CN101810908A - Rapid transdermal delivery system of local anesthetics - Google Patents
Rapid transdermal delivery system of local anesthetics Download PDFInfo
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- CN101810908A CN101810908A CN200910058431.2A CN200910058431A CN101810908A CN 101810908 A CN101810908 A CN 101810908A CN 200910058431 A CN200910058431 A CN 200910058431A CN 101810908 A CN101810908 A CN 101810908A
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- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 claims abstract description 8
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- JBFHTYHTHYHCDJ-UHFFFAOYSA-N gamma-caprolactone Chemical compound CCC1CCC(=O)O1 JBFHTYHTHYHCDJ-UHFFFAOYSA-N 0.000 description 1
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Images
Abstract
The invention belongs to the technical field of transdermal delivery, in particular to a rapid transdermal delivery system of local anesthetics, which directly uses a preparation that is loaded with the local anesthetic, characterized by nano-materials and can control the release for transdermal delivery, or adds the preparation into thermo-sensitive gel poloxamer F127 solution with the concentration of 5%-40%, prepares a gel or a cream by regulating the temperature and directly uses the gel or the cream for transdermal delivery, or realizes the rapid transdermal delivery through pretreatment or an ultrasonic transmission device and/or an iontophoresis device treating the skin simultaneously under the common action of ultrasonic introduction, iontophoresis introduction or the combination of the two methods. The rapid transdermal delivery system can lead the transdermal permeation amount, the anesthetic onset time and the anesthetic potency of the local anesthetics, such as lidocaine, tetracaine, prilocaine, bupivacaine, ropivacaine, dicaine and the like to be better than those of the ordinary surface anesthetic preparation, solve the defects of long onset time of the existing surface anesthetic and limited action effects, eliminate the obvious skin irritation and be used for symptomatic treatment of skin anesthesia and neuropathic pain with skin invasive operation.
Description
Technical field: the invention belongs to the percutaneous dosing technical field, be specifically related to a kind of rapid transdermal delivery system of local anesthetics.
Background technology: the percutaneous dosing technology is to make medicine by the intact skin outside initiatively or passively infiltrate into hypodermic administering mode.Because the particularly cuticular barrier action of skin of skin, it is longer that medicine enters the required time of subcutaneous tissue, and the amount that enters is also more limited.The local anaesthetics transdermal administration has been mainly used in the operation of wound skin, inserts as conduit, and the aspects such as treatment of anesthesia of skin surfaces such as skin surgery operation and neuropathic pain are as pain behind the herpes zoster.At present the onset time of Related product still longer, be difficult to the anaesthetic effect that reaches satisfied in the short time, therefore clinical use limits to some extent.
Summary of the invention: the objective of the invention is to overcome the unfavorable technical barrier of anaesthetic effect that there is long and transdermal administration of onset time of local anesthetic transdermal administration in existing percutaneous dosing technology, for people provide the rapid transdermal delivery system of local anesthetics that a kind of onset time is short, anaesthetic effect is good.
The objective of the invention is to realize by following technical proposals.
Rapid transdermal delivery system of local anesthetics of the present invention, by be mounted with local anaesthetics with the nano material be feature can sustained release preparation be directly used in transdermal administration.
In the such scheme, described loading local anesthetic with the nano material be feature can sustained release preparation join in the heat-sensitive gel poloxamer F127 solution of 5%～40% concentration, make gel or ointment by attemperation, be directly used in transdermal administration.
In the such scheme, described loading local anesthetic with the nano material be feature can sustained release preparation be by pretreatment or handle the ultrasonic transmitter and/or the iontophoresis device of skin simultaneously, import or unite under above-mentioned two kinds of method combineds effect and realize rapid transdermal in ultrasonic importing, iontophoresis, described preparation can be gel or ointment.
In the such scheme, described loading local anesthetic with the nano material be feature can sustained release the consisting of of preparation: the polycaprolactone-polyethylene glycol-polycaprolactone nano-particle (PCEC) that loads local anesthetic, also can be the nano-particle of the loading local anesthetic that other can be medical, promptly be not limited only to polycaprolactone-polyethylene glycol-polycaprolactone nano-particle.
In the such scheme, described local anesthetic comprises other local anesthetics such as lignocaine, tetracaine, prilocaine, bupivacaine, ropivacaine, tetracaine.
In the such scheme, the concentration of described local anesthetic in the preparation (gel or ointment) of energy sustained release that with the nano material is feature is respectively 0.5%～10% lignocaine, 0.1%～5% tetracaine, 0.5%～6% prilocaine, 0.1%～5% bupivacaine, 0.1%～5% ropivacaine, 0.1%～5% tetracaine etc.
In the such scheme, its frequency of utilization of described ultrasonic transmitter is 20～100kHz, and intensity is 0.5～20W/cm
2Continuously or the impulse type low frequency ultrasound.
In the such scheme, its frequency range of described iontophoresis device is that 1kHz～5kHz is adjustable, and dutycycle 1/1～1/5 is variable, square wave and sinusoidal wave interchangeable constant current (0.5mA/cm
2).
The present invention is the inventor sums up the science practicality of groping out by long-term practice a technical scheme, compare with existing percutaneous dosing technology, what the present invention used the loading local anaesthetics is the controlled release preparation of feature with the nano material, and it is prepared into emulsifiable paste or gel, after using ultrasonic pretreatment skin, smear said preparation at processing skin place, or said preparation directly handled skin as ultrasonic coupling agent, or spread upon said preparation on the skin and use iontophoresis, or said preparation spread upon on the skin and combining ultrasonic short saturating/the iontophoresis leading-in technique makes the transdermal penetration amount of local anaesthetics, anesthesia onset time and anesthetic potency obviously are better than common topical anesthesia preparation, it is long to have solved present topical anesthetic onset time, the defective that action effect is limited does not have tangible skin irritation simultaneously.The present invention can be used for skin the skin anesthesia of wound operation and the symptomatic treatment of neuropathic pain.
The invention is further illustrated by the following examples, and the present invention is not limited only to described embodiment.
Description of drawings:
Fig. 1 is the ultrasonic importing schematic diagram of the present invention.
Fig. 2 is the The general frame of the ultrasonic generating means of the present invention system.
Fig. 3 is ultrasonic drive circuit figure.
Fig. 4 is the sketch map of ultrasonic method coupling local anaesthetics sustained release preparation of the present invention.
Fig. 5 is iontophoretic principle figure of the present invention.
Fig. 6 iontophoresis The general frame.
Fig. 7 iontophoresis circuit diagram.
The specific embodiment:
The present invention by be mounted with local anaesthetics with the nano material be feature can sustained release preparation, the administration experiment of local anesthetic nanometer formulation rapid transdermal and effect as described below.
Embodiment one: be the preparation of the biodegradation nano-particle gel of example with the benefit caine
Load the preparation process of the nano controlled release preparation of local anesthetic lignocaine:
A. with the stannous octoate catalyst; adopt PEG 4000 (molecular weight is 4000 Polyethylene Glycol) and 6-caprolactone (mass ratio is 1: 24); under the nitrogen protection; 100 degrees centigrade of polyreactions 5 hours; placed 160 degrees centigrade of vacuum then 20 minutes; be cooled to room temperature under the nitrogen protection, obtain the PCEC polymer, the relative molecular weight of this triblock polymer is 1 * 10
4～5 * 10
4
B. will be dissolved in the dichloromethane according to the PCEC polymer that step a makes, and heavily extract, obtain the PCEC polymer of purification with cold petroleum ether.
C. the purification PCEC copolymer and the lignocaine alkali that will make according to step b, under 4 degrees centigrade, be dissolved in the ethyl acetate, in mixing material, add the F127 aqueous solution and with 100,000 rotating speed stirs, and adopts the rotary evaporation legal system must load the nanometer sustained release preparation (aqueous) of lignocaine.
The nanometer sustained release preparation of the aqueous loading lignocaine that d. will make is under 4 degrees centigrade, directly be dissolved in 5%～40% the heat-sensitive gel Pluronic F127 solution, make the nanometer sustained release preparation (gel) that loads lignocaine under the room temperature, also can make ointment by attemperation.
The mean diameter of the nano controlled release preparation nanometer of the loading lignocaine of method for preparing is 20～300 nanometers, and polydispersity index is 0.01～0.2, and nanoparticle surface Zeta potential is-15～35mV.Above parameter adopts Ma Erwen particle size determination instrument fixed.It is 10～400 nanometers that its parameter areas of local anesthetic such as loading tetracaine, prilocaine, bupivacaine, ropivacaine, tetracaine are controlled at mean diameter, and polydispersity index is 0.01～0.3, and nanoparticle surface Zeta potential is-10～40mV.
Embodiment two: be the rapid transdermal medication and the compliance test result of example biodegradation nano-particle gel with the benefit caine
Lignocaine alkali, white crystal, 75～79 degrees centigrade of fusing points, water-soluble, ethanol, benzene, chloroform, oils, its hydrochlorate commonly used.Imitate local anesthetic in commonly used, be applicable to topical anesthesia, infiltration anesthesia and conduction block.Be applied in intact skin merely and do not have the skin anaesthetic effect.It is the congruent melting system of commercially available lignocaine and prilocaine that grace is received emulsifiable paste, contains 2.5% lignocaine and 2.5% prilocaine, and the surface is smeared back onset time and reached one hour.Be unfavorable for clinical use.In order to accelerate the onset time of skin anesthesia, strengthen anaesthetic effect, the present invention has prepared the nano-particle gel that loads lignocaine, and the short physical method such as saturating of the ultrasonic short saturating or iontophoresis of coupling has carried out the diffusion cell permeability test of isolated skin and in the body zoopery.
The compliance test result method of above-mentioned local anesthetic rapid transdermal administration is: adopt two Room diffusion cells to carry out isolated rat skin transdermal experiment and investigate the isolated skin osmotic effect; Adopt rat whipping The effects use said method at the body anesthetic potency, anesthesia onset time and animal skin zest.
1, the diffusion cell transdermal experiment:
Being grouped into of transdermal administration: marketed drugs matched group (grace receive emulsifiable paste), the nano controlled release preparation group of above-mentioned loading lignocaine; Ultrasonic pretreatment Jia Enna group; Ultrasonic pretreatment adds the nano controlled release preparation group of loading lignocaine; Iontophoresis Jia Enna group; Iontophoresis adds the nano controlled release preparation group of loading lignocaine.
Adopt two Room diffusion cells (diffusion cell diameter 9mm, diffusion area 0.63585cm
2, accept pool volume 5.0ml) to accept to be full of in the pond and contain 5% alcoholic acid PBS liquid as acceptable solution, isolated rat skin is sandwiched between two Room, and epidermis side is to supply pool.On epidermis, place pharmaceutical preparation.Accept the pond and keep 37 degrees centigrade of waters bath with thermostatic control, constant speed stirs in the pond, rotating speed 300rbp.Took out the 0.6ml acceptable solution, and adopted the GC-MS method to measure wherein medicament contg, and in accepting the pond, replenish isopyknic blank acceptable solution in the 10th, 30 and 60 minute behind the placement medicine.Ultrasonic pretreated method is: isolated rat skin and ultrasonic emitting probe are dipped in the water, and stratum corneum side is to probe, at a distance of 1mm.After the ultrasonication 10 minutes, take out skin, place on the diffusion cell.The method of iontophoresis is: anelectrode is inserted supply pool, touch the medicine of skin surface, anelectrode inserts and accepts in the liquid in pond, and electrode area equates with the diffusion cell area.Medicine was placed the back closed circuit 10 minutes.Utilize the GC-MS method to measure different time and accept drug level in the pond, according to accept cell body long-pending and effectively the skin diffusion area try to achieve drug per unit area infiltration capacity (the unit are accumulation drug osmotic amount that will reach stable state obtains the transdermal penetration speed of straight slope as medicine with the time recurrence).
2, the experiment of rat whipping:
Rat whipping experimental technique is that rat is put in the holder, and afterbody exposes.Afterbody veutro China and foreign countries 1/3rd intersections as test point, are marked with marking pen.This is disposed on the heat launch hole of rat whipping instrument.The heat of emission constant intensity, the time that the beginning emitting heat quantity is thrown away to the Mus tail from launch hole is whipping time delay.According to the whipping time delay before and after handling and set in advance for to prevent that the dwell time of skin burn from calculating anaesthetic effect (accounting for the percentage rate of holonarcosis), and judge thus and anaesthetize onset time and anesthetic potency.
This example experiment grouping is with external test grouping.48 healthy adult SD rats are divided into 6 groups at random, male and female half and half, body weight 250～350 grams.Measure the whipping time reference line before being tried, every group of rat gives skin surface respectively and smears grace and receive emulsifiable paste, skin surface and smear and smear grace after the nano controlled release preparation of above-mentioned loading lignocaine, the ultrasonic pretreatment and receive and smear the nano controlled release preparation, the skin surface that load lignocaine after emulsifiable paste, the ultrasonic pretreatment and smear grace and receive that emulsifiable paste associating iontophoresis imports, skin surface is smeared the processing such as nano controlled release preparation associating iontophoresis importing of loading lignocaine, in one hour, measure whipping time expand in per 10 minutes one time, and calculate anaesthetic effect.In the experiment and experiment end back 2 all situations that the local skin tissue has not damaged or irritative response of handling of observing.
Experimental result shows the physical method use in conjunction local anaesthetics nanometer formulation that adopts ultrasonic and iontophoresis, and transdermal penetration amount in the isolated experiment and infiltration rate are apparently higher than commercially available contrast (grace receive emulsifiable paste) and medicament-carried nano preparation; Anaesthetize onset time obviously than commercially available contrast and the simple local anaesthetics nanometer formulation weak point of using in body is tested, anesthetic potency is obviously higher; And do not observe the damage and the irritative response of skin.It is long to have solved present commercially available surperficial local anaesthetics preparation onset time, and the problem that anaesthetic effect is limited because the nanometer formulation material of local anaesthetics is a biodegradation material, has been avoided the zest of medicine to skin simultaneously.The present invention can be applicable to the treatment that skin has preoperative skin anesthesia of wound and neuropathic pain.See table 1 for details.
Lignocaine nano controlled release preparation (gel) transdermal experiment of table 1 different disposal and at body experimental result (n=6)
Experimental result shows that ultrasonic pretreatment or iontophoresis are handled the transdermal penetration amount of associating nanometer formulation group, anaesthetized onset time, anesthetic potency obviously is better than commercially available matched group, and does not have tangible skin irritation.
As shown in Figure 1: ultrasonic gatherer of the present invention, the principle of its ultrasonic importing is: when low-frequency ultrasonic waves acts on skin surface, because " cavitation " of sound wave causes the structural change of keratodermatitis, form water miscible passage, thereby promote medicine to see through skin.Ultrasound wave is closely related to intensity, frequency, the action time of the damage of skin and sound wave, can cause damage to skin hardly during low-intensity.To the skin ultrasonic pretreatment, the nanometer formulation that will load lignocaine then is applied to skin surface earlier, and the water solublity passage that medicine will cause on skin by ultrasound wave rapidly enters subcutaneous.
As shown in Figure 5: iontophoresis gatherer of the present invention, the principle that its iontophoresis imports is: after lignocaine is loaded in the nano-particle, nano-particle has the characteristic of surface charging in solution, reflect the index of its surface charging character and size with Zeta potential.The nano-particle that is loaded with lignocaine is used for transdermal, can utilizes its charged characteristic, the transdermal horny layer enters subcutaneous tissue under the effect of electric field force, plays the local skin anesthetic action.Result of study shows, electronegative nano-particle can improve the transdermal penetration speed and the transdermal penetration amount of medicine as pharmaceutical carrier, and the negative charge in electronegative nano-particle and the skin repels mutually, forms the water solublity passage medicine is comparatively fast passed through.Because selecting nano material for use is biodegradable material, can reduce stimulation and damage to skin, and the electric osmose electric field that applies is faint, harmless.
The principle that above-mentioned ultrasonic importing of the present invention and iontophoresis import use in conjunction is: utilize cavitation effect of ultrasonic waves to cause cuticular temporary water solublity passage, and utilize the extra electric field power of iontophoresis simultaneously, make the nano controlled release preparation molecule of charged loading local anaesthetics enter subcutaneous tissue by above-mentioned water solublity passage and the appendages of skin own fast.
As Fig. 2～rapid transdermal delivery system of local anesthetics of the present invention shown in Figure 4, be to use the feature and the schedulable low frequency ultrasound generator of frequency, intensity, waveform releasing mode that skin is carried out pretreatment or processing simultaneously: frequency of utilization is 20～100kHz, and intensity is 0.5～20W/cm
2Continuously or the impulse type low frequency ultrasound skin is carried out pretreatment and effect, the sketch map such as the Figure of description 4 of ultrasonic method coupling local anaesthetics sustained release preparation, the The general frame of ultrasonic generator such as Figure of description 2, the drive circuit of ultrasonic transducer such as Figure of description 3.
Among Fig. 4: (a) use ultrasonic pretreatment skin; (b) smear said preparation at processing skin place; (c) said preparation is directly handled skin as ultrasonic coupling agent.Among the figure: A: the ultrasound emission probe, B: ultrasonic coupling agent, C: skin, D: what load local anaesthetics is the controlled release preparation of feature with the nano material.
As Fig. 5～rapid transdermal delivery system of local anesthetics of the present invention shown in Figure 7, be to use electric field action, iontophoresis that skin is handled and synergism: frequency range 1kHz～5kHz is adjustable, dutycycle 1/1～1/5 is variable, square wave and sinusoidal wave interchangeable constant current (0.5mA/cm
2), the skin that medicine contacted is handled.Iontophoretic principle figure such as Figure of description 5, The general frame such as Figure of description 6, Key Circuit such as Figure of description 7.
Every technological parameter of the above-mentioned preparation method of the present invention can be adjusted in proper range, is not limited only to described embodiment.The basic skills that adopts above-mentioned preparation to load the nano controlled release preparation of lignocaine can make the nano controlled release preparation (gel or ointment) of anesthetics such as loading tetracaine, prilocaine, bupivacaine, ropivacaine, tetracaine equally, its medication and administration experiment are also basic identical, and can obtain good effect equally, the present invention is an example with the nano controlled release preparation that loads lignocaine only, and all the other are in this not statement one by one.The concentration of described local anesthetic in the preparation (gel or ointment) of energy sustained release that with the nano material is feature is respectively 0.5%～10% lignocaine, 0.1%～5% tetracaine, 0.5%～6% prilocaine, 0.1%～5% bupivacaine, 0.1%～5% ropivacaine, 0.1%～5% tetracaine etc.
Claims (8)
1. rapid transdermal delivery system of local anesthetics, it is characterized in that be by be mounted with local anaesthetics with the nano material be feature can sustained release preparation be directly used in transdermal administration.
2. according to the described rapid transdermal delivery system of local anesthetics of claim 1, it is characterized in that described loading local anesthetic with the nano material be feature can sustained release preparation join in the heat-sensitive gel poloxamer F127 solution of 5%～40% concentration, make gel or ointment by attemperation, be directly used in transdermal administration.
3. according to claim 1 or 2 described rapid transdermal delivery system of local anesthetics, it is characterized in that described loading local anesthetic with the nano material be feature can sustained release preparation be by pretreatment or handle the ultrasonic transmitter and/or the iontophoresis device of skin simultaneously, import or unite under above-mentioned two kinds of method combineds effect and realize rapid transdermal in ultrasonic importing, iontophoresis, described preparation is gel or ointment.
4. according to claim 1 or 2 described rapid transdermal delivery system of local anesthetics, it is characterized in that described loading local anesthetic with the nano material be feature can sustained release the consisting of of preparation: load the polycaprolactone-polyethylene glycol-polycaprolactone nano-particle (PCEC) of local anesthetic or the nano-particle of the loading local anesthetic that other can be medical.
5. according to the described rapid transdermal delivery system of local anesthetics of claim 1～4, it is characterized in that described local anesthetic comprises lignocaine, tetracaine, prilocaine, bupivacaine, ropivacaine, tetracaine.
6. according to the described rapid transdermal delivery system of local anesthetics of claim 5, it is characterized in that the concentration of described local anesthetic in the preparation (gel or ointment) of energy sustained release that with the nano material is feature is respectively 0.5%～10% lignocaine, 0.1%～5% tetracaine, 0.5%～6% prilocaine, 0.1%～5% bupivacaine, 0.1%～5% ropivacaine, 0.1%～5% tetracaine.
7. according to the described rapid transdermal delivery system of local anesthetics of claim 3, it is characterized in that its frequency of utilization of described ultrasonic transmitter is 20～100kHz, intensity is 0.5～20W/cm
2Continuously or the impulse type low frequency ultrasound.
8. according to the described rapid transdermal delivery system of local anesthetics of claim 3, it is characterized in that its frequency range of described iontophoresis device is that 1kHz～5kHz is adjustable, dutycycle 1/1～1/5 is variable, square wave and sinusoidal wave interchangeable constant current (0.5mA/cm
2).
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