WO2014169816A1 - 戈舍瑞林缓释微球药物组合物 - Google Patents
戈舍瑞林缓释微球药物组合物 Download PDFInfo
- Publication number
- WO2014169816A1 WO2014169816A1 PCT/CN2014/075441 CN2014075441W WO2014169816A1 WO 2014169816 A1 WO2014169816 A1 WO 2014169816A1 CN 2014075441 W CN2014075441 W CN 2014075441W WO 2014169816 A1 WO2014169816 A1 WO 2014169816A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- goserelin
- microspheres
- poloxamer
- pharmaceutical composition
- polyethylene glycol
- Prior art date
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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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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- 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
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
Definitions
- the invention relates to the field of pharmaceutical preparations, in particular to a goserelin long-acting sustained-release microsphere composition, a preparation method and application thereof.
- Gonadotropin-releasing hormone also known as progesterone-releasing hormone (LHRH)
- LHRH progesterone-releasing hormone
- GnRH Gonadotropin-releasing hormone
- LHRH progesterone-releasing hormone
- Luteinizing hormone-releasing hormone analogues competitively inhibit the secretion of LH and FSH by binding to most of the receptors of the pituitary luteinizing hormone releasing hormone, thereby inhibiting the production of ovarian estrogen and achieving the therapeutic effect of drug-induced ovariectomy. Studies have shown that administration of luteinizing hormone-releasing hormone analogues (such as goserelin) after radiation therapy can prolong the lives of patients with prostate cancer.
- Goserelin preparations have been approved for marketing in France in 1987 and were approved by the FDA on December 29, 1989.
- the trade name is "Norad".
- the dosage form is an implant, and the dose is injected once a month: 3. 6 mg / support, 3. 6 mg once every 28 days, subcutaneous injection of the anterior abdominal wall, but "Noride abdominal subcutaneous injection, its drug pre- Placed in a disposable syringe, the injection needle is equivalent to a 16-gauge needle, and the length is about 30 mm. Therefore, compared with the general drug subcutaneous injection, the degree of pain caused by the injection is large, and the subcutaneous bleeding after injection is more. "Chinese Journal of Modern Clinical Medicine", July 2008, Volume 6, Issue 7.
- microsphere preparations in the injection of patients will significantly reduce the pain and bleeding of patients when injected into the patient.
- LHRH analogue microspheres are mostly such release modes.
- leuprolide microspheres Such as leuprolide microspheres.
- the pharmacokinetic study of the microspheres prepared in the animal shows that the organism The degree of utilization is low and the effect cannot be fully exerted.
- the present invention provides a goserelin sustained-release microsphere pharmaceutical composition
- a goserelin sustained-release microsphere pharmaceutical composition comprising goserelin or a salt thereof, lactide-glycolide copolymer (PLGA) and poloxamer or polyethylene glycol;
- the poloxamer or polyethylene glycol is present in an amount of from 1 to 10% by weight, preferably from 1 to 6%, more preferably from 1 to 4%.
- the weight fraction of goserelin or a salt thereof in the pharmaceutical composition is 1-10%, preferably 1-8%, more preferably 1-5%; the weight ratio of the lactide-glycolide copolymer is 80-98% Preferably, it is 86-98%, more preferably 91-98%.
- Lactide-glycolide copolymer English name is Poly(lactide-co-glycolide), referred to as PLGA.
- the molar ratio of lactide to glycolide of the PLGA is 90: 10- 10: 90, preferably 75: 25-25: 75, more preferably 60: 40-40: 60, especially 50: 50.
- the lactide-glycolide copolymer has an intrinsic viscosity of 0.10 to 0.40 dL/g, preferably a range of 0.10 to 0.35 dL/g, more preferably a range of 0.10 to 0.30 dL/g.
- Intrinsic viscosity of PLGA Determination method PLGA was prepared into a solution of about 0.5% (w/v) with chloroform, and its intrinsic viscosity was measured at 30 °C using a Cannon-Fenske glass capillary viscometer.
- the lactide-glycolide copolymer (PLGA) of the present invention has a molecular weight of from 4,000 to 45,000 Daltons, preferably from 4,000 to 35,000 Daltons, more preferably from 4,000 to 30,000 Daltons.
- the molecular weight refers to "weight average molecular weight”, abbreviated as "molecular weight”.
- PLGA 50/50, 0.14, 7200
- the molar ratio of lactide to glycolide is 50:50
- the intrinsic viscosity is 0.14 dl/g
- the molecular weight is 7200 daltons. Ester copolymer.
- the poloxamer of the present invention is a polyoxyethylene polyoxypropylene ether block copolymer, which is copolymerized with an appropriate amount of polyoxypropylene and an appropriate amount of polyoxyethylene to form a compound having a different lipophilic water balance value, preferably a poloxamer. 188 or poloxamer 407, more preferably poloxamer 188.
- polyethylene glycol of the present invention also known as ⁇ -hydrogen_ ⁇ -hydroxy (oxy-1,2-ethanediyl) polymer, polyethylene oxide (PE0-LS), is a general term for ethylene glycol polymers. .
- Preferred is polyethylene glycol 2000, polyethylene glycol 4000 or polyethylene glycol 6000, more preferably polyethylene glycol 6000.
- Encapsulation ratio (%) measured drug loading of the drug in the microsphere / theoretical drug loading (mg/mg) of the drug in the microsphere at the time of preparation ⁇ 100%.
- the salt of goserelin in the sustained-release microspheres provided by the present invention may be a water-soluble salt such as acetate.
- the goserelin sustained-release microspheres provided by the invention are prepared by the s/o/w solvent volatilization method as follows: Weighing the mixture of goserelin acetate, poloxamer or polyethylene glycol for pretreatment, forming a solid Powder mixture; PLGA is dissolved in an organic solvent to form an oil phase, and the solid powder mixture is added to the oil phase, and shear emulsified to obtain s/o colostrum. The colostrum is then added to an aqueous solution containing an emulsifier, homogenized and emulsified to obtain s/o/w double emulsion, then the organic solvent is removed, washed, and filtered to obtain microspheres.
- the organic solvent of the present invention may be ethyl acetate, chloroform or dichloromethane; preferably dichloromethane.
- the emulsifier of the present invention is a hydrophilic emulsifier, and may be Tween, polyethylene glycol octylphenyl ether (Triton), benzze (Brij), polyvinylpyrrolidone or polyvinyl alcohol, preferably poly Vinyl alcohol (PVA).
- the concentration of the emulsifier of the present invention in the aqueous solution is in the range of 0.01% to 5%, preferably 0.02% to 2%, more preferably 0.5% to 1.0%.
- the invention further provides the use of goserelin microspheres for the preparation of a medicament for treating prostate cancer, precocious puberty, endometriosis, female infertility, uterine fibroids.
- the microspheres provided by the present invention can be prepared in the form of a sterile powder containing a goserelin microsphere composition and mannitol, which can be prepared as follows: a sustained release microsphere composition, rinsed with water for injection Transfer to lyophilized tray, add mannitol and appropriate amount of water for injection, freeze-dry in a freeze dryer; freeze-dried product is sieved and mixed, aseptically packed, and rolled to obtain a sterile powder.
- Sterile powder is suspended in an acceptable dispersing vehicle, which is one of a suspending agent, a P H adjusting agent, an isotonicity adjusting agent, and a surfactant, before administration to a patient.
- the suspending agent may be one or more of sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, glycerin, the isotonic adjustment
- the agent may be one or more of sodium chloride, glucose, mannitol, sorbitol, etc.
- the surfactant is a nonionic surfactant, such as a polysorbate series (such as polysorbate 80, poly sorbate). Ester 60, etc.).
- the goserelin sustained release microspheres provided by the present invention are administered by muscle or subcutaneous injection.
- the goserelin sustained-release microspheres provided by the invention have the following advantages: 1. Adding poloxamer or polyethylene glycol The microencapsulation prepared by pretreatment with goserelin can achieve a drug encapsulation rate of more than 90%; 2. The microspheres have a high bioavailability in the body after administration, and the drug is fully exerted.
- the particle size span of the present invention refers to the Chinese Pharmacopoeia 2010 Appendix XIX E Microcapsules, Microspheres and Lipid System Guiding Principles
- D90, D50, and D10 respectively refer to the particle diameters corresponding to 90%, 50%, and 10% in the cumulative distribution map of the particle size, and the smaller the span, the narrower the particle size, that is, the uniformer the particle size.
- Figure 1 Comparison of drug release in rats with different proportions of poloxamer or polyethylene glycol plus no added goserelin microspheres
- Figure 2 Comparison of drug release in different PLGA preparations with different proportions of poloxamer or polyethylene glycol and no added goserelin microspheres
- Figure 3 Comparison of drug release in rats before and after 6 months stability of goserelin microspheres without control of acetic acid content
- Figure 4 Control of acetic acid content Goserelin microspheres 6 months stability before and after drug release in rats Comparison of specific embodiments
- the colostrum was added to 1000 ml of 0.5% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form S/O/W double emulsion.
- the organic solvent was removed by stirring and evaporation, and the mixture was washed and lyophilized to obtain a powdery microsphere.
- the microspheres had a drug loading of 9.01% and an encapsulation efficiency of 90.1%.
- the goserelin acetate and poloxamer 188 were weighed and dissolved in water to form a clear solution, and the resulting solution was spray-dried to obtain a solid powder mixture.
- the spray-dried mixture of goserelin and poloxamer 188 was accurately weighed and placed in a vial of 47 mg (measured with goserelin 23 mg).
- 1.951 g of PLGA (65/35, 0.29, 32000) was weighed and dissolved in 10 ml of dichloromethane to form an oil phase.
- the treated solid powder was added to the above oil phase and emulsified in a high shear emulsifier (6500 rpm, 3min), get S/0 colostrum.
- the colostrum was added to a 6 V 1000 ml 0.5% PVA solution at a homogenization of 1800 rpm and emulsified for 2 min to form a S/0/W double emulsion. Continue to stir and volatilize to remove the organic solvent, collect and wash, and freeze-dry to obtain powdery microspheres.
- the microspheres had a drug loading of 1.02% and an encapsulation efficiency of 90.1%.
- the colostrum was added to 1000 ml of 0.5% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion.
- the organic solvent was removed by stirring and volatilization, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 3.62% and an encapsulation efficiency of 91.4%.
- goserelin acetate measured with goserelin 72 mg was weighed, and 41 mg of poloxamer 188 was dissolved in 10 ml of water to form a clear solution; the resulting solution was lyophilized to obtain a solid powder for use.
- the colostrum was added to 1000 ml of 0.5% PVA solution at 6 ° C under homogenization of 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion.
- the organic solvent was removed by stirring and stirring, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 3.56% and an entrapment efficiency of 98.6%.
- 91 mg of goserelin acetate (measured with goserelin 79 mg) 10 mg of poloxamer 188 dissolved in 20 ml of water were weighed to form a clear solution, and the resulting solution was lyophilized to obtain a solid powder mixture.
- the colostrum was added to 1000 ml of 0.5% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion.
- the organic solvent was removed by stirring and volatilization, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 3.58% and an encapsulation efficiency of 90.2%.
- the colostrum was added to a 1000 ml 0.5% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form a S/0/W double emulsion.
- the organic solvent was removed by stirring and stirring, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 2.54% and an entrapment efficiency of 97.3%.
- the colostrum was added to 1000 ml of 0.5% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion.
- the organic solvent was removed by stirring and stirring, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 1.15% and an encapsulation efficiency of 95.8%.
- the colostrum was added to a 1000 ml 0.5% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form a S/0/W double emulsion.
- the organic solvent was removed by stirring and stirring, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 5.31% and an encapsulation efficiency of 98.0%.
- the colostrum was added to 1000 ml of 0.5% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion. Stirring was continued to remove the organic solvent, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 2.98% and an encapsulation efficiency of 76.1%.
- the colostrum was added to 1000 ml of 0.5% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion.
- the organic solvent was removed by stirring and stirring, collected and washed, and then lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 3.64% and an entrapment efficiency of 92.9 %.
- the colostrum was added to 1000 ml of 0.5% PVA solution at 6 ° C under homogenization of 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion.
- the organic solvent was removed by stirring and stirring, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 3.43% and an entrapment efficiency of 90.1%.
- the colostrum was added to 1000 ml of 0.5% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion. Stirring was continued to remove the organic solvent, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 3.59% and an encapsulation efficiency of 90.4%.
- the colostrum was added to 1000 ml of 0.5% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion.
- the organic solvent was removed by stirring and stirring, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 2.12% and an encapsulation efficiency of 52.4%.
- Test Example 1 Example, Comparative Example Encapsulation Rate Detection
- Detection method accurately weighed about 25mg of goserelin reference substance, dissolved in pure water to make a solution of about 0.02mg goserelin per 1ml, as a reference solution; weighed about 20 of Goserelin microspheres The mg was placed in a 10 ml volumetric flask, dissolved in an appropriate amount of pure acetic acid, then slowly added to the mark with pure water, and the supernatant was centrifuged for high performance liquid chromatograph analysis.
- Table 1 Test results of the encapsulation ratio of the examples and the control examples
- goserelin microspheres are prepared by pretreatment with goserelin and poloxamer or polyethylene glycol, while poloxamer or polyethylene glycol is 1% by weight of the total weight of the microspheres. Above, the encapsulation efficiency of the microspheres can reach more than 90%; the encapsulation efficiency of the goserelin microspheres without the addition of poloxamer or polyethylene glycol is about 50%.
- Test Example 2 In vivo release comparison test of different ratios of poloxamer or polyethylene glycol with no added goserelin microspheres
- Test drug Goserelin microspheres prepared according to Examples 11, 4, 5, 6, and 7 respectively contained 0.3% (w/w), 1% (w/w), 2% (w/w), 5% (w/w), 10% (w/w) poloxamer 188 of goserelin microspheres; prepared as in Example 12 2% PEG6000 goserelin microspheres; the polymers used in the samples are all PLGA (50/50, 0.14, 7200)
- Control group Goserelin microspheres containing no poloxamer or polyethylene glycol were prepared in accordance with Comparative Example 1 with a drug loading of about 2.42%.
- SD rat (Shandong Green Leaf Pharmaceutical Co., Ltd. animal house).
- the goserelin microspheres are relative to no poloxamer or poly.
- the bioavailability of goserelin microspheres of ethylene glycol is increased by more than 20%.
- the colostrum was added to 1000 ml of 1.0% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion. Stirring was continued to remove the organic solvent, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 2.76% and an encapsulation efficiency of 74.6 %.
- the colostrum was added to 1000 ml of 1.0% PVA solution at 6 ° C and emulsified for 2 min to form S/0/W double emulsion.
- the organic solvent was removed by stirring and stirring, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 3.49% and an entrapment efficiency of 90.1%.
- the colostrum was added to 1000 ml of 1.0% PVA solution at 6 ° C and homogenized at 1800 rpm for 2 min to form S/0/W double emulsion.
- the organic solvent was removed by stirring and volatilization, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 3.67% and an encapsulation efficiency of 95.7%.
- the colostrum was added to 1000 ml of 1.0% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion. Stirring was continued to remove the organic solvent, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 3.74% and an encapsulation efficiency of 99.3%.
- the colostrum was added to 1000 ml of 1.0% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion. Stirring was continued to remove the organic solvent, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 3.38% and an encapsulation efficiency of 91.2%.
- the colostrum was added to 1000 ml of 1.0% PVA solution at 6 ° C under homogenization of 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion.
- the organic solvent was removed by stirring and stirring, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 3.51% and an entrapment efficiency of 90.1%.
- the colostrum was added to 1000 ml of 1.0% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion.
- the organic solvent was removed by stirring and stirring, collected and washed, and then lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 3.57% and an entrapment efficiency of 90.7%.
- the colostrum was added to 1000 ml of 1.0% PVA solution at 6 ° C under homogenization at 1800 rpm, and emulsified for 2 min to form S/0/W double emulsion.
- the organic solvent was removed by stirring and stirring, collected, washed, and lyophilized to obtain powdery microspheres.
- the microspheres had a drug loading of 2.86% and an encapsulation efficiency of 57.1%.
- Test Example 3 In vivo release test of different proportions of poloxamer or polyethylene glycol with no added goserelin microspheres
- Test drug Goserelin microspheres prepared according to Examples 15, 16, 17, 18, 19, 20, containing 0.3% (w/w), 1% (w/w), 2% (w/w, respectively) , 3.5% (w/w), 6.0% (w/w), 10% (w/w) poloxamer 188 of goserelin microspheres; preparation of 3.5% PEG6000 containing Gosher as in Example 21 Ruilin microspheres; the polymers used in the samples are all PLGA (50/50, 0.20, 16000).
- Control group The drug-loaded preparation prepared according to Comparative Example 2 was about 2.74% of Gossere without poloxamer or polyethylene glycol. Lin microsphere.
- SD rat (Shandong Green Leaf Pharmaceutical Co., Ltd. animal house).
- the column is 10 m long and has an inner diameter of 0.32 mm.
- the inner layer is coated with a FFAP-CB fused silica capillary column of 0.33 ⁇ m.
- Inlet temperature 22CTC; Detector temperature: 250°C; Split ratio 100: 1;
- Column temperature program Starting temperature 50°C, residence time 0. 10 minutes, heating rate 30°C / minute, final temperature 230 °C, residence time 5 minutes; injection volume ⁇ ⁇ ⁇ ; theoretical plate number should be not less than 5000 according to the peak of acetic acid, the separation of acetic acid peak and internal standard peak should meet the requirements.
- Correction factor determination Take positive 16 ⁇ 1. 0ml in a 50ml volumetric flask, add 30ml of dimethylformamide to dissolve and dilute to the mark, shake well, as an internal standard solution.
- Another acetic acid reference substance is about 625mg, accurately weighed, placed in a 100ml volumetric flask, dissolved in dimethylformamide and diluted to the mark, shaken, and set aside.
- the goserelin microspheres prepared in Examples 22, 23, and 24 were taken up to about 50 mg, accurately weighed, placed in a 2 ml volumetric flask, dissolved in 1 ml of dimethylformamide, and accurately added to 100.
- ⁇ 1 internal standard solution diluted to the mark with dimethylformamide, shake well. Take ⁇ ⁇ ⁇ into the gas chromatograph and calculate according to the internal standard method.
- Test drug Goserelin microspheres prepared according to Examples 15, 16, 17, 18, 19, 20, respectively, contained 0.3% (w/w), 1% (w/w), 2% (w/w ), 3.5% (w/w), 6.0% (w/w), 10% (w/w) poloxamer 188 of goserelin microspheres; the polymers used in the samples are all PLGA (50) /50, 0.20, 16000).
- Control group The Goserelin microspheres containing no poloxamer or polyethylene glycol were prepared in accordance with Comparative Example 2 with a drug loading of about 2.74%.
- microspheres prepared by controlling the particle size of colostrum have relatively the maximum difference in the span of microspheres prepared by colostrum. 10 times, so controlling the colostrum particle size can obtain a microsphere product with a more uniform particle size.
- the encapsulation efficiency of the microsphere prepared by the invention can reach more than 90%, and the provided goserelin sustained release microspheres have high bioavailability after administration, and the drug is fully exerted and is suitable for industrial application.
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ES14785916T ES2716384T3 (es) | 2013-04-18 | 2014-04-16 | Composición farmacéutica de microesferas de liberación sostenida de goserelina |
RU2015149431A RU2694901C2 (ru) | 2013-04-18 | 2014-04-16 | Фармацевтические композиции микросфер гозерелина с пролонгированным высвобождением |
PL14785916T PL2987484T3 (pl) | 2013-04-18 | 2014-04-16 | Kompozycja farmaceutyczna mikrosfery o przedłużonym uwalnianiu gosereliny |
JP2016507993A JP6151848B2 (ja) | 2013-04-18 | 2014-04-16 | ゴセレリン徐放性マイクロスフェア医薬組成物 |
EP14785916.9A EP2987484B1 (en) | 2013-04-18 | 2014-04-16 | Goserelin sustained release microsphere pharmaceutical composition |
US14/877,976 US20160022584A1 (en) | 2013-04-18 | 2015-10-08 | Pharmaceutical compositions of goserelin sustained release microspheres |
US15/789,091 US10258572B2 (en) | 2013-04-18 | 2017-10-20 | Pharmaceutical compositions of goserelin sustained release microspheres |
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CN (1) | CN104107434B (zh) |
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GB201805191D0 (en) * | 2018-03-29 | 2018-05-16 | Camurus Ab | Compositions |
KR20200051916A (ko) * | 2018-11-05 | 2020-05-14 | 주식회사 메디포럼제약 | 고세렐린을 포함하는 실리카 하이드로겔 조성물 |
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CN101461786A (zh) * | 2009-01-08 | 2009-06-24 | 上海交通大学 | 用水包油-油包固体制备的pla/plga壳-核微球及其制备方法 |
CN101721370A (zh) * | 2008-10-10 | 2010-06-09 | 深圳清华大学研究院 | 戈舍瑞林缓释微球制剂及其制备方法、检测方法 |
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IE52535B1 (en) * | 1981-02-16 | 1987-12-09 | Ici Plc | Continuous release pharmaceutical compositions |
MY118835A (en) * | 1997-04-18 | 2005-01-31 | Ipsen Pharma Biotech | Sustained release compositions and the process for their preparation |
IE980115A1 (en) * | 1998-02-16 | 2000-02-09 | Biovail Internat Ltd | Solubilizing delivery systems and method of manufacture |
DE50108114D1 (de) * | 2000-12-13 | 2005-12-22 | Merckle Gmbh | Mikropartikel mit verbessertem freisetzungsprofil und verfahren zu deren herstellung |
US20090123556A1 (en) * | 2005-03-01 | 2009-05-14 | Sun Pharmaceutical Industries Limited | Sustained release pharmaceutical compositions |
US8293819B2 (en) | 2006-11-24 | 2012-10-23 | Canon Kabushiki Kaisha | Method for producing particles and particles |
JP5350620B2 (ja) * | 2006-11-24 | 2013-11-27 | キヤノン株式会社 | 粒子の製造方法、及び粒子 |
KR100816065B1 (ko) | 2006-11-27 | 2008-03-24 | 동국제약 주식회사 | 초기 방출억제 특성이 우수한 서방출성 마이크로캡슐의제조방법 및 이에 의해 제조되는 마이크로캡슐 |
JP5158835B2 (ja) * | 2006-12-06 | 2013-03-06 | 独立行政法人産業技術総合研究所 | 生分解性高分子リン酸カルシウム複合ナノ粒子及びその製造方法 |
GB0625322D0 (en) * | 2006-12-19 | 2007-01-24 | Pharmakodex Ltd | Pharmaceutical compositions |
EP2315571A4 (en) * | 2008-07-16 | 2013-05-01 | Surmodics Pharmaceuticals Inc | METHOD FOR PRODUCING MICROPARTICLES WITH BIOACTIVE PEPTIDES |
KR101113044B1 (ko) * | 2008-08-29 | 2012-02-27 | 동국제약 주식회사 | 용매교류증발법에 의한 서방출성 미립구의 제조방법 |
CA2742680C (en) | 2008-11-07 | 2013-12-31 | Samyang Corporation | Pharmaceutical compositions for release control of methylphenidate |
GB201110601D0 (en) * | 2011-06-23 | 2011-08-03 | Controlled Therapeutics Scotland Ltd | Improved bioresorbable |
JP6174023B2 (ja) * | 2011-07-22 | 2017-08-02 | インノコア テクノロジーズ ビー.ブイ. | 生物活性化合物の制御放出のための生物分解性、半結晶性、相分離、熱可塑性マルチブロックコポリマー |
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CN101461786A (zh) * | 2009-01-08 | 2009-06-24 | 上海交通大学 | 用水包油-油包固体制备的pla/plga壳-核微球及其制备方法 |
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"for the subcutaneous injection of Zoladex at anterior abdominal, the stype is preloaded in a disposable syringe, and the syringe needle is equivalent in size to the size 16 puncture needle which is 30mm long, therefore as compared with subcutaneous injection of common drugs, the degree of pain cause", JOURNAL OF MODERN CLINICAL MEDICAL, vol. 6, no. 7, July 2008 (2008-07-01) |
See also references of EP2987484A4 |
TAKAHIRO MORITA ET AL.: "Protein encapsulation into biodegradable microspheres by a novel S/O/V emulsion method using poly(ethylene glycol) as a protein micronization adjuvant", JOURNAL OF CONTROLLED RELEASE, 31 December 2000 (2000-12-31), pages 435 - 444, XP004221293 * |
Also Published As
Publication number | Publication date |
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EP2987484B1 (en) | 2018-12-19 |
PL2987484T3 (pl) | 2019-07-31 |
JP2016516785A (ja) | 2016-06-09 |
CN104107434B (zh) | 2017-02-01 |
ES2716384T3 (es) | 2019-06-12 |
US20180036246A1 (en) | 2018-02-08 |
US10258572B2 (en) | 2019-04-16 |
US20160022584A1 (en) | 2016-01-28 |
JP6151848B2 (ja) | 2017-06-21 |
CN104107434A (zh) | 2014-10-22 |
EP2987484A4 (en) | 2017-03-08 |
EP2987484A1 (en) | 2016-02-24 |
RU2015149431A (ru) | 2017-05-24 |
RU2694901C2 (ru) | 2019-07-18 |
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