CN104382850B - A kind of rotigotine micro emulsion and micro emulsion gel - Google Patents
A kind of rotigotine micro emulsion and micro emulsion gel Download PDFInfo
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- CN104382850B CN104382850B CN201410554031.1A CN201410554031A CN104382850B CN 104382850 B CN104382850 B CN 104382850B CN 201410554031 A CN201410554031 A CN 201410554031A CN 104382850 B CN104382850 B CN 104382850B
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Abstract
The present invention relates to a kind of rotigotine micro emulsion and micro emulsion gel, belong to pharmaceutics field.Rotigotine micro emulsion, comprising active constituents of medicine and pharmaceutical carrier, the active constituents of medicine is rotigotine, and the pharmaceutical carrier is oil-in-water microemulsion, and the oil-in-water microemulsion includes emulsifying agent, assistant for emulsifying agent, oil phase and aqueous phase；The rotigotine micro emulsion forms according to following percentage by weight：Rotigotine 0.1% 10%, oil phase 1% 30%, emulsifying agent 3.5% 45%, assistant for emulsifying agent 1.5% 20%, aqueous phase 10% 90%；Rotigotine micro emulsion gel, including above-mentioned rotigotine micro emulsion, in addition to Macromolecule glue material, the percentage by weight of the Macromolecule glue material and the rotigotine micro emulsion are 0.3% 3%.Rotigotine stability of microemulsion is good and with infiltration facilitation；Rotigotine micro emulsion gel bioavilability is high.
Description
Technical field
The present invention relates to a kind of rotigotine micro emulsion and micro emulsion gel, belong to pharmaceutics field.
Background technology
Rotigotine is a kind of new dopamine-receptor stimulant, and its poorly water-soluble, the content of dispersion of the aqueous solution is low, and is passed through
Skin osmotic effect is poor；Because its first pass effect of hepar is obvious, metabolic rate is exceedingly fast, thus is not suitable for oral or injection administration.
Rotigotine structural formula：
Rotigotine is typically used with a kind of rotigotine percutaneous plaster of a daily patch in the prior art, and the paster is with silicon
Ketone is matrix, and 24h bioavilabilities are 44.4%.But clinical research shows, skin can be produced using patient's nearly half of the paster
Skin local reaction, such as erythema, dermatitis and itch.And have an easily oxidized hydroxyl in rotigotine structure on phenyl ring,
There is transformation of crystal phenomenon, rotigotine listing patch was once called back because producing flakes crystallization.
Current further improved technology is that rotigotine is made into rotigotine microballoon, but rotigotine microballoon is injection
Administration, and preparation technology is complicated, can use chloroform, dichloromethane alkanes solvent in preparation process, its residue can produce to human body
Side effect.
Therefore, it is necessary to propose effective technical scheme, solve the above problems.
The content of the invention
The present invention is directed to above-mentioned the deficiencies in the prior art, there is provided a kind of stability is good and with sieve of infiltration facilitation
For dagger-axe spit of fland micro emulsion.
The technical scheme that the present invention solves above-mentioned technical problem is as follows：A kind of rotigotine micro emulsion, comprising pharmaceutical activity into
Point and pharmaceutical carrier, the active constituents of medicine be rotigotine, the pharmaceutical carrier is oil-in-water microemulsion, the oil-in-water
Type microemulsion includes emulsifying agent, assistant for emulsifying agent, oil phase and aqueous phase；The rotigotine micro emulsion forms according to following percentage by weight：
Preferably, rotigotine micro emulsion forms according to following percentage by weight：
Preferably, the oil phase be glyceride type and or fatty acid.
Preferably, the oil phase is oleic acid LABRAFIL M 1944CS class and/or caprylic capric triglycerin esters.
Preferably, the emulsifying agent be sorbitan fatty acid ester polyvinylether, Labraso,
One or more combination thing in Emulsifier EL-60, Crodaret.
Preferably, the assistant for emulsifying agent is ethanol, propane diols, glycerine, polyethylene glycol, ethoxydiglycol, polyglycereol
One or more combination thing in oleate, polyglycereol isostearate, sorbitan ester.
Preferably, the aqueous phase is deionized water or distilled water.
Preferably, the particle diameter of the rotigotine micro emulsion is 10-100nm.
The present invention also provides a kind of bioavilability high rotigotine micro emulsion gel.
Including above-mentioned rotigotine micro emulsion, in addition to Macromolecule glue material, the Macromolecule glue material and sieve
Percentage by weight for dagger-axe spit of fland micro emulsion is 0.3%-3%.
Preferably, the Macromolecule glue material is carbomer.
Micro emulsion is transparent and homogeneous and thermodynamics, the heterogeneous system of dynamic stabilization, by oil, water, emulsifying agent and assistant for emulsifying agent
Composition, particle diameter is between 10-100nm.Micro emulsion is a kind of " Critical Solution ", because it not only has the property of emulsion, together
When also there is the property of many solutions, for example there is the saturation solubility of medicine in micro emulsion, the distribution coefficient of no usual vehicle,
The features such as interfacial tension, Thermodynamically stable are not detected between oil and water.
The present invention prepares the oil phase, emulsifying agent and assistant for emulsifying agent of micro emulsion, also plays a part of medicine penetrating agent sometimes.Can
See, microemulsion may promote the percutaneous absorbtion of medicine as pharmaceutical carrier.Carrier using micro emulsion as rotigotine micro emulsion, is prepared micro-
The key of breast is the selection of component and the design of each component ratio.
The rate-limiting step of medicine microemulsion liquid percutaneous dosing mainly wants two, first, medicine phase and outer alternate distribution inside
Journey, second, the process of osmosis of drug percutaneous skin.The design of microemulsion composition can influence two above step.For by adjusting micro emulsion
Compositing formula control the percutaneous absorbtion of medicine to provide possibility.
The present invention adds Macromolecule glue material into microemulsion, transparent, stable network structure can be formed, in network
In contain microemulsion droplets, referred to as microemulsion gel, the tridimensional network of gel stability can prevent the precipitation of drug precipitation, this
It is a little very significant for administration for the rotigotine with polymorphism.Investigate different gel-type vehicles and same
The influence that matrix various concentrations are formed to micro emulsion gel, so as to obtain high osmosis, high drug load rotigotine micro emulsion gel
Preparation.Inventive gel has good compatibility, small to the excitant of skin.
Brief description of the drawings
Fig. 1 is the Electron Microscope images figure of rotigotine micro emulsion；
Fig. 2 is embodiment 2.1-2.7 and lists plasma drug level-time plot of the patch after rat abdomen administration.
Embodiment
The principles and features of the present invention are described below, and the given examples are served only to explain the present invention, is not intended to limit
Determine the scope of the present invention.
The gross weight of embodiment 1 is the preparation of 100g rotigotine micro emulsion
Embodiment 1.1
The oil phase of above-mentioned weight, emulsifying agent, assistant for emulsifying agent, rotigotine are sufficiently mixed uniformly, in room temperature, magnetic agitation
Under the conditions of the water of above-mentioned weight is added dropwise, continue stirring 30 minutes, produce rotigotine micro emulsion.
In the preparation process of micro emulsion, the temperature of mixing time and environment is including but not limited to described above, is finally
It is successfully prepared and is defined by micro emulsion.
Embodiment 1.2
Preparation method is the same as embodiment 1.1.
Embodiment 1.3
Preparation method is the same as embodiment 1.1.
Embodiment 1.4
Preparation method is the same as embodiment 1.1.
Embodiment 1.5
Preparation method is the same as embodiment 1.1.
Embodiment 1.6
Preparation method is the same as embodiment 1.1.
Embodiment 1.7
Preparation method is the same as embodiment 1.1.
Embodiment 1.8
Preparation method is the same as embodiment 1.1.
Embodiment 1.9
Preparation method is the same as embodiment 1.1.
Embodiment 1.10
Preparation method is the same as embodiment 1.1.
Embodiment 1.11
Preparation method is the same as embodiment 1.1.
Embodiment 1.12
Preparation method is the same as embodiment 1.1.
Reference examples 1.13
The preparation of rotigotine olive oil saturated solution, 10g rotigotines and 100g olive oil are sufficiently mixed, 25 DEG C of perseverances
Tepidarium 24h, 3600r/min centrifugation 10 minutes, takes supernatant, rotigotine olive oil saturated solution is made.
Reference examples 1.14
The preparation of rotigotine suspension, 90g water and 10g rotigotines are mixed, are vortexed 10 minutes, rotigotine is made
Aqueous suspension.
Rotigotine micro emulsion prepared by above-described embodiment 1.1-1.12, and reference examples 1.13,1.14 are detected, and are surveyed
Determine method and result is as follows：
1st, rotigotine micro emulsion droplet measurement
Instrument：DeisaTMNano C Particle Size Analyzers (BECKMAN COULTER companies of the U.S.) temperature is 25 DEG C, refractive power
Rate is 1.3328.Particle size measurement is shown in Table 1.
2nd, rotigotine micro emulsion vitro permeation assay detects
Test method：Rat abdomen hair is carefully sloughed with shaver, raises 24h, skin of abdomen is peeled off, carefully except peeling
Lower adipose tissue, musculature and adhesion thing, filter paper suck dry moisture.Mouse skin is placed between supply pool and reception tank, assembled
Franz diffusion cells, effective diffusion area are 1.34cm2, for stratum corneum side to supply pool, skin corium is fixed towards reception tank.Supplying
To addition rotigotine micro emulsion 2mL (rotigotine content 1%) in pond.To reach sink conditions, 40%PEG physiological saline is selected
For reception liquid.Quantitative reception liquid and magnetic agitation are added in reception tank, liquid is regularly taken and supplements the reception liquid of equivalent, test
Carried out under the conditions of 37 DEG C of waters bath with thermostatic control.HPLC methods determine and calculate 24h accumulation infiltration capacities Q24(Q24To be given on unit skin area
24 hours total amounts for adding up transdermal rotigotine of medicine).
Chromatographic condition is chromatographic column：Discovery C18 (250mm × 4.6mm, 5 μm), mobile phase：The phosphorus of acetonitrile -0.3%
Sour water (34:66), Detection wavelength：223nm, flow velocity：1.0mL·min-1, column temperature：35 DEG C, sample size：20μL.
Vitro permeation assay testing result is shown in Table 1.
The rotigotine micro emulsion granularity of table 1. and vitro permeation assay detection table
Table 1 lists embodiment 1.1-1.12, and the particle diameter of reference examples 1.13,1.14 and carries out body in the manner described above
After outer transdermal penetration experiment, the accumulative transdermal penetration amount of 24 hours.
As seen from Table 1, the aqueous suspension of rotigotine carries out in-vitro percutaneous experiment 24 hours according to above-mentioned experiment method
Fail the release of detection rotigotine afterwards.Because only that the medicine of dissolving is only possible to pass through skin.Therefore it is concluded that：Sieve
It can increase the transdermal penetration amount of the rotigotine in aqueous medium for the design of dagger-axe spit of fland micro emulsion.
After rotigotine micro emulsion carries out Ligustrazine hydrochloride experiment in the manner described above, the accumulative transdermal penetration amount of 24 hours
Also rotigotine olive oil saturated solution can be much higher than.Further demonstrating rotigotine microemulsion promotes rotigotine percutaneous
The effect of infiltration.
The preparation of the rotigotine micro emulsion gel of embodiment 2.
Embodiment 2.1
100g rotigotines micro emulsion prepared by embodiment 1.4 is mixed with the carbomer gel matrix that weight content is 1g,
Fully swelling, obtains rotigotine micro emulsion gel.Wherein fully swelling refer at room temperature swelling overnight or under the conditions of 40 DEG C it is molten
Swollen more than 2 hours.Above-mentioned micro emulsion gel swelling process includes but is not limited to listed temperature, time, is finally to reach
Swelling purpose is defined.
Can also be added in above-mentioned rotigotine micro emulsion or rotigotine micro emulsion gel preservative, antioxidant, water-loss reducer etc. into
Point.
Embodiment 2.2
100g rotigotines micro emulsion prepared by embodiment 1.5 is mixed with the carbomer gel matrix that weight content is 1g,
Fully swelling, obtains rotigotine micro emulsion gel.
Embodiment 2.3
100g rotigotines micro emulsion prepared by embodiment 1.6 is mixed with the carbomer gel matrix that weight content is 1g,
Fully swelling, obtains rotigotine micro emulsion gel.
Embodiment 2.4
100g rotigotines micro emulsion prepared by embodiment 1.10 is mixed with weight content for 0.3g carbomer gel matrix
Close, fully swelling, obtain rotigotine micro emulsion gel.
Embodiment 2.5
100g rotigotines micro emulsion prepared by embodiment 1.10 is mixed with weight content for 0.5g carbomer gel matrix
Close, fully swelling, obtain rotigotine micro emulsion gel.
Embodiment 2.6
100g rotigotines micro emulsion prepared by embodiment 1.10 is mixed with the carbomer gel matrix that weight content is 1g,
Fully swelling, obtains rotigotine micro emulsion gel.
Embodiment 2.7
100g rotigotines micro emulsion prepared by embodiment 1.10 is mixed with the carbomer gel matrix that weight content is 5g,
Fully swelling, obtains rotigotine micro emulsion gel.
Rotigotine micro emulsion gel prepared by above-described embodiment 2.1-2.7 is detected, assay method and result are as follows：
1st, the measure of rotigotine micro emulsion gel viscosity
With the viscosity of viscosimeter detection micro emulsion gel, temperature is 25 DEG C, shear rate 50rpm.Viscosity measurement is shown in
Table 2.
2nd, the Ligustrazine hydrochloride experiment of rotigotine micro emulsion gel
The assembling of the acquisition methods, Franz diffusion cells of skin and assay method are the same as " the in-vitro percutaneous of rotigotine micro emulsion is oozed
Experiment thoroughly ".Embodiment 2.1-2.7 rotigotine micro emulsion gels 2g is added in supply pool.Ligustrazine hydrochloride test measurement knot
Fruit is shown in Table 2.
The rotigotine micro emulsion gel viscosity of table 2. and Ligustrazine hydrochloride testing inspection table
3rd, rotigotine micro emulsion gel bioavailability study after rat abdomen administration
LC-MS/MS conditions：Internal standard compound：(S) -5,6,7,8- tetrahydrochysenes -6- [propyl group [4- fluorobenzene ethyl] amino] -1- naphthols
Hydrochloride.
Chromatographic condition：Chromatographic column：Lichrospher C18Mobile phase：Methanol：Water (70:30,0.1mmol ammonium acetates,
0.05% glacial acetic acid)；Column temperature：25℃；Detection wavelength：271.5nm；Flow velocity：0.2mL·min-1；Sample size：20μL.
Mass Spectrometry Conditions：Ion gun：Electro-spray ionization source (ESI)；Ion injection electric：4000v；Detection mode：Just from
Sub- detection mode；Sheath atmospheric pressure：30psi；Auxiliary atmospheric pressure：5psi；Capillary transfer pipe temperature：350℃；Scan mode：Selection is anti-
It should detect (SRM)；Collision energy：25ev；Rotigotine, internal standard compound ion pair：316.0/147.1,328.1/147.1.
Sampled plasma and processing：Embodiment 2.1-2.7 and the transdermal patch of listing(9mg is pasted-1).Will be big
It is administered after putting 24h in a suitable place to breed after the depilation of mouse belly, dosage 1.20mgkg-1, and according to the dosage by the rotigotine of corresponding weight
Gel is spread evenly across 0.8 × 0.8cm2On waterproof membrane, rat abdomen is fixed on medical adhesive tape.List patch
By 1.20mgkg-1Corresponding paster (9mg/20cm2) area cuts out, fixed form is same as above.After administration 1,2,
4th, 6,8,10,12,24,48h takes blood 0.5mL to be placed in 3600rmin in the 1.5mLEP pipes containing 20 μ L heparin-1Centrifuge 10min
Afterwards, -20 DEG C of freezen protectives of upper plasma are taken out.
Test method：100 μ L blank plasmas are taken in glass centrifuge tube with liquid-transfering gun, move the inner mark solution for adding 10 μ L
(5.0ng·mL-1), mixed 30s is vortexed, 3mL extractant (n-hexane is added with pipette:Dichloromethane:Isopropanol=2:1:
0.1), 3600rmin after vortex 3min-110min is centrifuged, supernatant liquor is taken in another teat glass with pipette, in nitrogen
Drying is flowed down, 100 μ L mobile phases vortex 1min is then added and is redissolved, 13000rmin-110min is centrifuged, takes supernatant to use
LC-MS chromatography determination content.Testing result is shown in Table 3.
4th, pharmacokinetics is analyzed
The pharmacokinetic parameters after the administration of rotigotine micro emulsion gel are calculated with WinNonlin6.3 softwares.Blood concentration-when
Half interval contour is shown in Fig. 2.
Bioavilability and pharmacokinetics detection table after the administration of the rotigotine micro emulsion gel of table 3.
Note：AUC0→24And AUC0→48The song of 24 hours and 48 hours respectively after blood concentration-time curve (Fig. 2) administration
Area under line.24hF and 48hF is respectively 24 hours and 48 hours after being administered, and rotigotine micro emulsion gel is relative to listing patchRelative bioavailability.
As seen from Table 3, the design of rotigotine micro emulsion gel can improve the bioavilability after rotigotine administration, special
It is not the bioavilability of 24 hours after being administered.
5th, skin irritatin Journal of Sex Research
Healthy rat 12 is taken only to be randomly divided into two groups, every group 6, first group of rat replaces dagger-axe to sieve described in embodiment 2.6
Spit of fland micro emulsion gel 45mg, second group is given listing patch, administration area is 2cm2, consolidated respectively with medical adhesive tape
It is fixed.Observed after 3d is administered and count the skin injury situation of two groups of rats, skin injury score is as follows:There is no erythema, note 0
Point；Red stain quantity<5, remember 1 point；Red stain quantity 5-10, remember 2 points；Red stain quantity>10, remember 3 points.
As a result show, erythema is not observed in micro emulsion gel group, is scored at 0；Listing patch group observes obvious erythema,
It is scored at 1.33 ± 0.52.As a result it is expressed as mean value ± S.D. (n=6).Therefore, it is red can to reduce skin for rotigotine micro emulsion gel
The incidence of spot.
6th, stability experiment
Rotigotine micro emulsion gel prepared by embodiment 2.1-2.7 is divided into two parts, portion is placed in 4 DEG C of refrigerator cold-storages, separately
Portion is placed under room temperature condition.Sampled respectively at 0.5,1,2,3,6 month, centrifuge 10min, rotating speed 3600rmin-1, observation
Whether there are lamination or precipitation to produce.
By the study on the stability of 6 months, do not occur being separated or producing precipitation through centrifugation.
Rotigotine micro emulsion gel of the present invention can be processed further and obtain other preparations, such as patch, cataplasm.
The present invention can be summarized with others without prejudice to the concrete form of the spirit or essential characteristics of the present invention.Therefore, nothing
By from the point of view of which point, the embodiment above of the invention can only all be considered the description of the invention and can not limit this hair
Bright, claims indicate the scope of the present invention, and above-mentioned explanation does not point out the scope of the present invention, therefore, with this
Any change in claims of invention suitable implication and scope, is all considered as the scope for being included in claims
It is interior.The present invention includes but is not limited to rotigotine micro emulsion and is processed further that micro emulsion gel is made, in addition to rotigotine micro emulsion enters
Spray, film, in-situ gel etc. is made in the processing of one step, falls within the scope of protection of the invention.
Claims (5)
1. a kind of rotigotine micro emulsion, includes active constituents of medicine and pharmaceutical carrier, it is characterised in that the active constituents of medicine
For rotigotine, the pharmaceutical carrier is oil-in-water microemulsion, and the oil-in-water microemulsion includes emulsifying agent, helps emulsification
Agent, oil phase and aqueous phase；The rotigotine micro emulsion forms according to following percentage by weight：
The oil phase is oleic acid LABRAFIL M 1944CS and/or caprylic capric glyceryl ester；
The emulsifying agent is sorbitan fatty acid ester APEO, Labraso, polyoxyethylene
One or more combination thing in castor oil, Crodaret；
The assistant for emulsifying agent is the one or more combination in ethanol, propane diols, glycerine, polyethylene glycol, ethoxydiglycol
Thing.
2. rotigotine micro emulsion according to claim 1, it is characterised in that the aqueous phase is deionized water or distilled water.
3. rotigotine micro emulsion according to claim 1, it is characterised in that the particle diameter of the rotigotine micro emulsion is 10-
100nm。
4. a kind of rotigotine micro emulsion gel, including the rotigotine micro emulsion described in claim any one of 1-3, its feature exist
In, in addition to Macromolecule glue material, the high-molecular gel material usage are 0.3 weight percent of the rotigotine micro emulsion
Than -3 percentage by weights.
5. rotigotine micro emulsion gel according to claim 4, it is characterised in that the Macromolecule glue material is card ripple
Nurse.
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| CN101229121A (en) * | 2008-01-23 | 2008-07-30 | 山东大学 | Penciclovir microemulsion gel preparation and preparing method thereof |
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| EP1386605A1 (en) * | 2002-07-30 | 2004-02-04 | Schwarz Pharma Ag | Improved transdermal delivery system for the administration of rotigotine |
| CA2767068C (en) * | 2009-12-22 | 2016-09-27 | Ucb Pharma Gmbh | Polyvinylpyrrolidone for the stabilization of a solid dispersion of the non-crystalline form of rotigotine |
| CN102499906B (en) * | 2011-10-12 | 2013-04-17 | 长春健欣生物医药科技开发有限公司 | Rotigotine hydrochloride or free alkali film-forming gel preparation and preparation method thereof |
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| CN101229121A (en) * | 2008-01-23 | 2008-07-30 | 山东大学 | Penciclovir microemulsion gel preparation and preparing method thereof |
Non-Patent Citations (2)
| Title |
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| 不同助表面活性剂对o/w型微乳形成的影响;王雨青 等;《中国医药工业杂志》;20111231;第42卷(第12期);摘要，第908-909页2.1空白微乳的制备、3讨论 * |
| 罗替戈汀透皮贴剂的研究进展;张晓军 等;《药物评价研究》;20120229;第35卷(第1期);第69－70页4上市后进展 * |
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