CN101199497A - Polypeptide protein class-medicament under-tongue instant nanometer emulsion and 3D printing preparing method thereof - Google Patents
Polypeptide protein class-medicament under-tongue instant nanometer emulsion and 3D printing preparing method thereof Download PDFInfo
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- CN101199497A CN101199497A CNA2007100472750A CN200710047275A CN101199497A CN 101199497 A CN101199497 A CN 101199497A CN A2007100472750 A CNA2007100472750 A CN A2007100472750A CN 200710047275 A CN200710047275 A CN 200710047275A CN 101199497 A CN101199497 A CN 101199497A
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Abstract
The invention relates to a sublingual instant nanometer medical membrane of a polypeptide protein drug and the related three-dimensional printing preparation method. The medical membrane is formed by multiple layers of powder through bounding. The top and bottom layers of the membrane are made from binding liquid which contains permeation enhancer through bonding. The central zones of the middle layers are made from binding agents of a micro-emulsion containing medical polypeptide protein and soybean phospholipid; the peripheral zones are made from binding liquid which is the same with that of the top and bottom layers through bonding. The preparation of the invention comprises the following steps: prepare the medical polypeptide protein micro-emulsion through nano-technique; print and position the micro-emulsion at the center of the membrane through three-dimensional printing technique and smear binding agents containing transmembrane permeation enhancer at the peripheral zones with another printing head to bond medical membrane. The medical membrane can be quickly dissolved at the sublingual to give off the micro-emulsion granules which contain medicines, and under the effects of the transmembrane permeation enhancer, the membrane can permeate the sublingual mucous membrane and enter the circulation system. The whole technique is simple in process, high in automation and good in reproducibility.
Description
Technical field
The invention belongs to polypeptide protein class drug delivery system field, particularly relate to a kind of polypeptide protein class-medicament under-tongue instant nanometer emulsion and 3 D printing preparation method thereof thereof.
Background technology
By (US patent such as the Sachs of the Massachusetts Institute of Technology, NO.5204055,1993) (Three Dimensional Print, 3DP) forming technique prepares the object with special external form or complex internal structure according to the notion of " successively print, be layering " to the 3 D-printing that at first proposes of people.This technology with the powder be material, the course of processing very flexibly, forming speed is fast, operating cost is low and reliability is high, is one of the most vital new technique in the quick shaping industry.The key equipment of this technology---three-dimensional printer generally is made up of terminal, powder-processed system (comprising powder feed, shop layer and recovery), shower nozzle and adhesive supplying device, precision surface plate and mobile device.
The 3DP forming technique has the height process flexibility of having no precedent on traditional manufacturing industry, and the various tool in need not conventional powder machine-shaping is not subjected to the restriction of any geometry.Because the position of spraying, spraying number of times, spraying rate can arbitrarily be controlled; Different materials can be by different shower nozzle sprayings; Spraying substance can be solution, suspension, emulsion and melt substance etc., so the 3DP forming technique can be controlled local material composition, microstructure and surface characteristic at an easy rate.Simultaneously owing to numerous conventional processes are unified for constantly repeat to bond such process on a machine; be easy to design studies; in the commercial production conversion process, there is not the problem of scale, can saves plenty of time and fund, the advantage of real embodiment Rapid Prototyping technique.Compare with other Rapid Prototyping technique, the 3DP forming technique has its unique advantage: compare with the laser selective sintering, device fabrication cost and technology operating cost are all much lower; Compare with fusion sediment, can operate at normal temperatures, move more convenient reliable; Adopt and spray the mode that agglutinating mode has avoided adopting laser or heating and melting, can not influence the activity of active component.Just because of this, the three-dimensional printing-forming technology has just begun various applied researcies in the pharmaceutics field from that time occurring.
At first adopt the 3DP forming technique to carry out the research of drug delivery implant systems produce as [J.control.Release, 1996,40 (1): 77-87] such as Wu; Katsta[J.control.Release, 2000 (66): 1-9] and Rowe[J control.Release, 2000 (66): 11-17] etc. usefulness adopts the 3DP forming technique to carry out oral slowly released and controlled-drug delivery system preparation research respectively; WO2000/29202 then discloses a kind of instant collapsing of sucking by the preparation of 3DP forming technique and has released sheet; US2003/0198677A1 discloses a kind of zero level slowly released and controlled-drug delivery system of the 3DP of utilization forming technique preparation, and this system axial is released with the hydroxypropyl emthylcellulose resistance, radially has the low drug level Gradient distribution of the high circumference in center; Surplus etc. [J Pharm Sci, 2007 (96): 2446-2456] adopt the 3DP forming technique to prepare a kind of oral administration system of releasing the Gradient distribution acquisition Zero order controlled releasing effect of material by rent.The medicine that is adopted in present all kinds of pertinent literatures all is to be model with the dyestuff, perhaps use micromolecule synthetic chemistry class medicine to be object of study, the applicant does not find the 3 D-printing technology is specifically applied to the research document and the patent of polypeptide protein class drug delivery system at present, more do not find the advantage of integrating three-dimensional printing technique and nanotechnology, the systematic account of preparation polypeptide protein class medicine oral administration.
Summary of the invention
The purpose of this invention is to provide a kind of polypeptide protein class-medicament under-tongue instant nanometer emulsion and 3 D printing preparation method thereof thereof, utilize the 3 D-printing technology can accurately control dosage and the position of medicine in preparation, and the good permeable membrane performance of phospholipid nanometer system, prepare a kind of can be in the Sublingual rapid dissolved Nano medication diaphragm, whole prepared process is simple, automatization is high, favorable reproducibility.
Polypeptide protein class-medicament under-tongue instant nanometer emulsion of the present invention, be a kind of by the multilamellar powder by cohering the diaphragm of molding, diaphragm-operated top layer and bottom are cohered by the binding liquid that contains penetrating agent and form, shaping is cohered by the adhesive of the microemulsion system that contains polypeptide protein class medicine and soybean phospholipid in the central area in intermediate layer, and the neighboring area forms by cohering with top, binding liquid that bottom is identical.
Described penetrating agent is can open that mucosa connects but the penetration enhancer that do not damage mucosa, as azone, sodium lauryl sulphate etc.;
The described binding liquid that contains penetrating agent is to contain the ethanol water of 0～8% penetrating agent as binding agent, preferably contains the ethanol water of 4% penetrating agent, and ethanol content is 60～100% in its ethanol water, preferred 90%;
Polypeptide protein class content of medicines in the described microemulsion system is 5～20%, preferred 10%;
The described adhesive that contains microemulsion system can be fit to the spraying system that three-dimensional printer uses.
The 3 D printing preparation method thereof of the Sublingual instant nanometer medicine film of polypeptide protein class medicine of the present invention comprises the following steps:
(1) adopt nanotechnology to prepare the microemulsion system of polypeptide protein class medicine, the neighboring area powder forming binding agent in layer powder and preparation top layer, bottom and intermediate layer is spread in preparation;
(2) the powder feed device of system is transported to pressed powder on the platform earlier, carry out roll extrusion shop layer by the shop rod, move on the speed double track of X-Y plane by 3 D-printing system upper nozzle subsequently, selectively in different regional spraying adhesive, with powder bonded together, form the two-dimensional layer sheet;
(2) on the Z axle, drive whole decline of powder bed and determine height (being powder shop layer thickness) by piston, carrying out new one deck powder shop layer and bonding prints, so repeat, machining 3 D article spray formation is finished up to institute, carries out suitable post processing (as drying, gumming, suitable compression etc.) and promptly gets the 3D solid finished product.
Described shop layer powder is that each layer all spread with identical mixed-powder, and powder constituent is Kollidon25 and lactose, and weight ratio is 60～90: 10～40, and especially suitable is 75: 25.
The Sublingual instant nanometer medicine film of polypeptide protein class medicine provided by the invention, because the hydrophilic of porous and composition adjuvant, can make diaphragm dissolving rapidly in the several seconds, under situation about need not drink water, discharge the penetrating agent of the neighboring area of top layer, bottom and intermediate surface earlier by order, discharge the microemulsion granule at intermediate surface center then.Under the effect of penetrating agent, the microemulsion granule can see through the Sublingual mucosa rapidly and enter blood circulation, avoids gastrointestinal tract and the liver first-pass effect Degradation to polypeptide protein class medicine.
Preparation method of the present invention is to utilize area of computer aided (CAD) design Sublingual instant nanometer medicine film, the drug-supplying system that contains material information model is provided, exchange interface routine by the drug-supplying system model with the forming machine data, directly control the operation preparation by the terminal output order; Be prepared by " successively print, be layering ", structure at all levels is spread with identical mixed-powder, and the zones of different of different aspects and each aspect can be cohered molding by the different adhesive of many shower nozzles three-dimensional printer spraying.
The invention provides the three-dimensional printing-forming technology and prepare determining and prioritization scheme of slowly released and controlled-drug delivery system technological parameter: by " dripping test " (binding agent is being dripped to outside the 3 D-printing system on the corresponding powder), bar girdle tests (with 3 D-printing system spraying coating line and band on corresponding powder bed) etc., also compare bond effect with microscopic examination, the bonding rate of drying, bonding after strain and contraction, number of defects in the bonding band, situations such as band intensity, determine to optimize interlayer blanking time, powder shop layer thickness, spray rate (spraying drop amount * spraying frequency), shaping preparation technology parameters such as spraying number of times.
Medicine film of the present invention can dissolve rapidly in the Sublingual, discharges the microemulsion granule that wherein contains medicine, under the effect of penetrating agent, sees through hypoglossis mucous membrane, enters blood circulation, and whole prepared process is simple, automatization is high, favorable reproducibility.
Description of drawings
Fig. 1 is a 3 D-printing technical matters process sketch map;
Fig. 2 is multi-layer nano medicine membrane structure figure;
Fig. 3 is microemulsion particle diameter laser particle analyzer mensuration figure;
Fig. 4 is the external pig lingual mucous membrane administration lab diagram of nanometer medicine film;
Fig. 5 is the saturating Sublingual of the insulin of medicine film, a microemulsion and contrast solution mucosa accumulation infiltration capacity.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
(1) insulin preparation of microemulsion
(24.5IUmL tires with insulin
-1) be dissolved in the phosphate buffered solution of pH7.4 and prepare 3.0mgmL
-1Insulin solutions.The ratio of soybean phospholipid in 1: 3 is dissolved in the propylene glycol under ultransonic condition.Make 1.5mgmL by also suitable supersound process in the propylene glycol solution that insulin solutions was added drop-wise in 1: 1 soybean phospholipid under stirring condition
-1The insulin microemulsion is as the printing liquid in medicine carrying district in the middle of the medicine film.
The detection of microemulsion particle diameter: adopt the particle diameter and the distribution thereof of laser scattering method microemulsion.Get the 1.2mL sample and put (Nano ZS90 type laser particle analyzer, Britain Ma Erwen Instr Ltd.) in people's laser particle analyzer, measure particle diameter and distribution thereof, the particle size analyzer working condition: light source is He-Ne, wavelength 633nm, and measuring temperature is 25 ℃.Microemulsion particle diameter laser particle analyzer mensuration figure sees Fig. 3.
(2) 3 D-printing powder allotment
Kollidon 25 and lactose are crossed 200 mesh sieves, get particle diameter less than the powder mixes of 74 μ m evenly the back as a shop layer powder; Take by weighing 2 gram penetrating agent azones and 15 gram Ju Yi Xi Bi Sour alkane ketone PVP30, be dissolved in the ethanol water of 100mL60%, be mixed with the neighboring area powder forming binding agent in top layer, bottom and intermediate layer.
The raw material composition and the content (by weight percentage) of middle mixed-powder are as follows:
25 10 parts of Kollidon
90 parts of lactose
(3) determine the three-dimensional printing-forming parameter
End face and bottom surface spray formation parameter:
Interlayer interval 2min
Powder shop layer thickness 100 μ m
Spray rate [spraying drop amount (amount of droplets * drop size) * spraying frequency] 4nL * 1200Hz
Spraying number of times 2 times
Middle pastille mixed-powder spray formation parameter:
Interlayer interval 4min
Powder shop layer thickness 100 μ m
Spray rate (spraying drop amount * spraying frequency) 4nL * 1200Hz
Spraying number of times 1 time
(4) preparation insulin nanometer medicine film
Directly control the operation preparation by the terminal output order, see Fig. 1.Shop one layer thickness, 100 μ m mixed-powders spray the binding agent that contains penetrating agent for 2 times and are shaped earlier, are the bottom surface of medicine film, and piston rod drives whole decline of powder bed of workbench subsequently, prepare new one deck shop powder.
Middle 3 layers of shop layer mixed-powder are constant, and shop layer thickness 100 μ m are binding agent with the microemulsion of insulin-containing, contain the binding agent shaping of penetrating agent in the most peripheral spraying.
Subsequently, repave a layer thickness 100 μ m mixed-powders, spray the binding agent that contains penetrating agent for 2 times and be shaped, be the bottom surface of medicine film.At last gained medicine film is carried out drying, gumming promptly, the structural map of medicine film is seen Fig. 2.
(5) nanometer medicine film Chinese medicine content analysis
Set up the rp-hplc analysis method and detect content of insulin in the nanometer medicine film.Chromatographic column is HypersilODS
2(250mm * 4.6mm, i.d.5 μ m); Chromatograph is analysed condition: mobile phase is 0.1molL
-1Sodium dihydrogen phosphate: 0.1molL
-1Sodium sulfate: acetonitrile=36: 36: 28, regulating pH with phosphoric acid is 3.0; Flow velocity 1.0mLmin
-1The ultraviolet detection wavelength is 214nm; Sample size 20 μ L, column temperature is 30 ℃.The medicine film with contain 0.15%TritonX-100 0.01M HCl solution standardize solution, shake up, sample introduction analysis behind the 0.45 μ m filtering with microporous membrane, adjuvant does not influence drug monitoring.
Through absorbance measurement, press regression equation C=1.67322 * 10
-4A+0.05702 (the range of linearity: 5～200 μ gmL
-1) calculating content of insulin in the medicine film, the result is 2.61 ± 0.07mg (n=6), and content difference is 2.68% between the medicine film, and tiring is 63.95 ± 1.75IU/ sheet.
(6) the external instant performance of nanometer medicine film
Measure the instant disintegration of medicine film according to 2005 editions appendix disintegrations of Chinese Pharmacopoeia algoscopy.Because the least unit of LD-2D type disintegration time mensuration instrument (Shanghai Huanghai Sea medicine inspection instrument plant) be minute, so carries out timing with stopwatch, 6 dissolving the separate times of fast dissolving film in 25 ℃ of water are 28.7 ± 3.6s after measured.4 medicine films is put into 100mL water be stirred to dispersion fully, but the homogeneous dispersion 'go'gage of formation is the screen cloth of 480 μ m that the dispersion liquid fineness meets the requirements.
(7) the saturating pig lingual mucous membrane administration performance of nanometer medicine film
The fresh pig tongue is taken from the adult healthy pig after just butchering, and separates and to remove the Sublingual mucous membrane tissue, and clean with normal saline, is cut into that a certain size is standby.As shown in Figure 4, fresh pig Sublingual mucosa is tight in the reception tank of diffusion cell and between for the medicine pond, mucous membrane surface is towards supplying the medicine pond, the mucosa inner layer surface is to reception tank, with alligator clamp fixedly behind the diffusion cell, put into constant temperature (37 ± 1) ℃ transdermal diffusion experiment instrument, add insulin nanometer film, insulin microemulsion and each 5mL of insulin contrast solution in the administration pond respectively, receiving liquid is 0.9% normal saline 5mL.Respectively at 10,20,30,60,90,120,180min regularly gets and receives liquid 1mL, and replenishes synthermal normal saline with volume, institute's sample thief detects insulin with high performance liquid chromatograph in 214nm wavelength place behind 0.45 μ m filtering with microporous membrane.
By regression equation C=1.67322 * 10
-4A+0.05702 calculates the accumulation transit dose of insulin, and to mapping sample time, the result as shown in Figure 5.Because the synergism of penetrating agent azone and phospholipid, the medicine film has good permeable membrane administration performance, and 180min insulin transit dose reaches (5.843 ± 0.322) IUmL
-1, be better than transit dose (5.591 ± 0.240) IUmL of microemulsion and insulin solutions
-1(2.457 ± 0.181) IUmL
-1Especially at initial 10 minutes, the insulin transit dose of medicine film reached (1.352 ± 0.235) IUmL
-1, much larger than transit dose (0.743 ± 0.110) IUmL of microemulsion and insulin solutions
-1(0.640 ± 0.090) IUmL
-1
Claims (9)
1. polypeptide protein class-medicament under-tongue instant nanometer emulsion, it is characterized in that: this medicine film is by cohering the diaphragm of molding by the multilamellar powder, diaphragm-operated top layer and bottom are cohered by the binding liquid that contains penetrating agent and form, shaping is cohered by the adhesive of the microemulsion system that contains polypeptide protein class medicine and soybean phospholipid in the central area in intermediate layer, and the neighboring area forms by cohering with top, binding liquid that bottom is identical.
2. polypeptide protein class-medicament under-tongue instant nanometer emulsion according to claim 1 is characterized in that: described penetrating agent is azone, sodium lauryl sulphate.
3. polypeptide protein class-medicament under-tongue instant nanometer emulsion according to claim 1 is characterized in that: the described binding liquid that contains penetrating agent is to contain 60～100% ethanol waters of 0～8% penetrating agent as binding agent.
4. polypeptide protein class-medicament under-tongue instant nanometer emulsion according to claim 3 is characterized in that: the described binding liquid that contains penetrating agent is 90% ethanol water that contains 4% penetrating agent.
5. polypeptide protein class-medicament under-tongue instant nanometer emulsion according to claim 1 is characterized in that: the polypeptide protein class content of medicines in the described microemulsion system is 5～20%.
6. polypeptide protein class-medicament under-tongue instant nanometer emulsion according to claim 5 is characterized in that: the polypeptide protein class content of medicines in the described microemulsion system is 10%.
7. the 3 D printing preparation method thereof of the Sublingual instant nanometer medicine film of polypeptide protein class medicine comprises the following steps:
(1) adopt nanotechnology to prepare the microemulsion system of polypeptide protein class medicine, the neighboring area powder forming binding agent in layer powder and preparation top layer, bottom and intermediate layer is spread in preparation;
(2) the powder feed device of system is transported to pressed powder on the platform earlier, carry out roll extrusion shop layer by the shop rod, move on the speed double track of X-Y plane by 3 D-printing system upper nozzle subsequently, selectively in different regional spraying adhesive, with powder bonded together, form the two-dimensional layer sheet;
(2) drive whole decline of powder bed by piston on the Z axle and determine height, carry out new one deck powder shop layer and bonding and print, so repeat, machining 3 D article spray formation is finished up to institute, carries out drying, gumming, suitably compression, promptly gets the 3D solid finished product.
8. the 3 D printing preparation method thereof of polypeptide protein class-medicament under-tongue instant nanometer emulsion according to claim 7, it is characterized in that: described powder shop layer is that each layer all spread with identical mixed-powder shop layer, powder constituent is Kollidon25 and lactose, and weight ratio is 60～90: 10～40.
9. the 3 D printing preparation method thereof of polypeptide protein class-medicament under-tongue instant nanometer emulsion according to claim 7, it is characterized in that: described Kollidon25 and lactose weight ratio are 75: 25.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107107463A (en) * | 2014-09-08 | 2017-08-29 | 中央兰开夏大学 | Solid dosage forms is produced |
| CN113891706A (en) * | 2019-05-21 | 2022-01-04 | 迪辅益制药有限及两合公司 | Lactose powder bed three-dimensional printing |
-
2007
- 2007-10-19 CN CN200710047275A patent/CN100579575C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107107463A (en) * | 2014-09-08 | 2017-08-29 | 中央兰开夏大学 | Solid dosage forms is produced |
| CN107107463B (en) * | 2014-09-08 | 2019-10-25 | 中央兰开夏大学 | Solid dosage forms production |
| CN111037913A (en) * | 2014-09-08 | 2020-04-21 | 中央兰开夏大学 | Production of solid dosage forms |
| CN111037913B (en) * | 2014-09-08 | 2022-04-01 | 中央兰开夏大学 | Production of solid dosage forms |
| US11771655B2 (en) | 2014-09-08 | 2023-10-03 | University Of Central Lancashire | Solid dosage form production |
| CN113891706A (en) * | 2019-05-21 | 2022-01-04 | 迪辅益制药有限及两合公司 | Lactose powder bed three-dimensional printing |
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| CN100579575C (en) | 2010-01-13 |
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