CN102525914B - The Injectable sustained release preparation of lhrh antagonist class material and preparation thereof - Google Patents
The Injectable sustained release preparation of lhrh antagonist class material and preparation thereof Download PDFInfo
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- CN102525914B CN102525914B CN201010623859.XA CN201010623859A CN102525914B CN 102525914 B CN102525914 B CN 102525914B CN 201010623859 A CN201010623859 A CN 201010623859A CN 102525914 B CN102525914 B CN 102525914B
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Abstract
The invention provides Injectable sustained release preparation comprising lhrh antagonist class material or the acceptable salt of its medicine and preparation method thereof.
Description
Technical field
The present invention relates to Injectable sustained release preparation comprising lhrh antagonist class material or the acceptable salt of its medicine and preparation method thereof.
Background technology
Luteinizing hormone releasing hormone (LHRH) is the neural parahormone of a kind of decapeptide of hypothalamus secretion, its Main Function promotes that hypophysis synthesizes and discharges lutropin (LH) and follicule-stimulating hormone (FSH) (FSH), excites Development in Puberty and regulate fertility and gonadal hormone correlated process.Chemical modification and transformation are carried out to the molecular structure of LHRH, replaces or leave out some amino acid residue, new active analogue thereof may be produced.Divide by function, these analog can be divided into the two large classes such as LHRH agonist and lhrh antagonist.P-GLU-HIS-TRP-SER-TYR-D-TRP-LEU-ARG-PRO-GLY-NH2 not only may be used for endocrine regulation, also may be used for the malignant tumor for the treatment of hormone dependence, as carcinoma of prostate, breast carcinoma etc.
LXT101 belongs to lhrh antagonist, and it has the chemical constitution of following formula (I).
LXT101 have effective fast, effect is strong, medication does not occur the advantages such as serum androgen upper punch in early days, is drugs for prostate cancer of new generation.Because its half-life is shorter, therefore the very low and toxic and side effects of its ordinary preparation bioavailability in blood increases; Conventional soln agent needs administration every day in addition, and the course for the treatment of is longer, and it is painful inconvenient with medication to bring to patient.In order to reduce administration frequency, improve the compliance of patient, the slow releasing preparation of development LXT101 is particularly important.
Summary of the invention
On the one hand, the invention provides Injectable sustained release preparation, described slow releasing preparation comprises the compound of formula (I) for the treatment of effective dose or the acceptable salt of its medicine, neutral phospholipid, acidic phospholipid or the acceptable salt of its medicine and oil-based solvent.
In some embodiments, Injectable sustained release preparation of the present invention comprise with described slow releasing preparation total weight 0.1% to 10%, preferably 0.3% to 8%, more preferably 0.5%, 1%, the neutral phospholipid of 2% and 4%.
In some embodiments, Injectable sustained release preparation of the present invention comprises one or more neutral phospholipid be selected from soybean lecithin (SPC), Ovum Gallus domesticus Flavus lecithin (EPC), phosphatidylcholine (PC), dipalmitoyl phosphatidyl choline (DPPC), distearoyl phosphatidylcholine (DSPC), dimyristoyl phosphatidyl choline (DMPC), sphingomyelins (SM), the similar thing of alkyl ether phosphatidylcholine and PHOSPHATIDYL ETHANOLAMINE (PE).
In some embodiments, Injectable sustained release preparation of the present invention comprises with the acidic phospholipid of described slow releasing preparation total weight 0.01% to 1% (w/w), preferably 0.03% to 0.8% (w/w), more preferably 0.05%, 0.1%, 0.2% and 0.4% (w/w) or the acceptable salt of its medicine.
In some embodiments, Injectable sustained release preparation of the present invention comprises and is selected from one or more acidic phospholipids in phosphatidic acid (PA), phosphatidyl glycerol (PG), phosphatidylinositols (PI), Phosphatidylserine (PS), two spermaceti phosphatidic acid (DCP), DPPG (DPPG) and DSPG (DSPG) or the acceptable salt of its medicine.
In some embodiments, Injectable sustained release preparation of the present invention also comprises other organic acid or the acceptable salt of its medicine or ester.
In some embodiments, Injectable sustained release preparation of the present invention also comprises antioxidant.
On the other hand, the method preparing Injectable sustained release preparation of the present invention is provided, said method comprising the steps of:
A the compound of formula (I) or the acceptable salt of its medicine are scattered in aqueous solvent by (), thus obtain aqueous liquid dispersion;
B acidic phospholipid or the acceptable salt of its medicine and neutral phospholipid are scattered in aqueous solvent by (), thus obtain aqueous liquid dispersion;
C aqueous liquid dispersion that step (a) obtains by () and the aqueous liquid dispersion Homogeneous phase mixing that step (b) obtains;
D mixed liquor obtained for step (c) is dried to solid by (); With
E solid dispersal that step (d) obtains by () is in oil-based solvent.
In some embodiments, the step (e) in preparation method of the present invention also comprises and described other organic acid or the acceptable salt of its medicine or ester is added described oil-based solvent.
In some embodiments, preparation method of the present invention also comprises step (f): antioxidant is added described oil-based solvent.
Detailed description of the invention
The invention provides Injectable sustained release preparation of contained (I) compound or the acceptable salt of its medicine and preparation method thereof.
injectable sustained release preparation
On the one hand, the invention provides Injectable sustained release preparation, described slow releasing preparation comprises formula (I) compound or the acceptable salt of its medicine for the treatment of effective dose, neutral phospholipid, acidic phospholipid or the acceptable salt of its medicine, and oil-based solvent.
active constituents of medicine
In Injectable sustained release preparation of the present invention, the compound of formula (I) is the active constituents of medicine that can be used for treating and/or preventing disease or morbid state.In addition, with regard to the charge property of formula (I) compound, it is positively charged in aqueous solvent.In this article, term " aqueous solvent " refers to water or adds acid or the aqueous solution of alkali or its salt, and it is acceptable that wherein said acid or alkali or its salt are preferably medicine.The example of aqueous solvent includes but not limited to, the buffer of pure distilled water, such as phosphate buffer, hydrochloric acid or acetic acid, sodium hydrate aqueous solution, sodium acetate aqueous solution and 0.9% sodium-chloride water solution.
Can use the compound of this area conventional method preparation formula (I), such method is documented in such as Chinese patent ZL90108955.9.
The active constituents of medicine of Injectable sustained release preparation of the present invention can also exist with the form of the acceptable salt of medicine.Acceptable salt of medicine of formula (I) compound and preparation method thereof is also well known to those skilled in the art.The acceptable salt of described compound medicine treat and/or prevent the effect in disease or morbid state also can by those skilled in the art's reasonable prediction.
The acceptable salt of medicine of exemplary formula (I) compound is the salt that formula (I) compound and mineral acid are formed, and described mineral acid is such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid or phosphoric acid; Or the salt that formula (I) compound and organic acid are formed, described organic acids is acetic acid, propanoic acid, hydroxacetic acid, lactic acid, acetone acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic, salicylic acid, p-aminosallcylic acid or pamoic acid in this way.
In Injectable sustained release preparation of the present invention, the compound of formula (I) or the acceptable salt of its medicine are formula (I) compound or the acceptable salt of its medicine for the treatment of effective dose.In this article, term " treatment effective dose " refer to when preparation be given mammal, preferably people time, its contained drug active component is enough to realize treatment to disease or morbid state or prevention in described mammal, preferably people.About described treatment effective dose, those skilled in the art can determine according to condition such as age, the body weight etc. of the disease of to be treated and/or prevention or morbid state and seriousness thereof, administration object.
In some embodiments, described treatment effective dose is with formula (I) compound of described slow releasing preparation total weight 0.1% to 10% (w/w), preferably 0.3% to 1% (w/w), or the acceptable salt of medicine of the formula of a great deal of (I) compound.For the acceptable salt of medicine of formula (I) compound, obviously, those skilled in the art according to the amount of formula (I) compound and concrete salt used, can determine by simply calculating described " a great deal of ".
neutral phospholipid and acidic phospholipid or the acceptable salt of its medicine
In Injectable sustained release preparation of the present invention, except formula (I) compound or the acceptable salt of its medicine, also comprise neutral phospholipid, and acidic phospholipid or the acceptable salt of its medicine.
Phospholipid (also claiming phospholipid, phospholipid) is the lipid containing phosphoric acid, belongs to complex liped.Phospholipid is amphipathic molecule, and its one end is the tail of hydrophilic nitrogenous or phosphorus, and the other end is hydrophobic long hydrocarbyl chain.As important amphipathic molecule, phospholipid is biomembranous important component, emulsifying agent and surfactant.Meanwhile, according to the charge property of phospholipid, phospholipid can be divided into neutral charge phospholipid (i.e. neutral phospholipid), negative charge phospholipid (i.e. acidic phospholipid) and positive charge phospholipid.
Injectable sustained release preparation of the present invention make use of the combination of the amphipathic and charge property of neutral phospholipid and acidic phospholipid.
In Injectable sustained release preparation of the present invention, residue on neutral phospholipid and acidic phospholipid or the acceptable salt of its medicine and pharmaceutically active molecule interacts, amphipathic by it, the electric charge of neutral phospholipid and acidic phospholipid or its medicine acceptable salt shielding pharmaceutically active molecule and polarity, and then increase the hydrophobicity of pharmaceutically active molecule, realize the dissolving of pharmaceutically active molecule in oil-based solvent or dispersion thus.
In addition, acidic phospholipid is electronegative in aqueous solvent, namely with pharmaceutically active molecule of the present invention with opposite charges, wherein said acidic phospholipid can also exist with the form of the acceptable salt of its medicine.Acidic phospholipid or there is stronger electrostatic interaction between the acceptable salt of its medicine and pharmaceutically active molecule, with pharmaceutically active molecule forming composite, increases lipotropy and the stability of pharmaceutically active molecule.Simultaneously, due to adding of acidic phospholipid or the acceptable salt of its medicine, negative charge on the micelle that neutral phospholipid is formed in aqueous solvent or vesicle surface band, increases the interaction of neutral phospholipid and pharmaceutically active molecule further, makes pharmaceutically active molecule by solubilising in oil-based solvent.The release of medicine is delayed thus.
Be understandable that, being combined in effect by neutral phospholipid, acidic phospholipid or the amount of the acceptable salt of its medicine and/or the impact of kind of described amphipathic and charge property.For for the amount of neutral phospholipid of the present invention, acidic phospholipid or the acceptable salt of its medicine and kind, do exemplary and nonrestrictive description as follows.
In some embodiments, the slow releasing preparation of injection of the present invention comprises with the neutral phospholipid of described slow releasing preparation total weight 0.1% to 10% (w/w), preferably 0.3% to 8% (w/w), more preferably 0.5%, 1%, 2% or 4% (w/w).
In Injectable sustained release preparation of the present invention, one or more neutral phospholipid can be comprised.Described neutral phospholipid can be selected from phosphatidylcholine (PC), dipalmitoyl phosphatidyl choline (DPPC), distearoyl phosphatidylcholine (DSPC), dimyristoyl phosphatidyl choline (DMPC), sphingomyelins (SM), the similar thing of alkyl ether phosphatidylcholine and PHOSPHATIDYL ETHANOLAMINE (PE).The material of described neutral phospholipid also can be its main component be neutral phospholipid, such as soybean lecithin (SPC) and Ovum Gallus domesticus Flavus lecithin (EPC).As can be seen from above-mentioned Exemplary neutral phospholipid, Injectable sustained release preparation of the present invention is not limited to the neutral phospholipid comprising synthesis, also can and preferably comprise natural neutral phospholipid.
Injectable sustained release preparation of the present invention comprises acidic phospholipid or the acceptable salt of its medicine.In acidic phospholipid, these three kinds of strength of spatial masking, hydrogen bond and electrostatic charge regulate the interaction of phospholipid head groups jointly.
Acceptable salt of medicine of acidic phospholipid and preparation method thereof is well known to those skilled in the art.The acceptable salt of medicine of exemplary acidic phospholipid is the alkali metal salt of acidic phospholipid, alkali salt, aluminum salt and ammonium salt, wherein said alkali metal salt particular certain cancers and potassium salt.
In some embodiments, Injectable sustained release preparation of the present invention comprises with the acidic phospholipid of described slow releasing preparation total weight 0.01% to 1% (w/w), preferably 0.03% to 0.8% (w/w), more preferably 0.05%, 0.1%, 0.2% and 0.4% (w/w).In other embodiments, the weight ratio of contained acid phosphatase and neutral phosphoric acid is 1: 100 to 1: 1, preferably 1: 80 to 4: 5, more preferably 1: 10.
The amount of the acceptable salt of the medicine for acidic phospholipid, obviously, those skilled in the art according to the amount of acidic phospholipid and concrete salt used, can determine by simply calculating.
Injectable sustained release preparation of the present invention can comprise one or more acidic phospholipids or the acceptable salt of its medicine.One or more in phosphatidic acid (PA), phosphatidyl glycerol (PG), phosphatidylinositols (PI), Phosphatidylserine (PS), two spermaceti phosphatidic acid (DCP), DPPG (DPPG) and DSPG (DSPG) can be selected from for acidic phospholipid of the present invention.
If it should be noted that neutral phospholipid used mainly containing neutral phospholipid, but also containing acidic phospholipid, so the amount of acidic phospholipid contained by this material or kind optionally can count the acidic phospholipid in Injectable sustained release preparation of the present invention.
In a preferred embodiment, described neutral phospholipid is Ovum Gallus domesticus Flavus lecithin, and described acidic phospholipid is DPPG or DSPG.
In another preferred embodiment, described neutral phospholipid is Ovum Gallus domesticus Flavus lecithin, and described acidic phospholipid is the sodium salt of DPPG or the sodium salt of DSPG.
In one more preferably embodiment, described neutral phospholipid is Ovum Gallus domesticus Flavus lecithin, described acidic phospholipid is DPPG or DSPG, and the weight ratio of described DPPG or DSPG and described Ovum Gallus domesticus Flavus lecithin is 1: 10.
oil-based solvent
Injectable sustained release preparation of the present invention comprises oil-based solvent.Above-mentioned active constituents of medicine is dispersed in oil-based solvent and forms dispersion.
In the present invention, the amount of described oil-based solvent is determined according to the total amount of all the other components in invention formulation usually, that is, when considering the amount of oil-based solvent, be usually denoted by: the total amount of all the other components outside the amount-removing oil-based solvent of invention formulation.In certain embodiments, preparation of the present invention comprises with the oil-based solvent of described slow releasing preparation total weight 60% to 99% (w/w), preferably 80% to 99% (w/w), more preferably 87%, 89%, 90% and 97% (w/w).
It is one or more that preferred oil-based solvent possesses in following character usually: stable chemical nature, the pharmacologically active not affecting active constituents of medicine and assay, odorless and toxicity are little.
In some embodiments, one or more in fatty oil, long-chain or medium chain length fatty acid triglyceride, IPM, ethyl oleate, polyoxyethylene oleic three ester, white oil and benzyl benzoate are selected from for oil-based solvent of the present invention.Comprise for fatty oil of the present invention and be not limited to natural or refining vegetable oil.In a preferred embodiment, injectable crude vegetal for oil-based solvent of the present invention, described vegetable oil be selected from soybean oil, Oleum Camelliae, Oleum sesami, Oleum Bulbus Allii, walnut oil, olive oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Cocois, Oleum Gossypii semen, Oleum Ricini one or more.
other organic acid or the acceptable salt of its medicine or ester
Except acidic phospholipid or the acceptable salt of its medicine, Injectable sustained release preparation of the present invention optionally comprises other organic acid or the acceptable salt of its medicine or ester.The exemplary other acceptable salt of organic acid medicine is other organic acid alkali metal salt, alkali salt, aluminum salt, zinc salt and ammonium salt, the preferred aluminum salt of wherein said salt and zinc salt.The exemplary other acceptable ester of organic acid medicine is other organic acid glyceride, methyl ester, ethyl ester, isopropyl ester, dimethyl ester, diethylester etc.
Described other organic acid or the acceptable salt of its medicine or ester contribute to the dispersion of pharmaceutically active molecule of the present invention in oil-based solvent.
In Injectable sustained release preparation of the present invention, contained other organic acid amount can get comparatively wide scope.In some embodiments, Injectable sustained release preparation of the present invention comprises with the described other organic acid of described slow releasing preparation total weight 0.1% to 30% (w/w), preferably 1% to 20% (w/w), more preferably 5% and 10% (w/w).In other embodiments, described other organic acid amount can with the mass ratio range of described other organic acid and acidic phospholipid, such as, the weight ratio of described other organic acid and contained acid phosphatase be 200: 1 to 5: 1, preferably 100: 1 to 10: 1, more preferably 50: 4 and 100: 2.In other embodiment, described other organic acid amount can with the mass ratio range of described other organic acid and neutral phospholipid, such as, the weight ratio of described other organic acid and described neutral phospholipid be 20: 1 to 1: 10, preferably 10: 1 to 1: 2, more preferably 50: 40 and 100: 20.In some embodiments again, described other organic acid amount can with the mass ratio range of described other organic acid and phospholipid total amount, such as, the weight ratio of described other organic acid and phospholipid total amount be 20: 1 to 1: 10, preferably 10: 1 to 1: 2, more preferably 50: 44 and 100: 22.
For the amount of the described other acceptable salt of organic acid medicine or ester, obviously, those skilled in the art according to described other organic acid amount and concrete salt used or ester, can determine by simply calculating.
Injectable sustained release preparation of the present invention can comprise organic acid other described in one or more or the acceptable salt of its medicine or ester.Preferably, described other organic acid is the organic acid being suitable for injectable preparation in safety.Such organic acid example includes but not limited to, oleic acid, linoleic acid, Palmic acid, linolenic acid, palmitic acid and arachidonic acid.More preferably, described other organic acid is oleic acid.More preferably, described other organic acid ester is the ester that anhydrous sorbitol and organic acid are formed, such as sorbester p17.
In a preferred embodiment, described neutral phospholipid is Ovum Gallus domesticus Flavus lecithin, described acidic phospholipid is DPPG or DSPG, described other organic acid is oleic acid, the weight ratio of described DPPG or DSPG and described Ovum Gallus domesticus Flavus lecithin is 1: 10, and the weight ratio of described other organic acid and acidic phospholipid is 50: 4.
In another preferred embodiment, described neutral phospholipid is Ovum Gallus domesticus Flavus lecithin, described acidic phospholipid is DPPG or DSPG, described other organic acid is oleic acid, the weight ratio of described DPPG or DSPG and described Ovum Gallus domesticus Flavus lecithin is 1: 10, and the weight ratio of described other organic acid and acidic phospholipid is 100: 2.
In addition, it should be noted that, in a preferred embodiment, Injectable sustained release preparation of the present invention is not included in unaccommodated toxicity or pungent in safety.
antioxidant
Injectable sustained release preparation of the present invention optionally comprises antioxidant, to increase the stability of described oil-based solvent.Those skilled in the art know this term of antioxidant, and easily can determine its amount in the formulation.In some embodiments, described antioxidant be selected from vitamin A, vitamin C, vitamin E, selenium, zinc, copper, manganese, 2,6-di-tert-butyl-4-methy phenols (BHT) and butylhydroxy anisole (BHA) one or more.In some embodiments, described antioxidant is with 0.01% to 2.0%, preferably 0.03% to 1.0%, more preferably 0.05% to 0.1% of described slow releasing preparation total weight.
the preparation method of Injectable sustained release preparation
On the other hand, the preparation method of Injectable sustained release preparation of the present invention is provided, said method comprising the steps of:
A the compound of formula (I) or the acceptable salt of its medicine are scattered in aqueous solvent by (), thus obtain aqueous liquid dispersion;
B acidic phospholipid or the acceptable salt of its medicine and neutral phospholipid are scattered in aqueous solvent by (), thus obtain aqueous liquid dispersion;
C aqueous liquid dispersion that step (a) obtains by () and the aqueous liquid dispersion Homogeneous phase mixing that step (b) obtains;
D mixed liquor obtained for step (c) is dried to solid by (); And
E solid dispersal that step (d) obtains by () is in oil-based solvent.
In this article, term " dispersion " refers to one or more materials (i.e. dispersate) are distributed in another kind of material (i.e. dispersant) and form mixing material (i.e. dispersion liquid), wherein according to the dispersate particle size in formed dispersion liquid, it can be divided into:
Solution-particle size: < 1nm
Colloidal sol-particle size: 1-100nm
Suspension, emulsion-particle size: > 100nm
Thus, in the step (a), (b) and (e) of preparation method of the present invention, described dispersion can be dissolve independently.
In the aqueous liquid dispersion of step (a) gained, the compound positively charged of formula (I), or, when add aqueous solvent be the medicine of the compound of formula (I) acceptable salt time, part (moiety) positively charged corresponding to formula (I) compound of described salt.
In some embodiments, after the compound of formula (I) or the acceptable salt of its medicine are scattered in aqueous solvent, without the need to operation bidirectional, the part (moiety) corresponding to formula (I) compound in the compound or its salt of formula (I) namely becomes positively charged.In other embodiments, utilize the pH value of acid or alkali adjustment dispersion liquid, the part (moiety) corresponding to formula (I) compound in the compound or its salt of formula (I) is become positively charged.
In the aqueous liquid dispersion of step (b) gained, acidic phospholipid is electronegative, or, when add aqueous solvent be the medicine of acidic phospholipid acceptable salt time, the part (moiety) corresponding to acidic phospholipid of described salt is electronegative.Meanwhile, because it is combined with neutral phospholipid, make neutral phospholipid also electronegative.
In some embodiments, after acidic phospholipid or the acceptable salt of its medicine are scattered in aqueous solvent, without the need to operation bidirectional, namely the part (moiety) corresponding to acidic phospholipid of acidic phospholipid or described salt brings negative electricity.In other embodiments, utilize the pH value of acid or alkali adjustment dispersion liquid, make the part (moiety) corresponding to acidic phospholipid of acidic phospholipid or described salt bring negative electricity.
In step (b), important, described dispersion is sufficient, and for disperseing the mixing carried out to be uniform.According to the character of dispersate, in step (b), can adopt and include but not limited to that the technique that ultrasonic dispersion, reverse evaporation, film dispersion method, injection method, MVL preparation method, pH gradient method, ammonium sulphate gradient or secondary are encapsulated is disperseed.In certain preferred aspects, ultrasonic dispersion, high pressure homogenize or micro jetting technology is adopted to disperse.
In step (b), according to the character of dispersate, the temperature of carrying out disperseing can be selected.In some embodiments, carry out under being dispersed in the temperature of 40 DEG C to 45 DEG C described in.
The enforcement of step (a) and step (b) is relatively independent, thus, first can carry out step (a) or step (b), or carry out simultaneously.
After the aqueous liquid dispersion of the aqueous liquid dispersion and step (b) that obtain step (a), by its Homogeneous phase mixing.The mixed liquor drying of mixing gained forms solid.In certain embodiments, described drying is selected from lyophilization and spraying dry.After this, by dry gained solid dispersal in oil-based solvent.The dispersion liquid formed includes but not limited to solution and suspension, preferred solution.By described solid dispersal in oil-based solvent time, optionally can add described other organic acid or the acceptable salt of its medicine or ester.
In some embodiments, the preparation method of Injectable sustained release preparation of the present invention also comprises, and adds the step of antioxidant to step (e) gained oily dispersion.
In addition, it should be noted that, of the present invention prepare Injectable sustained release preparation method, in the step (b) of the method, do not comprise the organic solvent being used in and safety being unsuitable for injection preparation especially, wherein said organic solvent includes but not limited to, dichloromethane, chloroform, ether, ethanol, methanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, the tert-butyl alcohol, acetone, acetonitrile and ethyl acetate.But unforeseeable, although do not use described organic solvent, Injectable sustained release preparation of the present invention has good dispersibility.
slow release effect
Preparation of the present invention make use of the amphipathic and charge of neutral phospholipid and acidic phospholipid, against expectation creates good slow release effect.Especially, this slow release effect is when not comprising thickening agent in slow releasing preparation of the present invention and obtainable, wherein, the example of described thickening agent includes but not limited to, stearate is if aluminium stearate, zinc stearate, magnesium stearate, calcium stearate and high molecular polymer are as PCL, PLGA and PLA.
Further slow releasing preparation of the present invention and preparation method thereof is exemplarily described by the following examples.But should be understood that, described embodiment does not form any restriction to the scope of the invention.
embodiment
embodiment 1: the preparation of Injectable sustained release preparation
Material and reagent
active constituents of medicine
LXT101: synthesized according to the method for Chinese patent ZL90108955.9 by the laboratory of inventor.
oil-based solvent
Injection midchain oil and injection soybean oil: all purchased from Chinese Tieling Beiya Medical Oil Co., Ltd..
other reagent
Vitamin E (VE): purchased from Zhejiang NHU Company Ltd;
Dipalmitoyl phosphatidyl choline (DPPG), distearoyl phosphatidylcholine (DSPG) and Ovum Gallus domesticus Flavus lecithin (EPC): all purchased from Chinese Shanghai Dong Shang Industrial Co., Ltd.;
Oleic acid: purchased from Shanghai Dong Shang Industrial Co., Ltd..
Pure distilled water
method
Preparation method comprises the steps:
A LXT101 is scattered in pure distilled water by ();
B DPPG or DSPG and EPC is scattered in pure distilled water by ();
C aqueous liquid dispersion that step (a) obtains by () and the aqueous liquid dispersion Homogeneous phase mixing that step (b) obtains;
D mixed liquor obtained for step (c) is dried to solid by ();
E solid dispersal that step (d) obtains by () is in the injection midchain oil or the injection soybean oil that add oleic acid; With
F () adds VE to step (e) gained oily dispersion.
The component of prepared preparation is as shown in table 1 below.
Injectable sustained release preparation prepared by table 1.
embodiment 2: pharmacodynamic study result in rat body
To 6 kinds of LXT101 Injectable sustained release preparations of preparation in rat muscle injection (i.m) embodiment 1.Upon administration different time (my god) measure testosterone concentration (ng/ml), with indirect determination LXT101 preparation slow release effect in vivo.Whole mensuration process utilizes BECKMANCOULTERAccessImmunoassaySystem Chemiluminescence Apparatus to complete.Result is suitable for following table 2.
As mentioned above, the slow release effect of LXT-101 preparation is evaluated by measuring testosterone levels in rat body.As shown in table 2, when dosage is 3.5mg/kg, the sustainable suppression testosterone of preparation 1 is 5 to 7 days to the time of castrate levels; When dosage is 3.5mg/kg, the sustainable suppression testosterone of preparation 2 is 7 to 9 days to the time of castrate levels; When dosage is 3.5mg/kg, the sustainable suppression testosterone of preparation 3 is 5 to 7 days to the time of castrate levels; When dosage is 3.5mg/kg, the sustainable suppression testosterone of preparation 4 is 9 to 12 days to the time of castrate levels; When dosage is 3.5mg/kg, the sustainable suppression testosterone of preparation 5 is 12 to 15 days to the time of castrate levels; With when dosage is 3.5mg/kg, the sustainable suppression testosterone of preparation 6 is 17 to 20 days to the time of castrate levels.
Table 2.LXT-101 preparation is on the impact of normal rabbit serum testosterone levels
Numerical value and numerical range
It will be appreciated by those skilled in the art that and be, the numerical value occurred herein is not limited only to numerical point itself, also comprises any value near this point.Similarly, any end value of the numerical range occurred herein is all not limited to numerical point itself, also comprises any value near this point.
Need it is once more emphasized that, although by above-mentioned detailed description of the invention (comprising embodiment), invention has been described, the present invention should not be understood to be limited to described detailed description of the invention (comprising embodiment).Those skilled in the art can disclosing according to the application, when without prejudice to spirit of the present invention, improves any technical characteristic in above-mentioned embodiment and convert, and these improve and convert the technical scheme produced and all belong to scope of the present invention.
Claims (50)
1. Injectable sustained release preparation, described slow releasing preparation comprises
The compound of the formula (I) for the treatment of effective dose or the acceptable salt of its medicine,
Neutral phospholipid,
Acidic phospholipid or the acceptable salt of its medicine, and
Oil-based solvent
Wherein said slow releasing preparation does not comprise thickening agent, and the preparation of described slow releasing preparation comprises the following steps:
A described formula (I) compound or the acceptable salt of its medicine are scattered in aqueous solvent by (), thus obtain aqueous liquid dispersion;
B described acidic phospholipid or the acceptable salt of its medicine and neutral phospholipid are scattered in aqueous solvent by (), thus obtain aqueous liquid dispersion;
C aqueous liquid dispersion that step (a) obtains by () and the aqueous liquid dispersion Homogeneous phase mixing that step (b) obtains;
D mixed liquor obtained for step (c) is dried to solid by (); With
E solid dispersal that step (d) obtains by () is in oil-based solvent.
2. slow releasing preparation as claimed in claim 1, it comprises with the neutral phospholipid of described slow releasing preparation total weight 0.1% to 10% (w/w).
3. slow releasing preparation as claimed in claim 1, it comprises with the neutral phospholipid of described slow releasing preparation total weight 0.3% to 8% (w/w).
4. slow releasing preparation as claimed in claim 1, it comprises with the neutral phospholipid of described slow releasing preparation total weight 0.5% (w/w).
5. slow releasing preparation as claimed in claim 1, it comprises with the neutral phospholipid of described slow releasing preparation total weight 1% (w/w).
6. slow releasing preparation as claimed in claim 1, it comprises with the neutral phospholipid of described slow releasing preparation total weight 2% (w/w).
7. slow releasing preparation as claimed in claim 1, it comprises with the neutral phospholipid of described slow releasing preparation total weight 4% (w/w).
8. the slow releasing preparation as described in aforementioned arbitrary claim, wherein said neutral phospholipid be selected from soybean lecithin (SPC), Ovum Gallus domesticus Flavus lecithin (EPC), phosphatidylcholine (PC), dipalmitoyl phosphatidyl choline (DPPC), distearoyl phosphatidylcholine (DSPC), dimyristoyl phosphatidyl choline (DMPC), sphingomyelins (SM), the similar thing of alkyl ether phosphatidylcholine and PHOSPHATIDYL ETHANOLAMINE (PE) one or more.
9. the slow releasing preparation according to any one of claim 1-7, it comprises with the acidic phospholipid of described slow releasing preparation total weight 0.01% to 1% (w/w) or the acceptable salt of its medicine.
10. the slow releasing preparation according to any one of claim 1-7, it comprises with the acidic phospholipid of described slow releasing preparation total weight 0.03% to 0.8% (w/w) or the acceptable salt of its medicine.
11. slow releasing preparation according to any one of claim 1-7, it comprises with the acidic phospholipid of described slow releasing preparation total weight 0.05% (w/w) or the acceptable salt of its medicine.
12. slow releasing preparation according to any one of claim 1-7, it comprises with the acidic phospholipid of described slow releasing preparation total weight 0.1% (w/w) or the acceptable salt of its medicine.
13. slow releasing preparation according to any one of claim 1-7, it comprises with the acidic phospholipid of described slow releasing preparation total weight 0.2% (w/w) or the acceptable salt of its medicine.
14. slow releasing preparation according to any one of claim 1-7, it comprises with the acidic phospholipid of described slow releasing preparation total weight 0.4% (w/w) or the acceptable salt of its medicine.
15. slow releasing preparation as claimed in claim 8, it comprises with the acidic phospholipid of described slow releasing preparation total weight 0.01% to 1% (w/w) or the acceptable salt of its medicine.
16. slow releasing preparation as claimed in claim 8, it comprises with the acidic phospholipid of described slow releasing preparation total weight 0.03% to 0.8% (w/w) or the acceptable salt of its medicine.
17. slow releasing preparation as claimed in claim 8, it comprises with the acidic phospholipid of described slow releasing preparation total weight 0.05% (w/w) or the acceptable salt of its medicine.
18. slow releasing preparation as claimed in claim 8, it comprises with the acidic phospholipid of described slow releasing preparation total weight 0.1% (w/w) or the acceptable salt of its medicine.
19. slow releasing preparation as claimed in claim 8, it comprises with the acidic phospholipid of described slow releasing preparation total weight 0.2% (w/w) or the acceptable salt of its medicine.
20. slow releasing preparation as claimed in claim 8, it comprises with the acidic phospholipid of described slow releasing preparation total weight 0.4% (w/w) or the acceptable salt of its medicine.
21. slow releasing preparation according to any one of claim 1-7 and 15-20, it comprises and is selected from one or more acidic phospholipids in phosphatidic acid (PA), phosphatidyl glycerol (PG), phosphatidylinositols (PI), Phosphatidylserine (PS), two spermaceti phosphatidic acid (DCP), DPPG (DPPG) and DSPG (DSPG) or the acceptable salt of its medicine.
22. slow releasing preparation as claimed in claim 8, it comprises and is selected from one or more acidic phospholipids in phosphatidic acid (PA), phosphatidyl glycerol (PG), phosphatidylinositols (PI), Phosphatidylserine (PS), two spermaceti phosphatidic acid (DCP), DPPG (DPPG) and DSPG (DSPG) or the acceptable salt of its medicine.
23. slow releasing preparation as claimed in claim 9, it comprises and is selected from one or more acidic phospholipids in phosphatidic acid (PA), phosphatidyl glycerol (PG), phosphatidylinositols (PI), Phosphatidylserine (PS), two spermaceti phosphatidic acid (DCP), DPPG (DPPG) and DSPG (DSPG) or the acceptable salt of its medicine.
24. slow releasing preparation as claimed in claim 10, it comprises and is selected from one or more acidic phospholipids in phosphatidic acid (PA), phosphatidyl glycerol (PG), phosphatidylinositols (PI), Phosphatidylserine (PS), two spermaceti phosphatidic acid (DCP), DPPG (DPPG) and DSPG (DSPG) or the acceptable salt of its medicine.
25. slow releasing preparation as claimed in claim 11, it comprises and is selected from one or more acidic phospholipids in phosphatidic acid (PA), phosphatidyl glycerol (PG), phosphatidylinositols (PI), Phosphatidylserine (PS), two spermaceti phosphatidic acid (DCP), DPPG (DPPG) and DSPG (DSPG) or the acceptable salt of its medicine.
26. slow releasing preparation as claimed in claim 12, it comprises and is selected from one or more acidic phospholipids in phosphatidic acid (PA), phosphatidyl glycerol (PG), phosphatidylinositols (PI), Phosphatidylserine (PS), two spermaceti phosphatidic acid (DCP), DPPG (DPPG) and DSPG (DSPG) or the acceptable salt of its medicine.
27. slow releasing preparation as claimed in claim 13, it comprises and is selected from one or more acidic phospholipids in phosphatidic acid (PA), phosphatidyl glycerol (PG), phosphatidylinositols (PI), Phosphatidylserine (PS), two spermaceti phosphatidic acid (DCP), DPPG (DPPG) and DSPG (DSPG) or the acceptable salt of its medicine.
28. slow releasing preparation as claimed in claim 14, it comprises and is selected from one or more acidic phospholipids in phosphatidic acid (PA), phosphatidyl glycerol (PG), phosphatidylinositols (PI), Phosphatidylserine (PS), two spermaceti phosphatidic acid (DCP), DPPG (DPPG) and DSPG (DSPG) or the acceptable salt of its medicine.
29. slow releasing preparation according to any one of claim 1-7,15-20 and 22-28, described slow releasing preparation also comprises other organic acid or the acceptable salt of its medicine or ester.
30. slow releasing preparation as claimed in claim 8, described slow releasing preparation also comprises other organic acid or the acceptable salt of its medicine or ester.
31. slow releasing preparation as claimed in claim 9, described slow releasing preparation also comprises other organic acid or the acceptable salt of its medicine or ester.
32. slow releasing preparation as claimed in claim 10, described slow releasing preparation also comprises other organic acid or the acceptable salt of its medicine or ester.
33. slow releasing preparation as claimed in claim 11, described slow releasing preparation also comprises other organic acid or the acceptable salt of its medicine or ester.
34. slow releasing preparation as claimed in claim 12, described slow releasing preparation also comprises other organic acid or the acceptable salt of its medicine or ester.
35. slow releasing preparation as claimed in claim 13, described slow releasing preparation also comprises other organic acid or the acceptable salt of its medicine or ester.
36. slow releasing preparation as claimed in claim 14, described slow releasing preparation also comprises other organic acid or the acceptable salt of its medicine or ester.
37. slow releasing preparation as claimed in claim 21, described slow releasing preparation also comprises other organic acid or the acceptable salt of its medicine or ester.
38. slow releasing preparation according to any one of claim 1-7,15-20,22-28 and 30-37, described slow releasing preparation also comprises antioxidant.
39. slow releasing preparation as claimed in claim 8, described slow releasing preparation also comprises antioxidant.
40. slow releasing preparation as claimed in claim 9, described slow releasing preparation also comprises antioxidant.
41. slow releasing preparation as claimed in claim 10, described slow releasing preparation also comprises antioxidant.
42. slow releasing preparation as claimed in claim 11, described slow releasing preparation also comprises antioxidant.
43. slow releasing preparation as claimed in claim 12, described slow releasing preparation also comprises antioxidant.
44. slow releasing preparation as claimed in claim 13, described slow releasing preparation also comprises antioxidant.
45. slow releasing preparation as claimed in claim 14, described slow releasing preparation also comprises antioxidant.
46. slow releasing preparation as claimed in claim 21, described slow releasing preparation also comprises antioxidant.
47. slow releasing preparation as claimed in claim 29, described slow releasing preparation also comprises antioxidant.
The method of the Injectable sustained release preparation of 48. preparations described in aforementioned arbitrary claim, said method comprising the steps of:
A described formula (I) compound or the acceptable salt of its medicine are scattered in aqueous solvent by (), thus obtain aqueous liquid dispersion;
B described acidic phospholipid or the acceptable salt of its medicine and neutral phospholipid are scattered in aqueous solvent by (), thus obtain aqueous liquid dispersion;
C aqueous liquid dispersion that step (a) obtains by () and the aqueous liquid dispersion Homogeneous phase mixing that step (b) obtains;
D mixed liquor obtained for step (c) is dried to solid by (); With
E solid dispersal that step (d) obtains by () is in oil-based solvent;
Wherein said method does not comprise the step adding thickening agent.
49. preparation methoies as claimed in claim 48, wherein step (e) also comprises and described other organic acid or the acceptable salt of its medicine or ester is added described oil-based solvent.
50. preparation methoies as described in claim 48 or 49, also comprise (f) and described antioxidant are added described oil-based solvent.
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| CN201010623859.XA CN102525914B (en) | 2010-12-31 | 2010-12-31 | The Injectable sustained release preparation of lhrh antagonist class material and preparation thereof |
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| CN101647772A (en) * | 2008-08-12 | 2010-02-17 | 中国人民解放军军事医学科学院毒物药物研究所 | Sustained release preparation for injection of LHRH antagonist substances and preparation thereof |
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