CN1233413C - Nano particle feeding system for oral use - Google Patents
Nano particle feeding system for oral use Download PDFInfo
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- CN1233413C CN1233413C CN 02153918 CN02153918A CN1233413C CN 1233413 C CN1233413 C CN 1233413C CN 02153918 CN02153918 CN 02153918 CN 02153918 A CN02153918 A CN 02153918A CN 1233413 C CN1233413 C CN 1233413C
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- 239000002105 nanoparticle Substances 0.000 title claims abstract description 48
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims abstract description 67
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- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 1
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- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
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- LUJQXGBDWAGQHS-UHFFFAOYSA-N ethenyl acetate;phthalic acid Chemical compound CC(=O)OC=C.OC(=O)C1=CC=CC=C1C(O)=O LUJQXGBDWAGQHS-UHFFFAOYSA-N 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a medicinal formulation and a technology for preparing the same, particularly to an oral enteric soluble nanoparticle administration system. Enteric soluble nanoparticles of cyclosporin A are obtained by a nanotechnology, and highly dispersed characteristic of the nanoparticles can be utilized to increase the contact with an intestinal absorption part; the cyclosporin A is simultaneously dispersed in the skeleton of an enteric soluble material, and highly dispersed cyclosporin A molecules are released when the enteric soluble material is dissolved in the intestinal canal.
Description
Technical field:
The present invention relates to a kind of pharmaceutical dosage form and preparation technique, particularly relate to the oral enteric solubility nanoparticle drug-supplying system of a kind of confession.
Background technology:
Ciclosporin A (English name: Cyclosporine A, write a Chinese character in simplified form: CyA) be a kind of novel efficient immunosuppressant, contain 11 amino acid whose ring type polypeptides.It is the metabolite of fungus, at first succeeds in developing by the Sandoz Pharma Ltd., and nineteen eighty-three, check and approve through U.S. food and drug administration (FDA), CyA is used as the immunosuppressant of kidney, liver and heart transplantation.
CyA just is used to bone marrow transplantation at late nineteen seventies, makes the aplastic anemia of 60-80% and the leukaemic of 10-70% become for a long time (＞3 ~ 5 years) asymptomatic survivor.Be extensive use of CyA in the worldwide now and carry out the renal transplantation operation.The use of CyA makes the survival rate after the renal transplantation bring up to more than 90% from 50%.Renal transplantation has become the better selection of treatment end-stage renal disease, is considered to than dialysis treatment on effect and more superior economically.The use of CyA makes 5 annual survival rates of heart transplantation surpass 75%, and 90% heart transplantation patient can recover general work.Only there was the heart transplantation less than 100 examples in the preceding whole world in 1980, till 1987, had successfully carried out 2000 many cases heart transplant operations in the world.Because the appearance of CyA, in 20 years, liver transplantation also obtains a very large progress in the past, and it is 60% that transplanting back patient's 1 annual survival rate reaches 70%, 5 annual survival rate.Except that above-mentioned organ transplantation, the human body that is implanted in of lung, pancreas, intestinal etc. is also succeedd.Therefore, the exploitation of CyA with use the new era started organ transplantation.
But CyA is owing to reasons such as solubility property (water insoluble, as also to be insoluble to oil), and bioavailability is quite low, and influenced factor is many, and the individual variation of pharmacokinetic parameter is very big.As peak time is 1-8hr, and absorption rate is 0.6-4.7hr-1, and bioavailability is 5-50%, most below 30%.
The preparation of CyA has venoclysis and oral administration two series products.Because CyA needs long term administration,, only before operation, use and drug administration by injection is general so oral formulations is used a lot.
Former Sandoz LTD (Sandoz now integrates with Novartis company) has some preparation patents of CyA.The first generation product of former Sandoz LTD is cyclosporin A oral liquid (Sandimmun, a trade name).Its typical case's prescription is 100mg CyA, 300mg Labrafil M 1944CS (a kind of surfactant), 100mg dehydrated alcohol, 425mg olive oil.Owing to contain surfactant and oil phase in this preparation, therefore meet the just automatic emulsified formation Emulsion of energy of water or gastro-intestinal Fluid, the self-emulsified drug delivery system so this drug-supplying system is otherwise known as (Self-Emulsified Drug Delivery System, SEDDS).The cyclosporin A oral liquid can form the conventional Emulsion that mean diameter is 1 μ m after meeting the water self emulsifying.
Norsantonin scholar company has released a kind of new regeneration product sandimmun neoral (Sandimmun Neoral) again through research on the basis of CyA self-emulsified drug delivery system (cyclosporin A).Typical case's prescription of sandimmun neoral is 100mg CyA, 200mg 1, the Semen Maydis oil of 2-propylene glycol, 320mg refined glycerine-transesterification and 380mg Cremophor RH40 (surfactant).The automatic emulsified formation mean diameter of sandimmun neoral chance water energy is the Emulsion about 30nm.The emulsion droplet of this Emulsion is so little, can make: 1) absorption of CyA obviously increases, and the average bioavailability of sandimmun neoral is high by 29% than cyclosporin A, nearly doubles, and therefore can reduce dosage with sandimmun neoral, reduces cost; 2) absorption of CyA is rapider.Shift to an earlier date 1hr during the average out to peak; 3) the CyA nano-emulsion can make its body giving drugs into nose improve for dynamic stability, and the individual variation between the patient diminishes, and influenced by the gastrointestinal tract physiological status and diminishes.Sandimmun neoral has become the leading products in present market.
Nanosecond science and technology are the novel high-tech that grow up the eighties, current one of the important scientific and technological forward position gazed in the whole world that become.Nanosecond science and technology the application of biological medicine be one crucial aspect.The possible application of nanotechnology just comprises the gastrointestinal absorption that increases insoluble drug.
The mechanism that nanoparticle improves the absorption of medicine gastrointestinal may comprise the following aspects: 1) nanoparticle can enter blood circulation by peyer ' the s knot of small intestinal, and the nano-carrier that particle diameter is little also can pass mesenteric mesaraic iuntercellular path and enter circulation; 2) because the dispersibility of nanoparticle height and huge surface area, can increase the dissolubility and the dissolution rate of insoluble drug, also can increase and the contacting of gastrointestinal tract wall, thereby increase the chance that absorbs, improve the bioavailability of insoluble drug; 3) nanoparticle more can be caught by duodenal microtriche than solution, and is detained the long period, further prolong drug and cell wall time of contact, the absorption rate and the absorbance of raising medicine; 4) nano-carrier can be protected some labile drug, makes it not by enzyme or acid-base catalysis degraded.
Nanotechnology is applied to ciclosporin A makes enteric coated preparation, solve the low problem of its bioavailability, do not have bibliographical information at present.
Summary of the invention:
The invention provides a kind of CyA new oral drug-supplying system of applying nano technology preparation.
The present invention can utilize the characteristic of nanoparticle high degree of dispersion by the enteric solubility nanoparticle of nanotechnology acquisition ciclosporin A, and increase contacts with the intestinal absorption position; Simultaneously, ciclosporin A is dispersed in the skeleton of enteric material,, discharges the ciclosporin A molecule of high degree of dispersion when enteric material dissolved while in intestinal.
Drug-supplying system of the present invention is made by therapeutic ingredient ciclosporin A and synthetic enteric material.
The said synthetic enteric material of the present invention comprises cellulose acetate phthalate ester (celluloseacetate phthalate, CAP), hypromellose phthalate ester (hydroxypropylmethylcellulose phthalate, HPMCP), cellulose acetate succinate (hydroxypropylmethylcellulose acetate succinate, HPMCAS), enteric solubility acrylic resin (acrylicacid resin), polyvinyl acetate phthalic acid ester (polyvinyl acetate phthalate, PVAP), trimellitic acid cellulose acetate (cdllulose acetate trimellitate, the combination of CAT) one or more.
In the drug-supplying system of the present invention, the ratio of ciclosporin A and synthetic enteric material is 1: 1-50.
Drug-supplying system of the present invention prepares by the solvent-nonsolvent method.
The preparation of drug-supplying system of the present invention need be used organic solvent, and organic solvent comprises one or more combination of ethanol, acetone, benzyl alcohol.
The preparation of drug-supplying system of the present invention need be used stabilizing agent.Stabilizing agent comprises one or more the combination of F68, PVA.
When preparation drug-supplying system of the present invention, ciclosporin A, organic solvent and water three's ratio is 1: 0.5-10: 1-50 (mg/ml/ml).
The oral enteric solubility nanoparticle of said confession can be dispersed in aqueous solution or the gel solution; Or be dispersed in the pressed powder of pharmaceutic adjuvant.
The oral enteric solubility nanoparticle drug-supplying system of confession of the present invention can prepare in the following manner:
Get the beaker of suitable size, add the distilled water of recipe quantity, the surfactant of getting recipe quantity is dissolved in the distilled water, constitutes water; The beaker that fills water can be placed on the ice bath.
Take by weighing the CyA and the enteric material of recipe quantity, be dissolved in the organic solvent of recipe quantity, constitute organic facies.
Organic facies by the suitable syringe needle of pore size, is injected the aqueous phase that is stirring rapidly.After injection finishes, continue to stir appropriate time; Remove organic solvent by suitable mode then, and be concentrated into the volume of regulation, promptly get the colloid solution of CyA enteric solubility nanoparticle with suitable mode.
Can in the colloid solution of above-mentioned CyA enteric solubility nanoparticle, add suitable thickening agent, gel or stabilizing agent etc.; Also can in the colloid solution of above-mentioned CyA enteric solubility nanoparticle, add proper pharmaceutical excipients, carry out lyophilization or spray drying then.
The present invention combines the characteristics of solid dispersion technology and nanotechnology, and the ciclosporin A molecule of slightly solubility is obviously increased in the absorption of intestinal, and its bioavailability surpasses the sandimmun neoral at present leading market.Simple, the suitable large-scale production of drug-supplying system preparation method of the present invention, the material that the present invention uses is easy to get, and is with low cost, the product taking convenience.
The specific embodiment:
Further specify the present invention by the following examples.
Embodiment 1
Ciclosporin A enteric nanoparticle
Get Pluronic F68 750mg, add the 300ml water dissolution as water; Other gets cyclosporin A 60mg and HP-50 420mg, adds the stirring of 90ml acetone and makes dissolving, as organic facies.Get organic facies and inject the aqueous phase that 1000rpm stirs rapidly, continue to stir 5min with the 7# lumbar puncture needle.Move in 60 ℃ of waters bath with thermostatic control, stir volatilization acetone 6-7h.Be concentrated into the cyclosporin A that contains 3.0mg among every 1ml, promptly get the enteric nanoparticle of CyA.
The particle diameter of above-mentioned cyclosporin A enteric nanoparticle is 60-70nm, and the envelop rate of cyclosporin A is 97.6%.
Embodiment 2
Ciclosporin A enteric nanoparticle
Get Pluronic F68 750mg, add the 300ml water dissolution as water; Other gets cyclosporin A 60mg and HP-55 360mg, adds the stirring of 90ml acetone and makes dissolving, as organic facies.Get organic facies and inject the aqueous phase that 1000rpm stirs rapidly, continue to stir 5min with the 7# lumbar puncture needle.Move in 60 ℃ of waters bath with thermostatic control, stir volatilization acetone 6-7h.Be concentrated into and contain the 3.0mg cyclosporin A among every 1ml, promptly get the enteric nanoparticle of CyA.
The particle diameter of above-mentioned cyclosporin A enteric nanoparticle is 60-70nm, and the envelop rate of cyclosporin A is 98.4%.
Embodiment 3
Ciclosporin A enteric nanoparticle
Get Pluronic F68 50mg, add the 25ml water dissolution as water; Other gets cyclosporin A 10mg and Eudragit L100 70mg, adds the stirring of 15ml ethanol and makes dissolving, as organic facies.Get organic facies and inject the aqueous phase that 1000rpm stirs with the 7# lumbar puncture needle with the speed of 1ml/sec, syringe needle and stirring paddle copline apart from 3mm, continue to stir 5min.Move in 60 ℃ of waters bath with thermostatic control, 1000rpm stirs volatilization ethanol, puts coldly, is concentrated into and contains 2.0mg ciclosporin A enteric nanoparticle among every 1ml.
The particle diameter of above-mentioned ciclosporin A enteric nanoparticle is 84 ± 13nm.The envelop rate of ciclosporin A is 97.65%.The drug loading of enteric nanoparticle is 14.38%.
Embodiment 4
Ciclosporin A enteric nanoparticle
Get Pluronic F68 50mg, add the 25ml water dissolution as water; Other gets cyclosporin A 10mg and Eudragit S100 70mg, adds the stirring of 15ml ethanol and makes dissolving, as organic facies.Get organic facies and inject the aqueous phase that 1000rpm stirs with the 7# lumbar puncture needle with the speed of 1ml/sec, syringe needle and stirring paddle copline apart from 3mm, continue to stir 5min.Move in 60 ℃ of waters bath with thermostatic control, 1000rpm stirs volatilization ethanol, puts coldly, is concentrated into and contains 2.0mg ciclosporin A enteric nanoparticle among every 1ml.
The particle diameter of above-mentioned ciclosporin A enteric nanoparticle is 61 ± 12nm.The envelop rate of ciclosporin A is 99.93%.The drug loading of enteric nanoparticle is 14.35%.
Embodiment 5
Ciclosporin A enteric nanoparticle
Get Pluronic F68 50mg, add the 25ml water dissolution as water; Other gets cyclosporin A 10mg and Eudragit L100-55 70mg, adds the stirring of 15ml ethanol and makes dissolving, as organic facies.Get organic facies and inject the aqueous phase that 1000rpm stirs with the 7# lumbar puncture needle with the speed of 1ml/sec, syringe needle and stirring paddle copline apart from 3mm, continue to stir 5min.Move in 60 ℃ of waters bath with thermostatic control, 1000rpm stirs volatilization ethanol, puts coldly, is concentrated into and contains 2.0mg ciclosporin A enteric nanoparticle among every 1ml.
The particle diameter of above-mentioned ciclosporin A enteric nanoparticle is 59 ± 6nm.The envelop rate of ciclosporin A is 97.80%.The drug loading of enteric nanoparticle is 14.50%.
Embodiment 6
The bioavailability test
The basic goal of this research is to increase CyA to absorb at gastrointestinal, so most important evaluation is the bioavailability experiment.Below be experiment condition and result.
Reference preparation: sandimmun neoral (external patented product also is the market leading products at present)
Test preparation: contain the nanoparticle of CyA, comprise nanoparticle A (HP-50), nanoparticle B (HP-55)
Experimental animal: the wistar rat, body weight 230-290g, 8 every group, sample concentration all is adjusted to: 1.5mg CyA/ml, oral dose: 1ml/100g body weight.
Plasma concentration curve after two kinds of cyclosporin A nano-grain colloid solution rats are oral is seen accompanying drawing 1.
According to the blood drug level data, the AUC value that calculates reference preparation (sandimmun neoral) and test preparation (nanoparticle A, nanoparticle B) is respectively 32531.08,38914.88 and 26788.14 (ng/mlh), the relative bioavailability that calculates nanoparticle A thus again is 82.4%, and the relative bioavailability of nanoparticle B is 119.6%.
Experimental result shows after CyA is attached on the enteric solubility nanoparticle, behind the rat oral administration, tangible absorption is arranged in the body, and the bioavailability that wherein has has surpassed commercially available leading products sandimmun neoral.This means that this enteric solubility drug-supplying system has very bright application prospect.
Description of drawings:
Fig. 1 is the plasma concentration curve (Neoral: reference preparation sandimmun neoral behind the oral ciclosporin A reference preparation of rat and the two kinds of nanoparticle solution; HP-55: with HP-55 is the cyclosporin A nano-grain of carrier; HP-50: with HP-50 is the cyclosporin A nano-grain of carrier).
Claims (10)
1. the enteric solubility nanoparticle drug-supplying system that confession is oral is characterized in that, is made by therapeutic ingredient ciclosporin A and synthetic enteric material.
2. drug-supplying system as claimed in claim 1 is characterized in that, the ratio of ciclosporin A and synthetic enteric material is 1: 1-50.
3. drug-supplying system as claimed in claim 1, it is characterized in that wherein synthetic enteric material comprises: the combination of one or more of cellulose acetate phthalate ester, hypromellose phthalate ester, cellulose acetate succinate, enteric solubility acrylic resin, polyvinyl acetate phthalic acid ester, trimellitic acid cellulose acetate.
4. drug-supplying system as claimed in claim 1 is characterized in that, this drug-supplying system prepares by the solvent-nonsolvent method.
5. drug-supplying system as claimed in claim 1 is characterized in that, the preparation of this drug-supplying system need be used organic solvent, and organic solvent comprises one or more combination of ethanol, acetone, benzyl alcohol.
6. drug-supplying system as claimed in claim 1, it is characterized in that, the preparation of this drug-supplying system need be used stabilizing agent or surfactant, comprises one or more combination of Pluronic F68 (Poloxamer 188), polyvinyl alcohol, phospholipid, Tweens, spans.
7. drug-supplying system as claimed in claim 1 is characterized in that, when preparing this drug-supplying system, ciclosporin A: organic solvent: the ratio of water is 1: 0.5-10: 1-50 (mg/ml/ml).
8. drug-supplying system as claimed in claim 1 is characterized in that, the oral ciclosporin A enteric solubility nanoparticle of said confession can be dispersed in aqueous solution or the gel solution; Or be dispersed in the pressed powder of pharmaceutic adjuvant.
9. the preparation method of drug-supplying system as claimed in claim 1 is characterized in that, comprises the steps:
A. surfactant or stabilizing agent is soluble in water, constitute water;
B. with ciclosporin A and enteric material, be dissolved in the organic solvent, constitute organic facies;
C. organic facies is passed through syringe needle, inject the aqueous phase that is stirring, stir; Remove organic solvent then, concentrate, promptly get the colloid solution of ciclosporin A enteric solubility nanoparticle.
10. preparation method as claimed in claim 9 is characterized in that, also comprises, adds thickening agent, gel or stabilizing agent in the colloid solution of ciclosporin A enteric solubility nanoparticle; Or adding pharmaceutic adjuvant postlyophilization or spray drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02153918 CN1233413C (en) | 2002-12-05 | 2002-12-05 | Nano particle feeding system for oral use |
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| CN 02153918 CN1233413C (en) | 2002-12-05 | 2002-12-05 | Nano particle feeding system for oral use |
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| CN1418703A CN1418703A (en) | 2003-05-21 |
| CN1233413C true CN1233413C (en) | 2005-12-28 |
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