CN1555886A - Brilliant bingruilin acetate solid lipid nano particle oral preparation and its preparation method - Google Patents
Brilliant bingruilin acetate solid lipid nano particle oral preparation and its preparation method Download PDFInfo
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- CN1555886A CN1555886A CNA2004100138465A CN200410013846A CN1555886A CN 1555886 A CN1555886 A CN 1555886A CN A2004100138465 A CNA2004100138465 A CN A2004100138465A CN 200410013846 A CN200410013846 A CN 200410013846A CN 1555886 A CN1555886 A CN 1555886A
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Abstract
An orally applied lipid nanoparticle diameter 20nm-1 microns of leuprorelin acetate in the form of freeze dried powder is prepared from leuprorelin acetate, fatty acid, phosphatide, phosphate buffer liquid containing hydrophilic surfactant and freeze drying protector. Its advantages are durable slow releasing and high biologic utilization rate.
Description
Technical field
The invention belongs to solid lipid nanoparticle oral formulations of polypeptide compounds and preparation method thereof, especially solid lipid nano-particle preparation of gonadotropin releasing hormone analogues leuprorelin acetate and preparation method thereof.
Background technology
Synthetic gonadotropin releasing hormone (GnRH) analog is the GnRH antagonist, belong to polypeptide drug, its absorb feature be the half-life short, plasma clearance is high, molecular weight is big, destruction, the non-injection administration bioavailability of permeable membrane ability, easy receptor endoenzyme and antibacterial and body fluid are low, generally all only be a few percent, be lower than 3% as the bioavailability of the oral leuprorelin acetate of Canis familiaris L..Leuprorelin acetate is the GnRH analog, short-term interaction energy stimulate gonadal hormone secretion, thereby improve the concentration of testosterone and dihydrotestosterone in the blood.After one week of medication, the receptor decreased number, gonadotrophin secretion reduces.After medication 2-4 week, the concentration of testosterone and dihydrotestosterone is reduced to the castration level.This product is applicable to the prostate patient who can not or be reluctant to do male castration, and is also effective in cure to breast carcinoma.Behind leuprorelin acetate orally give rat and the people, owing to the degraded that subjects to enzyme such as chymase in the small intestinal and to reasons such as biomembranous permeability differences, blood drug level is lower than 0.2ng/ml mostly, and is oral invalid.
At present, it is still less to study its oral administered dosage form.Though when the oral formulations of preparation leuprorelin acetate, use the activity that protease inhibitor, cholate, chelating agent etc. can inhibitory enzymes, the absorption of using penetration enhancer can improve medicine.But the prolonged application of protease inhibitor may cause the especially disorder of digestive function of gastrointestinal tract normal physiological, and there are much relations in the short suction effect of micromolecule penetration enhancer and small intestinal biochemistry and tissue injury.
Solid lipid nanoparticle is different with the liposome bilayer structure that with phospholipid is main component, solid lipid nanoparticle is the solid particle that is formed by multiple lipid materials such as fatty acid, aliphatic alcohol, fatty acid ester and phospholipid etc., the parcel that mainly is suitable for insoluble drug is as intravenous injection or topical.Solid lipid nanoparticle is less as the research of water soluble polypeptide and protein carrier, and envelop rate is low.
Summary of the invention
The technical problem to be solved in the present invention is to study the oral administration carrier of solid lipid nanoparticle as water soluble polypeptide class macromolecular drug.At the chemical constitution and the physicochemical property of water soluble polypeptide leuprorelin acetate, screen suitable lipid materials and solvent system, working in coordination with and proportioning between the research lipid materials further increases the envelop rate of water soluble drug.Finally make medicine can continue slow release, improve blood drug level, prolong circulation time in blood, significantly improved the oral organism-absorbing availability of leuprorelin acetate.The technical problem to be solved in the present invention also relates to the preparation method of water soluble polypeptide leuprorelin acetate solid lipid nanoparticle, comprises its lyophilized formulations.
For addressing the above problem, the invention provides following technical scheme.
A kind of solid lipid nanoparticle of leuprorelin acetate comprises by weight: 1 part of leuprorelin acetate, fatty acid 1-100 part, phosphatidase 12-100 part, the phosphate buffer of pH3-6.9 that contains the 0.1%-5% hydrophilic surfactant active is an amount of.
When hydrophilic surfactant actives such as Pu Lang stream Buddhist nun, Tween 80, Brij, Myrij are dissolved in the buffer of pH value scope at 3-6.9, guarantee that a part leuprorelin acetate carries one or two unit positive charge, helps drug encapsulation.
The present invention can use phospholipid commonly used, comprises soybean lecithin, Ovum Gallus domesticus Flavus lecithin or synthetic phospholipid.The content of phosphatidylcholine can be between 76%-100% in the phospholipid, preferred purity＞93%.
Described solid lipid nanoparticle can be: 1 part of leuprorelin acetate, fatty acid 10-80 part, phosphatidase 11 0-80 part, the pH4.5-6.0 phosphate buffer that contains the 1%-3% hydrophilic surfactant active are an amount of, and acetone and/or chloroform are an amount of.
Described solid lipid nanoparticle proportioning preferably is: 1 part of leuprorelin acetate, fatty acid 20-60 part, phosphatidase 12 0-70 part; Fatty acid is selected from one or more in stearic acid, myristic acid, Palmic acid, the arachidic acid; Phospholipid is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, the synthetic phospholipid; The hydrophilic surfactant active is selected from one or more in Pu Lang stream Buddhist nun, Tween 80, Brij, the Myrij; Acetone and chloroform ratio are 1-9: 9-1.
The even more ideal proportioning of described solid lipid nanoparticle is: 1 part of leuprorelin acetate, fatty acid 25-50 part, phosphatidase 13 0-60 part; Phosphate buffer pH5.0-5.6; Acetone and chloroform ratio are 8-5: 2-3; Fatty acid is selected from stearic acid; Phospholipid is selected from soybean lecithin, palmitoylphosphatidyl choline; The hydrophilic surfactant active is selected from Pu Lang stream Buddhist nun and/or Tween 80.
The best proportioning of solid lipid nanoparticle of the present invention is: 1 part of leuprorelin acetate, fatty acid 20-40 part, phosphatidase 12 0-40 part.
The preparation method of aforementioned solid lipid nanoparticle comprises the steps:
Will be by weight 1 part of leuprorelin acetate, fatty acid 1-100 part, phosphatidase 12-100 part, be heated to 70-85 ℃ and form oil phase; The 1%-5% hydrophilic surfactant active is dissolved in 70-85 ℃ the phosphate buffer of pH3-6.9 and forms water, after under agitation oil phase being added to aqueous phase formation colostrum, can adopt the even or sedimentary method of emulsifying of high pressure breast, cooling back forms the solid lipid nanoparticle of leuprorelin acetate, lyophilization or preserve under 3-5 ℃ of condition.In the described preparation method, can be with the acetone and/or the chloroformic solution of dissolved fat acid 1-100 part and phosphatidase 12-100 part, add the water liquid that contains 1 part of leuprorelin acetate, form colostrum, again colostrum is added in the pH3-6.9 phosphate buffer that contains the 1%-5% surfactant, emulsifying under the 3-5 ℃ of condition must contain the solid lipid nanoparticle of leuprorelin acetate, preserves under lyophilization or the 3-5 ℃ condition.
The lyophilized powder of aforementioned solid lipid nanoparticle is made up of solid lipid nanoparticle and lyophilized preparation dextran, monosaccharide, disaccharidase and/or the polysaccharide of leuprorelin acetate basically; The amount of lyophilized preparation is by the gross weight of fatty acid and phospholipid, and 1 part of gross weight adds the lyophilized preparation of 0.05-4.0 part; Weight proportion is preferably, and 1 part of gross weight adds the mannitol and/or the glucose of 0.2-1.0 part.
The preparation method of the lyophilized powder of described solid lipid nanoparticle is got solid lipid nanoparticle and lyophilized preparation dextran, monosaccharide, disaccharidase and/or the polysaccharide of leuprorelin acetate; The amount of lyophilized preparation is by the gross weight of fatty acid and phospholipid, and 1 part of gross weight adds the lyophilized preparation of 0.05-4.0 part, after the dissolving, and lyophilization.
A kind of preparation method of leuprorelin acetate solid lipid nanoparticle, through following step preparation, with 1 part of leuprorelin, stearic acid 1-100 part and phosphatidase 15-100 part, be heated to 80 ℃ and form oil phase, water soluble surfactant active (1%-5%) is dissolved in 80 ℃ of buffer (pH3-6.9), under agitation oil phase is added to aqueous phase, form colostrum.Disperse with methods such as high pressure breast are even then.The cooling back forms the sodium stearate grain of rice.Lyophilization or under 4 ℃ of conditions, preserve.The preparation method of leuprorelin solid lipid nanoparticle is preferably, 1 part of leuprorelin, stearic acid 10-30 part and phospholipid (5-40 part) are heated to 80 ℃ form oil phase, water soluble surfactant active (1%-2%) is dissolved in 80 ℃ of phosphate buffers (pH4-6.9), under agitation oil phase is added to aqueous phase, form colostrum.Disperse with methods such as high pressure breast are even then.The cooling back forms the sodium stearate grain of rice.Lyophilization or under 4 ℃ of conditions, preserve.
Because leuprorelin acetate is an alkalescent medicine, the present invention selects fatty acid, but not aliphatic alcohol or fatty acid ester (for example Glyceryl Behenate) as the framework material of nanoparticle, form ion pair by leuprorelin acetate and fatty acid and improve its envelop rate.The pH value of the phosphate buffer that the present invention adopts is lower than 7, guarantees that leuprorelin acetate carries one or two unit positive charge, helps forming ion pair.In prescription, add a large amount of phospholipid, improve the strong hydrophobicity of nanoparticle, further increase sealing of water soluble drug.By the sterically hindered enzymolysis that reduces medicine of nanoparticle, utilize the lipotropy of nanoparticle and small particle diameter increases medicine by lymph circulation absorption.Medicine in the nanoparticle continues slowly to discharge, and improves blood drug level, prolongs circulation time in blood, thereby improved the oral organism-absorbing availability of leuprorelin acetate.
The lyophilized powder of described leuprorelin acetate solid lipid nanoparticle is characterized in that envelop rate is 70%-90%, improves because advantage of the present invention is exactly an envelop rate, and particle diameter is 20nm-1 μ m.Medicine in the nanoparticle continues slowly to discharge, and improves blood drug level, prolongs circulation time in blood, thereby improve leuprorelin acetate oral organism-absorbing availability.
After leuprorelin acetate solid lipid nanoparticle of the present invention is given the rat oral gavage administration, compare with the subcutaneous injection leuprorelin, relative bioavailability is 12.47 ± 1.75%, demonstrate steadily and the blood drug level of slow release through the time change, average residence time is 2.71 ± 0.05h.Give the leuprorelin solution if irritate stomach, then relative bioavailability has only 0.85 ± 0.59%.
But the present invention has also solved the preparation method of the suitability for industrialized production of described leuprorelin acetate solid lipid nanoparticle and lyophilized powder thereof.
Description of drawings
Fig. 1, leuprorelin solid lipid nanoparticle and leuprorelin solution irritate behind the stomach with normal injection agent rat skin lower injection through the time curve (n=3)
The specific embodiment
With leuprorelin acetate 10mg, stearic acid 100mg and soybean lecithin 100mg are heated to 80 ℃ and form oil phase, water soluble surfactant active Tween 80 (1%) is dissolved in formation water in 80 ℃ of isotonic phosphate buffer liquid (pH5.0), under agitation oil phase is added to aqueous phase, form colostrum.Disperse with methods such as high pressure breast are even then.The cooling back forms the sodium stearate grain of rice.Add mannitol (3%), the dissolving postlyophilization.With cryodesiccated solid lipid nanoparticle 40 ℃ store 3 months after, leuprorelin acetate content is 95.5%, and to add the nanoparticle envelop rate that the entry reorganization obtains be 76%, particle diameter is 250nm.
Leuprorelin acetate 5mg is dissolved in the aqueous solution (0.5ml), Palmic acid 100mg and Ovum Gallus domesticus Flavus lecithin 150mg are dissolved in the mixed solvent 10ml of acetone and chloroform (9: 1), the leuprorelin acetate aqueous solution added in the acetone contain stearic acid, phospholipid and the chloroform mixed solvent form colostrum, drop to the phosphate buffer (pH5.6 that contains general sieve stream Buddhist nun 188 (2%) again, 40ml), emulsifying 0.5h under 4 ℃ of conditions continues to stir 4h promptly.Add glucose (6%), the dissolving postlyophilization.At room temperature storage after 1 year, leuprorelin acetate content is 99.5% with cryodesiccated solid lipid nanoparticle, and to add the nanoparticle envelop rate that the entry reorganization obtains be 82%, and particle diameter is 160nm.
Embodiment 3
With leuprorelin acetate 5mg, stearic acid 100mg and palmitoylphosphatidyl choline 50mg are heated to 80 ℃ and form oil phase, water soluble surfactant active's Myrij (1.6%) is dissolved in formation water in 80 ℃ of phosphate buffers (pH6.0), under agitation oil phase is added to aqueous phase, form colostrum.Disperse with methods such as high pressure breast are even then.The cooling back forms sodium stearate grain of rice suspension.Preserve half a year for 4 ℃, the nanoparticle envelop rate is 73%, and particle diameter is 340nm.
Leuprorelin acetate solid lipid nanoparticle rat body giving drugs into nose is for the examination of kinetic property:
A. administration with get the blood scheme:
15 rat overnight fastings are divided into 3 groups, and 5 every group, one group of subcutaneous injection leuprorelin acetate solution (113 μ g/kg) is as positive control; Irritate stomach for one group and give leuprorelin acetate solution (1.5mg/kg) as negative control; Irritate stomach for one group and give the sodium stearate grain of rice (1.5mg/kg).In different time 0,0.5, the eyeground vein clump was got blood 0.5ml in 1,1.5,2,4,6,8,12,24 hours, centrifuging and taking serum, and the application of radiation immunization is surveyed serum-concentration.
B. through the time curve, referring to Fig. 1.
After leuprorelin acetate solid lipid nanoparticle of the present invention is given the rat oral gavage administration, in 0.5 hour, arrive blood drug level peak value 4.32 ± 0.66ng/ml, blood drug level is reduced to 2.77 ± 1.11ng/ml behind the 1hr, but keeping this blood drug level just descends to 4hr, demonstrate steadily and the blood drug level of slow release through the time change, average residence time is 2.71 ± 0.05h.Compare with the subcutaneous injection leuprorelin acetate, relative bioavailability is 12.47 ± 1.75%.Give the leuprorelin acetate solution and irritate stomach, relative bioavailability has only 0.85 ± 0.59%.
Claims (10)
1, a kind of solid lipid nanoparticle of leuprorelin acetate comprises by weight: 1 part of leuprorelin acetate, fatty acid 1-100 part, phosphatidase 12-100 part, the phosphate buffer of pH3-6.9 that contains the 0.1%-5% hydrophilic surfactant active is an amount of.
2, the described solid lipid nanoparticle of claim 1, it is characterized in that: 1 part of leuprorelin acetate, fatty acid 10-80 part, phosphatidase 11 0-80 part, the pH4.5-6.0 phosphate buffer that contains the 1%-3% hydrophilic surfactant active are an amount of, and acetone and/or chloroform are an amount of.
3, the described solid lipid nanoparticle of claim 2 is characterized in that: 1 part of leuprorelin acetate, fatty acid 20-60 part, phosphatidase 12 0-70 part; Fatty acid is selected from one or more in stearic acid, myristic acid, Palmic acid, the arachidic acid; Phospholipid is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, the synthetic phospholipid; The hydrophilic surfactant active is selected from one or more in Pu Lang stream Buddhist nun, Tween 80, Brij, the Myrij; Acetone and chloroform ratio are 1-9: 9-1.
4, the described solid lipid nanoparticle of claim 3 is characterized in that: 1 part of leuprorelin acetate, fatty acid 25-50 part, phosphatidase 13 0-60 part; Phosphate buffer pH5.0-5.6; Acetone and chloroform ratio are 8-5: 2-3; Fatty acid is selected from stearic acid; Phospholipid is selected from soybean lecithin, Ovum Gallus domesticus Flavus lecithin, palmitoylphosphatidyl choline; The hydrophilic surfactant active is selected from Pu Lang stream Buddhist nun and/or Tween 80 and/or Myrij.
5, the described solid lipid nanoparticle of claim 4 is characterized in that: 1 part of leuprorelin acetate, fatty acid 20-40 part, phosphatidase 12 0-40 part.
6, the preparation method of the described solid lipid nanoparticle of one of claim 1-5 is characterized in that comprising the steps:
Will be by weight 1 part of leuprorelin acetate, fatty acid 1-100 part, phosphatidase 12-100 part, be heated to 70-85 ℃ and form oil phase; The 1%-5% hydrophilic surfactant active is dissolved in 70-85 ℃ the phosphate buffer of pH3-6.9 and forms water, after under agitation oil phase being added to aqueous phase formation colostrum, even or the emulsifying precipitation of high pressure breast, cooling back forms the solid lipid nanoparticle of leuprorelin acetate, lyophilization or preserve under 3-5 ℃ of condition.
7, the preparation method of the described solid lipid nanoparticle of one of claim 1-5, it is characterized in that: with the acetone and/or the chloroformic solution of dissolved fat acid 1-100 part and phosphatidase 12-100 part, add the water liquid that contains 1 part of leuprorelin acetate, form colostrum, again colostrum is added in the pH3-6.9 phosphate buffer that contains the 1%-5% surfactant, emulsifying under the 3-5 ℃ of condition must contain the solid lipid nanoparticle of leuprorelin acetate, preserves under lyophilization or the 3-5 ℃ condition.
8, the lyophilized powder of the described solid lipid nanoparticle of one of claim 1-5 is characterized in that: be made up of solid lipid nanoparticle and lyophilized preparation dextran, monosaccharide, disaccharidase and/or the polysaccharide of leuprorelin acetate substantially; The amount of lyophilized preparation is by the gross weight of fatty acid and phospholipid, and 1 part of gross weight adds the lyophilized preparation of 0.05-4.0 part.
9, the lyophilized powder of the described leuprorelin acetate solid lipid nanoparticle of claim 8 is characterized in that: the amount of lyophilized preparation is by the gross weight of fatty acid and phospholipid, and 1 part of gross weight adds the mannitol and/or the glucose of 0.2-1.0 part.
10, the preparation method of the lyophilized powder of the described solid lipid nanoparticle of claim 9 is got solid lipid nanoparticle and lyophilized preparation dextran, monosaccharide, disaccharidase and/or the polysaccharide of leuprorelin acetate; The amount of lyophilized preparation is by the gross weight of fatty acid and phospholipid, and 1 part of gross weight adds the lyophilized preparation of 0.05-4.0 part, after the dissolving, and lyophilization.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100367953C (en) * | 2006-03-06 | 2008-02-13 | 山东大学 | Quercetin solid liposome nano particle preparation and its preparing method |
| CN100529757C (en) * | 2004-12-28 | 2009-08-19 | 中国人民解放军军事医学科学院毒物药物研究所 | Method for measuring leuprorelin acetate in minute quantities and application |
| CN101199481B (en) * | 2007-10-17 | 2010-06-02 | 浙江工业大学 | Process for preparing solid lipide nano particle |
| CN116270492A (en) * | 2023-03-30 | 2023-06-23 | 北京博恩特药业有限公司 | Leuprolide acetate sustained-release microsphere for injection and preparation method and application thereof |
-
2004
- 2004-01-08 CN CNA2004100138465A patent/CN1555886A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100529757C (en) * | 2004-12-28 | 2009-08-19 | 中国人民解放军军事医学科学院毒物药物研究所 | Method for measuring leuprorelin acetate in minute quantities and application |
| CN100367953C (en) * | 2006-03-06 | 2008-02-13 | 山东大学 | Quercetin solid liposome nano particle preparation and its preparing method |
| CN101199481B (en) * | 2007-10-17 | 2010-06-02 | 浙江工业大学 | Process for preparing solid lipide nano particle |
| CN116270492A (en) * | 2023-03-30 | 2023-06-23 | 北京博恩特药业有限公司 | Leuprolide acetate sustained-release microsphere for injection and preparation method and application thereof |
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