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CN105497880A - Medicine composition sustained release micro-sphere preparation for treating osteoporosis and preparing method thereof - Google Patents

Medicine composition sustained release micro-sphere preparation for treating osteoporosis and preparing method thereof Download PDF

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Publication number
CN105497880A
CN105497880A CN201510989483.7A CN201510989483A CN105497880A CN 105497880 A CN105497880 A CN 105497880A CN 201510989483 A CN201510989483 A CN 201510989483A CN 105497880 A CN105497880 A CN 105497880A
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China
Prior art keywords
teriparatide
sustained
calcitonin
release
emulsion
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CN201510989483.7A
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Inventor
姚志勇
支钦
李新宇
曹演威
周莹
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SHENZHEN CITY JIANYUAN PHARMACEUTICAL TECHNOLOGY Co Ltd
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SHENZHEN CITY JIANYUAN PHARMACEUTICAL TECHNOLOGY Co Ltd
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Priority to CN201510989483.7A priority Critical patent/CN105497880A/en
Publication of CN105497880A publication Critical patent/CN105497880A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • 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
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K9/1605—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
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

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Abstract

The invention relates to a medicine composition sustained release micro-sphere preparation for treating osteoporosis and a preparing method thereof. The preparation is characterized in that one or more of teriparatide and bisphosphonate, or calcitonin or estrogen are wrapped by a degradable macro-molecule material carrier composed according to a certain proportion, and a sustained release micro-sphere is prepared and used for injection, so that the long-acting sustained release effect is achieved. The sustained release period of the sustained release micro-sphere injection is as long as a few days or a few months, while the number of times for drug use is reduced obviously, complementation of action mechanisms can be achieved by means of the drug combination, adverse drug reaction is reduced, and the preparation is beneficial for clinical treatment.

Description

Treat osteoporotic pharmaceutical composition sustained release microsphere agents and preparation method thereof
Technical field
The present invention relates to sustained release microsphere agents technical field, particularly relate to one and treat osteoporotic pharmaceutical composition sustained release microsphere agents and preparation method thereof.
Background technology
Osteoporosis (Osteoporosis, OP) is that a kind of bone loss of being caused by many reasons and bone mass decline, and causes bone fragility to increase, until there is the metabolic osteopathy of fracturing.Osteoporosis can be divided into constitutional and secondary sexual type, and I primary osteoporosis betides postmenopausal women, and II type primary osteoporosis sees old people.Survey data shows, and the patient existing about 8,400 ten thousand of China's osteoporosis, expect mid-21st Century and can increase to 2.2 hundred million, that causes fracture reaches 130-160 ten thousand.The risk of fractures that osteoporosis causes, has a strong impact on psychosoma and the quality of life of patient.Osteoporosis is often early stage without significant clinical symptoms, and be " quiet killer " so called, therefore early prevention and treatment have great importance.The normal medicine adopted mainly contains promotion bone mineralising class, anti-bone resorption class and strengthens bone synthesis class three major types medicine clinically at present.
The medicine strengthening bone synthesis is mainly parathyroid hormones (PTH), and teriparatide is then a kind of parathyroid hormone (rhPTH1-34) of synthesis, can increase release and the absorption of bone calcium, reduces the calcium amount promoting bone growing removed from kidney.By increasing the formation of new bone, PTH can improve the microstructure of skeleton, increases bone amount, improves bone strength, thus reduces the incidence rate that the risk that fracture occurs reduces fracture, is applicable to various types of osteoporosis.
Anti-bone resorption class drug main will comprise diphosphonic acid salt, calcitonin class and estrogens.Due to the difference of the mechanism of action of these medicines, clinically frequent by this few class Drug combination in osteoporotic treatment, to improve therapeutic effect, reduce untoward reaction and toleration.The combination dosage form occurred diphosphonates or calcitonin class and calcium preparation or vitamin D on the market at present, but with regard to teriparatide, also there is not corresponding drug combination dosage form, and there is certain complementation in teriparatide and diphosphonates, calcitonin class etc. on mechanism of action, therefore now the medicine of teriparatide and other classifications is made drug combination, be prepared into injectable sustained-release micro-spheres dosage form simultaneously, play long-acting slow-release effect.This sustained-release microspheres injection slow-release period reaches a couple of days or several months, while obviously reducing times for spraying, can also be realized the complementation on mechanism of action by drug combination, reduces adverse drug, is conducive to clinical treatment.
Summary of the invention
The object of the present invention is to provide one to treat osteoporotic pharmaceutical composition sustained-release microspheres injection and preparation method thereof, to improve therapeutic effect, reduce untoward reaction and toleration, simultaneously prolong drug action time, reduce administration number of times.Particularly, this drug regimen sustained-release microspheres injection with one or more in teriparatide and diphosphonates, calcitonin class, estrogen for principal agent, principal agent is wrapping in the degradable high polymer material carrier be made up of certain proportion, is prepared into sustained-release micro-spheres, for injection.
Described pharmaceutical composition sustained-release microspheres injection, it is characterized in that, described sustained release microsphere agents comprises the pharmaceutical composition active component accounting for microspheres weight 0.1%-30% (w/w), the molecular weight accounting for microspheres weight 60%-80% is 5,000-200, the 000 daltonian biodegradable and macromolecular material of tool biocompatibility, and account for the excipient of microspheres weight 0.1%-20%.
Described sustained-release microspheres injection, its pharmaceutical composition active component by teriparatide and have with it in synergistic diphosphonates, calcitonin or estrogen one or more form, teriparatide and diphosphonates mass mixing ratio are teriparatide: diphosphonates=(2-60 μ g): (100-15000 μ g); The mass mixing ratio of teriparatide and calcitonin class is teriparatide: calcitonin class=(2-60 μ g): (0.3-300 μ g); The mass mixing ratio of teriparatide and estrogens is teriparatide: estrogens=(2-60 μ g): (20-10000 μ g).Wherein the kind of diphosphonates is selected from Alendronate sodium, for Shandong sodium phosphate, risedronate sodium, ibandronate, Sodium Pamidronate, her sodium benzene phosphinate, Zoledronate sodium, one or more in chloromethane disodium phosphonate and etidronate, the kind of calcitonin class is selected from salmon calcitonin, clcatonin, pig calcitonin, cattle calcitonin, one or more in sheep calcitonin, the kind of estrogens is selected from estradiol, formic acid estradiol, estradiol valerate, estriol, estrone, ethinylestradiol, quinestrol, nilestriol, the female alkene in general Shandong, one or more in diethylstilbestrol.
Use in described sustained-release microspheres injection biodegradable and macromolecular material that is tool biocompatibility are selected from one in polylactide, PGA, polylactide-co-glycolide, polyalkylcyanoacrylate, pla-pcl, poly hydroxybutyric acid, poly-hydroxyl valeric acid, poly-capric acid, condensing model, Polyhydroxybutyrate-co-hydroxyvalerate, polylactic acid-polyglycol and polyglycolic acid-Polyethylene Glycol or its mixture.
Described sustained-release microspheres injection, its other adjuvants pharmaceutically acceptable are gelatin, glycerol, emulsion stabilizer, one or more in solubilizing agent and excipient, gelatin amount ranges is 0.1%-5%, glycerol amount ranges is 0.1%-5%, its emulsion stabilizer is polyvinyl alcohol, its amount ranges is 0.1%-5%, solubilizing agent is selected from dehydrated alcohol, propylene glycol one wherein or its mixture, its amount ranges is 0.1%-5%, excipient is selected from sorbitol, mannitol, lactose, sucrose one wherein or its mixture, its amount ranges is 0.1%-10%.
Described sustained-release microspheres injection, its preparation process is: by soluble in water for one or more in teriparatide and cooperative drug thereof and gelatin, glycerol, emulsion stabilizer, solubilizing agent, obtain aqueous phase; Pharmaceutically acceptable macromolecular material is dissolved in organic solvent, obtains oil phase; By described aqueous phase and oil phase mix homogeneously, form water-in-oil emulsion, described water-in-oil emulsion is added in emulsion stabilizer aqueous solution, mix homogeneously, obtain water-in-oil-in water emulsion; Described water-in-oil-in water emulsion is evaporated, removing organic solvent, centrifugal, collecting precipitation, is undertaken described precipitation washing, centrifugal, gets precipitation, add excipient, lyophilization, obtain the composition sustained-release microsphere preparation of described teriparatide and cooperative drug thereof.The organic solvent used in the process is selected from dichloromethane, ethyl acetate, ether, acetone, oxolane.The sustained-release micro-spheres mean diameter prepared by the method is 5 μm ~ 40 μm.
Detailed description of the invention
For enabling above-mentioned purpose of the present invention, feature and advantage become apparent more, are described in detail below to the specific embodiment of the present invention.Set forth a lot of detail in the following description so that fully understand the present invention.But the present invention can be much different from alternate manner described here to implement, those skilled in the art can when without prejudice to doing similar improvement when intension of the present invention, therefore the present invention is by the restriction of following public concrete enforcement.
Embodiment 1
Take 20 μ g teriparatides, 10mg fosamax, 5mg gelatin, 5mg glycerol, 10ml0.5% poly-vinyl alcohol solution, be dissolved in distilled water, obtain interior aqueous phase; Taking 400mg polylactide is dissolved in dichloromethane, obtains oil phase.First aqueous phase is moved into oil phase, be placed under room temperature on emulsion dispersion machine with the rotating speed of 30000rpm, even 30 seconds of breast, then the w/o type Emulsion of gained is transferred in polyvinyl alcohol water solution, be placed on emulsion dispersion machine with the rotating speed of 5000rpm, even 2 minutes of breast, obtain W/O/W type emulsion, with the rotating speed stirring at low speed 2.5 hours of 500rpm under room temperature, removing organic solvent, ultracentrifugation, collect thus obtained microsphere, repeatedly wash with distilled water, and then collected by centrifugation, add 45mg sorbitol, lyophilization, obtain medicinal composition for injections sustained-release micro-spheres, particle diameter 20-50 μm.Particle diameter D 50: 20-50 μm
The pharmaceutical composition sustained release microsphere agents 100mg that precision takes embodiment 1 preparation is dissolved in 1mL dichloromethane, gradation adds 30mL and 20mL purified water extraction medicine, vortex extraction 1min, the centrifugal 3min of 15000rpm, draw and merge supernatant, pipette supernatant 0.5mL and be settled to 5mL with purified water, sample introduction 20 μ l, HPLC measures content, drawing standard curve, calculate teriparatide content in the pharmaceutical composition sustained release microsphere agents of embodiment 1 preparation according to standard curve, computational envelope rate is 91.4% accordingly.Best more than 90%.
Embodiment 2
Take 40 μ g teriparatides, 1mg fosamax, 0.5mg gelatin, 0.5mg glycerol, 5ml0.5% poly-vinyl alcohol solution, be dissolved in distilled water, obtain interior aqueous phase; Taking 10mg PGA is dissolved in dichloromethane, obtains oil phase.First aqueous phase is moved into oil phase, be placed under room temperature on emulsion dispersion machine with the rotating speed of 30000rpm, even 30 seconds of breast, then the w/o type Emulsion of gained is transferred in polyvinyl alcohol water solution, be placed on emulsion dispersion machine with the rotating speed of 5000rpm, even 2 minutes of breast, obtain W/O/W type emulsion, with the rotating speed stirring at low speed 2.5 hours of 500rpm under room temperature, removing organic solvent, ultracentrifugation, collect thus obtained microsphere, repeatedly wash with distilled water, and then collected by centrifugation, add 1.5mg mannitol, lyophilization, obtain medicinal composition for injections sustained-release micro-spheres, particle diameter 10-20 μm.A scope is looked within 100 μm
The pharmaceutical composition sustained release microsphere agents 5mg that precision takes embodiment 1 preparation is dissolved in 1mL dichloromethane, gradation adds 30mL and 20mL purified water extraction medicine, the centrifugal 3min of vortex extraction 1min, 15000rpm, draws and merges supernatant, pipette supernatant 0.5mL and be settled to 5mL with purified water, sample introduction 20 μ l, HPLC measures content, drawing standard curve, calculate teriparatide content in the pharmaceutical composition sustained release microsphere agents of embodiment 1 preparation according to standard curve, computational envelope rate is 92.3% accordingly
Embodiment 3
Take 10mg teriparatide, 200000IU salmon calcitonin, 30mg gelatin, 30mg glycerol, 20ml0.5% poly-vinyl alcohol solution, be dissolved in distilled water, obtain interior aqueous phase; Taking 500mg polylactide-co-glycolide is dissolved in dichloromethane, obtains oil phase.First aqueous phase is moved into oil phase, be placed under room temperature on emulsion dispersion machine with the rotating speed of 30000rpm, even 30 seconds of breast, then the w/o type Emulsion of gained is transferred in polyvinyl alcohol water solution, be placed on emulsion dispersion machine with the rotating speed of 5000rpm, even 2 minutes of breast, obtain W/O/W type emulsion, with the rotating speed stirring at low speed 2.5 hours of 500rpm under room temperature, removing organic solvent, ultracentrifugation, collect thus obtained microsphere, repeatedly wash with distilled water, and then collected by centrifugation, add 30mg mannitol, lyophilization, obtain medicinal composition for injections sustained-release micro-spheres, particle diameter 10-30 μm.
The pharmaceutical composition sustained release microsphere agents 5mg that precision takes embodiment 1 preparation is dissolved in 1mL dichloromethane, gradation adds 30mL and 20mL purified water extraction medicine, vortex extraction 1min, the centrifugal 3min of 15000rpm, draw and merge supernatant, pipette supernatant 0.5mL and be settled to 5mL with purified water, sample introduction 20 μ l, HPLC measures content, drawing standard curve, calculate teriparatide content in the pharmaceutical composition sustained release microsphere agents of embodiment 1 preparation according to standard curve, computational envelope rate is 91.5% accordingly.
Embodiment 4
Take 50mg teriparatide, 300IU salmon calcitonin, 10mg gelatin, 10mg glycerol, 20ml0.5% poly-vinyl alcohol solution, be dissolved in distilled water, obtain interior aqueous phase; Take 100mg polylactide-co-glycolide and 100mg polylactide is dissolved in dichloromethane, obtain oil phase.First aqueous phase is moved into oil phase, be placed under room temperature on emulsion dispersion machine with the rotating speed of 30000rpm, even 30 seconds of breast, then the w/o type Emulsion of gained is transferred in polyvinyl alcohol water solution, be placed on emulsion dispersion machine with the rotating speed of 5000rpm, even 2 minutes of breast, obtain W/O/W type emulsion, with the rotating speed stirring at low speed 2.5 hours of 500rpm under room temperature, removing organic solvent, ultracentrifugation, collect thus obtained microsphere, repeatedly wash with distilled water, and then collected by centrifugation, add 10mg mannitol, lyophilization, obtain medicinal composition for injections sustained-release micro-spheres, the average 20-40 μm of particle diameter.
The pharmaceutical composition sustained release microsphere agents 10mg that precision takes embodiment 1 preparation is dissolved in 1mL dichloromethane, gradation adds 30mL and 20mL purified water extraction medicine, vortex extraction 1min, the centrifugal 3min of 15000rpm, draw and merge supernatant, pipette supernatant 0.5mL and be settled to 5mL with purified water, sample introduction 20 μ l, HPLC measures content, drawing standard curve, calculate teriparatide content in the pharmaceutical composition sustained release microsphere agents of embodiment 1 preparation according to standard curve, computational envelope rate is 90.7% accordingly.
Embodiment 5
Take 5mg teriparatide, 1000mg estriol, 160mg gelatin, 160mg glycerol, 20ml0.5% poly-vinyl alcohol solution, 20ml dehydrated alcohol, 10ml propylene glycol be dissolved in distilled water, obtain interior aqueous phase; Take 1400g polylactide-co-glycolide and 1200g PGA is dissolved in dichloromethane, obtain oil phase.First aqueous phase is moved into oil phase, be placed under room temperature on emulsion dispersion machine with the rotating speed of 30000rpm, even 30 seconds of breast, then the w/o type Emulsion of gained is transferred in polyvinyl alcohol water solution, be placed in the rotating speed of 5000rpm on emulsion dispersion machine, even 2 minutes of breast, obtains W/O/W type emulsion, with the rotating speed stirring at low speed 2.5 hours of 500rpm under room temperature, removing organic solvent, ultracentrifugation, collects thus obtained microsphere, repeatedly wash with distilled water, and then collected by centrifugation, add 200g sucrose, lyophilization, obtain medicinal composition for injections sustained-release micro-spheres, particle diameter 10-40 μm.
The pharmaceutical composition sustained release microsphere agents 100mg that precision takes embodiment 1 preparation is dissolved in 1mL dichloromethane, gradation adds 30mL and 20mL purified water extraction medicine, vortex extraction 1min, the centrifugal 3min of 15000rpm, draw and merge supernatant, pipette supernatant 0.5mL and be settled to 5mL with purified water, sample introduction 20 μ l, HPLC measures content, drawing standard curve, calculate teriparatide content in the pharmaceutical composition sustained release microsphere agents of embodiment 1 preparation according to standard curve, computational envelope rate is 92.2% accordingly.
Embodiment 6
Take 60mg teriparatide, 1000mg estradiol, 200mg gelatin, 200mg glycerol, 20ml0.5% poly-vinyl alcohol solution, 20ml dehydrated alcohol, 10ml propylene glycol be dissolved in distilled water, obtain interior aqueous phase; Take 3000g polylactide and 1000g PGA is broad in dichloromethane, obtain oil phase.First aqueous phase is moved into oil phase, be placed under room temperature on emulsion dispersion machine with the rotating speed of 30000rpm, even 30 seconds of breast, then the w/o type Emulsion of gained is transferred in polyvinyl alcohol water solution, be placed on emulsion dispersion machine with the rotating speed of 5000rpm, even 2 minutes of breast, obtain W/O/W type emulsion, with the rotating speed stirring at low speed 2.5 hours of 500rpm under room temperature, removing organic solvent, ultracentrifugation, collect thus obtained microsphere, repeatedly wash with distilled water, and then collected by centrifugation, add 250g sucrose, 250g sorbitol, lyophilization, obtain medicinal composition for injections sustained-release micro-spheres, particle diameter 20-40 μm.
The pharmaceutical composition sustained release microsphere agents 100mg that precision takes embodiment 1 preparation is dissolved in 1mL dichloromethane, gradation adds 30mL and 20mL purified water extraction medicine, vortex extraction 1min, the centrifugal 3min of 15000rpm, draw and merge supernatant, pipette supernatant 0.5mL and be settled to 5mL with purified water, sample introduction 20 μ l, HPLC measures content, drawing standard curve, calculate teriparatide content in the pharmaceutical composition sustained release microsphere agents of embodiment 1 preparation according to standard curve, computational envelope rate is 92.6% accordingly.
Embodiment 7
Investigate the tablets in vitro situation of embodiment 1-6, method is as follows:
The respectively composition sustained-release microsphere preparation of Example 1-6, every part of 50mg, is placed in the cillin bottle of 35 10mL respectively, every part of NaH adding Na2HPO4 and 0.1M containing 0.1M 2pO 4the phosphate buffer solution of pH7.4, be placed in 37 DEG C of waters bath with thermostatic control, took out at the 0th, 1,4,8,12,16,20,24,28,35,40,50 day respectively, centrifugal, again acetate dichloromethane buffer (1:1v/v) is dispersed in, chromatographic column is C1850 × 2mm, mobile phase is containing 0.1% trifluoracetic acid and containing 1% trifluoroacetic 55% acetonitrile mixed solution of 1:1, flow velocity 1.0ml/min, detect at 256nm place, measure remaining dose in microsphere, calculate accumulative releasing degree according to external standard method.In the composition sustained-release microsphere preparation of embodiment 1-6, teriparatide accumulative releasing degree is as shown in table 1 below.
Teriparatide accumulative releasing degree in the composition sustained-release microsphere preparation of table 1 embodiment 1-6
As seen from Table 1, the sustainable release of composition sustained-release microsphere preparation of embodiment 1 ~ 6 reaches 50 days, and release can reach more than 90%, has good slow release effect.Preferably provide curve chart, whether have explanation slow-release time simultaneously.
Embodiment 8
The composition sustained-release microsphere preparation of investigation prepared by embodiment 1-6 is to the therapeutic effect of model rat with osteoporosis.
Laboratory animal: SD female rats 140, about body weight 200g, uses 1% cellulose solution to add retinoic acid and is deployed into debita spissitudo, and according to the continuous gavage of 80mg/kg/d 20 days, every day carried out once, forms model rat with osteoporosis.
Experimental technique: rat model is divided into 7 groups at random, often organize 20, subcutaneous injection embodiment 1-6 composition injection, teriparatide injection (administration group dosage is converted by teriparatide human dose) respectively, continuous use 8 weeks, observes rat urine calcium, blood calcium, serium inorganic phosphorus, femoral bone mineral content.Experimental result is in table 2:
Table 4 different dosing group is on the impact of model rat with osteoporosis
Through statistics, two groups do not have significant difference on urine calcium, blood calcium, serium inorganic phosphorus content, and have significant difference on femoral bone mineral content.Composition injection group, while not affecting in rat body and urinating calcium, blood calcium and serium inorganic phosphorus metabolism, significantly can increase femoral bone mineral content, have practical significance.

Claims (10)

1. the osteoporotic pharmaceutical composition sustained-release microspheres injection for the treatment of, it is characterized in that, described sustained release microsphere agents comprises the pharmaceutical composition active component accounting for microspheres weight 0.1%-30% (w/w), the molecular weight accounting for microspheres weight 60%-80% is 5,000-200, the 000 daltonian biodegradable and macromolecular material of tool biocompatibility, and account for other adjuvants pharmaceutically acceptable of microspheres weight 0.1%-20%, its preparation method is emulsion-liquid drying method.
2. sustained-release microspheres injection according to claim 1, its pharmaceutical composition active component by teriparatide and have with it in synergistic diphosphonates, calcitonin or estrogen one or more form, teriparatide and diphosphonates mass mixing ratio are teriparatide: diphosphonates=(2-60ug): (100-15000ug); The mass mixing ratio of teriparatide and calcitonin class is teriparatide: calcitonin class=(2-60 μ g): (0.3-300IU); The mass mixing ratio of teriparatide and estrogens is teriparatide: estrogens=(2-60 μ g): (20-10000 μ g).
3. diphosphonates according to claim 2, its kind is selected from Alendronate sodium, for one or more in Shandong sodium phosphate, risedronate sodium, ibandronate, Sodium Pamidronate, she sodium benzene phosphinate, Zoledronate sodium, chloromethane disodium phosphonate and etidronate.
4. calcitonin class according to claim 2, its kind be selected from salmon calcitonin, clcatonin, pig calcitonin, cattle calcitonin, sheep calcitonin one or more.
5. estrogens according to claim 2, its kind be selected from estradiol, formic acid estradiol, estradiol valerate, estriol, estrone, ethinylestradiol, quinestrol, nilestriol, the female alkene in general Shandong, diethylstilbestrol one or more.
6. sustained-release microspheres injection according to claim 1, its macromolecular material that is biodegradable and tool biocompatibility is selected from one in polylactide, PGA, polylactide-co-glycolide, polyalkylcyanoacrylate, pla-pcl, poly hydroxybutyric acid, poly-hydroxyl valeric acid, poly-capric acid, condensing model, Polyhydroxybutyrate-co-hydroxyvalerate, polylactic acid-polyglycol and polyglycolic acid-Polyethylene Glycol or its mixture.
7. sustained release microsphere agents according to claim 1, is characterized in that, the mean diameter of described sustained-release micro-spheres is 5 μm-40 μm.
8. sustained-release microspheres injection according to claim 1, its other adjuvants pharmaceutically acceptable are gelatin, glycerol, emulsion stabilizer, one or more in solubilizing agent and excipient, gelatin amount ranges is 0.1%-5%, glycerol amount ranges is 0.1%-5%, its emulsion stabilizer is polyvinyl alcohol, its amount ranges is 0.1%-5%, solubilizing agent is selected from dehydrated alcohol, propylene glycol one wherein or its mixture, its amount ranges is 0.1%-5%, excipient is selected from sorbitol, mannitol, lactose, sucrose one wherein or its mixture, its amount ranges is 0.1%-10%.
9. sustained-release microspheres injection according to claim 1, its preparation process is:
By soluble in water for one or more in teriparatide and cooperative drug thereof and gelatin, glycerol, emulsion stabilizer, solubilizing agent, obtain aqueous phase; Pharmaceutically acceptable macromolecular material is dissolved in organic solvent, obtains oil phase;
By described aqueous phase and oil phase mix homogeneously, form water-in-oil emulsion, described water-in-oil emulsion is added in emulsion stabilizer aqueous solution, mix homogeneously, obtain water-in-oil-in water emulsion;
Described water-in-oil-in water emulsion is evaporated, removing organic solvent, centrifugal, collecting precipitation, is undertaken described precipitation washing, centrifugal, gets precipitation, add excipient, lyophilization, obtain the composition sustained-release microsphere preparation of described teriparatide and cooperative drug thereof.
10. sustained release microsphere agents preparation method according to claim 9, is characterized in that: its organic solvent is selected from dichloromethane, ethyl acetate, ether, acetone, oxolane.
CN201510989483.7A 2015-12-26 2015-12-26 Medicine composition sustained release micro-sphere preparation for treating osteoporosis and preparing method thereof Pending CN105497880A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112999364A (en) * 2021-03-15 2021-06-22 武汉理工大学 Preparation method of hollow mesoporous silica dual-drug sustained-release microspheres for treating osteoporosis
CN113925844A (en) * 2021-11-26 2022-01-14 郑州市中心医院 A kind of alendronate sodium preparation and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1739795A (en) * 2005-08-31 2006-03-01 上海交通大学 Preparation method of parathyroid hormone sustained-release microspheres
CN105169394A (en) * 2015-10-28 2015-12-23 深圳市健元医药科技有限公司 Medicine composite for treating osteoporosis and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1739795A (en) * 2005-08-31 2006-03-01 上海交通大学 Preparation method of parathyroid hormone sustained-release microspheres
CN105169394A (en) * 2015-10-28 2015-12-23 深圳市健元医药科技有限公司 Medicine composite for treating osteoporosis and preparation method thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112999364A (en) * 2021-03-15 2021-06-22 武汉理工大学 Preparation method of hollow mesoporous silica dual-drug sustained-release microspheres for treating osteoporosis
CN112999364B (en) * 2021-03-15 2022-06-17 武汉理工大学 Preparation method of hollow mesoporous silica double-drug sustained-release microspheres for osteoporosis treatment
CN113925844A (en) * 2021-11-26 2022-01-14 郑州市中心医院 A kind of alendronate sodium preparation and preparation method thereof

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