention has the following advantages: compared with Tween nonionic surfactants, the product is safer, has no hemolytic property, and no skin and eye irritation, and improves the safety of the medicine; the solubilizing power is more excellent, the solubilizing power of the compound to different hydrophobic drugs can be linearly increased along with the increase of the concentration, the dosage of a solubilizing agent can be reduced, and the medication safety is improved; in addition, the viscosity of the surfactant is gradually increased along with the concentration, and low injection pain at high concentration can be realized, so that the compliance of a patient is increased.
Detailed Description
The present invention will be further described with reference to specific examples to assist understanding of the invention.
1. The specifications of the auxiliary materials used are shown in table 1:
TABLE 1
2. Bulk drug particle size control
In order to ensure the redispersibility and stability of the product, the particle size of the main drug needs to be controlled. The conventional particle size control method mainly comprises 1) recrystallization, 2) jet milling and 3) ball milling.
Taking lauroyl aripiprazole as an example, the in vitro release condition of the suspension injection prepared from the main drug and the excipient after being treated under different jet milling conditions is shown in figure 1, the release rate increases with the increase of jet milling pressure, but the particle size of the main drug is not obviously reduced after a certain pressure is reached, and the release rate does not change obviously with the increase of the milling pressure. Therefore, in the range of the selected particle size (D10: 2-10 μm, D50: 10-30 μm and D90 less than 65 μm), the suspension injection type injection prepared by the invention can be released continuously, can meet clinical requirements and realizes long-term effectiveness.
In addition, it is preferable that the optical microscope observation results of the prepared preparation and the reference preparation in the prior art showing the particle size of the main ingredient are shown in fig. 2 (including fig. 2A and fig. 2B), wherein fig. 2A shows the reference preparation in the prior art, and fig. 2B shows the preparation of example 1. The preparation in the example 1 has the similar shape under a microscope with the original preparation, and is irregular crystals which are partially aggregated; the particle size ranges are also similar.
3. Pharmaceutical compositions prepared in examples 1 to 5
According to the above results of the primary particle size screening, all of the following examples and comparative examples were prepared using the above-described primary drug particles.
3.1 recipe ratios are shown in Table 1:
TABLE 1
3.2 preparation method
Examples 1-6 were prepared as follows:
s1: weighing according to the above proportion
HS-15 and span 20, adding a proper volume of water for injection to dissolve the water, and preparing an auxiliary material mixed solution; s2: weighing sodium chloride and pH regulators of disodium hydrogen phosphate and sodium dihydrogen phosphate according to the above ratio, and preparing into aqueous medium; s3: fully mixing the auxiliary material mixed solution of S1 with the aqueous medium of S2, and then addingPreparing medicinal liquid from main drugs with proper particle size, and fully preparing the medicinal liquid by using a homogenizer.
3.3 Experimental results: can form suspension emulsion without oily precipitate, and can be suspended for a long time without irreversible precipitation.
4. Preparation of comparative examples 1 to 3
4.1 comparative example 1
Prescription:
the preparation method comprises the following steps:
the span 20 and the Tween 80 are weighed according to the proportion of the prescription, the proper volume of water for injection is added for dissolving, the prescription amount of sodium chloride and the pH regulator are weighed, and after the sodium chloride and the pH regulator are fully dissolved, the water for injection is supplemented to the full amount to prepare the injection medium. Adding the main drug with proper particle size into the prepared injection vehicle, and mixing the main drug and the vehicle by using a homogenizer.
The experimental results are as follows: the solution is turbid after the span 20 and the Tween 80 are mixed, and subsequent preparation cannot be carried out, which indicates that the compatibility of the span 20 and the Tween 80 is poor.
4.2 comparative example 2
Prescription:
| raw and auxiliary materials (g) | Dosage of |
| Lauroyl aripiprazole | 27.56 |
| |
0.10 |
| |
0.38 |
| Sodium chloride | 0.60 |
| Disodium hydrogen phosphate | 0.05 |
| Sodium dihydrogen phosphate | 0.05 |
| Water for injection | To 100g |
The preparation method comprises the following steps:
the span 20 and the Tween 20 are weighed according to the proportion of the prescription, the proper volume of water for injection is added for dissolving, the prescription amount of sodium chloride and the pH regulator are weighed, and after the sodium chloride and the pH regulator are fully dissolved, the water for injection is supplemented to the full amount to prepare the injection medium. Adding the main drug with proper particle size into the prepared injection vehicle, and mixing the main drug and the vehicle by using a homogenizer.
The experimental results are as follows: after the span 20 and the Tween 20 are mixed, suspension emulsion can be formed, oil-free precipitation occurs, irreversible sedimentation occurs after 60 days, and the stability is poor, so that subsequent research is not carried out.
4.3 comparative example 3
Prescription:
| raw and auxiliary materials (g) | Dosage of |
| Lauroyl aripiprazole | 27.56 |
| |
0.15 |
| |
0.38 |
| Sodium chloride | 0.60 |
| Disodium hydrogen phosphate | 0.05 |
| Sodium dihydrogen phosphate | 0.05 |
| Water for injection | To 100g |
The preparation method comprises the following steps:
the span 20 and the Tween 20 are weighed according to the proportion of the prescription, the proper volume of water for injection is added for dissolving, the prescription amount of sodium chloride and the pH regulator are weighed, and after the sodium chloride and the pH regulator are fully dissolved, the water for injection is supplemented to the full amount to prepare the injection medium. Adding the main drug with proper particle size into the prepared injection vehicle, and mixing the main drug and the vehicle by using a homogenizer.
The experimental results are as follows: the span 20 and the Tween 20 can form suspension emulsion after being mixed, have no oily precipitate and can be suspended for a long time without irreversible precipitation.
And (4) conclusion: from the comparison results of examples 1 and 2 and comparative examples 1 to 3, it can be seen that the surfactant used in example 1 of the present invention is the lowest in amount, but the prepared drug solution is more stable and has better safety, while the formulation of comparative example 2 is unstable, so that subsequent studies are not performed.
5. Effect test-viscosity
The method comprises the following steps: measurement of injection viscosity Using viscometer
As a result: in this experiment, the viscosity of example 1 and example 2 was lower than that of comparative example 3, and the high viscosity solution irritated the vascular system, causing injection pain and reducing patient compliance, so it can be seen that the pharmaceutical composition prepared by the prescription of the present invention has better patient compliance.
6. Effect test-in vitro hemolysis test
The method comprises the following steps: hemolysis test by visual observation
The experimental conditions are as follows:
the experimental results are as follows:
| time (h) | Negative control | Positive control | Example 1 | Example 2 | Comparative example 3 |
| 0.25 | - | + | - | - | - |
| 0.5 | - | ++ | - | - | - |
| 0.75 | - | ++ | - | - | - |
| 1 | - | ++ | - | - | - |
| 2 | - | ++ | - | - | - |
| 4 | - | ++ | - | - | + |
| 6 | - | ++ | - | - | + |
Note: + denotes complete hemolysis, + denotes partial hemolysis, -denotes no hemolysis
As a result: over time, the negative control and examples 1 and 2 were not hemolyzed at the end of the test, the positive control was significantly hemolyzed, and comparative example 3 was slightly hemolyzed at the end of the test, indicating that the pharmaceutical composition prepared according to the prescription of the present invention has better safety.
7. Effect test-serum Histamine levels
The method comprises the following steps: determination of Histamine content in Guinea pig serum Using enzyme-linked immunosorbent assay (ELASA method)
As a result: examples 1, 2 and comparative example 3 all resulted in an increase in serum histamine levels in guinea pigs, and examples 1, 2 resulted in a lower magnitude increase in serum histamine levels than comparative example 3, whereas example 1 used the lowest concentration of solubilizer, which resulted in the lowest magnitude increase in serum histamine levels and the fastest rate of fall-back of serum histamine levels. The pharmaceutical composition prepared by the prescription used in the invention has better safety.
Claims (4)
1. A pharmaceutical composition comprising the following components:
(a) a water-insoluble antipsychotic agent which is lauroyl aripiprazole having the following structural formula:
having a particle diameter of D10：2µm~10µm, and D50：10µm~30µm, and D90：＜65µm accounts for 10-30% of the mass fraction of the pharmaceutical composition;
(b) 15-hydroxystearic acid polyethylene glycol ester accounting for 0.05-1% of the mass of the pharmaceutical composition;
(c) sorbitan laurate accounting for 0.05-1% of the pharmaceutical composition by mass, wherein the mass ratio of the 15-hydroxystearic acid polyethylene glycol ester to the sorbitan laurate is 1: 1-1: 4;
(d) the pH regulator comprises an aqueous medium, water, sodium chloride and a pH regulator, wherein the pH regulator is disodium hydrogen phosphate and sodium dihydrogen phosphate;
the pharmaceutical composition forms an aqueous, injectable suspension.
2. A process for preparing a pharmaceutical composition according to claim 1, comprising the steps of:
s1: weighing 15-hydroxystearic acid polyethylene glycol ester and sorbitan laurate according to the proportion, adding a proper volume of water for injection to dissolve the polyethylene glycol ester and the sorbitan laurate, and preparing an auxiliary material mixed solution;
s2: weighing sodium chloride and pH regulator according to the above ratio, and preparing into aqueous medium;
s3: and (3) fully mixing the auxiliary material mixed solution of the S1 and the aqueous vehicle of the S2, adding the water-insoluble antipsychotic drugs with proper particle size to prepare liquid medicine, and fully mixing the liquid medicine by using a homogenizer to obtain the antipsychotic drug.
3. Use of a pharmaceutical composition according to any one of claims 1 to 2 in the preparation of a medicament for the treatment of psychosis.
4. The use according to claim 3, wherein the psychiatric medication is a medication for the treatment of schizophrenia or schizophreniform disorder.
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