CN104382850A - Rotigotine micro emulsion and micro emulsion-based gel - Google Patents
Rotigotine micro emulsion and micro emulsion-based gel Download PDFInfo
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- CN104382850A CN104382850A CN201410554031.1A CN201410554031A CN104382850A CN 104382850 A CN104382850 A CN 104382850A CN 201410554031 A CN201410554031 A CN 201410554031A CN 104382850 A CN104382850 A CN 104382850A
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Abstract
The invention relates a rotigotine micro emulsion and micro emulsion-based gel, and belongs to the field of medicinal preparations. The rotigotine micro emulsion comprises a medicinal active ingredient and a medicine carrier; the medicinal active ingredient is rotigotine; the medicine carrier is an oil-in-water type emulsion; the oil-in-water type emulsion comprises emulsifying agents, co-emulsifiers, oil phases and water phases; the rotigotine micro emulsion comprises, by weight, 0.1%-10% of rotigotine, 1%-30% of the oil phases, 3.5%-45% of the emulsifying agents, 1.5%-20% of the co-emulsifiers and 10%-90% of the water phases; the rotigotine micro emulsion-based gel comprises the rotigotine micro emulsion, and further comprises polymer gel materials; the weight percentage of the polymer gel materials to the rotigotine micro emulsion ranges from 0.3% to 3%. The rotigotine micro emulsion is good in stability and has the permeation acceleration effect; and the bioavailability of the rotigotine micro emulsion-based gel is high.
Description
Technical field
The present invention relates to a kind of rotigotine microemulsion and micro emulsion gel, belong to pharmaceutics field.
Background technology
Rotigotine is a kind of novel dopamine-receptor stimulant, its poorly water-soluble, and the content of dispersion of aqueous solution is low, and transdermal penetration weak effect; Because its first pass effect of hepar is obvious, metabolic rate is exceedingly fast, and is thus not suitable for oral or drug administration by injection.
Rotigotine structural formula:
In prior art, rotigotine generally uses with the rotigotine percutaneous plaster pasted a kind of every day one, and this paster take silicone as substrate, and 24h bioavailability is 44.4%.But clinical research shows, use patient's nearly half of this paster can produce local skin reaction, such as erythema, dermatitis and pruritus.And in rotigotine structure, phenyl ring has an easily oxidized hydroxyl, have transformation of crystal phenomenon, rotigotine listing patch was once called back because produce flakes crystallization.
The technology improved further is at present that rotigotine is made rotigotine microsphere, but rotigotine microsphere is drug administration by injection, and complicated process of preparation, can use chloroform, dichloromethane kind solvent in preparation process, its residue can have side effects to human body.
Therefore, be necessary to propose effective technical scheme, solve the problem.
Summary of the invention
The present invention is directed to above-mentioned the deficiencies in the prior art, a kind of good stability is provided and there is the rotigotine microemulsion permeating facilitation.
The technical scheme that the present invention solves the problems of the technologies described above is as follows: a kind of rotigotine microemulsion, comprise active constituents of medicine and pharmaceutical carrier, described active constituents of medicine is rotigotine, described pharmaceutical carrier is oil-in-water microemulsion, and described oil-in-water microemulsion comprises emulsifying agent, co-emulsifier, oil phase and aqueous phase; Described rotigotine microemulsion forms according to following percentage by weight:
Preferably, rotigotine microemulsion forms according to following percentage by weight:
Preferably, described oil phase be glyceride type and or fatty acid.
Preferably, described oil phase is oleic acid polyethyleneglycol glyceride class and/or caprylic capric triglycerin esters.
Preferably, described emulsifying agent is the one or more combination thing in sorbitan fatty acid ester polyvinylether, Labraso, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini.
Preferably, described co-emulsifier is the one or more combination thing in ethanol, propylene glycol, glycerol, Polyethylene Glycol, ethoxydiglycol, polyglycerol acrylate, polyglyceryl-isostearate, sorbitan ester.
Preferably, described aqueous phase is deionized water or distilled water.
Preferably, the particle diameter of described rotigotine microemulsion is 10-100nm.
The rotigotine micro emulsion gel that the present invention also provides a kind of bioavailability high.
Comprise above-mentioned rotigotine microemulsion, also comprise Macromolecule glue material, the percentage by weight of described Macromolecule glue material and described rotigotine microemulsion is 0.3%-3%.
Preferably, described Macromolecule glue material is carbomer.
Microemulsion is transparent and homogeneous and the heterogeneous system of thermodynamics, dynamic stabilization, and be made up of oil, water, emulsifying agent and co-emulsifier, particle diameter is between 10-100nm.Microemulsion is a kind of " Critical Solution ", because it not only has the character of emulsion, also has the character of many solutions simultaneously, there is the saturation solubility of medicine in such as microemulsion, without the partition coefficient of usual vehicle, between You Heshui, do not detect interfacial tension, the features such as Thermodynamically stable.
The present invention prepares the oil phase of microemulsion, emulsifying agent and co-emulsifier, sometimes also plays a part medicine penetrating agent.Visible, microemulsion may promote the percutaneous absorbtion of medicine as pharmaceutical carrier.Take microemulsion as the carrier of rotigotine microemulsion, the key preparing microemulsion 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, one be medicine at interior and outer alternate assigning process, two is processes of osmosis of drug percutaneous skin.The design of microemulsion composition can affect above two steps.The percutaneous absorbtion controlling medicine for the compositing formula by adjusting microemulsion provides possibility.
The present invention adds Macromolecule glue material in microemulsion, transparent, stable network structure can be formed, in a network containing microemulsion droplets, be called microemulsion gel, the tridimensional network of gel stability can prevent the precipitation of drug precipitation, and this point is very significant for the administration of the rotigotine with polymorphism.Investigate the impact that different gel-type vehicle and same substrate variable concentrations are formed micro emulsion gel, thus obtain the rotigotine microemulsion gel preparation of high osmosis, high drug load.Inventive gel has the good compatibility, little to the zest of skin.
Accompanying drawing explanation
Fig. 1 is the Electron Microscope images figure of rotigotine microemulsion;
Fig. 2 is embodiment 2.1-2.7 and the plasma drug level-time plot of listing patch after rat abdomen administration.
Detailed description of the invention
Be described principle of the present invention and feature below, example, only for explaining the present invention, is not intended to limit scope of the present invention.
Embodiment 1 gross weight is the preparation of the rotigotine microemulsion of 100g
Embodiment 1.1
By the oil phase of above-mentioned weight, emulsifying agent, co-emulsifier, the abundant mix homogeneously of rotigotine, under room temperature, magnetic agitation condition, drip the water of above-mentioned weight, continue stirring 30 minutes, obtain rotigotine microemulsion.
In the preparation process of microemulsion, the temperature of mixing time and environment includes but are not limited to: the above, is finally to be successfully prepared with microemulsion to be as the criterion.
Embodiment 1.2
Preparation method is with embodiment 1.1.
Embodiment 1.3
Preparation method is with embodiment 1.1.
Embodiment 1.4
Preparation method is with embodiment 1.1.
Embodiment 1.5
Preparation method is with embodiment 1.1.
Embodiment 1.6
Preparation method is with embodiment 1.1.
Embodiment 1.7
Preparation method is with embodiment 1.1.
Embodiment 1.8
Preparation method is with embodiment 1.1.
Embodiment 1.9
Preparation method is with embodiment 1.1.
Embodiment 1.10
Preparation method is with embodiment 1.1.
Embodiment 1.11
Preparation method is with embodiment 1.1.
Embodiment 1.12
Preparation method is with embodiment 1.1.
Reference examples 1.13
The preparation of rotigotine olive oil saturated solution, fully mixes 10g rotigotine with 100g olive oil, and centrifugal 10 minutes of 25 DEG C of water bath with thermostatic control 24h, 3600r/min, get supernatant, obtained rotigotine olive oil saturated solution.
Reference examples 1.14
The preparation of rotigotine suspension, by 90g water and the mixing of 10g rotigotine, vortex 10 minutes, obtained rotigotine aqueous suspension.
Rotigotine microemulsion prepared by above-described embodiment 1.1-1.12, and reference examples 1.13,1.14 detects, assay method and result as follows:
1, rotigotine microemulsion droplet measurement
Instrument: Deisa
tMnano C Particle Size Analyzer (BECKMAN COULTER company of the U.S.) temperature is 25 DEG C, and index of refraction is 1.3328.Particle size measurement is in table 1.
2, rotigotine microemulsion vitro permeation assay detects
Test method: carefully slough rat abdomen hair with shaver, raises 24h, peels off skin of abdomen, carefully removes subcutaneus adipose tissue, muscular tissue and adhesion thing, filter paper suck dry moisture.Be placed in by Corium Mus between supply pool and reception tank, assembling Franz diffusion cell, effective diffusion area is 1.34cm
2, stratum corneum side is to supply pool, and skin corium is towards reception tank, fixing.Rotigotine microemulsion 2mL (rotigotine content 1%) is added in supply pool.For reaching sink conditions, 40%PEG normal saline is selected to be receiving liquid.Add quantitative receiving liquid in reception tank and magnetic agitation, timing is got liquid and is supplemented the receiving liquid of equivalent, tests and carries out under 37 DEG C of water bath with thermostatic control conditions.HPLC method measures and calculates 24h accumulation infiltration capacity Q
24(Q
24total amount for the 24 hours accumulative transdermal rotigotines of administration on unit skin area).
Chromatographic condition is chromatographic column: Discovery C18 (250mm × 4.6mm, 5 μm), mobile phase: acetonitrile-0.3% phosphoric acid water (34:66), determined wavelength: 223nm, flow velocity: 1.0mLmin
-1, column temperature: 35 DEG C, sample size: 20 μ L.
Vitro permeation assay testing result is in table 1.
Table 1. rotigotine microemulsion granularity and vitro permeation assay detect table
Table 1 lists embodiment 1.1-1.12, and the particle diameter of reference examples 1.13,1.14 and after carrying out Ligustrazine hydrochloride test in the manner described above, the accumulative transdermal penetration amount of 24 hours.
As seen from Table 1, the aqueous suspension of rotigotine carries out according to above-mentioned experiment method in-vitro percutaneous experiment fails to detect rotigotine release after 24 hours.Because only have the medicine of dissolving just may through skin.Therefore can reach a conclusion: the design of rotigotine microemulsion can increase the transdermal penetration amount of the rotigotine in aqueous medium.
After rotigotine microemulsion carries out Ligustrazine hydrochloride test in the manner described above, the accumulative transdermal penetration amount of 24 hours also can be much higher than rotigotine olive oil saturated solution.Further demonstrate the effect that rotigotine microemulsion promotes rotigotine transdermal penetration.
The preparation of embodiment 2. rotigotine micro emulsion gel
Embodiment 2.1
100g rotigotine microemulsion and the weight content embodiment 1.4 prepared are that the carbomer gel substrate of 1g mixes, fully swelling, obtain rotigotine micro emulsion gel.Wherein abundant swelling finger is at room temperature swelling spends the night or under 40 DEG C of conditions swelling more than 2 hours.Above-mentioned micro emulsion gel swelling process includes but not limited to listed temperature, time, is finally to reach swelling object to be as the criterion.
Also the compositions such as antiseptic, antioxidant, water-retaining agent can be added in above-mentioned rotigotine microemulsion or rotigotine micro emulsion gel.
Embodiment 2.2
100g rotigotine microemulsion and the weight content embodiment 1.5 prepared are that the carbomer gel substrate of 1g mixes, fully swelling, obtain rotigotine micro emulsion gel.
Embodiment 2.3
100g rotigotine microemulsion and the weight content embodiment 1.6 prepared are that the carbomer gel substrate of 1g mixes, fully swelling, obtain rotigotine micro emulsion gel.
Embodiment 2.4
100g rotigotine microemulsion and the weight content embodiment 1.10 prepared are that the carbomer gel substrate of 0.3g mixes, fully swelling, obtain rotigotine micro emulsion gel.
Embodiment 2.5
100g rotigotine microemulsion and the weight content embodiment 1.10 prepared are that the carbomer gel substrate of 0.5g mixes, fully swelling, obtain rotigotine micro emulsion gel.
Embodiment 2.6
100g rotigotine microemulsion and the weight content embodiment 1.10 prepared are that the carbomer gel substrate of 1g mixes, fully swelling, obtain rotigotine micro emulsion gel.
Embodiment 2.7
100g rotigotine microemulsion and the weight content embodiment 1.10 prepared are that the carbomer gel substrate of 5g mixes, fully swelling, obtain rotigotine micro emulsion gel.
The rotigotine micro emulsion gel prepared by above-described embodiment 2.1-2.7 detects, assay method and result as follows:
1, the mensuration of rotigotine micro emulsion gel viscosity
Detect the viscosity of micro emulsion gel with viscometer, temperature is 25 DEG C, and shear rate is 50rpm.Viscosity measurement is in table 2.
2, the Ligustrazine hydrochloride test of rotigotine micro emulsion gel
The acquisition methods of skin, the assembling of Franz diffusion cell and assay method are with " the Ligustrazine hydrochloride test of rotigotine microemulsion ".Embodiment 2.1-2.7 rotigotine micro emulsion gel 2g is added in supply pool.Ligustrazine hydrochloride test measurement result is in table 2.
Table 2. rotigotine micro emulsion gel viscosity and Ligustrazine hydrochloride testing inspection table
3, rotigotine micro emulsion gel is tested at rat abdomen administration artifact availability
LC-MS/MS condition: internal standard substance: (S)-5,6,7,8-tetrahydrochysene-6-[propyl group [4-fluorobenzene ethyl] is amino]-1-naphthalenol hydrochloride.
Chromatographic condition: chromatographic column: Lichrospher C
18mobile phase: methanol: water (70:30,0.1mmol ammonium acetate, 0.05% glacial acetic acid); Column temperature: 25 DEG C; Determined wavelength: 271.5nm; Flow velocity: 0.2mLmin
-1; Sample size: 20 μ L.
Mass Spectrometry Conditions: ion source: electro-spray ionization source (ESI); Ion injection electric: 4000v; Detection mode: cation detection mode; Sheath atmospheric pressure: 30psi; Auxiliary atmospheric pressure: 5psi; Capillary transfer pipe temperature: 350 DEG C; Scan mode: selective response detects (SRM); Collision energy: 25ev; Rotigotine, internal standard substance ion pair: 316.0/147.1,328.1/147.1.
The transdermal patch of sampled plasma and process: embodiment 2.1-2.7 and listing
(9mg pastes
-1).Put administration after 24h in a suitable place to breed after being lost hair or feathers by rat abdomen, dosage is 1.20mgkg
-1, and according to this dosage, the rotigotine gel of corresponding weight is spread evenly across 0.8 × 0.8cm
2on waterproof membrane, be fixed on rat abdomen with medical adhesive tape.Listing patch
by 1.20mgkg
-1corresponding paster (9mg/20cm
2) area cuts out, fixed form is the same.Respectively at 1 after administration, 2,4,6,8,10,12,24,48h gets blood 0.5mL and is placed in 1.5mLEP pipe 3600rmin containing 20 μ L heparin
-1after centrifugal 10min, take out upper plasma-20 DEG C of freezen protective.
Test method: get 100 μ L blank plasmas in glass centrifuge tube with liquid-transfering gun, move the inner mark solution (5.0ngmL adding 10 μ L
-1), eddy current mixes 30s, adds the extractant (normal hexane: dichloromethane: isopropyl alcohol=2:1:0.1) of 3mL again, 3600rmin after eddy current 3min with pipet
-1centrifugal 10min, gets the supernatant in another teat glass with pipet, dries up under nitrogen flowing, then adds 100 μ L mobile phase eddy current 1min and redissolves, 13000rmin
-1centrifugal 10min, gets supernatant LC-MS chromatography determination content.Testing result is in table 3.
4, pharmacokinetic analyses
By the pharmacokinetic parameters after the administration of WinNonlin6.3 computed in software rotigotine micro emulsion gel.Blood concentration-time curve is shown in Fig. 2.
Table 3. rotigotine micro emulsion gel administration artifact availability and pharmacokinetics detect table
Note: AUC
0 → 24and AUC
0 → 48to be respectively after blood concentration-time curve (Fig. 2) administration the area under curve of 24 hours and 48 hours.24hF and 48hF to be respectively after administration 24 hours and 48 hours, and rotigotine micro emulsion gel is relative to listing patch
relative bioavailability.
As seen from Table 3, the design of rotigotine micro emulsion gel can improve the bioavailability of after bioavailability, particularly administration after rotigotine administration 24 hours.
5, skin irritation Journal of Sex Research
Get healthy rat 12 and be divided into two groups at random, often organize 6, first group of rat, to the rotigotine micro emulsion gel 45mg described in embodiment 2.6, gives listing patch for second group
, administration area is 2cm
2, fix with medical adhesive tape respectively.Observe after administration 3d and add up the skin injury situation of two groups of rats, skin injury score is as follows: do not have erythema, remembers 0 point; Red stain quantity <5, remembers 1 point; Red stain quantity 5-10, remembers 2 points; Red stain quantity >10, remembers 3 points.
Result shows, micro emulsion gel group does not observe erythema, must be divided into 0; Listing patch group observes obvious erythema, must be divided into 1.33 ± 0.52.Result is expressed as mean value ± S.D. (n=6).Therefore, rotigotine micro emulsion gel can reduce the incidence rate of skin erythema.
6, stability experiment
The rotigotine micro emulsion gel prepared by embodiment 2.1-2.7 is divided into two parts, and portion is placed in 4 DEG C of refrigerator cold-storages, under another part is placed in room temperature condition.Respectively at 0.5, sampling in 1,2,3,6 months, centrifugal 10min, rotating speed is 3600rmin
-1, observe and whether have lamination or precipitation to produce.
Through the study on the stability of 6 months, be separated through centrifugal appearance or produce precipitation.
Rotigotine micro emulsion gel of the present invention can be processed further and obtain other preparations, as patch, cataplasma etc.
The present invention can summarize with other the concrete form without prejudice to spirit of the present invention or principal character.Therefore, no matter from which point, above-mentioned embodiment of the present invention all can only be thought explanation of the present invention and can not limit the present invention, claims indicate scope of the present invention, and scope of the present invention is not pointed out in above-mentioned explanation, therefore, any change in the implication suitable with claims of the present invention and scope, all should think to be included in the scope of claims.The present invention includes but be not limited to rotigotine microemulsion and process obtained micro emulsion gel further, also comprise rotigotine microemulsion and process obtained spray, membrane, in-situ gel etc. further, also belong to the scope of protection of the invention.
Claims (10)
1. a rotigotine microemulsion, comprise active constituents of medicine and pharmaceutical carrier, it is characterized in that, described active constituents of medicine is rotigotine, described pharmaceutical carrier is oil-in-water microemulsion, and described oil-in-water microemulsion comprises emulsifying agent, co-emulsifier, oil phase and aqueous phase; Described rotigotine microemulsion forms according to following percentage by weight:
。
2. rotigotine microemulsion according to claim 1, is characterized in that, rotigotine microemulsion forms according to following percentage by weight:
。
3. rotigotine microemulsion according to claim 1, is characterized in that, described oil phase be glyceride type and or fatty acid.
4. rotigotine microemulsion according to claim 3, is characterized in that, described oil phase is oleic acid polyethyleneglycol glyceride class and/or caprylic capric triglycerin esters.
5. rotigotine microemulsion according to claim 1, it is characterized in that, described emulsifying agent is the one or more combination thing in sorbitan fatty acid ester polyvinylether, Labraso, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini.
6. rotigotine microemulsion according to claim 1, it is characterized in that, described co-emulsifier is the one or more combination thing in ethanol, propylene glycol, glycerol, Polyethylene Glycol, ethoxydiglycol, polyglycerol acrylate, polyglyceryl-isostearate, sorbitan ester.
7. rotigotine microemulsion according to claim 1, is characterized in that, described aqueous phase is deionized water or distilled water.
8. rotigotine microemulsion according to claim 1, is characterized in that, the particle diameter of described rotigotine microemulsion is 10-100nm.
9. a rotigotine micro emulsion gel, comprises the rotigotine microemulsion described in claim 1-8, it is characterized in that, also comprise Macromolecule glue material, and the percentage by weight of described Macromolecule glue material and described rotigotine microemulsion is 0.3%-3%.
10. a rotigotine micro emulsion gel, is characterized in that, described Macromolecule glue material is carbomer.
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Cited By (1)
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| CN112089684A (en) * | 2020-10-30 | 2020-12-18 | 华东医药（西安）博华制药有限公司 | Levoornidazole/ornidazole oil-in-water emulsion temperature-sensitive gel suppository and preparation method thereof |
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| CN112089684A (en) * | 2020-10-30 | 2020-12-18 | 华东医药（西安）博华制药有限公司 | Levoornidazole/ornidazole oil-in-water emulsion temperature-sensitive gel suppository and preparation method thereof |
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