CN101647772A - Sustained release preparation for injection of LHRH antagonist substances and preparation thereof - Google Patents
Sustained release preparation for injection of LHRH antagonist substances and preparation thereof Download PDFInfo
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- CN101647772A CN101647772A CN200810134642A CN200810134642A CN101647772A CN 101647772 A CN101647772 A CN 101647772A CN 200810134642 A CN200810134642 A CN 200810134642A CN 200810134642 A CN200810134642 A CN 200810134642A CN 101647772 A CN101647772 A CN 101647772A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
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Abstract
The invention relates to a sustained release preparation for injection of LHRH antagonist substances and a preparation method thereof. The sustained release preparation comprises a therapeutic effective dose of an active component in a structure of a formula (I) or pharmaceutically acceptable salts or prodrugs thereof, and oily solvent.
Description
Technical field
The present invention relates to Injectable sustained release preparation of lhrh antagonist class material and preparation method thereof, relate in particular to Injectable sustained release preparation of LXT101 and preparation method thereof.
Background technology
Luteinizing hormone releasing hormone (LHRH) is the neural parahormone of the excretory a kind of decapeptide of hypothalamus, it mainly acts on is to promote that hypophysis is synthetic and discharge lutropin (LH) and follicule-stimulating hormone (FSH) (FSH), excites adolescence to grow and adjusting fertility and gonadal hormone correlated process.Molecular structure to LHRH carries out chemical modification and transformation, replaces or leaves out some amino acid residue, may produce new active analogue thereof.Divide by function, these analog can be divided into two big classes such as LHRH agonist and lhrh antagonist.The LHRH analog not only can be used for endocrine regulation, also can be used for the treatment of the malignant tumor that hormone relies on, as carcinoma of prostate, breast carcinoma etc.
LXT101 belongs to lhrh antagonist, and it has the chemical constitution suc as formula (I):
LXT101 has that produce effects is fast, effect is strong, advantages such as serum androgen upper punch do not appear in medication in early days, are prostate cancer therapy medicines of new generation.Because its half-life is shorter, so the bioavailability of its ordinary preparation in blood is very low and toxic and side effects increases; The conventional soln agent needs administration every day in addition, and the course of treatment is longer, brings painful and medication inconvenience to the patient.In order to reduce administration frequency, to improve patient's compliance, development LXT slow releasing preparation is particularly important.
Summary of the invention
The purpose of this invention is to provide the Injectable sustained release preparation, described slow releasing preparation comprises active component LXT101 or acceptable salt of its medicine or prodrug, and oil-based solvent.
Another object of the present invention provides the preparation method of the Injectable sustained release preparation of above-mentioned LXT101, and described method comprises the LXT101 drug powder is added in the oil-based solvent, stirs to make the gained mixture be uniformly dispersed packing.
The specific embodiment
Usually, be that solvent is made suspension or solution can have slow release effect with the oil-based solvent with hydrophobic drug.Yet when having higher water miscible medicine such as bio-pharmaceutical suspendible or being partly dissolved in the oil phase, because its higher water/oil content distribution coefficient, medicine easily enters aqueous phase after arriving oil/water termination.Therefore for having, adopt simple oiliness suspensoid to be difficult to reach ideal slow release effect than highly-water-soluble or strong polar bio-pharmaceutical.
The LHRH analog is polypeptide compounds from molecular structure, and generally has a plurality of hydrophilic radicals, and hydrophilic is higher, therefore adopts oil-based solvent to make suspensoid or the very difficult slow release effect of realizing of solution.Yet the inventor is surprised to find, and is that non-aqueous solution agent and the suspensoid that solvent prepares has good slow releasing function with the oil-based solvent with LXT101.
Therefore, an aspect of of the present present invention relates to the Injectable sustained release preparation of LXT101, and described slow releasing preparation comprises treatment effective amount of actives LXT101 or acceptable salt of its medicine or prodrug, and oil-based solvent.
Can or obtain the powder of described active component LXT101 by its aqueous solution lyophilization by pulverizing or abrasive method.With this drug powder dispersion or be dissolved in the oil-based solvent.The granular size of described drug powder in suspensoid is no more than 15 μ m.
In certain embodiments of the invention, described active component can be the acceptable salt of its medicine or other derivant.
The acceptable salt of the medicine of described active component is known those acid-addition salts of those skilled in the art.Exemplary acid comprises mineral acid for example hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, boric acid, phosphoric acid etc.; Organic acid is acetic acid, maleic acid, tartaric acid, salicylic acid, citric acid, benzoic acid, pamoic acid, sulfonic acid etc. for example.
Acceptable other derivant of the medicine of described active component be those skilled in the art known those, include but not limited to its prodrug.
" prodrug " is meant can be under physiological condition or change into the chemical compound of active constituents of medicine by solvolysis.Therefore, term " prodrug " is meant that the medicine of active component described in the slow releasing preparation of the present invention can accept metabolic precursor thereof.The example of prodrug includes but not limited to acetas, formic acid esters, benzoate, phosphate ester, sulfonate derivatives of the alcohol functional group of active component described in the slow releasing preparation of the present invention etc.; The amide derivatives of amine functional group etc.
The amount that contains active component in the present composition is a benchmark to reach the treatment effective dose.
" treatment effective dose " is meant the amount of active component in the slow releasing preparation of the present invention, when it is given mammal, is preferably man-hour, is enough to described mammal, is preferably philtrum and realizes the to be treated/disease of prevention or the treatment/prevention of morbid state.The amount of active component in the slow releasing preparation of the present invention of formation " treatment effective dose ", condition such as age, body weight etc. according to morbid state to be treated and seriousness and administration object change, but can be determined according to its own knowledge and the application's disclosure by persons skilled in the art routinely.
The amount that contains active component LXT101 in the described Injectable sustained release preparation is generally 0.001% to 30% (w/w) based on described slow releasing preparation gross weight, in certain embodiments, the amount that contains active component in the Injectable sustained release preparation of the present invention is 0.01% to 20% (w/w) based on described slow releasing preparation total amount.In certain embodiments, the amount that contains active component in the Injectable sustained release preparation of the present invention is 0.1% to 10% (w/w) based on described slow releasing preparation total amount.
Oil-based solvent in the Injectable sustained release preparation of the present invention is those that use always in the pharmaceutical field.Exemplary oil-based solvent includes but not limited to crude vegetal such as 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, Semen Ricini wet goods; Refined plant oil; Long-chain or medium chain length fatty acid triglyceride; The Semen Myristicae isopropyl ester; Ethyl oleate; Polyoxyethylene oleic acid triglyceride; White oil; And benzyl benzoate etc.
In certain embodiments, described oil-based solvent can be above-mentioned one or more combination.
In some preferred embodiment, described oil-based solvent uses soybean oil, long-chain or medium chain length fatty acid triglyceride.
The amount of oil-based solvent requires not strict, and those skilled in the art can select suitable amount as required.Usually can be 30% to 99.9% (w/w) based on described slow releasing preparation gross weight.In certain embodiments, the addition of described oil-based solvent is 50% to 99% (w/w) based on described slow releasing preparation total amount.In certain embodiments, the addition of described oil-based solvent is 60% to 99% (w/w) based on described slow releasing preparation total amount.
In certain embodiments, also can comprise thickening agent in the slow releasing preparation of the present invention.Can be used for thickening agent of the present invention and comprise stearates such as aluminium stearate, zinc stearate, magnesium stearate, calcium stearate; And high molecular polymer such as PCL, PLGA, PLA etc.The addition of described thickening agent is 0.05% to 10% (w/w) based on described slow releasing preparation total amount, preferred 0.5% to 3.0% (w/w).
The adding of stearate makes the oil-based solvent gelation on the one hand, increases the viscosity of medium, thereby causes drug molecule to have lower diffusion coefficient, discharges slack-off; On the other hand, because the hydrophobicity stearate has been wrapped up on the drug particles surface, therefore be difficult for being arrived, thereby drug release is significantly delayed by the aqueous tissue fluid.
In certain embodiments, also can comprise dispersant in the slow releasing preparation of the present invention.The adding of dispersant is in order to make the drug powder can homodisperse, and makes drug powder keep stable in dispersion.Can be used for dispersant of the present invention and can be selected from oil soluble surfactant such as phospholipid, cholesterol, sorbitan fatty acid ester class, stearic acid esters, polyethers or its mixture etc.
In certain embodiments, described phospholipid is selected from natural phospholipid such as soybean lecithin (SPC) or Ovum Gallus domesticus Flavus lecithin (EPC), synthetic phospholipid such as dipalmitoyl phosphatidyl choline (DPPC), DSPE (DSPE), hydrogenated soy phosphatidyl choline (HSPC) or Phosphatidylserine (PS) etc.
In certain embodiments, described sorbitan fatty acid ester class is selected from span 20, span 40, sorbester p18 or sorbester p17 etc.
In certain embodiments, described stearic acid esters is selected from distearyl acid second diester or glyceryl monostearate etc.
In certain embodiments, described polyethers is Pluronic L31.
The addition of described dispersant is 0.05% to 30.0% (w/w) based on described slow releasing preparation total amount, preferred 0.1% to 20.0% (w/w).
In certain embodiments, also can comprise antioxidant in the slow releasing preparation of the present invention, to guarantee the stability of oil for injection.Can be used for antioxidant of the present invention and can be selected from VE (vitamin E), BHT (di-tertiary butyl methyl phenol), BHA (butylhydroxy anisole) or its mixture etc.The addition of described antioxidant is 0.01% to 2.0% (w/w) based on described slow releasing preparation total amount, preferred 0.05% to 1.0% (w/w).
Preparation of the present invention makes the slowly effect of release of LXT101 except having, and active component after the said preparation injection, can guarantee that active LXT101 is more stable in the injection site, can steadily discharge always in oil medium inside in whole dispose procedure.This slow releasing injection can be kept in thoughtful one month one and discharge the effective active polypeptide.
Another aspect of the present invention relates to the preparation method of the Injectable sustained release preparation of LXT101.This method comprises the LXT101 drug powder is added in the oil-based solvent, stirs to make the mixture that obtains be uniformly dispersed packing.
With specific embodiment the present invention is further specified below.Should be appreciated that these embodiment do not constitute any restriction to the scope of the invention.
Embodiment
Material and reagent
Active component
LXT101: the laboratory by the inventor is synthetic according to the method for Chinese patent ZL 90108955.9;
Oil-based solvent
Injection midchain oil, injection soybean oil are all available from Chinese Tieling Beiya Medical Oil Co., Ltd.;
Other reagent
Sorbester p17: available from becoming to contain the chemicals company limited;
VE: available from Zhejiang NHU Company Ltd;
BHT: available from the pretty industrial chemicals company limited of Guangzhou literary composition;
Ovum Gallus domesticus Flavus lecithin (EPC), cholesterol: all available from Chinese Shanghai Dong Shang Industrial Co., Ltd.;
Aluminium stearate: become the chemical industry company limited available from Chinese Shanghai nation.
Embodiment 1: the preparation of preparation
Prepare preparation of the present invention according to following conventional method: LXT101 is ground or pulverizes the back and cross 100 mesh sieves, join in other mixture of ingredients, stir or grind, use high pressure homogenizer to disperse, make the granular size in the LXT101 suspensoid be no more than 15 μ m, packing obtains preparation.
Different preparations as shown in table 1 have been prepared.
The different preparations that table 1. the present invention is prepared
Embodiment 2: the mensuration that cumulative in vitro discharges
Getting the active component reference substance adds water and is mixed with the standard activity composition solution that concentration is respectively 10 μ g/mL, 20 μ g/mL, 30 μ g/mL, 50 μ g/mL, 100 μ g/mL, 200 μ g/mL, adopt forint phenol method to measure absorbance A, with absorbance A concentration is returned, set up the standard curve regression equation.
The LXT101 slow releasing preparation of getting preparation places 50mL tool plug conical flask in right amount, and to the PBS buffer solution that wherein adds 10mL pH 7.2.Place 37 ± 1 ℃ of constant temperature shaking tables to vibrate conical flask, frequency of oscillation is 70r/m.Respectively at different time points quantitative liquid getting 200 μ L, mend the PBS buffer solution 200 μ L of pH7.2 simultaneously.12, under the 000r/m condition centrifugal 10 minutes, get supernatant, as sample solution.With method working sample solution absorbency, the substitution regression equation calculation promptly gets the concentration of active component in the sample solution.
The accumulation medication amount of calculating is compared the calculating drug accumulation with adding medicine total amount discharge percent.The release in vitro performance of some preparation that the present invention is prepared is as shown in table 2, and wherein each data point is the meansigma methods of twice test.
The cumulative in vitro of table 2. preparation of the present invention discharges
The data of table 2 show that the preparation of being tested can slowly discharge external in 7 to 13 days time.
Embodiment 3: pharmacodynamics result of study in the rat body
Give the Different L XT-101 preparation (comprising various dose) of preparation among rat muscle injection (i.m) embodiment 1 according to following table 3, different time after the administration (my god) measure the testosterone concentration (ng/ml) in the serum, with indirect determination LXT101 oiliness slow releasing preparation releasing effect in vivo.Whole mensuration process is finished by preset program automatically by BECKMAN COULTER Access Immunoassay System Chemiluminescence Apparatus.The results are shown in following table 3.
Estimate the slow release effect of LXT-101 preparation by measuring testosterone levels in the rat blood serum, as can be known from Table 3, preparation 1 is 5 to 7 days when the time that dosage can significantly suppress testosterone levels in the serum during for 3.5mg/kg; Preparation 2 is 9 to 10 days when the time that dosage can significantly suppress testosterone levels in the serum during for 3.5mg/kg; Preparation 3 is 7 to 9 days when the time that dosage can significantly suppress testosterone levels in the serum during for 3.5mg/kg; Preparation 6 when dosage be that the time that 1mg/kg can significantly suppress testosterone levels in the serum is 9 to 10 days; Preparation 5 when dosage be that the time that 1mg/kg can significantly suppress testosterone levels in the serum is 5 to 7 days, when dosage is that the time that 3.5mg/kg can significantly suppress testosterone levels in the serum is 21 to 28 days.
It will be understood by those skilled in the art that " for example " used herein, " such as " all the expression " including but not limited to ".
Though the present invention is described by the above-mentioned specific embodiment and specifying, not with this as restriction.Those skilled in the art can improve and conversion the technical characterictic in the above-mentioned embodiment under the situation of spirit of the present invention according to the disclosing of the application, and these improve and conversion all should belong to scope of the present invention.
Claims (11)
1. Injectable sustained release preparation, it comprises active component or the acceptable salt of its medicine or the prodrug suc as formula (1) structure for the treatment of effective dose, and oil-based solvent:
2. slow releasing preparation as claimed in claim 1, wherein said active component is scattered in the described oil-based solvent with powder type, and described particles of powder size is no more than 15 μ m.
3. slow releasing preparation as claimed in claim 1 or 2, the amount of wherein said active component are 0.001% to 30% (w/w) based on described slow releasing preparation gross weight, preferred 0.05% to 5.0% (w/w).
4. the described slow releasing preparation of arbitrary as described above claim, wherein said oil-based solvent is selected from unsaturated fatty acid, refined plant oil, long-chain or medium chain length fatty acid triglyceride, benzyl benzoate or its multiple mixture of injectable with crude vegetal, different carbon chain, and is preferably selected from injectable soybean oil, long-chain or medium chain length fatty acid triglyceride.
5. the described slow releasing preparation of arbitrary as described above claim, wherein said slow releasing preparation also comprises thickening agent, and described thickening agent is selected from stearates such as aluminium stearate, zinc stearate, magnesium stearate, calcium stearate; Or high molecular polymer such as PCL, PLGA, PLA.
6. slow releasing preparation as claimed in claim 5, the addition of wherein said thickening agent are 0.05% to 10% (w/w) based on described slow releasing preparation total amount, preferred 0.5% to 3.0% (w/w).
7. the described slow releasing preparation of arbitrary as described above claim, wherein said slow releasing preparation also comprises dispersant, described dispersant is an oil soluble surfactant, described oil soluble surfactant is selected from phospholipid for example natural phospholipid such as soybean lecithin (SPC) or Ovum Gallus domesticus Flavus lecithin (EPC), synthetic phospholipid such as dipalmitoyl phosphatidyl choline (DPPC), DSPE (DSPE), hydrogenated soy phosphatidyl choline (HSPC) or Phosphatidylserine (PS); Cholesterol; The sorbitan fatty acid ester class is span 20, span 40, sorbester p18 or sorbester p17 for example; The stearic acid esters is distearyl acid second diester or glyceryl monostearate for example; Polyethers is Pluronic L31 for example; Or the mixture of above-mentioned substance.
8. slow releasing preparation as claimed in claim 7, the addition of wherein said dispersant are 0.05% to 30.0% (w/w) based on described slow releasing preparation total amount, preferred 0.1% to 20.0% (w/w).
9. the described slow releasing preparation of arbitrary as described above claim, wherein said slow releasing preparation also comprises antioxidant, and described antioxidant is selected from vitamin E, di-tertiary butyl methyl phenol, butylhydroxy anisole or its mixture.
10. slow releasing preparation as claimed in claim 9, the addition of wherein said antioxidant are 0.01% to 2.0% (w/w) based on described slow releasing preparation total amount, preferred 0.05% to 1.0% (w/w).
11. the preparation method of Injectable sustained release preparation, described method comprise being added in the oil-based solvent suc as formula the active component of (1) structure or the acceptable salt of its medicine or prodrug of treatment effective dose, stirs to make the mixture of gained be uniformly dispersed packing:
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810134642A CN101647772A (en) | 2008-08-12 | 2008-08-12 | Sustained release preparation for injection of LHRH antagonist substances and preparation thereof |
| PCT/CN2009/073034 WO2010017743A1 (en) | 2008-08-12 | 2009-07-31 | The injectable sustained-release formulation of lhrh antagonists and the preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810134642A CN101647772A (en) | 2008-08-12 | 2008-08-12 | Sustained release preparation for injection of LHRH antagonist substances and preparation thereof |
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| CN101647772A true CN101647772A (en) | 2010-02-17 |
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| CN200810134642A Pending CN101647772A (en) | 2008-08-12 | 2008-08-12 | Sustained release preparation for injection of LHRH antagonist substances and preparation thereof |
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| WO (1) | WO2010017743A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102525914A (en) * | 2010-12-31 | 2012-07-04 | 中国人民解放军军事医学科学院毒物药物研究所 | Injection sustained-release preparation of LHRH (luteinizing hormone releasing hormone) antagonist substance and preparation thereof |
| CN103070871A (en) * | 2011-10-26 | 2013-05-01 | 江苏正大天晴药业股份有限公司 | Pharmaceutical composition of fulvestrant |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4800191A (en) * | 1987-07-17 | 1989-01-24 | Schally Andrew Victor | LHRH antagonists |
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2008
- 2008-08-12 CN CN200810134642A patent/CN101647772A/en active Pending
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- 2009-07-31 WO PCT/CN2009/073034 patent/WO2010017743A1/en active Application Filing
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102525914A (en) * | 2010-12-31 | 2012-07-04 | 中国人民解放军军事医学科学院毒物药物研究所 | Injection sustained-release preparation of LHRH (luteinizing hormone releasing hormone) antagonist substance and preparation thereof |
| CN102525914B (en) * | 2010-12-31 | 2016-03-23 | 中国人民解放军军事医学科学院毒物药物研究所 | The Injectable sustained release preparation of lhrh antagonist class material and preparation thereof |
| CN103070871A (en) * | 2011-10-26 | 2013-05-01 | 江苏正大天晴药业股份有限公司 | Pharmaceutical composition of fulvestrant |
| CN103070871B (en) * | 2011-10-26 | 2015-04-15 | 正大天晴药业集团股份有限公司 | Pharmaceutical composition of fulvestrant |
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| Publication number | Publication date |
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| WO2010017743A1 (en) | 2010-02-18 |
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Application publication date: 20100217 |