CN105878250A - Aprepitant nano composition - Google Patents
Aprepitant nano composition Download PDFInfo
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- CN105878250A CN105878250A CN201410587198.8A CN201410587198A CN105878250A CN 105878250 A CN105878250 A CN 105878250A CN 201410587198 A CN201410587198 A CN 201410587198A CN 105878250 A CN105878250 A CN 105878250A
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Abstract
The invention discloses an aprepitant nano composition which is composed of aprepitant, an oil phase, an emulsifier, a co-emulsifier, a stabilizer, an auxiliary stabilizer and an optional solid adsorbent. The aprepitant nano composition significantly improves solubility, stability and bioavailability of the aprepitant.
Description
Technical field:
The invention belongs to pharmaceutical technology field, relate to nano-composition of a kind of aprepitant and preparation method thereof.I.e. by preparation
The nanometer formulation of aprepitant, improves the dissolubility of aprepitant, stability and bioavailability.
Background technology:
The Nausea and vomiting (CINV) that chemotherapy causes is the most modal untoward reaction of tumor chemotherapeutic drug, this
Untoward reaction makes the compliance of tumor patient reduce, and causes tumor to control effect undesirable, patient time serious, can be caused to be dehydrated,
Metabolism disorder, malnutrition and aspiration pneumonitis.Therefore, prevent and alleviate the Nausea and vomiting that chemotherapy causes timely and effectively,
The mental pressure of reduction of patient, improves antineoplaston effect, is urgent problem during chemotherapy of tumors.
Since nineteen ninety Ondansetron Hydrochloride lists, " department's fine jade " class medicine occupies the staple market of Bendectin always, successively goes up
Seven or eight products in city.Although the antiemetic effect of " department's fine jade " is significantly better than the medicine listed before, even if employing department fine jade+ground plug
The standard emesis scheme of meter Song, the patient still having more than 50% can occur Nausea and vomiting when accepting and highly causing and tell risk chemotherapy.
Aprepitant (Aprepitant) is the Bendectin of the brand-new mechanism of action of another class listed after " department's fine jade ", is first
Approval, for clinic, has neurokinine-1 (NK-1) receptor antagonist of new mechanism, and it can pass through blood brain barrier, with
Brain nk 1 receptor selective binding is to block the effect of Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2, thus produces antiemetic effect widely, and at Delayed onset CINV
Middle effect becomes apparent from.Its taking dose is: before chemotherapy, 1h is administered orally 125mg, takes 80mg respectively in the 2nd, the 3rd day morning.
Aprepitant can treat, with other antinanseant drug combinations, the patients undergoing chemotherapy that severe is vomitted.Various nauseants are drawn by aprepitant
The vomiting risen has antiemetic effect extensive, potent, and the effect to delayed emesis is especially prominent:
1, acute vomiting (chemotherapy occurred in 24 hours): aprepitant share, to acute vomiting with taking charge of fine jade+dexamethasone scheme
Effective percentage than department the high 11-15% of fine jade+dexamethasone.
2, delayed emesis (chemotherapy occurred after 24 hours): department's fine jade class medicine is slight to delayed emesis curative effect, and along with medication
The progress of the course for the treatment of, antiemetic effect also can reduce further；The effect of delayed emesis is highlighted by Aprepitant, is that FDA approval is used
In first medicine of prevention delayed emesis, the effective percentage that three medicines share is than the department high 19-21% of fine jade+dexamethasone, it is thus achieved that authority
US National comprehensive cancer network (NCCN), American Society of Clinical Oncology (ASCO), the multinational association of cancer supporting treatment
(MASCC) recommend, for share with dexamethasone, department's fine jade, prevent middle and high degree to cause to tell the vomiting that risk chemotherapy causes.This
Outward, aprepitant also has treatment depression and the effect of other mental sickness.At present, aprepitant is considered as that effect is best
One of chemotherapy antiemetic.
The chemical name of aprepitant is 5-[2 (R)-[1 (R)-[3,5-bis-(trifluoromethyl) phenyl] ethyoxyl]-3 (S)-(4-fluorophenyl) morpholine
-4-ylmethyl]-3,4-dihydro-2H-1,2,4-triazole-3-ketone, character is white or off-white color crystal, water insoluble, is slightly soluble in acetonitrile,
Dissolve in ethanol.There is the shortcomings such as synthesis step is various, severe reaction conditions, product yield are low in the synthesis of aprepitant so that
The cost of raw material remains high always.Additionally, aprepitant belongs to Biopharmaceutics Classification system (BCS) IV class medicine, mouth
Take bioavailability and be only 9%.In April, 2003, U.S. FDA approval Merck company produce aprepitant capsule listing,
Its trade name Emend, this aprepitant capsule have employed nanotechnology and prepares gained, specially Elan company
Nano-Crystal patented technology (media milling process), specification has 80mg and 125mg two kinds, and indication is that Prophylactic chemotherapy draws
The acute and delayed property Nausea and vomiting risen.In March, 2010, U.S. FDA ratifies again the aprepitant capsule that specification is 40mg
Listing, its indication is prevention of postoperative Nausea and vomiting.Compared with the aprepitant capsule that commonsense method prepares, use nanometer skill
The aprepitant capsule of art research and development significantly improves oral administration biaavailability, shows through In vivo study, with the common suspendible of aprepitant
Liquid phase ratio, after nanorize, the bioavailability of medicine is brought up to 65% by 9%.Further, nanocrystallization technology significantly reduces A Rui pyrrole
Smooth food effect, under state, conventional tablet bioavailability will increase by 4 times on the feed, and the life before and after the feed of nanorize preparation
Thing availability is without notable change.But, above-mentioned technology exists the quality of a problem merited attention, i.e. abrasive media and resistance to
By property, and the contamination of products that in preparation process, the abrasion of abrasive media is caused；Additionally, media milling process is the longest, one
The individual production cycle is several hours to several days, and this also makes troubles to production, causes the raising of production cost, and stability
Reduce, pollute the risk increased.
Summary of the invention:
The present invention relates to the novel nano compositions of aprepitant.The Pharmaceutical composition purposes of the present invention includes drawing for Prophylactic chemotherapy
Acute and the Delayed onset nausea and vomiting risen, and be used for preventing postoperative nausea and vomiting, its be advantageous in that add Ah
Dissolubility, stability and the digestive tract absorption that auspicious pyrrole is smooth.It addition, it has higher life relative to Emend of the prior art
Thing availability and faster rate of release.
Detailed Description Of The Invention:
Goal of the invention: aprepitant nano-composition and system thereof that a kind of dissolubility height, good stability, bioavailability are high are provided
Preparation Method, described aprepitant nano-composition can be effective to the outbreak of the acute and delayed property n or V after chemotherapy, also
Can be used for the treatment of major depressive disorder (with anxiety).
Technical scheme: a kind of novel aprepitant nano-composition, is characterized in that: described aprepitant nano-composition includes
Aprepitant or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier and/or adjuvant.
Described adjuvant includes following components:
Emulsifying agent, co-emulsifier, oil phase, stabilizer, auxiliary stabilizer and solid absorbent.
Preferably, described nano-composition has following release characteristics, in dissolution medium is 0.1mol/L hydrochloric acid solution, and 5 points
Clock release at least 20%, at least discharges 70% for 10 minutes, release at least 95% in 20 minutes.
Preferably, the bioavailability of described nano-composition, for Emend, for its 90-250%, preferably
120-200%, more preferably 140-180%.
Preferably, the particle diameter of described nano-composition is 10-600nm, preferably 20-400nm, more preferably 30-80nm.
Described emulsifying agent is selected from: polyoxyethylene hydrogenated Oleum Ricini, polyoxyethylene castor oil, Solutol HS15, octanoic acid
Capric acid polyethyleneglycol glyceride, Polyethylene Glycol glyceryl laurate ester, oleic acid polyethyleneglycol glyceride, polyoxyethylene sorbitan monoleate, or wherein
Two or more mixture；
Described co-emulsifier is selected from propylene glycol, PEG400, cetomacrogol 1000, Macrogol 2000, diethylene glycol list
Ethylether, ethanol or two of which or two or more mixture；
Described oil phase is selected from: long-chain oil triglycerides, isopropyl myristate, Ethyl linoleate, midchain oil triglyceride or its
In two or more mixture；
Described stabilizer is natural phospholipid, synthetic phospholipid and derivant thereof, or two of which or two or more mixture.Its
In, natural phospholipid includes phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, sphingomyelins, phosphatidic acid, phosphatidyl glycerol, phosphatidyl silk ammonia
Acid；Synthetic phospholipid include distearoyl phosphatidylcholine, DSPE, DSPG, two
The acid of distearoylphosphatidic acid, oleoyl phosphatidylcholine, oleoylphosphatidyl ethanolamine, oleoylphosphatidyl glycerol, oleoyl phospholipid, Petiolus Trachycarpi
Phosphatidyl choline, palmityl PHOSPHATIDYL ETHANOLAMINE, palmityl phosphatidyl glycerol, palmityl phosphatidic acid, myristoyl phosphatidyl
Choline, myristoyl PHOSPHATIDYL ETHANOLAMINE, myristoyl phosphatidyl glycerol, myristoyl phosphatidic acid, 22 phosphinylidyne phosphatidyls
Choline, 22 phosphinylidyne PHOSPHATIDYL ETHANOLAMINE, 22 phosphinylidyne phosphatidyl glycerols, 22 phosphinylidyne phosphatidic acid.
Described auxiliary stabilizer be ascorbyl palmitate, vitamin E, tocopheryl palmitate, thiourea, to benzene two
Phenol, disodium edetate, calcium disodium edetate, or two of which or two or more mixture.
Described solid absorbent is selected from: microcrystalline Cellulose, pluronic, micropowder silica gel, hydroxypropyl methyl cellulose, mannitol,
Sodium lauryl sulphate, polyvinylpyrrolidone, or two of which or two or more mixture.
By weight, described aprepitant is each component: 20-150 part, preferably 40-125 part, further preferably 80-125 part；Institute
State emulsifying agent: 40-900 part, preferably 60-800 part, further preferably 80-700 part, further preferably 90-600 part, further preferably 100-500
Part, further preferably 200-400 part；Described co-emulsifier: 20-1000 part, preferably 40-1000 part, further preferably 50-900 part, more excellent
Select 60-800 part, further preferably 80-700 part, further preferably 100-600 part, further preferably 150-500 part, further preferably 200-400 part；Institute
State oil phase: 10-250 part, preferably 15-220 part, further preferably 20-210 part, further preferably 30-200 part, further preferably 40-180 part,
Further preferably 50-160 part, further preferably 60-140 part, further preferably 80-120 part；Described solid absorbent: 0-1500 part, preferably
100-1400 part, further preferably 150-1200 part, further preferably 200-1100 part, further preferably 250-1000 part, further preferably 300-900 part,
Further preferably 400-800 part.Described stabilizer is: 50-500 part, preferably 60-450 part, further preferably 80-400 part, further preferably 80-350
Part, further preferably 100-300 part, further preferably 120-280 part, further preferably 150-250 part；Described auxiliary stabilizer: 10-50 part,
Preferably 15-45 part, further preferably 20-40 part, further preferably 22-35 part, further preferably 25-30 part.
Described aprepitant, with the percentages of compositions gross weight, proportion is 0.5-15%；Preferably 1-10% more preferably 3-7%.
In certain embodiments, when compositions is liquid nanometer compositions, described aprepitant, with the percentage of compositions gross weight
Than meter, proportion is 0.5-10%；Preferably 1-6 more preferably 2-5.In certain embodiments, when compositions be solid nano combination
During thing, described aprepitant, with the percentages of compositions gross weight, proportion is 0.515%；Preferably 0.8-8% is more excellent
Select 1-6%.
Described emulsifying agent, with the percentages of compositions gross weight, proportion is 2-60%, preferably 8-50%, more preferably 15-40%.
In certain embodiments, when compositions is liquid nanometer compositions, described emulsifying agent, with the percentages of compositions gross weight,
Proportion is 10-60%, preferably 20-50%, more preferably 25-40%.In certain embodiments, it is solid nano group when compositions
During compound, described emulsifying agent, with the percentages of compositions gross weight, proportion is 2-50%, preferably 8-45%, more preferably
15-40%.
Described co-emulsifier, with the percentages of compositions gross weight, proportion is 5-50, preferably 8-45%, more preferably 10-35%.
In certain embodiments, when compositions is liquid nanometer compositions, described co-emulsifier, with the percentages of compositions gross weight,
Proportion is 5-50%, preferably 8-45%, more preferably 10-40%.In certain embodiments, when compositions be solid nano combination
During thing, described co-emulsifier, with the percentages of compositions gross weight, proportion is 5-40%, preferably 8-35%, more preferably
10-30%.
Described oil phase, with the percentages of compositions gross weight, proportion is 0.2-10%, preferably 0.4-8%, more preferably 0.5-6%.
In certain embodiments, when compositions is liquid nanometer compositions, described oil phase, with the percentages of compositions gross weight, institute
Accounting example is 0.2-10%, preferably 0.5-8%, more preferably 1-6%.In certain embodiments, it is solid nano compositions when compositions
Time, described oil phase, with the percentages of compositions gross weight, proportion is 0.2-8%, preferably 0.4-7%, more preferably 0.5-6%.
Described stabilizer, with the percentages of compositions gross weight, proportion is 1-25%, preferably 2-19%, more preferably 3-18%.
In certain embodiments, when compositions is liquid nanometer compositions, described stabilizer, with the percentages of compositions gross weight,
Proportion is 1-25%.Preferably 2-20%, more preferably 3-18%.In certain embodiments, when compositions be solid nano combination
During thing, described stabilizer, with the percentages of compositions gross weight, proportion is 1-20%, preferably 2-18%, more preferably 3-14%.
Described auxiliary stabilizer, with the percentages of compositions gross weight, proportion is 0.2-7%, preferably 0.5-4.5%, more excellent
Select 1-4%.In certain embodiments, when compositions is liquid nanometer compositions, described stabilizer, with the hundred of compositions gross weight
Proportion by subtraction meter, proportion is 0.2-6%, preferably 0.5-5%, more preferably 1-4%.In certain embodiments, it is solid when compositions
During nano-composition, described emulsifying agent, with the percentages of compositions gross weight, proportion is 0.2-5%, preferably 0.5-4%,
More preferably 1-3%.
When compositions is solid composite, in certain embodiments, compositions contains solid absorbent, described solid absorbent,
With the percentages of compositions gross weight, proportion is 18-65%, preferably 20-50%, more preferably 25-45%.
" long-chain oil " of the present invention and the carbochain of each glyceride thereof refer to that carbon number is that 14-22, preferably carbon number are
16-20, more preferably carbon number are 16-18.
The carbochain of " midchain oil " of the present invention and each glyceride thereof refer to carbon number be 6-12, preferably carbon number be 7-11,
More preferably carbon number is 8-10.
In a preferred embodiment, aprepitant nano-composition of the present invention, wherein Aprepitant and the weight of emulsifying agent
Ratio is 1: 24～1: 1, preferably 1: 12～1: 2, more preferably 1: 8～1: 4.
In a preferred embodiment, aprepitant nano-composition of the present invention, wherein Aprepitant and the weight of co-emulsifier
Amount ratio is 1: 20～1: 0.8, preferably 1: 10～1: 2, more preferably 1: 8～1: 3.
In a preferred embodiment, aprepitant nano-composition of the present invention, wherein Aprepitant and the weight ratio of oil phase
It is 1: 5～5: 1, preferably 1: 3～3: 1, more preferably 1: 2～2: 1.
In a preferred embodiment, aprepitant nano-composition of the present invention, wherein Aprepitant and the weight of stabilizer
Ratio is 1: 8～1: 1, preferably 1: 6～1: 1.5, more preferably 1: 5～1: 2.
In a preferred embodiment, aprepitant nano-composition of the present invention, wherein Aprepitant and auxiliary stabilizer
Weight ratio is 1: 1～10: 1, preferably 2: 1～8: 1, more preferably 3: 1～7: 1.
Aprepitant nano-composition of the present invention, the Unit Weight of each component is: aprepitant: 20-150mg, preferably
40-125mg, further preferably 80-125mg.And/or emulsifying agent: 40-900mg, preferably 60-800mg, further preferably 80-700mg,
Further preferably 90-600mg, further preferably 100-500mg, further preferably 200-400mg.And/or co-emulsifier: 20-1000mg, excellent
Select 40-1000mg, further preferably 50-900mg, further preferably 60-800mg, further preferably 80-700mg, further preferably 100-600mg,
Further preferably 150-500mg, further preferably 200-400mg.And/or oil phase: 10-250mg, preferably 15-220mg, further preferably 20-210
Mg, further preferably 30-200mg, further preferably 40-180mg, further preferably 50-160mg, further preferably 60-140mg, further preferably 80-120
mg.And/or stabilizer: 50-500mg, preferably 60-450mg, further preferably 80-400mg, further preferably 80-350mg, more excellent
Select 100-300mg, further preferably 120-280mg, further preferably 150-250mg.And/or auxiliary stabilizer: 10-50mg, preferably
15-45mg, further preferably 20-40mg, further preferably 22-35mg, further preferably 25-30mg.And/or solid absorbent: 0-1500mg,
Preferably 100-1400mg, further preferably 150-1200mg, further preferably 200-1100mg, further preferably 250-1000mg, further preferably
300-900mg, further preferably 400-800mg.
Aprepitant nano-composition of the present invention, it is characterised in that may be used for oral solution, hard capsule, flexible glue
Wafer, dry suspension, suspensoid, tablet, injection, lyophilized injectable powder.
The preparation method of aprepitant nano-composition of the present invention, is characterized in that: described preparation method comprises the following steps:
A, proportionally weighing aprepitant and stabilizer, mix homogeneously, as mixture I；
B, proportionally weigh emulsifying agent, co-emulsifier, oil phase, auxiliary stabilizer, mix homogeneously with mixture I, by its point
Loading in appropriate vessel, airtight, room temperature keeps in Dark Place, and obtains aprepitant nano-composition.
Weigh solid absorbent in proportion, add in above-mentioned aprepitant nano-composition, and mix homogeneously, use suitable doing
Drying method is dried, and obtains the aprepitant nano-composition of solid state.
Inventor finds in laboratory preliminary study, and aprepitant dissolubility in oil is very poor, and dissolution velocity is the slowest, even if
Make it be dissolved in reluctantly in oil phase by reducing drug level, place at ambient temperature and also there will be precipitation bottom oil phase after a few days,
Show that medicine easily separates out solid in oil phase.Therefore, applicant attempts changing various oil phase, is simultaneously introduced emulsifying agent, but Ah
The solution shelf-stability formed after the smooth dissolving of auspicious pyrrole is the most undesirable.Applicant chances in screening process later:
When system adds after stabilizer, although can not be obviously improved the dissolution velocity of aprepitant, but A Rui pyrrole after long agitation
Smooth dissolubility substantially increases, the most surprisingly, the solution formed after adding stabilizer, placed the most not through tens of days
Separate out precipitation, be settled solution always.
On this basis, applicant is also found by further research, and the dissolubility of aprepitant is had a significant impact by order by merging,
Aprepitant is first sufficiently mixed uniformly with stabilizer, more can give full play to the effect of stabilizer.Additionally, in research process also
Finding, when stabilizer ratio is too low, aprepitant dissolubility in oil increases few, is not enough to improve its oral absorption energy
Power, this all will be understood by for all pharmaceutics workers；But surprisingly, when stabilizing agent dosage is excessive, and
Non-making aprepitant solvability strengthen as predicted, it is slack-off that the stabilizer of excess instead results in aprepitant dissolution velocity,
Substantially prolongs the time required for dissolving, and make the bad stability of system, after placement, be easily generated muddiness.Therefore, this
The bright ratio to aprepitant Yu stabilizer has carried out comprehensive careful research, and result shows that aprepitant exists with the ratio of stabilizer
Time in the range of 1: 5～1: 2, the dissolubility of aprepitant and the stability of system are best.
Additionally, present invention research also finds, the stabilizer at aforementioned proportion improves the excellent of aprepitant dissolubility in oil phase
Under character, in system, add the auxiliary stabilizer of suitable kind and consumption, will further improve the effect of stabilizer, though body
Tie up to 40 DEG C, place under the conditions of the Acceleration study of relative humidity 75%, the most relatively stable, solution does not occurs muddiness or precipitation.
Aprepitant is oral Bendectin, is made into oral formulations, not only needs to solve dissolution and the problem of bioavailability,
Its taste and mouthfeel are the most extremely important for the compliance of patient；And the oil-soluble adjuvant (the such as oil phase and breast that use in the present invention
Agent) mouthfeel is greasy, and therefore, originally applicant uses odor mask (powdered flavor, the sweet taste that pharmaceutics worker generally uses
Agent etc.), PRELIMINARY RESULTS shows, these odor masks have certain effect, but cannot eradicate the distinctive bad mouthfeel of oil-soluble adjuvant and taste
Road.Then, applicant finds the method for possible taste masking in wide range, investigates discovery through substantial amounts of, according to micro-
The solid adjuvant material such as crystalline cellulose or micropowder silica gel does adsorbent, not only can improve the state of material, it is often more important that can be abundant
Taste masking, therefore, the composition of aprepitant nano-composition of the present invention, original aprepitant, oil phase, emulsifying agent,
On the basis of coemulsifier, stabilizer and auxiliary stabilizer, add solid absorption odor mask so that said composition has mouth concurrently
Feel good, the big advantage of good absorbing two.
Beneficial effect:
The present invention uses above technical scheme, and aprepitant is made nano-composition, is improving aprepitant dissolubility, biology
The physical stability of aprepitant is improve, it is to avoid its crystallization while availability.Extraly, by aprepitant nanometer
When compositions is further prepared into solid nano compositions, substantially improving its bad mouthfeel and taste, this is for Bendectin
Speech, is a particularly important performance improvement so that the compliance that patient takes is greatly reinforced.Based on the life improving aprepitant
Thing availability, improving its stability and improve the beneficial effect of mouthfeel, the present invention has widened use crowd's scope of aprepitant；
While improve medicine stability in the composition and bioavailability, reduce the toxic and side effects of aprepitant treatment,
The outbreak of the acute and delayed property n or V after various chemotherapy can be effectively treated.So, aprepitant nano-composition has
Higher economic worth and society generalization is had to be worth.
Accompanying drawing illustrates:
Fig. 1 is that aprepitant nano-composition (embodiment 1) redispersibility tests grain size distribution；
Fig. 2 is the Dissolution profiles figure of aprepitant nano-composition；
Fig. 3 is the Drug-time curve figure after aprepitant nano-composition rat is administered.
Specific embodiment:
Embodiment 1:
A kind of aprepitant nano-composition of preparation, its constituent is as follows:
The preparation method of aprepitant nano-composition comprises the following steps:
Proportionally weighing aprepitant and phospholipid of natural soybean, mix homogeneously, as mixture I；Proportionally weigh polyoxy second
Alkene Oleum Ricini EL35, propylene glycol, ethanol, midchain oil triglyceride, vitamin E, mix homogeneously with mixture I, i.e. get A Rui
The smooth nano-composition of pyrrole；Being distributed in appropriate vessel, airtight, room temperature keeps in Dark Place；
Take above-mentioned prepared aprepitant nano-composition, mix homogeneously with micropowder silica gel, microcrystalline Cellulose according to usage ratio,
Employing spray drying method is dried, and obtains the aprepitant nano-composition of solid state.
Embodiment 2:
A kind of aprepitant nano-composition of preparation, its constituent is as follows:
The preparation method of aprepitant nano-composition comprises the following steps:
Proportionally weighing aprepitant and natural phosphatidyl choline, mix homogeneously, as mixture I；Proportionally weigh polyoxyethylene
Castor oil hydrogenated RH40, cetomacrogol 1000, ethanol, Ethyl linoleate, tocopheryl palmitate, mix all with mixture I
Even, obtain aprepitant nano-composition；Being distributed in appropriate vessel, airtight, room temperature keeps in Dark Place；
Take above-mentioned prepared aprepitant nano-composition, mix with Pluronic F68, hydroxypropyl methyl cellulose according to usage ratio
Close uniformly, use spray drying method to be dried, obtain the aprepitant nano-composition of solid state.
Embodiment 3:
A kind of aprepitant nano-composition of preparation, its constituent is as follows:
The preparation method of aprepitant nano-composition comprises the following steps:
Proportionally weighing aprepitant and PHOSPHATIDYL ETHANOLAMINE, mix homogeneously, as mixture I；Proportionally weigh poly-Pyrusussuriensis
Ester 80, Macrogol 2000, long-chain oil triglycerides, ascorbyl palmitate, mix homogeneously with mixture I, obtain Ah
The smooth nano-composition of auspicious pyrrole；Being distributed in appropriate vessel, airtight, room temperature keeps in Dark Place；
Take above-mentioned prepared aprepitant nano-composition, mix with micropowder silica gel, microcrystalline Cellulose, mannitol according to usage ratio
Close uniformly, use boulton process to be dried, obtain the aprepitant nano-composition of solid state.
Embodiment 4:
A kind of aprepitant nano-composition of preparation, its constituent is as follows:
The preparation method of aprepitant nano-composition comprises the following steps:
Proportionally weighing aprepitant and phosphatidylcholine, mix homogeneously, as mixture I；Proportionally weigh polyoxyethylene
Oleum Ricini EL35, propylene glycol, ethanol, midchain oil triglyceride, vitamin E, calcium disodium edetate, hydroquinone, and mix
Thing I mix homogeneously, obtains aprepitant nano-composition；Being distributed in appropriate vessel, airtight, room temperature keeps in Dark Place,
Obtain the aprepitant nano-composition of liquid condition.
Embodiment 5:
A kind of aprepitant nano-composition of preparation, its constituent is as follows:
The preparation method of aprepitant nano-composition comprises the following steps:
Proportionally weighing aprepitant and phospholipid of natural soybean, phosphatidyl glycerol, mix homogeneously, as mixture I；According to than
Example weighs Solutol HS15, PEG400, ethanol, midchain oil triglyceride, vitamin E, disodium edetate,
Mix homogeneously with mixture I, obtain aprepitant nano-composition；It is distributed in appropriate vessel, airtight, room temperature lucifuge
Preserve；
Take above-mentioned prepared aprepitant nano-composition, mix with microcrystalline Cellulose and sodium lauryl sulphate according to usage ratio
Uniformly, use freeze-drying to be dried, obtain the aprepitant nano-composition of solid state.
Embodiment 6:
A kind of aprepitant nano-composition of preparation, its constituent is as follows:
The preparation method of aprepitant nano-composition comprises the following steps:
Proportionally weighing aprepitant and Phosphatidylserine, mix homogeneously, as mixture I；Proportionally weigh the sad last of the ten Heavenly stems
Acid polyethylene glycol glyceride, TC, PEG400, isopropyl myristate, thiourea, with mixture I
Mix homogeneously, obtains aprepitant nano-composition；Being distributed in appropriate vessel, airtight, room temperature keeps in Dark Place；
Take above-mentioned prepared aprepitant nano-composition, mix with for powder silica gel, hydroxypropyl methyl cellulose according to usage ratio
Uniformly, use freeze-drying to be dried, obtain the aprepitant nano-composition of solid state.
Embodiment 7:
A kind of aprepitant nano-composition of preparation, its constituent is as follows:
The preparation method of aprepitant nano-composition comprises the following steps:
Proportionally weighing aprepitant and natural phosphatidyl choline, mix homogeneously, as mixture I；Proportionally weigh polyoxyethylene
Castor oil hydrogenated RH40, propylene glycol, cetomacrogol 1000, long-chain oil triglycerides, tocopheryl palmitate, and mix
Thing I mix homogeneously, obtains aprepitant nano-composition；Being distributed in appropriate vessel, airtight, room temperature keeps in Dark Place；
Take above-mentioned prepared aprepitant nano-composition, mix with sodium lauryl sulphate, microcrystalline Cellulose according to usage ratio
Uniformly, use freeze-drying to be dried, obtain the aprepitant nano-composition of solid state.
Embodiment 8:
A kind of aprepitant nano-composition of preparation, its constituent is as follows:
The preparation method of aprepitant nano-composition comprises the following steps:
Proportionally weighing aprepitant and phosphatidic acid, mix homogeneously, as mixture I；Proportionally weigh Polyethylene Glycol stearic
Acid esters 15, PEG400, midchain oil triglyceride, vitamin E, mix homogeneously with mixture I, obtains aprepitant and receives
Rice compositions；Being distributed in appropriate vessel, airtight, room temperature keeps in Dark Place；
Take above-mentioned prepared aprepitant nano-composition, according to usage ratio and mannitol, Pluronic F68, polyvinyl pyrrole
Alkanone mix homogeneously, uses freeze-drying to be dried, obtains the aprepitant nano-composition of solid state.
Specific experiment example:
Experimental example 1: the redispersibility test of aprepitant nano-composition
Comprise the following steps:
Taking different embodiment and prepare the aprepitant nano-composition of gained, be added thereto to the water of 20 times amount, magnetic agitation makes point
Dissipating uniformly, remove insoluble matter with 0.8 μm filtering with microporous membrane, filtrate measures its particle diameter with Malvern laser particle analyzer, and result is shown in
Following table and Fig. 1 grain size distribution of aprepitant nano-composition (embodiment 1 prepare).
The granularmetric analysis result of Malvern laser particle analyzer:
| Prescription number | Mean diameter (nm) | Polydispersity index (PDI) |
| Embodiment 1 | 43.5 | 0.256 |
| Embodiment 3 | 44.5 | 0.251 |
| Embodiment 5 | 41.4 | 0.228 |
| Embodiment 7 | 47.7 | 0.231 |
| Embodiment 8 | 49.3 | 0.219 |
By the above results it can be seen that the mean diameter after said composition redispersion is 40～50nm, particle diameter narrow distribution, many points
Dissipate index and be less than 0.27, meet the requirement of oral microparticle delivery system.
Experimental example 2: the Dissolution Rate Testing of aprepitant nano-composition
In order to evaluate aprepitant nano-composition (embodiment 1, embodiment 3, embodiment 5, embodiment 7 and embodiment 8)
In Vitro Dissolution effect, We conducted Dissolution Rate Testing, use dissolution test system, measure aprepitant nano-composition and exist
Dissolution medium is the dissolution percentage rate of different time in 0.1mol/L hydrochloric acid solution (simulated gastric fluid), and with commercially available product (A Rui pyrrole
Smooth capsule) compare.
Result: as shown in Figure 2, compared with commercially available aprepitant capsule, self-control aprepitant nano-composition has the most molten
Going out speed, when 20 minutes, dissolution percentage rate is close to 100%, hence it is evident that higher than commercially available product aprepitant capsule.
Experimental example 3: the pharmacokinetic trial of aprepitant nano-composition
In order to evaluate aprepitant nano-composition (embodiment 1, embodiment 3, embodiment 5, embodiment 7 and embodiment 8)
Body absorption effect, We conducted and receive with the commercially available product aprepitant capsule (80mg/ grain) aprepitant as reference preparation
The rat plasma pharmacokinetics research of rice compositions.Specific embodiments is as follows: health male SD rat is equally divided into two
Group, often group 6, fasting (can't help water) 12h before experiment, respectively organizes single dose gavage respectively and gives aprepitant nano-composition
Or commercially available product aprepitant capsule (with 5% carboxymethylcellulose sodium solution suspendible, dosage is all equivalent to aprepitant 7.2
mg·kg-1).0.5,1,2,3,4,6,8,12,24,36,48,72 hours retroorbital venous clumps after being administered
Take blood 0.5ml, be placed in preprepared heparin sodium anticoagulant tube, 5000r min-1Centrifugal 5min, draws supernatant separation blood
Slurry, puts-40 DEG C of refrigerator freezings and preserves to be measured.With albumen in acetonitrile precipitation blood plasma and extract medicine, take supernatant, use HPLC-MS
Measure wherein aprepitant content, matching Drug-time curve figure (see Fig. 3), and calculate its relative bioavailability, such as following table.
| Prescription number | Relative bioavailability (%) |
| Embodiment 1 | 153.3 |
| Embodiment 3 | 185.4 |
| Embodiment 5 | 161.3 |
| Embodiment 7 | 173.8 |
| Embodiment 8 | 188.1 |
According to pharmacokinetics statistical parameter calculate between aprepitant nano-composition group and commercially available product aprepitant Capsules group the most raw
Thing availability, all more than 150%, shows that oral administration nanometer technology is significantly increased for the body absorption of aprepitant.
Listed above is only some specific embodiments and the experimental example of the present invention, from owning that present disclosure is derived
Deformation, belongs to protection scope of the present invention.
Claims (11)
1. an aprepitant nano-composition, it is characterized in that: the particle diameter of described nano-composition meets 10-600nm, preferably 20-400nm, further preferably 30-80nm, and/or the release characteristics of described compositions meets: in dissolution medium is 0.1mol/L hydrochloric acid solution, release at least 20% in 5 minutes, within 10 minutes, at least discharge 70%, release at least 95% in 20 minutes, and/or the bioavailability of described compositions, for Emend, for its 90-250%, preferably 120-200%, more preferably 140-180%.
Aprepitant nano-composition the most according to claim 1, is characterized in that: described nano-composition includes aprepitant, oil phase, emulsifying agent, co-emulsifier and optional solid absorbent.
Aprepitant nano-composition the most according to claim 1, it is characterised in that
Described oil phase is selected from: long-chain oil triglycerides, isopropyl myristate, Ethyl linoleate, midchain oil triglyceride or two or more mixture therein；
Described emulsifying agent is selected from: polyoxyethylene hydrogenated Oleum Ricini, polyoxyethylene castor oil, Solutol HS15, Labraso, Polyethylene Glycol glyceryl laurate ester, oleic acid polyethyleneglycol glyceride, polyoxyethylene sorbitan monoleate, or two or more mixture therein；
Described co-emulsifier is selected from propylene glycol, PEG400, cetomacrogol 1000, Macrogol 2000, TC, ethanol or two or more mixture therein；
Described solid absorbent is selected from: microcrystalline Cellulose, pluronic, micropowder silica gel, hydroxypropyl methyl cellulose, mannitol, sodium lauryl sulphate, polyvinylpyrrolidone, or two of which or two or more mixture.
Aprepitant nano-composition the most according to claim 3, it is characterised in that each component by weight, for aprepitant: 20-150 part, preferably 40-125 part, further preferably 80-125 part；And/or emulsifying agent: 40-900 part, preferably 60-800 part, further preferably 80-700 part, further preferably 90-600 part, further preferably 100-500 part, further preferably 200-400 part；And/or co-emulsifier: 20-1000 part, preferably 40-1000 part, further preferably 50-900 part, further preferably 60-800 part, further preferably 80-700 part, further preferably 100-600 part, further preferably 150-500 part, further preferably 200-400 part；And/or oil phase: 10-250 part, preferably 15-220 part, further preferably 20-210 part, further preferably 30-200 part, further preferably 40-180 part, further preferably 50-160 part, further preferably 60-140 part, further preferably 80-120 part；And/or solid absorbent: 0-1500 part, preferably 100-1400 part, further preferably 150-1200 part, further preferably 200-1100 part, further preferably 250-1000 part, further preferably 300-900 part, further preferably 400-800 part.
5. according to the aprepitant nano-composition described in any one of claim 1-3, it is characterized in that: described nano-composition also includes stabilizer and auxiliary stabilizer.
Aprepitant nano-composition the most according to claim 5, it is characterised in that
Described stabilizer is natural phospholipid, synthetic phospholipid and derivant thereof, or two or more mixture therein.Wherein, natural phospholipid includes phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, sphingomyelins, phosphatidic acid, phosphatidyl glycerol, Phosphatidylserine；Synthetic phospholipid includes distearoyl phosphatidylcholine, DSPE, DSPG, G 12S3P, oleoyl phosphatidylcholine, oleoylphosphatidyl ethanolamine, oleoylphosphatidyl glycerol, oleoyl phospholipid acid, palmitoylphosphatidyl choline, palmityl PHOSPHATIDYL ETHANOLAMINE, palmityl phosphatidyl glycerol, palmityl phosphatidic acid, dimyristoylphosphatidycholine, myristoyl PHOSPHATIDYL ETHANOLAMINE, myristoyl phosphatidyl glycerol, myristoyl phosphatidic acid, 22 phosphinylidyne phosphatidylcholines, 22 phosphinylidyne PHOSPHATIDYL ETHANOLAMINE, 22 phosphinylidyne phosphatidyl glycerols, 22 phosphinylidyne phosphatidic acid；And/or
Described auxiliary stabilizer is ascorbyl palmitate, vitamin E, tocopheryl palmitate, thiourea, hydroquinone, disodium edetate, calcium disodium edetate, or two of which or two or more mixture.
Aprepitant nano-composition the most according to claim 5, it is characterised in that by weight,
Stabilizer is: 50-500 part, preferably 60-450 part, further preferably 80-400 part, further preferably 80-350 part, further preferably 100-300 part, further preferably 120-280 part, further preferably 150-250 part；
Auxiliary stabilizer: 10-50 part, preferably 15-45 part, further preferably 20-40 part, further preferably 22-35 part, further preferably 25-30 part.
8. according to the preparation method of the aprepitant nano-composition described in any one of claim 2-6, it is characterized in that: described preparation method comprises the following steps:
A, proportionally weighing aprepitant and stabilizer, mix homogeneously, as mixture I；
B, proportionally weighing emulsifying agent, co-emulsifier, oil phase, auxiliary stabilizer, mix homogeneously with mixture I, be distributed in appropriate vessel, airtight, room temperature keeps in Dark Place, and obtains aprepitant nano-composition.
Weigh solid absorbent in proportion, add in above-mentioned aprepitant nano-composition, and mix homogeneously, use suitable drying means to be dried, obtain the aprepitant nano-composition of solid state.
In the preparation method of aprepitant nano-composition the most according to claim 8, drying means is lyophilization, is vacuum dried or is spray-dried.
10. according to the aprepitant nano-composition described in any one of claim 1-7, it is characterized in that, described compositions may be used for following dosage form: oral solution, hard capsule, soft capsule, dry suspension, suspensoid, tablet, injection, lyophilized injectable powder.
11. are preparing, according to the aprepitant nano-composition described in any one of claim 1-10, the acute and Delayed onset nausea and vomiting that Prophylactic chemotherapy causes, and the application in the medicine preventing postoperative nausea and vomiting.
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| CN107260705A (en) * | 2017-06-08 | 2017-10-20 | 武汉励合生物医药科技有限公司 | A kind of preparation method of Aprepitant Nano capsule |
| CN108619525A (en) * | 2017-03-15 | 2018-10-09 | 和龙 | How smooth-mPEG-PLA nanoparticles of appropriate pyrrole and its preparation method and application |
| CN110996911A (en) * | 2017-06-26 | 2020-04-10 | 福多兹制药公司 | Aprepitant nano-microcapsule preparation as well as method and application thereof |
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| CN117503699A (en) * | 2023-12-08 | 2024-02-06 | 斯坦德医药研发(江苏)有限公司 | Aprepitant oral liquid preparation and preparation method thereof |
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| CN108619525A (en) * | 2017-03-15 | 2018-10-09 | 和龙 | How smooth-mPEG-PLA nanoparticles of appropriate pyrrole and its preparation method and application |
| CN108619525B (en) * | 2017-03-15 | 2020-12-29 | 和龙 | Netupidem-mPEG-PLA nanoparticle and preparation method and application thereof |
| CN107260705A (en) * | 2017-06-08 | 2017-10-20 | 武汉励合生物医药科技有限公司 | A kind of preparation method of Aprepitant Nano capsule |
| CN110996911A (en) * | 2017-06-26 | 2020-04-10 | 福多兹制药公司 | Aprepitant nano-microcapsule preparation as well as method and application thereof |
| US11260028B2 (en) | 2017-06-26 | 2022-03-01 | Fordoz Pharma Corp. | Nanosome formulations of aprepitant and methods and applications thereof |
| CN111514100A (en) * | 2019-02-01 | 2020-08-11 | 北京蓝丹医药科技有限公司 | Aprepitant injection |
| CN112168788A (en) * | 2019-07-01 | 2021-01-05 | 中国医学科学院药物研究所 | Aprepitant micelle sterile freeze-dried preparation for intravenous injection and preparation method thereof |
| CN116283947A (en) * | 2023-02-07 | 2023-06-23 | 成都医学院 | Aprepitant eutectic crystal and preparation method and application thereof |
| CN117503699A (en) * | 2023-12-08 | 2024-02-06 | 斯坦德医药研发(江苏)有限公司 | Aprepitant oral liquid preparation and preparation method thereof |
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