CN105188671A - Stable pharmaceutical composition of clopidogrel free base for oral and parenteral delivery - Google Patents
Stable pharmaceutical composition of clopidogrel free base for oral and parenteral delivery Download PDFInfo
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- CN105188671A CN105188671A CN201480007796.1A CN201480007796A CN105188671A CN 105188671 A CN105188671 A CN 105188671A CN 201480007796 A CN201480007796 A CN 201480007796A CN 105188671 A CN105188671 A CN 105188671A
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Abstract
The present disclosure provides ready-to-use, oil/water emulsion compositions with mean droplet size (intensity-average, nm) of 100-500 nm,, wherein the oil phase comprises clopidogrel free base dispersed in pharmaceutical acceptable oil(s). The emulsion uses clopidogrel free base or premix of clopidogrel free base in oil(s) as the starting materials and may also contain one or more excipients such as surfactant and or co-surfactant, osmotic agent, pH adjustment agent, antioxidant, preservative, sweetener, and/or suspending agent, etc. The emulsion formulations and method of manufacturing significantly improves the stability of clopidogrel over other aqueous based formulations (such as cyclodextrin-based formulations and emulsion made using clopidogrel salt as the starting materials) with respect to chiral degradation, hydrolytic, and thermal degradation. Ready-to-use emulsion compositions, which can be administered orally or parentally as a single high dose with up to 300 mg of clopidogrel dose, can be prepared and stored at room temperature for at least 19 weeks or at refrigeration temperature for at least 1 year. The compositions will provide rapid therapeutic action as anti-platelet agent for patient under emergence and intense care or who cannot swallow tablet dosage form.
Description
Priority
This application claims priority is February 6 2013 applying date, the patent No. 61/761, the U.S. Provisional Patent Application of 234, and the content of this temporary patent application is incorporated to herein by reference.
Technical field
The invention relates to clopidogrel oil/water emulsion compositions, said preparation, by being scattered in oil phase by clopidogrel free alkali, significantly improves clopidogrel for chiral inversion, hydrolysis, heat drop stability of solution; Invention describes and work as mammal, when especially human experimenter needs to use clopidogrel to treat, the preparation of clopidogrel composition and using method.
Background technology
Clopidogrel, its chemistry is by name: methyl (+)-(S)-α-(0-chlorphenyl)-6,7-dihydro-thiophene [3,2-C]) pyridine-5 (4H)-acetate, clopidogrel is a kind of anticoagulation, its by optionally to suppress the platelet receptor of adenosine diphosphate (ADP) (ADP) and ADP in conjunction with anticoagulant.It is widely used in prevention of arterial atherosclerotic disease event, as myocardial infarction, and apoplexy, peripheral arterial disease, acute coronary syndrome, cardiovascular death.The S-type enantiomer-specific structure of clopidogrel is as follows:
Clopidogrel (such as:
with other imitation medicines) product specification of having gone on the market is tablet formulation containing clopidogrel free alkali 75mg, clopidogrel is present in preparation with sulphate form.In commercialized product, not yet there is parenteral fluids preparation or oral liquid.
it is the anti-platelet aggregation medicinal of a minimizing thrombosis event ratified through U.S. food and Drug Administration (FDA) and acute coronary syndrome.For mean dose (300mg
clopidogrel) therapeutical effect (such as: anticoagulant) that reaches expection needs between 2-5h, and it is attributable to postpone to absorb, the availability of delay system, not good enough bioavailability.If need this Therapeutic Method immediately (such as, need percutaneous coronary intervention (pci) (PCI) being less than in 2 to 3 hours), then usually need to give patient the clopidogrel being greater than mean dose, realize quick acting according to this, but this may cause potential Fatal side effects, such as: hemorrhage and bleed for a long time.
Therefore, urgent needs is a kind of can be used for parenteral or oral to reach quick acting and progressively can control the clopidogrel liquid preparation of taking dose.The key using clopidogrel to prepare a kind of vein parenteral or oral liquid is to have biocompatibility solvent clopidogrel being placed in a kind of low side effect, having suitable pharmacodynamics curve, and is prepared into the ability of prescription; Fat-soluble because of clopidogrel, has pH dependency under physiological ph conditions and dissolubility is extremely low, and extreme chemical is unstable under alkaline pH environment, and this is for clopidogrel formulations, is a kind of stern challenge.
Clopidogrel to be a kind of pKa be 4.5 weak base, it is almost insoluble in neutral pH water, but easily molten in pH1 solution, and it is soluble in methanol, is partially dissolved in dichloromethane, is dissolved in ether hardly.Its specific optical rotation is approximately+56 °.Clopidogrel free alkali is the general grease of a kind of semi-solid high viscosity, and this can cause it in storage or the various problems of processing procedure.In addition, it is reported that clopidogrel free alkali is unsuitable for being prepared into pharmaceutical preparation, this is because unstable under the environment that increases in humidity and temperature of clopidogrel free alkali.Because clopidogrel free alkali is unstable at the proton of chiral centre and methyl ester group, clopidogrel free alkali is subject to racemization, oxidation, and the hydrolysis of methyl ester group.It is reported that antioxidant can not suppress it to degrade, higher pH value then can aggravate its unstability.Up to the present bibliographical information shows that clopidogrel only had before being prepared into preparation and just can guarantee its stability with acid in conjunction with salify.
Bisulfate clopidogrel, is applied to the oral tablet product gone on the market at present
(SanofiAventis), this product is the example that clopidogrel salt form is applied to oral formulations, the clopidogrel free alkali that it provides specification to be 75mg with Tabules.Similar with clopidogrel free alkali, bisulfate clopidogrel, because it is for the sensitivity of racemization, oxidation, methyl ester group hydrolysis, makes it relatively unstable under increase humidity, temperature, alkaline pH ambient condition.Clopidogrel is a chiral molecule, there is R, S enantiomer; Its S enantiomer has biological activity, and R enantiomer (impurity C) there is not any anticoagulating active and toleration is very poor; Animal can bring out convulsions under high dose condition.The most of clopidogrel entering systemic circulation upon administration changes into does not have activated carboxylic acid derivates, and it is formed by the hydrolysis of carboxy-lesterase catalysis ester functional group.Carboxylic acid derivates (+)-S-(o-chlorphenyl)-6,7-dihydro-thiophenes [3,2-c] pyridine-5 (4H)-acetic acid (clopidogrel acid, impurity A), its hydrolysis by ester functional group obtains; No matter carboxylic acid derivates, as hydrolyzate, carries out catalysis generation by external increase humidity, pH, temperature, or passes through the product of carboxy-lesterase catalytic action in body, is the main degradation products without pharmacological activity.This means, clopidogrel crude drug or formulation products must carry out meticulous control to the content of R-enantiomer and nonactive carboxylic acid derivates.The structure chart that clopidogrel major impurity is included in American Pharmacopeia 32 editions, European Pharmacopoeia is as follows:
Clopidogrel dissolubility in the aqueous solution of neutral pH is lower, causes it to be difficult to be developed to a kind of bioavailable and the stable formulation products of physical chemistry, particularly when needs of patients intravenously administrable or oral administration solution.And the dissolubility of clopidogrel has highly pH-dependent is developed to it a suitable, precipitate and the aqueous parenteral formulation of parenteral tract pain, phlebitis, blood vessel embolism can not be caused to form huge challenge with can not produce during bioresorbable.In addition, the chemical instability of clopidogrel, show the instability of clopidogrel under wet, heat, alkaline pH environment, eliminate and use aqueous solvent in prescription, it is with an organic solvent liquid preparation or the lyophilization solid preparation of substrate that its product prescription is confined to, and strictly need limit its storage requirement in lower storage temperature, such as cold preservation or freezing.
Many methods can be used for vein parenteral and the liquid oral compositions of preparing microsolubility or insoluble drug.These technology mainly comprise: Micellar Solubilization or the nano granule suspension by surfactant formation medicine; Compositions (hydroxypropylβ-cyclodextrin (HPBCD) and sulfobutyl ether-beta-cyclodextrin (SBECD)) is formed with cyclodextrin and derivant thereof; The use of multiple co-solvent system; With strong acid salify in low pH solution.But for micelle volume, its surfactant used and harmful effect have close association, such as: as haemolysis and histamine react and severe allergic reaction; For the system of nano suspension, because the nanometer particle size stability of drug particles needs a certain amount of polymer and surfactant, because of medicine and aqueous medium and periphery around the larger contact area of surfactant and cause medicine catalytic degradation to be in the news; Because free medicine has at aqueous medium the another large problem that higher concentration makes taste masking and parenteral pain become micelle/nano suspension system to face.As everyone knows, co-solvent system can cause precipitation, parenteral pain and phlebitis.Cyclodextrin and derivant thereof can cause potential nephrotoxicity and bradycardia and blood pressure to reduce; Secret worry existing for cyclodextrin is combined with the lipophilic drugs of co-administered is reported in media.In low pH solution, form alkalescence salt such as bisulfate clopidogrel with strong acid will cause the stability problem of drug-excipient and drug products, and sensory issues (clopidogrel has bitterness) will be caused, when medicine exists as free alkali form and pH neutral contacting blood can produce precipitation, cause stimulation and the pain at parenteral position.In sum, said method has its limitation, is all difficult to clopidogrel to be prepared into a kind ofly have suitable biocompatibility solvent, minimum side effect, the vein parenteral agent of appropriate pharmacodynamics curve or oral solution.
WO2008/060934 discloses a kind of emulsion compositions, and said composition is by micronization and add surfactant and make the oil droplet of the pure tetrahydropyridine antiplatelet drug of preparation reach stable.This dosage form does not use vegetable oil only to use pure antiplatelet drug and surfactant.Although mention this substrate in this patent to can be applicable to clopidogrel, but this patent only discloses the emulsion compositions using bisulfate clopidogrel as crude drug, use clopidogrel free alkali to prepare emulsion compositions as crude drug and be not published in this patent; The impact that this dosage form distributes for the relative substance of clopidogrel for the impact, particularly said composition of the product stability of clopidogrel free alkali or the various salt form of clopidogrel is not published in this patent.
CN102697724 discloses a kind of bisulfate clopidogrel and amino acid salts thereof of using and prepares the method for oil in water emulsion as crude drug.But, this patent does not include the method using clopidogrel free alkali to prepare emulsion compositions as crude drug, and clopidogrel forms concentration too low (≤0.15%w/v) in the preparation of emulsion compositions final, and this may need a large amount of emulsions to reach the volume requirements of 300mg; And this dosage form for the various salt form of clopidogrel on the impact of product stability, the impact that particularly this combination distributes for the relative substance of clopidogrel is not published in this patent.
Summary of the invention
For the defect in solution prior art and problem, be necessary to develop clopidogrel liquid dosage form in the art, particularly steady quality, immediately can use, single dose intravenous parenteral 300mg clopidogrel dosage, rapid-onset can be provided, and the parenteral formulation with storage can be prepared under room temperature or refrigerated storage temperature.This patent provides following compositions, said composition can be patient in emergency and Intensive Care Therapy, or patient cannot provide antiplatelet drug when oral administration.The stability of this product and purity all meet the preparation requirement for pharmaceutical preparation of U.S. food and Drug Administration (FDA) and GMP.
Consider the problems referred to above, the invention provides one and comprise clopidogrel free alkali, mean diameter is 100-500nm, immediately uses, and take water as substrate, the parenteral of oil/water or oral latex emulsion compositions.Wherein said oil phase comprises clopidogrel free alkali and is dispersed in the oil of surfactant containing acceptable concentration limit and/or cosurfactant, 9-10 is about when oil phase is placed in pH, or in the autoclaving environment of water or steam, surprisingly obtain a kind ofly to have good stability, the product of impurity profile excellence; Through storage for a long time, this product still has superior quality.
The invention describes when being placed in pharmaceutical composition using clopidogrel as effective active matter, clopidogrel impurity content is controlled meeting the method in the clopidogrel sheet impurity content prescribed limit formulated in American Pharmacopeia (USP) 32 editions.Compared to other aqueous matrix prescriptions (such as cyclodextrin substrate prescription), use clopidogrel salt form prescription (such as bisulfate clopidogrel), this Emulsion prescription improves the stability in chiral inversion, hydrolysis, thermal degradation of clopidogrel significantly.
1, one aspect of the invention is the hydrolysis that the aqueous matrix emulsion prepared significantly reduces methyl ester group (impurity A); Although clopidogrel is from very unstable in alkaline pH environment, but emulsion prescription of the present invention is prepared in pH9-10 environment to be made clopidogrel reach in the hydrolysis of its shelf life to minimize, however the clopidogrel not being prepared to preparation only use in the solution identical with above-mentioned condition using NaOH preparation 5 minutes namely degradable.
2, another aspect of the present invention is the thermal degradation that the emulsion prepared effectively inhibits clopidogrel.According to the literature, because the proton of the chiral centre of clopidogrel is unstable, makes it be easy to oxidized, also fail to suppress it to degrade even if add antioxidant.Contrary with document conclusion, Emulsion prescription of the present invention, when not using antioxidant, effectively inhibits the thermal degradation of clopidogrel.
3, another aspect of the present invention is that emulsion prepared by the present invention effectively inhibits clopidogrel from S-enantiomer (having biological activity) to the chiral inversion (impurity C<1.5%) of R-enantiomer (there is not any anti-agglutination activity and toleration is poor).In contrast, clopidogrel salt form (such as bisulfate clopidogrel) is used all in preparation or storage process, to define a considerable number of R-enantiomer as the cyclodextrin clathrate solution of crude drug or emulsion.
4, another aspect of the present invention uses the pharmaceutical composition prepared by preparation technology described in the invention no matter in preparation process or storage process, and the impurity content relevant to medicine all reaches and minimize or reduce.
A) be noted that especially.The pharmaceutical composition that the present invention describes uses clopidogrel as effective active matter, and the content of impurity meets in American Pharmacopeia (USP) 32 editions and specifies for the impurity of clopidogrel tablet.
B) in particular, the pharmaceutical composition that the present invention describes uses clopidogrel as effective active matter, pharmaceutical composition only comprises the chlorine pyrrole lattice related substance A being no more than 1.2%, be no more than the clopidogrel related substance C of 1.5%, all the other single medicine related impuritieses are all no more than 0.2% (except related substance B of clopidogrel), and total impurities is no more than 2.5% (except related substance B of clopidogrel).
5. in addition on the one hand, invention needs this preparation to carry out treating or palliate a disease the method for state as experimenter, comprise and provide a kind of using clopidogrel free alkali as effective active matter to experimenter, and containing effective dose of medicine compositions, this pharmaceutical composition impurity content is less or reach and minimize, and impurity content is no more than 2.5% (except related substance B of clopidogrel) of overall drug content.Any disease or the state of such as hereinbefore part all can use the medicine comprising clopidogrel, such as, with this prevention of arterial atherosclerotic disease event, myocardial infarction, and apoplexy, peripheral arterial disease, acute coronary syndrome, the cardiovascular disease such as cardiovascular and cerebrovascular vessel are dead.
An object of the present invention is to provide a kind of stable, containing Nano grade oil droplet, oil/water emulsion composition, this Emulsion can be used for parenteral or oral, this Emulsion by the clopidogrel free alkali be scattered in oil phase, surfactant, optional cosurfactant, substantially the aqueous phase not containing clopidogrel, pH adjusting agent forms.
Another one target of the present invention is to provide a kind of method for the preparation of stable, parenteral or oil in water emulsion compositions that is oral, that include Nano grade oil droplet, and the method mainly contains following steps: a) clopidogrel free alkali is scattered in oiliness carrier and prepares oil phase; B) preparation contains the aqueous phase of water and pH adjusting agent; C) surfactant or optional cosurfactant are added in aqueous phase or oil phase; D) oil phase is scattered in aqueous phase forms coarse emulsion, if necessary and pH is adjusted to ~ 9; E) emulsion of steps d is formed final emulsion by supersound process or high pressure homogenize process, and pH is adjusted between 5.5-10; F) final emulsion is filtered; G) biological load amount or the sterility of product is controlled by aseptic processing or terminal sterilization.
Another one target of the present invention is for needing the patient of clopidogrel single high dose administration to provide a kind of Therapeutic Method, the method comprises: liquid preparation a) providing a kind of oil/water emulsion compositions, and this liquid preparation is by being scattered in oiliness carrier by clopidogrel free alkali; Water and a kind of pH adjusting agent are prepared into aqueous phase; Oil phase is entered in aqueous phase by supersound process or high pressure homogenize process dispersion the oil droplet forming nanometer particle size, is finally prepared from; B) single oral or parenteral said composition, the single dose of said composition contains the clopidogrel free alkali up to 300mg.
Accompanying drawing explanation
Fig. 1 describes at high-pressure sterilizing pot, or Freezing-Melting Condition, or be placed on the emulsion average droplet particle diameter (mean intensity, nm) that by clopidogrel free alkali (embodiment 10) or bisulfate clopidogrel (embodiment 8) be prepared into of refrigerated condition (-5 DEG C) after 1 year
Fig. 2 describes clopidogrel free alkali emulsion (embodiment 10) and is being placed in the HPLC chromatogram of refrigerated condition (-5 DEG C) after 1 year.
Fig. 3 compares clopidogrel emulsion of the present invention (embodiment 10) and clopidogrel-HPBCD and the SBECD compositions at about pH8, after three stores under being all placed in 40 DEG C of conditions, clopidogrel is from S-enantiomer to the percentage rate of R-enantiomer chiral inversion.
Fig. 4 compares clopidogrel emulsion of the present invention (embodiment 10) and clopidogrel-HPBCD and the SBECD compositions at about pH8, three stores under being all placed in 25 DEG C of conditions, and clopidogrel is from S-enantiomer to the percentage rate of R-enantiomer chiral inversion.
Fig. 5 stores under comparing and clopidogrel emulsion of the present invention (embodiment 10) and clopidogrel salt form emulsion (embodiment 8) being all placed in 40 DEG C of conditions, and clopidogrel is from S-enantiomer to the percentage rate of R-enantiomer chiral inversion.
Fig. 6 by the samples of latex newly configured, the samples of latex of storage after at room temperature 19 weeks, be stored in 40 DEG C of samples of latex after 19 weeks, the microdroplet grain size distribution of three superposes, and three is the emulsion described by embodiment 6.
Detailed description of the present invention
" clopidogrel crude drug " or " clopidogrel free alkali " are defined as: methyl (+)-(S)-α-(0-chlorphenyl)-6,7-dihydro-thiophenes [3,2-C]) pyridine-5 (4H)-acetate.
" clopidogrel related substance A " or " impurity A " are defined as: (+)-S-(o-chlorphenyl)-6,7-dihydro-thiophenes [3,2-c] pyridine-5 (4H)-acetic acid.
" related substance B of clopidogrel " or " impurity B " is defined as: methyl (±)-(o-chlorphenyl)-4,5-dihydro-thiophenes [2,3-c] pyridine-6 (7H)-acetate.
" clopidogrel related substance C " or " impurity C " are defined as: methyl (-)-(R)-(o-chlorphenyl)-6,7-dihydro-thiophenes [3,2-c] pyridine-5 (4H)-acetate.
The invention provides the aqueous matrix oil/water Emulsion prescription compages thing that a kind of mean diameter is 100-500nm, be included in the clopidogrel free alkali in oil, surfactant and/or cosurfactant, and water liquid carrier.Prescription of the present invention is composed as follows:
A) clopidogrel free alkali;
B) oil phase;
C) surfactant and/or cosurfactant;
D) water and pH adjusting agent.
The optional composition of emulsion prescription also comprises: chelating agen, antioxidant, penetrating agent, suspending agent, antiseptic, buffer agent.
In certain embodiments, in prescription, further comprises solubilizing agent, correctives, sweeting agent, viscosifier, electrolyte, another kind of therapeutic agent, or their compositions.
Clopidogrel in the amount ranges allowed and the various combination of other compositions, as described in the claims in the present invention, can be used to as the invention provides different embodiments.Present invention provides a kind of medication that immediately can use clopidogrel, clopidogrel free alkali is dissolved in oil phase by the method, and oil phase is wrapped and in aqueous phase.
Emulsion of the present invention has better stability and less side effect relative to the preparation (such as: cyclodextrin matrix formulations) of other organic substrates or aqueous matrix.The emulsion of oil/water also can suppress lipophilic clopidogrel to adhere on the tube wall of plastics parenteral device.The invention provides to prepare under room temperature or refrigerated condition and also can keep stable clopidogrel emulsion, and this administering mode is without the need to through dilution.In addition, this emulsion has the advantage of rapid release, rapid-onset compared to other oral tablets.
In certain embodiments, use preparation administration is carried out to patient before without the need to diluting.In other embodiments, liquid preparation can dilute, and ensures not occur that clopidogrel precipitates.Preparation of the present invention can single dose administration or multiple dose administration.
The administering mode of the liquid preparation of some embodiments of the present invention comprises parenteral, oral administration or intestinal canal administration.The invention provides a kind of Therapeutic Method, this method can prevent or reduce the generation of platelet aggregation complication, or effectively can treat and need clopidogrel to carry out the symptom for the treatment of, and this method includes experimenter for administering mode required for the present invention.Present invention also offers and a kind of use clopidogrel formulations of the present invention, give the parenteral needed for experimenter, oral administration, intestinal canal administration mode, the method that treatment onset time or minimizing reach desired therapeutical effect required time can be reduced.Preparation of the present invention can reduce treatment onset time compared to oral tablet or minimizing reaches desired therapeutical effect required time.Preparation of the present invention allows the clopidogrel giving low dosage to reach desired therapeutical effect, such as, for bleeding time or anticoagulant target, compared to solid orally ingestible, the clopidogrel using preparation of the present invention to give low dosage can reach identical desired therapeutical effect
According to one embodiment of present invention, emulsion comprises
A) clopidogrel free alkali of 0.01-10%w/w;
B) oil phase of 1-30%w/w;
C) surfactant of 0.5-5.4%w/w;
D) any cosurfactant of 0-0.5%; With
D) water of 60-99%w/w and pH adjusting agent, such as, use sodium hydroxide heightening pH
Clopidogrel free alkali uses its S-enantiomer as crude drug.S-enantiomer has biological activity, and R enantiomer (impurity C) there is not any anticoagulating active and toleration is very poor.
According to American Pharmacopeia (USP) 32 editions, be used in the active pharmaceutical ingredient bisulfate clopidogrel mainly S-enantiomer of listing tablet, and wherein containing the clopidogrel related substance A being no more than 0.2%, be no more than the first enantiomer related substance B of clopidogrel of 0.3%, be no more than the clopidogrel related substance C of 1.0%, be no more than other any drug related impurities found of 0.1%, the content of total drug related impurities is no more than 1.5%.
According to American Pharmacopeia (USP) 32 editions, as the tablet of listing, with storage process after preparation completes, the content of clopidogrel related substance A is no more than 1.2%, the content of clopidogrel related substance C is no more than 1.5%, the content of any single contaminant is no more than 0.2% (except related substance B of clopidogrel), and the content of medicine total impurities is no more than 2.5% (except related substance B of clopidogrel).
Because chlorine pyrroles thunder free alkali is more unstable under the condition of temperature, humidity increase, and its methyl ester group is easy to racemization, oxidation, hydrolysis; Chlorine pyrroles thunder free alkali need before being prepared into pharmaceutical preparation first acidify salify just can reach stable; Therefore generally believe that chlorine pyrroles thunder free alkali is unsuitable for for the preparation of pharmaceutical preparation.The discovery that the present invention is a surprised new phenomenon, the conventional wisdom before being different from, show stability more better than the Emulsion made with chlorine pyrroles thunder salt with chlorine pyrroles thunder free alkali after the Emulsion made.Because the dissolubility of chlorine pyrroles thunder salt in the oil that can be used for preparation prescription is lower, so its allocation proportion in oil phase and aqueous phase is lower.Therefore the envelop rate of chlorine pyrroles thunder salt in oil phase is lower.Except the non-usage very surfactant of high dose or solvent, otherwise use chlorine pyrroles thunder salt to be prepared into Emulsion as crude drug, and in the dosage range that the single dose of administration can bear, (such as 300mg is at the solvent of 100ml solvent or less volume) reaches higher drug loading (chlorine pyrroles thunder free alkali drug loading >0.15%), is obviously unaccommodated.Otherwise chlorine pyrroles thunder can may be separated out from oil phase, dissolve in aqueous phase or precipitation; This will cause the homogeneity problem (there are two kinds of discrete form, one is that chlorine pyrroles thunder is dissolved in oil phase, and another kind is that free chlorine pyrroles thunder is suspended in aqueous medium) of product; Being directly exposed in water as chlorine pyrroles thunder, the result of ionizing catalytic degradation reaction, will there is stability problem in chlorine pyrroles thunder; The parenteral position stimulation/pain of parenteral formulation, the taste masking problem of oral formulations, the problems such as the physical stability (sedimentation) of vein parenteral also will occur.In one embodiment of the invention, adopt chlorine pyrroles thunder free alkali as crude drug, be dissolved in the oil that can be used for preparation prescription and be prepared into compositions; In another embodiment, the technology adopting chlorine pyrroles thunder salt to change into free alkali obtains chlorine pyrroles thunder free alkali, before preparation prescription, isolate gegenion from free alkali.
In prescription, the preferable range of chlorine pyrroles thunder free alkali is 0.15-10%, and most preferred range is 0.2-3%.
Oil phase in Emulsion is pharmaceutical grade oil, preferably glycerine three esters, such as, but be not limited only to soybean oil, safflower oil, olive oil, Oleum Gossypii semen, Oleum Helianthi, fish oil (comprising omega 3 fatty acids, eicosapentaenoic acid (EPA), docosahexenoic acid (DHA)), Oleum Ricini, Oleum sesami, Oleum Arachidis hypogaeae semen, Semen Maydis oil, median chain triglyceride oil (such as Miglyol812or810).Surfactant and/or cosurfactant may be included, such as Ovum Gallus domesticus Flavus lecithin, soybean lecithin, other lecithin, propylene glycol diesters, oleic acid or monoglyceride (such as: single-acetyl triglyceride) in oil phase.Oil phase also may be a kind of composition of mixing.
Preferred oil phase is soybean oil, median chain triglyceride oil (MCT), olive oil, fish oil, may be separate constituent also may be the mixture becoming phase-splitting to mix with other.
Most preferred oil phase is soybean oil.Preferred oily carrier scope is 5-30%, and most preferred oily carrier scope is 10-20%.
Surfactant is arbitrary, pharmaceutically useful surfactant, the phospholipids compounds preferably extracted from egg yolk or Semen sojae atricolor, the phosphatldylcholine of synthesis, the phosphatldylcholine of purification from plant.Also the derivant of hydrogenation may be used, such as: hydrogenation phosphatldylcholine (egg yolk) and hydrogenation phosphatldylcholine (Semen sojae atricolor).Surfactant also may be nonionic surfactant, such as: poloxamer (such as: PLURONICS F87, poloxamer188), Lip river husky amine, stearic acid polyoxyethylene, polyoxyethylene sorbitan fatty acid ester or fatty acid esters of sorbitan.Ionic surfactant also may be used, such as: cholic acid,
Preferred surfactant is Ovum Gallus domesticus Flavus lecithin.Preferred scope is 0.6-2.4%, and most preferred scope is 1.2-1.8%.
Cosurfactant is selected from the mixture of oleic acid, enuatrol, cholic acid, sodium cholate, deoxycholic acid, sodium deoxycholate or mentioned component; Wherein, cosurfactant of the present invention scope is in the composition 0-0.5w/v%.
The scope of the water of preferred buffer is 70-90%.
Emulsion also may comprise cosolvent or other solubility enhancing agent, chelating agen, antiseptic, antioxidant, stabilizing agent, pH adjusting agent or tension regulator, such as: glycerol, as the polymer of suspensoid, and sweeting agent, etc.
Desirable Emulsion be average droplet particle diameter at 100-1000nm, present white to linen stabilisation systems.Preferred average droplet particle diameter is at 100-500nm; The average droplet particle diameter of override choosing is at 100-300nm.
Preferred Emulsion is more than 5.5 and 5.5 with the pH scope of lay up period after the production.Wherein in an embodiment, the pH scope control of emulsion is at 5.5-7; In another embodiment, the pH scope control of emulsion is at 7-10.The pH scope of preferred emulsion is 6.5-9.PH adjusting agent can be a kind of buffer agent or sodium hydroxide or other pH adjusting agent, or the mixture of mentioned component.
Emulsion of the present invention is prepared by following method: for aqueous phase, by the aqueous dispersion of pharmaceutical grade in container, and should be heated to 40-80 DEG C, and add Ovum Gallus domesticus Flavus lecithin and glycerol in aqueous phase, finally by pH regulator to 9-10.For oil phase, soybean oil should be scattered in another container, and be heated to 40-80 DEG C; Subsequently chlorine pyrroles thunder and arbitrary cosurfactant are added in soybean oil, and are heated to 40-80 DEG C; In addition, Ovum Gallus domesticus Flavus lecithin also may be injected towards in oil phase.Use high-shear mixer to be mixed with oil phase by aqueous phase, form coarse emulsion.By supersound process, high pressure homogenize process or microfluidization, be 5000-15000psi at pressure, temperature is coarse emulsion is prepared into the emulsion with desirable microdroplet particle diameter under 5-60 DEG C of condition.By pH adjusting agent (such as: 1N sodium hydroxide solution) by pH regulator to 5.5-10.Wherein in an embodiment, need by pH regulator to 9-10; In another embodiment, need by pH regulator to 7-10; Also have an embodiment, need by pH regulator to 8-10.Be scattered in the bottle of clean level by sample filtering, external environment condition imposes nitrogen protection usually, fill in silication bottle closure of rubber, finally uses aluminium lid sealing.This product should be prepared by sterile working or carry out terminal sterilization.Preferred dosage unit is the aseptic and stable emulsion obtained by autoclave techniques.Wherein in an embodiment, emulsion should under 121 DEG C of conditions autoclaving 15-20 minute.In another embodiment, emulsion, when not using autoclave techniques, should be prepared in an aseptic environment.
The present invention is described now by way of non-limiting example.The present invention is described in detail by the embodiment of embodiment and each side of invention and forms.Accordingly, the present invention includes the single factors of the embodiment of embodiment and the various combination of each aspect of the present invention as described in this article.In addition, the present invention includes technology is set forth and related example makes those skilled in the art derive other features, advantage and the embodiment by following chapters and sections.Open text herein comprises change and the modification of all possible factor and method.In addition, the definition of embodiment and demonstration are in order to exemplary role, and do not mean that the present invention is exclusive or be only limitted to described content.This invention comprises and those of skill in the art will recognize that and do not departing from the various change and modification that spirit of the present invention carries out down in advance.
Embodiment 1.
The comparison of bisulfate clopidogrel and the medicament distribution ratio of chlorine pyrroles thunder free alkali between oil phase and aqueous phase
In order to measure the allocation proportion of chlorine pyrroles thunder in oil phase and aqueous phase, the present invention measures clopidogrel hydrogen sulfate and the allocation proportion of chlorine pyrroles thunder free alkali in oil phase and aqueous phase respectively, and the medicine weighing 600mg adds one and includes in the beaker of soybean oil and deionized water (each 20g).At room temperature be uniformly mixed 24 hours.Afterwards, sample middlely to be separated respectively from biphase, and uses the HPLC chromatographic condition described by embodiment 14 to test.And measure the pH of aqueous phase.
When table 1 shows to use clopidogrel hydrogen sulfate to test, the chlorine pyrroles thunder of about 50% will enter in aqueous phase.In contrast, when using chlorine pyrroles thunder free alkali to test, the chlorine pyrroles thunder of denier is only had to enter in aqueous phase.This shows, if we expect to make chlorine pyrroles thunder enter quantity in aqueous phase to minimize, so chlorine pyrroles thunder free alkali is more suitable for as Emulsion than clopidogrel hydrogen sulfate crude drug.Otherwise preparation prescription will there will be the problem of homogenization and stability.
Medicament distribution between table 1. oil phase and aqueous phase
Embodiment 2 uses the chlorine pyrroles thunder free alkali obtained from suppliers to prepare emulsion
| Formula | Quantity: |
| Gram | |
| Chlorine pyrroles thunder free alkali | 0.20 |
| Soybean oil | 10.0 |
| Ovum Gallus domesticus Flavus lecithin | 1.2 |
| Glycerol | 2.25 |
| Sodium hydroxide | Regulate pH9-10 |
| Gastrointestinal exterior-applied liquid medicine | To 100g |
All preparation process are carried out all under nitrogen protection.
The preparation process of the sterile aqueous oil in water emulsion of parenteral is as follows:
1. use glycerol and gastrointestinal exterior-applied liquid medicine to prepare aqueous phase.The sodium hydroxide solution of 1N is used to regulate aqueous phase pH to 9-10.Keep agitation mixes, and is heated to 60 DEG C.
2. aqueous phase uses the metre filter of 0.22 micron, and loads mixer.
3. simultaneously, by the soybean oil through the metre filter of 0.22 micron, chlorine pyrroles thunder free alkali, Ovum Gallus domesticus Flavus lecithin is placed in mixer, prepares oil phase.Keep agitation mixes, and is heated to 60 DEG C, until all the components dissolves all.
4. mixed oil phase is added in aqueous phase.
5. use high-shear mixer (PolytronPT3100), with the rotary speed stirring mixture 5 minutes of 10,000rpm, obtain thick emulsion.Emulsion pH is adjusted to 9-10.
6. use sonicator (FisherScientificSonicDismembrator, Model500) by ultrasonic for thick emulsion 30 minutes.And product temperature is controlled at 45 DEG C.
7. the oil-in-water emulsion cooling will obtained; If necessary, pH to 9-10 is adjusted; Finally emulsion is transferred in container filling.
8. use 0.45 micron filter emulsion under nitrogen protection, and by emulsion fill as in container.Last at the temperature of 121 DEG C autoclaving 20 minutes.
9. the pH of end product is 8.
Embodiment 3 uses the chlorine pyrroles thunder free alkali obtained from suppliers to prepare emulsion
| Formula | Quantity: |
| Gram | |
| Chlorine pyrroles thunder free alkali | 0.6 |
| Soybean oil | 10.0 |
| Ovum Gallus domesticus Flavus lecithin | 1.8 |
| Glycerol | 2.25 |
| Sodium hydroxide | Regulate pH9-10 |
| Gastrointestinal exterior-applied liquid medicine | To 100g |
All preparation process are carried out all under nitrogen protection.
The preparation process of the sterile aqueous oil in water emulsion of parenteral is as follows:
1. use Ovum Gallus domesticus Flavus lecithin, glycerol and gastrointestinal exterior-applied liquid medicine to prepare aqueous phase.The sodium hydroxide solution of 1N is used to regulate aqueous phase pH to 9-10.Keep agitation mixes, and is heated to 60 DEG C.
2. aqueous phase uses the metre filter of 0.22 micron, and loads mixer.
3. simultaneously, by the soybean oil through the metre filter of 0.22 micron, chlorine pyrroles thunder free alkali, is placed in mixer, prepares oil phase.Keep agitation mixes, and is heated to 60 DEG C, until all the components dissolves all.
4. mixed oil phase is added in aqueous phase.
5. use high-shear mixer (PolytronPT3100), with the rotary speed stirring mixture 5 minutes of 10,000rpm, obtain thick emulsion.Emulsion pH is adjusted to 9-10.
6. use high pressure homogenize instrument (APV2000) to be 10 cycles of homogenizing at pressure by thick emulsion under the condition of 10,000psi.And product temperature is controlled at 45 DEG C.
7. the oil-in-water emulsion cooling will obtained; If necessary, pH to 9-10 is adjusted; Finally emulsion is transferred in container filling.
8. use 0.45 micron filter emulsion under nitrogen protection, and by emulsion fill as in container.Last at the temperature of 121 DEG C autoclaving 20 minutes.
9. the pH of end product is 8.
Embodiment 4 uses the chlorine pyrroles thunder free alkali obtained from suppliers to prepare emulsion
| Formula | Quantity: |
| Gram | |
| Chlorine pyrroles thunder free alkali | 3.0 |
| Soybean oil | 10.0 |
| Ovum Gallus domesticus Flavus lecithin | 1.2 |
| Glycerol | 2.25 |
| Sodium hydroxide | Regulate pH9-10 |
| Gastrointestinal exterior-applied liquid medicine | To 100g |
All preparation process are carried out all under nitrogen protection.
The preparation process of the sterile aqueous oil in water emulsion of parenteral is as follows:
1. use glycerol and gastrointestinal exterior-applied liquid medicine to prepare aqueous phase.The sodium hydroxide solution of 1N is used to regulate aqueous phase pH to 9-10.Keep agitation mixes, and is heated to 60 DEG C.
2. aqueous phase uses the metre filter of 0.22 micron, and loads mixer.
3. simultaneously, by the soybean oil through the metre filter of 0.22 micron, lecithin, chlorine pyrroles thunder free alkali, is placed in mixer, prepares oil phase.Keep agitation mixes, and is heated to 60 DEG C, until all the components dissolves all.
4. mixed oil phase is added in the aqueous phase of lasting high-speed stirred.
5. use high-shear mixer (PolytronPT3100), with the rotary speed stirring mixture 5 minutes of 10,000rpm, obtain thick emulsion.Emulsion pH is adjusted to 9-10.
6. use high pressure homogenize instrument (APV2000) to be 10 cycles of homogenizing at pressure by thick emulsion under the condition of 10,000psi.And product temperature is controlled at 45 DEG C.
7. the oil-in-water emulsion cooling will obtained; If necessary, pH to 9-10 is adjusted; Finally emulsion is transferred in container filling.
8. use 0.45 micron filter emulsion under nitrogen protection, and by emulsion fill as in container.Last at the temperature of 121 DEG C autoclaving 20 minutes.
9. the pH of end product is 8.
Embodiment 5, by aseptic processing, uses the chlorine pyrroles thunder free alkali obtained from suppliers to prepare emulsion
The chlorine pyrroles thunder free alkali obtained from suppliers is used to prepare emulsion as crude drug
| Formula | Quantity: |
| Gram | |
| Chlorine pyrroles thunder free alkali | 3.0 |
| Soybean oil | 10.0 |
| Ovum Gallus domesticus Flavus lecithin | 1.8 |
| Glycerol | 2.25 |
| Vitamin E | 0.06 |
| Sodium hydroxide | Regulate pH8-10 |
| Gastrointestinal exterior-applied liquid medicine | To 100g |
All preparation process are carried out all under nitrogen protection.
The preparation process of the sterile aqueous oil in water emulsion of parenteral is as follows:
1. use glycerol and gastrointestinal exterior-applied liquid medicine to prepare aqueous phase.The sodium hydroxide solution of 1N is used to regulate aqueous phase pH to 9-10.Keep agitation mixes, and is heated to 60 DEG C.
2. aqueous phase uses the metre filter of 0.22 micron, and loads mixer.
3. simultaneously, by the soybean oil through the metre filter of 0.22 micron, lecithin, chlorine pyrroles thunder free alkali, is placed in mixer, prepares oil phase.Keep agitation mixes, and is heated to 60 DEG C, until all the components dissolves all.
4. mixed oil phase is added in aqueous phase.
5. use high-shear mixer (PolytronPT3100), with the rotary speed stirring mixture 5 minutes of 10,000rpm, obtain thick emulsion.Emulsion pH is adjusted to 9-10.
6. use high pressure homogenize instrument (APV2000) to be 10 cycles of homogenizing at pressure by thick emulsion under the condition of 10,000psi.And product temperature is controlled at 45 DEG C.
7. the oil-in-water emulsion cooling will obtained; If necessary, pH to 8-10 is adjusted; Finally emulsion is transferred in container filling.
8. use 0.45 micron filter emulsion under nitrogen protection, and by emulsion fill as in container.
9. the pH of end product is 8
Embodiment 6, by aseptic processing, uses and obtains chlorine pyrroles thunder free alkali from suppliers and prepare emulsion
| Formula | Quantity: |
| Gram | |
| Chlorine pyrroles thunder free alkali | 3.0 |
| Soybean oil | 10.0 |
| Ovum Gallus domesticus Flavus lecithin | 1.2 |
| Glycerol | 2.25 |
| Sodium hydroxide | Q.s. to pH8-10 |
| Gastrointestinal exterior-applied liquid medicine | To 100g |
All preparation process are carried out all under nitrogen protection.
The preparation process of the sterile aqueous oil in water emulsion of parenteral is as follows:
1. use glycerol and gastrointestinal exterior-applied liquid medicine to prepare aqueous phase.The sodium hydroxide solution of 1N is used to regulate aqueous phase pH to 9-10.Keep agitation mixes, and is heated to 60 DEG C.
2. aqueous phase uses the metre filter of 0.22 micron, and loads mixer.
3. simultaneously, by the soybean oil through the metre filter of 0.22 micron, lecithin, chlorine pyrroles thunder free alkali, is placed in mixer, prepares oil phase.Keep agitation mixes, and is heated to 60 DEG C, until all the components dissolves all.
4. mixed oil phase is added in the aqueous phase of lasting high-speed stirred.
5. use high-shear mixer (PolytronPT3100), with the rotary speed stirring mixture 5 minutes of 6,000rpm, obtain thick emulsion.Emulsion pH is adjusted to 9-10.
6. use high pressure homogenize instrument (APV2000) to be 10 cycles of homogenizing at pressure by thick emulsion under the condition of 10,000psi.And product temperature is controlled at 45 DEG C.
7. the oil-in-water emulsion cooling will obtained; If necessary, pH to 8-10 is adjusted; Finally emulsion is transferred in container filling.
8. use 0.45 micron filter emulsion under nitrogen protection, and by emulsion fill as in container.
9. the pH of end product is about 8.
Embodiment 7 uses and obtains chlorine pyrroles thunder free alkali from suppliers and prepare emulsion
Use chlorine pyrroles thunder free alkali as crude drug, lecithin is as surfactant, and oleic acid prepares emulsion as cosurfactant
| Formula | Quantity: |
| Gram | |
| Chlorine pyrroles thunder free alkali | 0.2 |
| Soybean oil | 10.0 |
| Ovum Gallus domesticus Flavus lecithin | 1.2 |
| Oleic acid | 0.03 |
| Glycerol | 2.25 |
| Sodium hydroxide | Regulate pH9-10 |
| Gastrointestinal exterior-applied liquid medicine | To 100 |
All preparation process are carried out all under nitrogen protection.
The preparation process of the sterile aqueous oil in water emulsion of parenteral is as follows:
1. use glycerol, Ovum Gallus domesticus Flavus lecithin and gastrointestinal exterior-applied liquid medicine to prepare aqueous phase.The sodium hydroxide solution of 1N is used to regulate aqueous phase pH to 9-10.Keep agitation mixes, and is heated to 60 DEG C.
2. aqueous phase uses the metre filter of 0.22 micron, and loads mixer.
3. simultaneously, by the soybean oil through the metre filter of 0.22 micron, oleic acid, chlorine pyrroles thunder free alkali, is placed in mixer, prepares oil phase.Keep agitation mixes, and is heated to 60 DEG C, until all the components dissolves all.
4. mixed oil phase is added in the aqueous phase of lasting high-speed stirred.
5. use high-shear mixer (PolytronPT3100), with the rotary speed stirring mixture 5 minutes of 10,000rpm, obtain thick emulsion.Emulsion pH is adjusted to 9-10.
6. use sonicator (FisherScientificSonicDismembrator, Model500) by ultrasonic for thick emulsion 30 minutes.And product temperature is controlled at 45 DEG C.
7. the oil-in-water emulsion cooling will obtained; Adjustment pH to 9-10; Finally emulsion is transferred in container filling.
8. use 0.45 micron filter emulsion under nitrogen protection, and by emulsion fill as in container.Last at the temperature of 121 DEG C autoclaving 20 minutes.
9. the pH of end product is about 8.
Embodiment 8 uses clopidogrel hydrogen sulfate to prepare emulsion (reference preparation)
The present embodiment preparation process describes identical with embodiment 2 but without the need to carrying out autoclaving.End product pH is 7.4.
Embodiment 9 uses chlorine pyrroles thunder free alkali to prepare emulsion
| Formula | Quantity: |
| Gram | |
| Chlorine pyrroles thunder free alkali | 2.0 |
| Soybean oil | 10.0 |
| Ovum Gallus domesticus Flavus lecithin | 1.2 |
| Glycerol | 2.25 |
| Sodium hydroxide | Regulate pH9-10 |
| Gastrointestinal exterior-applied liquid medicine | To 100 |
The present embodiment preparation process describes identical with embodiment 2.End product pH is 8.
Embodiment 10 be used in premix in soybean oil chlorine pyrroles thunder free alkali prepare emulsion;
Before emulsion preparation, clopidogrel hydrogen sulfate is changed into chlorine pyrroles thunder free alkali, and sulfate ion is separated from chlorine pyrroles thunder free alkali.
All preparation process are carried out all under nitrogen protection.
Chlorine pyrroles thunder free alkali is mixed in advance the preparation method in soybean oil.
Bisulfate clopidogrel is dissolved in enough water.Under Keep agitation state, required soybean oil is scattered in aqueous phase, the sodium hydroxide solution of 1N is progressively instilled as in aqueous mixture, until aqueous phase pH reaches more than 6.5 or 6.5.The oil phase comprising clopidogrel free alkali is isolated from the aqueous phase comprising sulfate ion and sodium ion; If necessary, need wash oil phase.
The preparation process of the sterile aqueous oil in water emulsion of parenteral is as follows:
1. medicine-oily pre-composition stirs under 60 DEG C of conditions, by oil phase by 0.22 micron filter, and loads mixer.
2. use glycerol, Ovum Gallus domesticus Flavus lecithin and gastrointestinal exterior-applied liquid medicine to prepare aqueous phase.The sodium hydroxide solution of 1N is used to regulate aqueous phase pH to 9-10.Keep agitation mixes, and is heated to 60 DEG C.
3. aqueous phase uses the metre filter of 0.22 micron, and loads mixer.
4. mixed oil phase is added in the aqueous phase of lasting high-speed stirred.
5. use high-shear mixer (PolytronPT3100), with the rotary speed stirring mixture 5 minutes of 10,000rpm, obtain thick emulsion.
6. use high pressure homogenize instrument to be 5 cycles of homogenizing at pressure by thick emulsion under the condition of 10,000psi.And product temperature is controlled at 45 DEG C.
7. the oil-in-water emulsion cooling will obtained; Adjustment pH to 9-10; Finally emulsion is transferred in container filling.
8. use 0.45 micron filter emulsion under nitrogen protection, and emulsion is filled in container.Last at the temperature of 121 DEG C autoclaving 20 minutes.
9. the pH of end product is 8.
Embodiment 11 uses chlorine pyrroles thunder free alkali to prepare emulsion
| Formula | Quantity: |
| Gram | |
| Chlorine pyrroles thunder free alkali | 0.20 |
| Soybean oil | 10.0 |
| Ovum Gallus domesticus Flavus lecithin | 1.8 |
| Glycerol | 2.25 |
| Vitamin E | 0.06 |
| Sodium hydroxide | Regulate pH9-10 |
| Gastrointestinal exterior-applied liquid medicine | To 100g |
The present embodiment preparation process describes identical with embodiment 3.End product pH is 8.
Embodiment 12 uses chlorine pyrroles thunder free alkali to prepare emulsion
| Formula | Quantity: |
| g | |
| Chlorine pyrroles thunder free alkali | 2.8g |
| Soybean oil | 0.17g |
| Ovum Gallus domesticus Flavus lecithin | 0.54 |
| Glycerol | 2.25 |
| Sodium hydroxide | Regulate pH9-10 |
| Gastrointestinal exterior-applied liquid medicine | To 100g |
The present embodiment preparation process describes identical with embodiment 3.End product pH is 8.
Embodiment 13 compares by NanoZetasizer use chlorine pyrroles thunder free alkali and the emulsion prepared by clopidogrel hydrogen sulfate at microdroplet Size Distribution different
The emulsion using embodiment 8 and embodiment 10 to prepare carries out particle size distribution test.MalvernZetasizerNano-ZSZEN3600 is used to test the microdroplet particle size distribution of emulsion.Fig. 1 shows the emulsion average droplet particle diameter (mean intensity, nm) using chlorine pyrroles's thunder free alkali (embodiment 10) and clopidogrel hydrogen sulfate (embodiment 8) to prepare respectively.The emulsion using chlorine pyrroles thunder free alkali to prepare is through autoclaving, freeze thawing, store after 1 year very stable under refrigerated condition, but emulsion prepared by use clopidogrel hydrogen sulfate is through autoclaving, demonstrates violent change after freeze thawing in grain diameter.
Embodiment 14 compares use emulsion of the present invention and SB-E-CD compositions, HP-B-CD compositions in chemical stability different
HPLC chromatographic condition
Use chiral liquid chromatography checked for impurities and Enantiomeric excess.Immobile phase uses ULTRONES-OVM post, 5um (4.6mm × 150mmi.d.).Consisting of of mobile phase: A phase, adds 1.36g sodium dihydrogen phosphate (NaH in 1L pure water
2pO
4.H
2o); B phase, acetonitrile; Isocratic clution is carried out, 18 minutes running times with the constant flow rate of 1.0mL/min; Sampling volume is 5-10ul; UV determined wavelength is 220nm.
The principal degradation impurity of the chlorine pyrroles thunder Emulsion prepared by the present invention is impurity C (R-enantiomer); According to the observation, hydrolysate impurities A (<1.2%) less appearance and do not have significant change in product emulsion.Therefore, the monitoring index for the chemical stability of emulsion of the present invention is impurity C (Fig. 2).Compared to the chlorine pyrroles thunder solution of cyclodextrin substrate, the emulsion using chlorine pyrroles thunder free alkali to prepare has better stability data (Fig. 3, Fig. 4).
Fig. 3 shows after chlorine pyrroles-HPBCD, chlorine pyrroles thunder-SBECD compositions (US20100292268) that the chlorine pyrroles thunder emulsion (embodiment 10) the present invention prepared and pH be approximately 8 store under 40 DEG C of conditions, and chlorine pyrroles thunder chiral structure is from S enantiomer to the conversion percentage of R enantiomer.
Fig. 4 shows after chlorine pyrroles-HPBCD, chlorine pyrroles thunder-SBECD compositions (US20100292268) that the chlorine pyrroles thunder emulsion (embodiment 10) the present invention prepared and pH be approximately 8 store under 25 DEG C of conditions, and chlorine pyrroles thunder chiral structure is from S enantiomer to the conversion percentage of R enantiomer.
Embodiment 15 compares and uses chlorine pyrroles's thunder free alkali (embodiment 10) and different in chemical stability of the emulsion prepared by clopidogrel hydrogen sulfate (embodiment 8)
Identical with described by embodiment 14 of HPLC chromatographic condition.
Compared to the emulsion using clopidogrel hydrogen sulfate to prepare, the emulsion using chlorine pyrroles thunder free alkali to prepare has better stability data (Fig. 5).
After Fig. 5 shows and emulsion (embodiment 8) prepared by the emulsion (embodiment 10) using chlorine pyrroles thunder free alkali to prepare and use clopidogrel hydrogen sulfate stored under 40 DEG C of conditions, chlorine pyrroles thunder chiral structure is from S enantiomer to the conversion percentage of R enantiomer.
The stability of emulsion data summarization of embodiment 16 embodiment 10
Table 2 shows the stability data emulsion of embodiment 10 being stored at least 52 weeks under refrigerated condition
The emulsion of table 2. embodiment 10 is stored in the stability data under refrigerated condition
The stability of emulsion data summarization of embodiment 17 embodiment 6
Table 3, table 4 show and the emulsion of embodiment 6 are stored in refrigerated condition (-5 DEG C) and (-25 DEG C) under room temperature condition at least 19 stability data in week
Table 3. case study on implementation 6 stability (25 degrees Celsius)
Table 4. case study on implementation 6 stability (5 degrees Celsius)
Claims (24)
1. for parenteral or oral administration, containing nano level oil droplet, stable medicine oil/water emulsion compositions, comprise following composition:
Be scattered in the chlorine pyrroles thunder free alkali in oil phase;
Surfactant and optional cosurfactant;
Substantially the aqueous phase not containing chlorine pyrroles thunder; And
PH adjusting agent.
2. compositions according to claim 1, wherein said compositions also comprises the compositions of one or more compositions in the group being selected from chelating agen, antioxidant, penetrating agent, antiseptic, suspending agent and buffer agent composition.
3. compositions according to claim 1, wherein mean oil droplet particle diameter (mean intensity, nm) is 100-500nm.
4. compositions according to claim 3, wherein mean oil droplet particle diameter (mean intensity, nm) is 100-300nm.
5. compositions according to claim 1, wherein said compositions comprises the impurity A not surpassing 1.2%, do not surpass the impurity C of 1.5%, and the pH of wherein said compositions is higher than 5.5.
6. compositions according to claim 5, the pH of wherein said compositions is 5.5-10.
7. compositions according to claim 1, wherein said oil phase in the composition ratio is about 5 to 30% (w/v).
8. compositions according to claim 1, wherein said oil phase is selected from the group of pharmaceutically acceptable oil, described pharmaceutically acceptable oil comprises: triglyceride, such as: soybean oil, safflower oil, olive oil, Oleum Helianthi, fish oil, Oleum Ricini, Oleum sesami, Oleum Arachidis hypogaeae semen, Semen Maydis oil; Medium chain triglyceride; Or the mixture of mentioned component.
9. compositions according to claim 8, wherein said oil is selected from the mixture of soybean oil, fish oil, medium chain triglyceride, olive oil or mentioned component.
10. compositions according to claim 9, wherein said oil is soybean oil.
11. compositionss according to claim 1, wherein said compositions comprises the chlorine pyrroles thunder free alkali of 0.1-10% (w/v).
12. compositionss according to claim 11, wherein said compositions comprises the chlorine pyrroles thunder free alkali of 0.15-3% (w/v).
13. compositionss according to claim 1, the gross weight of wherein said surfactant and optional cosurfactant is the 0.5-6% (w/v) of described compositions.
14. compositionss according to claim 13, comprise the surfactant of 0.5-5.5% (w/v) and the optional cosurfactant of 0-0.5% (w/v):
Wherein said surfactant is selected from the acceptable surfactant of pharmacy, comprises the phospholipid extracted from egg yolk or Semen sojae atricolor, the phosphatidylcholine of synthesis or the phosphatidylcholine of purification from plant, hydrogenated phospholipid derivant; Non-ionic surface active agent comprises poloxamer (such as PLURONICS F87, poloxamer188), the husky amine in Lip river, stearic acid polyoxyethylene, polyoxyethylene sorbitan fatty acid ester or fatty acid esters of sorbitan; Ionic surfactant comprises cholic acid, deoxycholic acid or its surface activity derivant and its esters; Optional cosurfactant is selected from the mixture of oleic acid, enuatrol, cholic acid, sodium cholate, deoxycholic acid, sodium deoxycholate or mentioned component.
15. compositionss according to claim 14, comprise the surfactant of 0.6-2.4% (w/v) and the optional cosurfactant of 0.0-0.5% (w/v); Wherein said surfactant is Ovum Gallus domesticus Flavus lecithin and described cosurfactant is oleic acid or enuatrol.
16. compositionss according to claim 1, wherein said compositions comprises the clopidogrel free alkali of 0.15-3% (w/v), the soybean oil of 10-20% (w/v), the Ovum Gallus domesticus Flavus lecithin of 1.2-1.8% (w/v), glycerol, sodium hydroxide and the water of 2.25% (w/v).
17. for the preparation of parenteral or oral administration, method containing nano level oil droplet, stable medicine oil/water emulsion compositions, described method comprises the following steps:
A) oil phase is prepared by being scattered in oily carrier by clopidogrel free alkali;
B) preparation comprises the aqueous phase of water and pH adjusting agent;
C) surfactant or optional cosurfactant are added in described oil phase or aqueous phase;
D) described oil phase is scattered in described aqueous phase forms thick emulsion, and regulate pH to about 9;
E) thick emulsion steps d prepared by ultrasonic or high pressure homogenize is prepared into final emulsion, and is 5.5-10 by pH regulator;
F) described final emulsion is filtered; And
G) biological load amount or the aseptic of product is controlled by aseptic processing or terminal sterilization.
18. methods according to claim 17, wherein chlorine pyrroles thunder free alkali obtains by clopidogrel hydrogen sulfate being changed into chlorine pyrroles thunder free alkali and being separated from chlorine pyrroles thunder free alkali by sulfate ion.
19. methods according to claim 17, wherein clopidogrel free alkali provides in free alkali-oily carrier pre-composition mode.
20. methods according to claim 17, wherein said oily carrier is soybean oil, fish oil, medium chain triglyceride, olive oil or their mixture, and described surfactant is Ovum Gallus domesticus Flavus lecithin.
21. methods according to claim 17, wherein the product pH regulator of step e is 7-10.
22. 1 kinds for needing the Therapeutic Method of the patient of single high dose clopidogrel, described method comprises:
A) the medicine oil/water emulsion compositions of liquid form is provided; Said composition is obtained by following method: clopidogrel free alkali is scattered in oily carrier and prepares oil phase, uses water and pH adjusting agent to prepare aqueous phase, is scattered in by oil phase in aqueous phase, finally uses oil droplet that is ultrasonic or high pressure homogenize process formation nanometer particle size; And
B) give containing Single dose compositions by oral or parenteral, single dose should include the clopidogrel free alkali reaching 300mg.
23. methods according to claim 22, wherein the said composition of single dose should comprise the impurity A being no more than 1.2%, is no more than the impurity C of 1.5%.
24. methods according to claim 22, wherein described in step a, compositions pH is adjusted to 7-10.
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| PCT/US2014/015097 WO2014124132A1 (en) | 2013-02-06 | 2014-02-06 | Stable pharmaceutical composition of clopidogrel free base for oral and parenteral delivery |
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| US20100062066A1 (en) * | 2006-11-14 | 2010-03-11 | Acusphere, Inc | Formulations of Tetrahydropyridine Antiplatelet Agents for Parenteral or Oral Administration |
| CN102697724A (en) * | 2012-06-07 | 2012-10-03 | 沈阳药科大学 | Clopidogrel and salt submicron emulsion injection thereof as well as preparation method of same |
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| US20100062066A1 (en) * | 2006-11-14 | 2010-03-11 | Acusphere, Inc | Formulations of Tetrahydropyridine Antiplatelet Agents for Parenteral or Oral Administration |
| CN102697724A (en) * | 2012-06-07 | 2012-10-03 | 沈阳药科大学 | Clopidogrel and salt submicron emulsion injection thereof as well as preparation method of same |
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Application publication date: 20151223 |