CN107137715B - A kind of 9-hydroxy-risperidone polyethylene glycol conjugation prodrug and preparation - Google Patents
A kind of 9-hydroxy-risperidone polyethylene glycol conjugation prodrug and preparation Download PDFInfo
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- CN107137715B CN107137715B CN201710280407.8A CN201710280407A CN107137715B CN 107137715 B CN107137715 B CN 107137715B CN 201710280407 A CN201710280407 A CN 201710280407A CN 107137715 B CN107137715 B CN 107137715B
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
Abstract
A kind of invention of new drug 9-hydroxy-risperidone polyethylene glycol conjugation prodrug (PEG- 9-hydroxy-risperidone), it is related to its preparation and application, the PEG- 9-hydroxy-risperidone has shown in following general formula: including carrier (polyethylene glycol, PEG), linking arm (AA) and 9-hydroxy-risperidone, wherein carrier is single armed polyethylene glycol, it is also possible to both arms and four arm polyethylene glycol, the degree of polymerization 10~500；Linking arm is amino acid or the oligopeptides that is made of amino acid.By carrying out PEGylated modification transformation to 9-hydroxy-risperidone, drug half-life is extended, can achieve 1 times a week or even monthly 1 time, improve using compliance；The water solubility for increasing drug enables to be made into normal injection agent, avoids the super difficult technique using nanocrystalline durative action preparation, reduces production difficulty and application risk.This preparation process is easy to operate, environmentally protective, low in cost, easy to industrialized production.General formula is as follows: single armed:Both arms:
Description
Technical field
The invention belongs to medicine and the field of chemical synthesis, and in particular to a kind of new drug 9-hydroxy-risperidone polyethylene glycol conjugation prodrug
Invention, the application also provide 9-hydroxy-risperidone polyethylene glycol conjugation prodrug preparation method and application.
Background technique
9-hydroxy-risperidone (Paliperidone) is the atypical antipsychotics of Johnson company of U.S. exploitation listing,
Belong to the 5-HT antagonist of benzo Isoxazole derivative class.9-hydroxy-risperidone (Paliperidone) be also 9-hydroxy-risperidone (9-
It hydroxy-risperidone), is the major active metabolite product of Risperidone (Risperidone), pharmacological characteristic and benefit
It is similar to train ketone, antipsycholic action is mainly played by antagonism 5-hydroxytryptamine receptor and dopamine D Z receptor, with other atypia
Anti-semen antibody is compared, and higher receptor affinity has been shown, and therapeutic effect is good.
The chemical name of 9-hydroxy-risperidone: (±) -3-2- [4- (fluoro- 1, the 2- benzo isoxazole -3- base of 6-) -1- piperidyl] second
Base] -6,7,8,9- tetrahydro -9- hydroxy-2-methyl -4H- pyrido [1,2-a] pyrimidin-4-ones, molecular formula C23H27FN4O3, change
Learn structural formula:
Schizophrenia is the unknown common mental disease of one group of cause of disease, has perception, thinking, emotion, will and behavior etc.
Various obstacles, characterized by by the uncoordinated of cerebration or being divorced from reality.The usual Consciousness of patient, how intact intelligence is,
The course of disease is delayed more, the decline that some patientss can develop as cerebration.The easy recurrent exerbation of schizophrenia, protracted course, patient
The characteristics of poor compliance, also brings certain difficulty to clinical treatment.
9-hydroxy-risperidone half-life period is very short, cannot be made into common oral preparation, the 9-hydroxy-risperidone sustained release tablets only deposited in the market by
Poor in patient's compliance, using effect is bad.Palm fibre puts the palm fibre that sour 9-hydroxy-risperidone is a kind of 9-hydroxy-risperidone and puts Esterification product, utilizes
Its slightly solubility and nanometer crystal technique, Janssen Pharmaceutica have developed novel 2 generation antipsychotic drug-palm fibre and put sour 9-hydroxy-risperidone injection
Liquid (kind think of reaches@) is that the current country uniquely can be quick in acute stage for the treatment of schizophrenia acute stage and maintenance phase
Recurrence can effectively be prevented in long term maintenance therapy again by working, and monthly inject 1 novel antipsychotic drug.Palm fibre puts acid
9-hydroxy-risperidone is a kind of prodrug, into resolving into 9-hydroxy-risperidone and work after in vivo.
But palm fibre puts sour 9-hydroxy-risperidone injection (kind to think to reach) to be white to linen suspension, there is following defect:
(1) research and development difficulty is big, and preparation equipment requires high, nanocrystalline particles size and distribution to be difficult to control, and it is special that production aspect needs
Nanocrystal technology and corresponding special installation, domestic production equipment is difficult to reach and the detection device without response at present；(2) matter
Control requires height, and quality aspect also needs to control weight suspension ability and consistence test, partial size point in addition to it need to control injection conventional project
The special items such as cloth, release, storage stability, uniformity of dosage units；(3) expensive, every (1ml:100mg) import 2000
Yuan；(4) dosage needs strict control, it is proposed that patient injects kind think of in the initial treatment first day and reaches 150mg, after a week again
The injection site of secondary injection 100mg, preceding 2 doses of initial treatment drugs are deltoid muscle.Maintenance therapy dosage is monthly 75mg, according to
The tolerance situation and/or curative effect of patient can increase or decrease injection dosage monthly in the range of 25-150mg.2nd dose of medicine
After object, monthly the position of 1 injection can be deltoid muscle or gluteus.Every month can adjust the dosage of maintenance therapy.It adjusts
When whole dosage, some months need to may be needed in view of the sustained release feature that kind think of reaches, the generated whole effects of dosage adjustment
Time can just embody；(5) administration mode is complicated: only using that (first 2 times are deltoid muscle, later can be with for intramuscular injection
It is gluteus or deltoid muscle), per injection must all be operated by the health workers of profession, when injection, should slowly inject flesh
Meat deep.It is careful not to enter drug injection in blood vessel.Every dose of drug all should be injected disposably and be finished, and fractional injection is unable to.No
By drug injection to intravascular or subcutaneous；(6) composition of injection is complicated, has used surfactant Polysorbate 20
It is (kind to think up to composition to be Polysorbate 20, Macrogol 4000, Citric Acid Mono, disodium hydrogen phosphate, a water biphosphate
Sodium, sodium hydroxide and water for injection).
It is (kind to think why to be made into the durative action preparation of such complexity up to@) in addition to drug itself that palm fibre puts sour 9-hydroxy-risperidone injection
Outside physicochemical property, the considerations of there are also pharmacoeconomics: (1) 9-hydroxy-risperidone molecule half-life period itself is very short, cannot be made into common mouth
Formulation；(2) the oral absolute bioavailability of 9-hydroxy-risperidone sustained release tablets is low (28% or so)；(3) it is most to put sour 9-hydroxy-risperidone for palm fibre
Pipe half-life period effectively extends, but water-soluble very poor；(4) nanometer crystal technique is especially combined by nanocrystalline different particle size distribution
Slightly solubility achievees the purpose that sustained release, is the very high proprietary technology of technology content, it is difficult to imitated；(5) although palm fibre puts sour pa benefit
Piperazine ketone injection (kind to think to reach@) has drug to enter the potential risk that blood vessel is likely to form thrombus, but due to mental patient's medication
Particularity, the product or income are much larger than risk.
Polyethylene glycol (PEG) be U.S. FDA approval a few can be used for one of synthetic polymer of intravenously administrable,
PEG modification technique is the novel medicine feeding technology developed rapidly in recent years, is mainly used in injection delivery systems.
Pass through polyethyleneglycol modified technology using the hydroxyl in 9-hydroxy-risperidone for the above problem existing for 9-hydroxy-risperidone
Prepare 9-hydroxy-risperidone polyethylene glycol conjugation prodrug, make its obviously increase it is water-soluble simultaneously, also significantly extend 9-hydroxy-risperidone
Half-life period.Polyethylene glycol 9-hydroxy-risperidone can be made Aqueous injection agent can be by design requirement in body after injection enters in vivo
It is interior that 9-hydroxy-risperidone is released with certain hydrolysis rate, it generates schizophrenia acute stage and maintains the response to treatment of phase, it can
Reach long-acting, slow release effect that palm fibre puts sour 9-hydroxy-risperidone injection (kind to think to reach@), in turn avoids its high production cost, using not
Convenient disadvantage reduces the medical expense of patient, improves medication compliance.Polyethylene glycol 9-hydroxy-risperidone is made into freeze-drying, injection
Required auxiliary material is relatively fewer, and composition is simple, avoids reducing not using surfactant (solubilization) Polysorbate 20
Good reaction；Preparation process is easy to the production of domestic industry metaplasia, avoids being produced into using nanocrystal technology and special production equipment
Originally it is greatly lowered.
Summary of the invention
The purpose of the present invention is to provide a kind of new 9-hydroxy-risperidone prodrug, i.e. prodrug is conjugated in 9-hydroxy-risperidone polyethylene glycol
(PEG- 9-hydroxy-risperidone) and preparation method.Compared with 9-hydroxy-risperidone and palmitinic acid 9-hydroxy-risperidone, it considerably increases water solubility,
It is decomposed into active 9-hydroxy-risperidone in vivo, plays drug effect, and by design, can make 1 day, 1 week, 2 weeks, 1
The even longer time moon injects the primary newtype drug with slow releasing function.
9-hydroxy-risperidone polyethylene glycol conjugation prodrug (PEG- 9-hydroxy-risperidone) has the following structure:
Single armed:
Both arms:
Four arms:
In aforementioned prodrugs structure, n is 20~500 integer in single armed, both arms PEG- 9-hydroxy-risperidone, represents polyethylene glycol
The degree of polymerization.(AA)w、(AA)vThe small molecule oligopeptides that identical or different amino acid or amino acid condensation are formed is represented, as connection
Group.W, v is the integer of 0-12, and represented amino acid quantity, preferably w, v are 1.
In aforementioned prodrugs structure, a, b, c, d are 10~200 integers in four arm PEG- 9-hydroxy-risperidones, represent polyethylene glycol
The degree of polymerization.(AA)w、(AA)v、(AA)x、(AA)yRepresent the small molecule that identical or different amino acid or amino acid condensation are formed
Oligopeptides, as linking group.W, v, x, y are the integers of 0-12, and represented amino acid quantity, preferably w, v, x, y are 1.
PEG- 9-hydroxy-risperidone is synthesized by certain technological means, is illustrated with flowering structure:
Single armed:
Both arms:
Four arms:
Present invention citing PEG- 9-hydroxy-risperidone structural formula, has single armed, both arms, four arms, as shown above (including but not limited to such as
On structure), for ease of understanding, the embodiment of the present invention has synthesized both arms PEG- 9-hydroxy-risperidone and four arm PEG- 9-hydroxy-risperidones and four
Arm PEG- glycine 9-hydroxy-risperidone.
The preparation of PEG- 9-hydroxy-risperidone: 9-hydroxy-risperidone reacts into ester with polyethylene glycol acetic acid direct polycondensation.
PEG- glycine 9-hydroxy-risperidone: 9-hydroxy-risperidone and glycine reactant at ester, then 9-hydroxy-risperidone glycinate again with
Polyethylene glycol acetic acid combines.
Another aspect of the present invention is provided comprising PEG- 9-hydroxy-risperidone or pharmaceutically acceptable pharmaceutical composition
Object, in some embodiments, pharmaceutical composition may be constructed injection, freeze-dried powder, subcutaneous injection agent, implant etc..This
The advantages of invention, is that the PEG- 9-hydroxy-risperidone prepared relative to palmitinic acid 9-hydroxy-risperidone, has good dissolubility energy, stabilization
Property and longer Half-life in vivo, realize the target of long-acting slow-release, at the same avoid nanometer crystal technique puzzlement and suspend cream
The potential preparation risk of agent.
Another aspect of the present invention provides PEG- 9-hydroxy-risperidone or pharmaceutically acceptable with pharmaceutic adjuvant composition
Dosage form, the treatment applied to schizophrenia acute stage and maintenance phase.
Specific embodiment
Following embodiment is used to illustrate the present invention, but is not limited to the present invention.
Embodiment 1 (preparation of both arms PEG- 9-hydroxy-risperidone):
By both arms polyethylene glycol acetic acid (average molecular weight 2000, breadth coefficient < 1.05) 20.0g (10.0mmol), two rings
Hexyl carbodiimide (DCC) 4.9g (24.0mmol), is dissolved at room temperature in 200mL anhydrous methylene chloride, stirring, and pa benefit is added
Piperazine ketone 9.4g (22.0mmol) and 0.12g (1.0mmol) DMAP, normal-temperature reaction 16h filter out insoluble matter, by solvent rotary evaporation
It removes, addition 100mL isopropanol (IPA) recrystallization, filtering, product vacuum is dry, obtains both arms polyethylene glycol -9-hydroxy-risperidone ester
16.7g。
1H-NMR (400MHz, CDCl3) δ: 7.75-7.68 (m, 2H), 7.25-7.21 (m, 2H), 7.07-7.01 (m, 2H),
5.80 (t, J=5.4Hz, 2H), 4.22 (s, 4H), 4.06-3.72 (m, 4H), 3.77-3.72 (m, 4H) 3.65-3.58 (m,
188H), 3.33-3.23 (m, 4H), 3.18-3.10 (m, 2H), 2.86-2.78 (m, 4H), 2.72-2.63 (m, 4H), 2.55-
2.36 (m, 4H), 2.30-1.92 (m, 22H).
Embodiment 2 (preparations of four arm PEG- 9-hydroxy-risperidones):
By four arm polyethylene glycol acetic acid (average molecular weight 20000, breadth coefficient < 1.05) 20.0g (1.0mmol), 1- (3-
Dimethylaminopropyl) -3- ethyl-carbodiimide hydrochloride (EDCI) 0.92g (4.8mmol), be dissolved at room temperature 200mL without
In water methylene chloride, 9-hydroxy-risperidone 1.88g (4.4mmol) and 0.01g (0.1mmol) DMAP, normal-temperature reaction 16h is added in stirring,
Insoluble matter is filtered out, solvent rotary evaporation is removed, addition 100mL isopropanol (IPA) recrystallization, filtering, product vacuum is dry, obtains
Four arm polyethylene glycol -9-hydroxy-risperidone ester 15.8g.
1H-NMR (400MHz, CDCl3) δ: 7.63-7.59 (m, 4H), 7.25-7.21 (m, 4H), 7.20-7.11 (m, 4H),
4.58-4.50 (m, 8H), 4.25 (s, 8H), 4.16-4.08 (m, 8H), 3.93-3.02 (m, 1830H), 3.01-2.87 (m,
8H), 2.50-2.48 (m, 8H), 2.38-2.05 (m, 44H), 1.90-1.73 (m, 8H).
Embodiment 3 (preparations of four arm PEG- glycine 9-hydroxy-risperidones):
Four arm polyethylene glycol-acetic acid (average molecular weight 20000, breadth coefficient < 1.04) 20.0g (1.0mmol), pa benefit piperazine
Ketone-glycinate 3.88g (8.0mmol), 4-dimethylaminopyridine (DMAP) 0.98g (8.0mmol), I-hydroxybenzotriazole
(HOBT) 1.08g (8.0mmol) is dissolved in 200ml methylene chloride, dicyclohexylcarbodiimide is added dropwise under nitrogen protection
(DCC) methylene chloride (16mL) solution of 1.65g (8.0mmol), drop finish, and nitrogen protection reaction is overnight.It is filtered to remove solids
Matter, excess of solvent rotary evaporation remove, and residue adds 200ml isopropanol (IPA) recrystallization, and filtering, product is vacuum dried,
Obtain four arm polyethylene glycol-glycine -9-hydroxy-risperidone 17.2g.
1H-NMR (400MHz, CDCl3) δ: 7.74-7.65 (m, 4H), 7.21-7.15 (m, 4H), 7.12-7.05 (m, 4H),
4.58-4.52 (m, 8H), 4.40-4.35 (m, 8H), 4.16 (s, 8H), 3.93-3.05 (m, 1852H), 3.12-2.78 (m,
8H), 2.55-2.43 (m, 8H), 2.32-2.03 (m, 44H), 1.92-1.78 (m, 8H).
Test the solubility comparative test of 1:PEG- 9-hydroxy-risperidone and palmitinic acid 9-hydroxy-risperidone
According to 2015 editions " Chinese Pharmacopoeias ", deliquescent investigation is carried out to embodiment: accurately weighing the sample (production of embodiment
Object) and 9-hydroxy-risperidone, palmitinic acid 9-hydroxy-risperidone it is each appropriate, after being separately added into a certain amount of purified water, shaken every 5min strength
30s, and observed, it is completely dissolved if being visible by naked eyes particles of solute in 30min and being considered as, the results are shown in Table 1.
The solubility comparative test result of table 1, PEG- 9-hydroxy-risperidone and 9-hydroxy-risperidone
It is obtained from above-mentioned experimental result, readily soluble in 9-hydroxy-risperidone polyethylene glycol conjugate water of the invention, opposite pa benefit piperazine
For ketone and palmitinic acid, water solubility is obviously increased.
Test 2: the stability test of injection PEG- 9-hydroxy-risperidone
Sample (product of embodiment 1,2,3) is soluble in water, and being configured to concentration is 2mg/ml (in terms of 9-hydroxy-risperidone)
Aqueous solution, addition mannitol is appropriate, is filtered with 0.22 micron membrane filter, and filtrate is sub-packed in 10ml cillin bottle (5ml/ branch), freezes
Dry, gland obtains embodiment 4,5,6.Sample after freeze-drying is placed 10 days under illumination, hot conditions respectively, acceleration environment (temperature
40 DEG C of degree, humidity 75%) June is placed, referring to the detection method of 9-hydroxy-risperidone raw material, detected whether using high performance liquid chromatograph
There is free 9-hydroxy-risperidone, as a result table 2.
Instrument: Shimadzu LC-16 high performance liquid chromatograph
Detection wavelength: 275nm
Column temperature: 35 DEG C
Flow velocity: 1.2ml/min
Mobile phase:
1ml formic acid is added in mobility A:0.01mol/L acetic acid amine aqueous solution 1000ml；Mobile phase B: taking 700ml acetonitrile, is added
300ml isopropanol adds 1ml formic acid.Mobile phase A: B=25:75
Retarder thinner: tetrahydrofuran-dimethylformamide=5:95
Table 2, injection PEG- 9-hydroxy-risperidone stability test result --- free 9-hydroxy-risperidone amount (%)
By above-mentioned test it is found that injection PEG- 9-hydroxy-risperidone accelerates 6 months, there is the sign of free 9-hydroxy-risperidone, but
It is the safety for not influencing the quality (clarity of solution) and clinic of product.
3 injection PEG- 9-hydroxy-risperidones are tested compared with the hydrolysis experiment that kind think of reaches
It makes respectively of 4,5,6 sample of embodiment and palmitinic acid 9-hydroxy-risperidone injection (kind to think to reach, comparison example) to having a competition
It tests:
1) the genial think of of 4,5,6 sample of Example reaches, and prepares 6 parts respectively, takes and (be equivalent to 10mg 9-hydroxy-risperidone/appearance in right amount
Measuring bottle) it is placed in 25ml volumetric flask；
2) above-mentioned all samples add sodium hydroxide (0.01%) aqueous dissolution of 10mL 0.0025mol/L, in 40 DEG C of water
Solution 0,5,10,30,60,90, the aqueous hydrochloric acid solution that is added 2mL 0.02mol/L after 150min terminate hydrolysis, solubilizer (tetrahydro furan
Mutter-dimethylformamide=5:95) it is diluted to scale, it shakes up；
3) hydrolysate -9-hydroxy-risperidone is measured with HPLC, detection method is the same as test 2.
Table 3, different samples hydrolyze test result
By above-mentioned test it is found that injection PEG- 9-hydroxy-risperidone can be hydrolyzed under certain environment, release effectively
Ingredient 9-hydroxy-risperidone, and it is apt to the hydrolysis rate for thinking to reach considerably slower than embodiment 4,5,6, analysis reason is that the Hydrolytic Mechanism of the two is deposited
In certain difference, embodiment is polyethylene glycol 9-hydroxy-risperidone direct hydrolysis, and it is by palmitinic acid 9-hydroxy-risperidone that kind think of, which reaches,
Granule size is first dissolved, then release 9-hydroxy-risperidone is hydrolyzed.In short, by the way that 9-hydroxy-risperidone is carried out structural modification -- it is poly-
Glycation can control its hydrolysis rate according to certain requirement, to achieve the effect that slow release, be allowed to be expected to become
1 times a week or even monthly 1 injection.
Claims (8)
1. prodrug, structural formula is conjugated in a kind of 9-hydroxy-risperidone polyethylene glycol are as follows:
Wherein,
N is 20~500 integer；
A, b, c and d are respectively 10~200 integer；
V, w, x and y are identical or different, respectively for 0~12 integer；And AA is selected from glycine, alanine, lysine, phenylpropyl alcohol ammonia
Acid, isoleucine, proline, valine, histidine, leucine, tryptophan, threonine or methionine or its condensation form small
Molecule oligopeptides group.
2. prodrug is conjugated in the 9-hydroxy-risperidone polyethylene glycol of claim 1, wherein v, w, x and y are respectively 1.
3. prodrug is conjugated in the 9-hydroxy-risperidone polyethylene glycol of claims 1 or 2, wherein AA indicates glycine.
4. the method for preparing the 9-hydroxy-risperidone polyethylene glycol conjugation prodrug of any one of claims 1 to 3, it includes the following steps:
Hydrophilic polyethylene glycol is modified, active function groups carboxyl is introduced, directly in conjunction with 9-hydroxy-risperidone, is obtained described
9-hydroxy-risperidone polyethylene glycol be conjugated prodrug；Or 9-hydroxy-risperidone first with amino acid or oligopeptides reacts into ester, then 9-hydroxy-risperidone
Amino-acid ester in conjunction with the carboxyl of polyglycolic acid, obtains the 9-hydroxy-risperidone polyethylene glycol conjugation prodrug again.
5. pharmaceutical composition, it includes 9-hydroxy-risperidone polyethylene glycol conjugation prodrug of any one of claims 1 to 3 and medicinal auxiliary
Material.
6. the pharmaceutical composition of claim 5, it is injection, freeze-dried powder or implant.
7. the pharmaceutical composition of claim 6 is injected weekly 1 time and is even monthly injected 1 time for injection or freeze-dried powder.
8. the 9-hydroxy-risperidone polyethylene glycol conjugation prodrug of any one of claims 1 to 3 is in preparation for treating schizophrenia urgency
Property the phase and maintain the phase drug in purposes.
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