CN101897977A - Application of ionic type cyclodextrin derivative in preparation of medicine preparation for iontophoresis transdermal administration - Google Patents
Application of ionic type cyclodextrin derivative in preparation of medicine preparation for iontophoresis transdermal administration Download PDFInfo
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Abstract
The invention discloses the application of ionic type cyclodextrin derivative in preparation of medicine preparation for iontophoresis transdermal administration. The ionic type cyclodextrin derivative comprises one or two of cationic cyclodextrin derivative and anionic cyclodextrin derivative; the medicine is selected from one or more of molecular type medicine, charged medicine with the dissolubility less than 1mg/ml, faintly acid charged medicine with the dissociation constant p Ka larger than 4, or alkalescent charged medicine with the dissociation constant p Ka less than 4. The ionic type cyclodextrin derivative applied to the iontophoresis transdermal administration improves the transdermal penetration rate of the molecular type medicinem and the charged medicine with low dissolubility or degree of dissociation.
Description
Technical field
The present invention relates to the application of cyclodextrin derivative, be specifically related to a kind of ion-type cyclodextrin derivative is used for the pharmaceutical preparation of iontophoresis transdermal administration in preparation application.
Background technology
Modern transdermal administration technology begins the fast development in more than 30 year through the seventies in last century of associating, by with the application that combines that comprises many technology such as physics, chemistry and biology, researched and developed out more than 30 kind of percutaneous plaster (TTS) product.The transdermal administration technology rapid development is because transdermal administration has the advantage of its uniqueness, can avoid the first pass effect of liver and medicine to degrade at gastrointestinal as transdermal administration; Medicine can speed on demand discharge, and keeps constant effective blood drug concentration, avoids the blood drug level peak valley phenomenon, has reduced toxicity; Can reduce administration number of times, improve patient's compliance.
At present, because the barrier action of keratodermatitis, most of medicine enters sanguimotor amount through skin and does not reach effective blood drug concentration.Therefore, researcheres are devoted to adopt the whole bag of tricks to promote the transdermal penetration of medicine, as use chemical penetrating agent, make prodrug, use the electroporation technology of iontophoresis technology and development recently etc.Iontophoresis (iontophoresis) technology is to utilize electric current that medicine ion is imported skin via positioning of electrode, enters local organization or sanguimotor a kind of method; Its operation principle is to place positive and negative two electrodes and import electric current at skin surface, electric current sees through skin and form the loop between two electrode, the potential difference that the skin both sides have (being electromotive force) promptly becomes the driving force of medicine ion by the skin transhipment, medicine ion is by the principle of electrically repelling each other, and cationic drug sees through skin at anode, anion medicine at negative electrode.The iontophoresis technology is a kind of very potential method that promotes the drug transdermal infiltration, it can solve the transdermal administration problem that is difficult to macromolecular drugs such as more transdermal medicines such as ionic drug and polypeptide, protein under the passive diffusion, significantly improve the transdermal penetration speed and the transdermal penetration amount of medicine, and safe, controlled, developed into a kind of important means of drug transdermal administration.The iontophoresis technology also can be used for the treatment of systemic disease except that the administration that is used for the local organization disease.But because the main effective object that the prior art intermediate ion imports is an ionic drug, the dissociated state of medicine is very big to the iontophoresis influence, and the drug utilization iontophoresis technology of nonionic (or degree of dissociation is little) is difficult to reach effective transdermal effect.
The maximum feature of cyclodextrin be can be in the molecule hole the organic and inorganic and even gas molecule that adapts of enclose size and shape and its hole, formation unimolecule clathrate, so be used for preparing cyclodextrin clathrate more.Cyclodextrin clathrate (Cyclodextrins inclusion compound) is meant that drug molecule is involved or embeds the ultra micron dispersion thing that forms in the tubular structure of cyclodextrin.After medicine is made cyclodextrin clathrate, have the following advantages: (1) improves the solubility property of medicine; (2) improve stability of drug; (3) improve the absorption of medicine and improve bioavailability; (4) toxic and side effects of reduction medicine and zest etc.But the raising to the transdermal penetration effect of medicine when cyclodextrin clathrate is directly used in transdermal administration is limited.And yet there are no the ion-type cyclodextrin in the domestic and foreign literature in the relevant report that promotes aspect the medicine ion importing.
Summary of the invention
The invention provides a kind of ion-type cyclodextrin derivative is used for the pharmaceutical preparation of iontophoresis transdermal administration in preparation application, not only can increase the dissolubility of medicine by the ion-type cyclodextrin derivative, but also can strengthen the reaction of medicine to electric field, improve the transdermal penetration speed of iontophoresis.
A kind of ion-type cyclodextrin derivative is used for the application of the pharmaceutical preparation of iontophoresis transdermal administration in preparation.
Because medicine can enter the inner chamber of ion-type cyclodextrin derivative, the part of drug molecule or some functional group are by enclose, perhaps medicine and ion-type cyclodextrin derivative combine by molecular separating force, ion-type cyclodextrin derivative enclose medicine or with after medicine combines, charged ion-type cyclodextrin derivative can carry medicine and passes through skin under electric field action.Therefore, in the iontophoresis transdermal administration, use ion-type cyclodextrin inclusion compound medicine or use the ion-type cyclodextrin and combine with medicine, not only can increase the dissolubility of medicine, but also can strengthen the reaction of medicine to electric field, improve the transdermal penetration speed and the drug transdermal infiltration capacity of iontophoresis.
As preferably:
Described ion-type cyclodextrin derivative comprises one or both in cationic cyclodextrin derivative, the anionic cyclodextrin derivative.
Described cationic cyclodextrin derivative is selected from any one or more in quaternaries cation type-beta-schardinger dextrin-.
Described anionic cyclodextrin derivative is selected from any one or more in carboxymethyl-beta-cyclodextrin, sulfo--beta-schardinger dextrin-, the sulphur butyl-beta-schardinger dextrin-.
The present invention finds, the ion-type cyclodextrin derivative can promote the transdermal penetration of medicine under electric field, especially can promote the transdermal penetration of molecule-type medicine under electric field, and promote the transdermal penetration of the electrically charged medicine that dissolubility is little or degree of dissociation is little (as dissolubility less than the electrically charged medicine of 1mg/ml, dissociation constant pKa greater than the electrically charged medicine of 4 faintly acid or dissociation constant pKa less than the electrically charged medicine of 4 alkalescence) under electric field, and medicine can exist with clathrate or alternate manner with the ion-type cyclodextrin derivative.Therefore, described medicine can select for use molecule-type medicine, dissolubility less than the electrically charged medicine of 1mg/ml, dissociation constant pKa greater than the electrically charged medicine of 4 faintly acid or dissociation constant pKa less than in the electrically charged medicine of 4 alkalescence any one or more.Can select molecule-type medicine hydrocortisone, prednisone, prednisolone, triamcinolone acetonide, dexamethasone, fluorine hydroxyl cortisone, fluocinolone acetonide, betamethasone, estradiol, Progesterone, ethinylestradiol, ethisterone etc. for use, any one or more in the electrically charged medicine meloxicam that dissolubility is little or degree of dissociation is little, Phenylbutazone, ibuprofen, ketoprofen, naproxen, indomethacin, the piroxicam etc.
Described pharmaceutical preparation can be made into and comprises the various dosage forms that are applicable to that iontophoresis is used, and is generally liquid preparation or semi-solid preparation, as dosage forms such as solution, suspensoid, gel, ointment or other external preparation, is used for part or whole body therapeutic.
Described pharmaceutical preparation Chinese medicine directly mixes with the ion-type cyclodextrin derivative or in advance medicine and ion-type cyclodextrin derivative is made the pharmaceutical pack compound.
During concrete operations, the ion-type cyclodextrin derivative can be dissolved in water or contain in the aqueous solution of other organic solvent (as ethanol, propylene glycol etc.), add the medicine stirring and dissolving, medicine enters in the cyclodextrin molecular hole, charged cyclodextrin derivative carries the electrode movement of medicine to opposite charges under electric field, finishes iontophoresis by skin.
Discover: with respect to the amount of medicine, increase along with ion-type cyclodextrin derivative consumption, the facilitation of iontophoresis also strengthens, but when the combination of medicine and ion-type cyclodextrin derivative is saturated, increase ion-type cyclodextrin derivative consumption, the facilitation that can not further strengthen iontophoresis can to a certain degree reduce the effect of iontophoresis on the contrary.Thereby the mass percentage concentration of described pharmaceutical preparation intermediate ion type cyclodextrin derivative is preferably smaller or equal to 20%.The optium concentration of described pharmaceutical preparation intermediate ion type cyclodextrin derivative, different and different with medicine, can screen by optimization experiment.
Iontophoresis is under electric field action, with the percutaneous process of ionic drug.There are three elements in the iontophoresis system, and they are power supply, drug depot system and the storage storehouse system that refluxes.When positive and negative two electrodes and the contact skin that are connected with power supply, the electron stream of power supply arrives the drug depot system transition and becomes ion flow, and ion flow imports skin through anelectrode or negative electrode, turns to the storage storehouse system that refluxes below skin, is transformed into electron stream again.The present invention adopt contain the aqueous solution of medicine and ion-type cyclodextrin derivative or contain medicine and ion-type cyclodextrin derivative and other organic aqueous medium (comprising solution, suspensoid, gel, ointment or other suitable external preparations etc.) as the drug depot system.The drug depot system places on the skin, and drug depot is put positive pole when using cationic cyclodextrin derivative, and drug depot is put negative pole when using the anionic cyclodextrin derivative.The after-potential of connecting with the mains is ordered about medicine to placing the opposite electrode on another position of skin to move.The ion-type cyclodextrin derivative can together add in the drug depot system with medicine; Also medicine and ion-type cyclodextrin derivative can be prepared into clathrate earlier adds in the drug depot system again.
Iontophoresis transdermal experiment method:
Adopt two Room iontophoresis diffusion cells or single chamber iontophoresis diffusion cell, supply reservoir is placed the drug depot system, insert anelectrode or negative electrode and (insert anelectrode in the drug depot system during cation type cyclodextrin derivative, insert negative electrode when containing the anionic cyclodextrin derivative in the drug depot system), place aqueous medium in the reception tank as acceptable solution, insert with the drug depot system in opposite electrical electrode.Isolated skin is sandwiched between two Room, and stratum corneum side is to supply reservoir, keeps constant speed to stir and 32 ℃ constant temperature water bath.Take out acceptable solution at the interval of setting respectively, replenish the equal-volume acceptable solution simultaneously.Adopt the HPLC method to measure the wherein content of active medicine.
Utilize the HPLC method to measure the concentration of different time acceptable solution Chinese medicine, according to reception tank volume, the effective diffusion area of skin, try to achieve unit are accumulation drug osmotic amount, the straight slope that the unit are accumulation drug osmotic amount that will reach stable state and time recurrence obtain is as the transdermal penetration speed of medicine.
Compared with prior art, the present invention has following advantage:
The present invention uses the ion-type cyclodextrin derivative in the iontophoresis transdermal administration, improved molecule-type medicine, dissolubility is little or the transdermal penetration speed of the little electrically charged medicine of degree of dissociation; Can be used for the treatment of local diseases such as bone, joint, soft tissue and skin; Medicine also can be absorbed and enter the body circulation, is used for the treatment of general disease.
The application of ion-type cyclodextrin derivative of the present invention not only makes uncharged molecule-type medicine that charged carrier has been arranged, and can also increase the dissolubility of medicine, improves the transdermal penetration speed that medicine ion imports; And strengthened of the reaction of the little or degree of dissociation little electrically charged medicine of dissolubility to electric field by the ion-type cyclodextrin derivative, improve the efficient of iontophoresis.
Description of drawings
Fig. 1 is the drug-time curve of hydrocortisone among the embodiment 1;
Fig. 2 is the drug-time curve of hydrocortisone among the embodiment 2;
Fig. 3 is the drug-time curve of estradiol among the embodiment 3;
Fig. 4 is the drug-time curve of meloxicam iontophoresis among the embodiment 4.
The specific embodiment
With sulphur butyl-beta-schardinger dextrin-is example, investigates the ion-type cyclodextrin derivative to molecule-type medicine hydrocortisone, estradiol, the raising effect of the iontophoresis transdermal penetration of the electrically charged medicine meloxicam that dissolubility is little or degree of dissociation is little.The result shows that drug transdermal infiltration capacity and infiltration rate are significantly higher than the common passive diffusion of medicine, also is significantly higher than the common medicine ion of ion-type cyclodextrin derivative that do not use and imports.
Embodiment 1
5% sulphur butyl-beta-schardinger dextrin-(SBE-CD) is to the promotion of hydrocortisone (HS) iontophoresis
It is the phosphate buffer solution (PBS) of 5% SBE-CD that the hydrocortisone that 1g is excessive places 100ml SBE-CD mass percentage concentration, and magnetic agitation forms the HS-SBE-CD inclusion complex in solution.
Other gets the 1g hydrocortisone and places 100ml phosphate buffer solution (PBS), and magnetic agitation is even, forms contrast liquid.
Remove the rat body skin that removes subcutaneous tissue, be fixed between the supply reservoir and reception tank of horizontal transdermal two Room iontophoresis diffusion cells, drain bubble, recirculated water keeps (32 ± 0.5) ℃.Place above-mentioned HS-SBE-CD inclusion complex in solution or contrast liquid in the supply reservoir, reception tank is acceptable solution with PBS, adds the speed stirring of stirrer with 500r/min, and electrode is Pt, and negative electrode imports, and current intensity is 0.4mA/0.79cm
2, carry out iontophoresis.Respectively at 0h, 3h, 5h, 7h, 9h gets the 1ml acceptable solution during 11h, and the acceptable solution of additional equivalent equality of temperature.The acceptable solution of obtaining filters with the microstrainer that 0.45 μ m microporous filter membrane is housed, and abandons filtrate just, gets subsequent filtrate and carries out high-efficient liquid phase analysis.
Chromatographic condition: Hewlett-Packard's 1100 high performance liquid chromatogram, chromatographic column Hypersil BDS-C18 (250mm * 4.6mm, 5 μ m), mobile phase is methanol-water (volume ratio of methanol and water is 7: 3), and flow velocity is 1ml/min, and the detection wavelength is 240nm, sample size is 20 μ l, and theoretical pedal number is not less than 3 * 10
3Measure peak area, outer marking quantitative.
After testing, the drug-time curve (iontophoresis) of hydrocortisone when adopting HS-SBE-CD inclusion complex in solution iontophoresis, and adopt the HS-SBE-CD inclusion complex in solution during the impassive diffusion of added electric field the drug-time curve (passive diffusion) of hydrocortisone as Fig. 1.The drug per unit area of HS-SBE-CD inclusion complex in solution iontophoresis and passive diffusion accumulation infiltration capacity Q (μ g/cm during 11h
2) be respectively (34.79 ± 2.623) μ g/cm
2(2.811 ± 0.612) μ g/cm
2, steady-state permeation speed J (the μ gcm of medicine
-2H
-1) be respectively (4.734 ± 0.397) μ gcm
-2H
-1(0.269 ± 0.061) μ gcm
-2H
-1(n=6).
The contrast liquid that hydrocortisone places phosphate buffer solution to form, under electric field under iontophoresis and the passive diffusion both of these case of added electric field not, in 0h, 3h, 5h, 7h, 9h, hydrocortisone concentration is very low in the 1ml acceptable solution of getting during 11h, all can not measure.
The above results shows, the pharmaceutical preparation of adopting the preparation of ion-type cyclodextrin derivative transdermal penetration amount and infiltration rate when being used for the iontophoresis transdermal administration are significantly higher than transdermal penetration amount and the infiltration rate during the impassive diffusion of added electric field of medicine, also are significantly higher than the transdermal penetration amount and the infiltration rate of the iontophoresis of the common medicine that does not use the ion-type cyclodextrin derivative.
10% sulphur butyl-beta-schardinger dextrin-(SBE-CD) is to the promotion of hydrocortisone (HS) iontophoresis
It is the phosphate buffer solution (PBS) of 10% SBE-CD that the hydrocortisone that 2g is excessive places 100ml SBE-CD mass percentage concentration, and magnetic agitation forms the HS-SBE-CD inclusion complex in solution.
Other gets the 2g hydrocortisone and places 100ml phosphate buffer solution (PBS), and magnetic agitation is even, forms contrast liquid.
Remove the rat body skin that removes subcutaneous tissue, be fixed between the supply reservoir and reception tank of horizontal transdermal two Room iontophoresis diffusion cells, drain bubble, recirculated water keeps (32 ± 0.5) ℃.Place above-mentioned HS-SBE-CD inclusion complex in solution or contrast liquid in the supply reservoir, reception tank is acceptable solution with PBS, adds the speed stirring of stirrer with 500r/min, and electrode is Pt, and negative electrode imports, and current intensity is 0.4mA/0.79cm
2, carry out iontophoresis.Respectively at 0.5h, 1h, 2h, 3h, 4h, 5h, 7h, 9h, 11h gets the 1ml acceptable solution during 13h, and the acceptable solution of additional equivalent equality of temperature.The acceptable solution of obtaining filters with the microstrainer that 0.45 μ m microporous filter membrane is housed, and abandons filtrate just, gets subsequent filtrate and carries out high-efficient liquid phase analysis.
Chromatographic condition is with embodiment 1.Measure peak area, outer marking quantitative.
After testing, the drug-time curve (iontophoresis) of hydrocortisone when adopting HS-SBE-CD inclusion complex in solution iontophoresis, and adopt the HS-SBE-CD inclusion complex in solution during the impassive diffusion of added electric field the drug-time curve (passive diffusion) of hydrocortisone as Fig. 2.The drug per unit area of HS-SBE-CD inclusion complex in solution iontophoresis and passive diffusion accumulation infiltration capacity Q (μ g/cm during 13h
2) be respectively (65.24 ± 16.94) μ g/cm
2(10.43 ± 7.55) μ g/cm
2, steady-state permeation speed J (the μ gcm of medicine
-2H
-1) be respectively (10.40 ± 2.94) μ gcm
-2H
-1(1.14 ± 0.63) μ gcm
-2H
-1(n=6).
The contrast liquid that hydrocortisone places phosphate buffer solution to form, under electric field under iontophoresis and the passive diffusion both of these case of added electric field not, in 0.5h, 1h, 2h, 3h, 4h, 5h, 7h, 9h, 11h, hydrocortisone concentration is very low in the 1ml acceptable solution of getting during 13h, all can not measure.
The above results shows, the pharmaceutical preparation of adopting the preparation of ion-type cyclodextrin derivative transdermal penetration amount and infiltration rate when being used for the iontophoresis transdermal administration are significantly higher than transdermal penetration amount and the infiltration rate during the impassive diffusion of added electric field of medicine, also are significantly higher than the transdermal penetration amount and the infiltration rate of the iontophoresis of the common medicine that does not use the ion-type cyclodextrin derivative.
Embodiment 3
Sulphur butyl-beta-schardinger dextrin-(SBE-CD) is to the promotion of estradiol (ES) iontophoresis
It is the phosphate buffer solution (PBS) of 5% SBE-CD that the estradiol that 1.5g is excessive places 10ml SBE-CD mass percentage concentration, and magnetic agitation forms the ES-SBE-CD inclusion complex in solution.
Remove the rat body skin that removes subcutaneous tissue, be fixed between the supply reservoir and reception tank of horizontal transdermal two Room iontophoresis diffusion cells, drain bubble, recirculated water keeps (32 ± 0.5) ℃.Place above-mentioned ES-SBE-CD inclusion complex in solution in the supply reservoir, reception tank is acceptable solution with PBS, adds the speed stirring of stirrer with 500r/min, and electrode is Pt, and negative electrode imports, and current intensity is 0.4mA/0.79cm
2, carry out iontophoresis.Respectively at 1h, 2h, 3h, 4h, 6h, 8h, 10h gets the 1ml acceptable solution during 12h, and the acceptable solution of additional equivalent equality of temperature.The acceptable solution of obtaining filters with the microstrainer that 0.45 μ m microporous filter membrane is housed, and abandons filtrate just, gets subsequent filtrate and carries out high-efficient liquid phase analysis.
Chromatographic condition: except mobile phase is methanol-water (volume ratio of methanol and water is 75: 25), flow velocity is 1ml/min, and the detection wavelength is 280nm, and sample size is 20 μ l, and all the other are with embodiment 1.Measure peak area, outer marking quantitative.
After testing, the drug-time curve (iontophoresis) of estradiol when adopting ES-SBE-CD inclusion complex in solution iontophoresis, and adopt the ES-SBE-CD inclusion complex in solution during the impassive diffusion of added electric field the drug-time curve (passive diffusion) of estradiol as Fig. 3.The drug per unit area of ES-SBE-CD inclusion complex in solution iontophoresis and passive diffusion accumulation infiltration capacity Q (μ g/cm during 12h
2) be respectively (207.686 ± 26.679) μ g/cm
2(45.198 ± 2.691) μ g/cm
2, steady-state permeation speed J (the μ gcm of medicine
-2H
-1) be respectively (18.82 ± 0.29) μ gcm
-2H
-1(3.94 ± 0.51) μ gcm
-2H
-1(n=6).
The concentration of estradiol is measured in the saturated solution that excessive estradiol is formed in the phosphate buffer solution of 5% SBE-CD, and the dissolubility that must find estradiol is (154092.1 ± 1851.525) μ gml
-1, and the dissolubility of estradiol is (114.78 ± 3.49) μ gml in the saturated solution that excessive estradiol forms in phosphate buffer solution
-1, as seen, sulphur butyl-beta-schardinger dextrin-can also increase the dissolubility of estradiol.Therefore, the transdermal penetration amount of estradiol that does not add the ion-type cyclodextrin derivative is very little, and electric field is to its not influence basically.
The above results shows, the pharmaceutical preparation of adopting the preparation of ion-type cyclodextrin derivative transdermal penetration amount and infiltration rate when being used for the iontophoresis transdermal administration are significantly higher than transdermal penetration amount and the infiltration rate during the impassive diffusion of added electric field of medicine, also are significantly higher than the transdermal penetration amount and the infiltration rate of the iontophoresis of the common medicine that does not use the ion-type cyclodextrin derivative.
Sulphur butyl-beta-schardinger dextrin-(SBE-CD) is to the promotion of meloxicam iontophoresis
It is pH7.4 phosphate buffer solution (PBS) 100ml of 10% SBE-CD that the 1g meloxicam is placed the SBE-CD mass percentage concentration, magnetic agitation, form meloxicam-SBE-CD suspension that iontophoresis is used, constant with the concentration that keeps the experimentation meloxicam.
Other gets the 1g meloxicam and places the pH7.4 phosphate buffer solution, and same preparation does not contain the meloxicam suspension of SBE-CD, forms contrast liquid.
Remove the rat body skin that removes subcutaneous tissue, be fixed between the supply reservoir and reception tank of horizontal transdermal two Room iontophoresis diffusion cells, drain bubble, recirculated water keeps (32 ± 0.5) ℃.Place above-mentioned meloxicam-SBE-CD suspension or contrast liquid in the supply reservoir, reception tank is that 20% ethanol pH7.4PBS liquid is acceptable solution with the ethanol concentration expressed in percentage by volume, adds stirrer and stirs with the speed of 500r/min, and electrode is Pt, negative electrode imports, and current intensity is 0.4mA/0.79cm
2, carry out iontophoresis.Respectively at 1h, 2h, 3h, 4h, 5h, 7h, 9h gets the 1ml acceptable solution during 11h, and the acceptable solution of additional equivalent equality of temperature.The acceptable solution of obtaining filters with the microstrainer that 0.45 μ m microporous filter membrane is housed, and abandons filtrate just, gets subsequent filtrate and carries out high-efficient liquid phase analysis.
Chromatographic condition: HP-1100 high performance liquid chromatography series adopts the C18ODS chromatographic column, and mobile phase is methanol-phosphate buffer (pH7.4,1: 1, V/V), flow velocity is 1ml/min, and the detection wavelength is 270nm, lowest detection is limited to 0.1 μ g.mol-1, and sample size is 20 μ l.Measure peak area, outer marking quantitative.
After testing, unit of account area meloxicam accumulation infiltration capacity Q (μ g/cm2) will accumulate infiltration capacity the time will be mapped, and get meloxicam iontophoresis transdermal penetration curve, see Fig. 4, try to achieve steady-state permeation speed by the slope of curve.(meloxicam-SBE-CD) the drug per unit area accumulation infiltration capacity Q (μ g/cm2) with contrast liquid (meloxicam phosphate buffer solution) iontophoresis is respectively (678.209 ± 83.029) μ g/cm2 and (176.109 ± 18.992) μ g/cm2 to meloxicam during 11h-SBE-CD suspension, the steady-state permeation speed of meloxicam-SBE-CD iontophoresis is (74.13 ± 11.12) μ gcm-2h-1, and the steady-state permeation speed of contrast liquid iontophoresis is (18.72 ± 2.99) μ gcm-2h-1.From then on the result can find out, sulphur butyl-beta-schardinger dextrin-can promote to dissociate but the iontophoresis of the little meloxicam of dissolubility.
The pKa of meloxicam is 4.08, therefore certain dissociating arranged in aqueous solution, but its dissolubility in water is little, document record dissolubility is 7.05 μ g/ml, recording its dissolubility in the pH7.4 phosphate buffer is (261.7 ± 8.16) μ g/ml, meloxicam is added dissolubility is (5601 ± 58.46) μ g/ml in 10% sulphur butyl-beta-schardinger dextrin-pH7.4 phosphate buffer.Therefore, sulphur butyl-beta-schardinger dextrin-not only can increase the reaction of meloxicam to electric field, and can increase the dissolubility of meloxicam, further promotes the iontophoresis of meloxicam.
Embodiment 5
Sulphur butyl-beta-schardinger dextrin-(SBE-CD) is to the promotion of meloxicam gel iontophoresis
According to operation preparation meloxicam-SBE-CD suspension among the embodiment 4 and contrast liquid, making for examination gel, control gel after respectively adding the hydroxypropyl methylcellulose swelling after filtering respectively, is 2% for the mass percentage concentration of trying hydroxypropyl methylcellulose in gel or the control gel.
Remove the rat body skin that removes subcutaneous tissue, be fixed in that (effectively diffusion area is 2.83cm between the supply reservoir and reception tank of single chamber iontophoresis diffusion cell
2, the reception tank capacity is 6.8ml), drain bubble, recirculated water keeps (37 ± 0.5) ℃.Place above-mentioned examination gel or the control gel of supplying in the supply reservoir, add lead electrode, connect power cathode.Reception tank is that 20% ethanol PBS liquid is acceptable solution with the ethanol concentration expressed in percentage by volume, with silver electrode, connects positive source.Add the speed stirring of stirrer with 300r/min, current intensity is 0.5mA/cm
2, carry out iontophoresis.Respectively at 1h, 2h, 3h, 4h, 6h, 8h gets the 1ml acceptable solution during 10h, and the acceptable solution of additional equivalent equality of temperature.The acceptable solution of obtaining detects according to operation among the embodiment 4.
After testing, accumulate infiltration capacity Q (μ g/cm for the examination gel and the unit are meloxicam of control gel during 10h
2) be respectively (452.68 ± 28.67) μ g/cm
2(103.24 ± 10.12) μ g/cm
2, steady-state permeation speed J (the μ gcm of meloxicam
-2H
-1) be respectively (42.82 ± 8.15) μ gcm
-2H
-1With 10.82 ± 1.62 μ gcm
-2H
-1From then on the result can find out, sulphur butyl-beta-schardinger dextrin-can promote to dissociate but the iontophoresis of the little meloxicam of dissolubility.
Claims (10)
1. an ion-type cyclodextrin derivative is used for the application of the pharmaceutical preparation of iontophoresis transdermal administration in preparation.
2. application according to claim 1 is characterized in that, described ion-type cyclodextrin derivative comprises one or both in cationic cyclodextrin derivative, the anionic cyclodextrin derivative.
3. application according to claim 2 is characterized in that, described cationic cyclodextrin derivative is selected from any one or more in quaternary ammonium salt cationic type-beta-schardinger dextrin-.
4. application according to claim 2 is characterized in that, described anionic cyclodextrin derivative is selected from any one or more in carboxymethyl-beta-cyclodextrin, sulfo--beta-schardinger dextrin-, the sulphur butyl-beta-schardinger dextrin-.
5. application according to claim 1, it is characterized in that, described medicine be selected from molecule-type medicine, dissolubility less than the electrically charged medicine of 1mg/ml, dissociation constant pKa greater than the electrically charged medicine of 4 faintly acid or dissociation constant pKa less than in the electrically charged medicine of 4 alkalescence any one or more.
6. application according to claim 5, it is characterized in that described medicine is selected from any one or more in hydrocortisone, prednisone, prednisolone, triamcinolone acetonide, dexamethasone, fluorine hydroxyl cortisone, fluocinolone acetonide, betamethasone, meloxicam, Phenylbutazone, ibuprofen, ketoprofen, naproxen, indomethacin, piroxicam, estradiol, Progesterone, ethinylestradiol, the ethisterone.
7. application according to claim 1 is characterized in that, the mass percentage concentration of described pharmaceutical preparation intermediate ion type cyclodextrin derivative is smaller or equal to 20%.
8. application according to claim 1 is characterized in that, described pharmaceutical preparation is liquid preparation or semi-solid preparation.
9. application according to claim 8 is characterized in that, the dosage form of described pharmaceutical preparation is solution, suspensoid, gel, ointment or other external preparation.
10. application according to claim 1 is characterized in that, described pharmaceutical preparation Chinese medicine directly mixes with the ion-type cyclodextrin derivative or in advance medicine and ion-type cyclodextrin derivative made the pharmaceutical pack compound.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US8383663B2 (en) | 2010-07-19 | 2013-02-26 | Supratek Pharma Inc. | Bendamustine anionic-catioinic cyclopolysaccharide compositions |
| CN104922693A (en) * | 2015-06-19 | 2015-09-23 | 南开大学 | Anionic-type cyclodextrin and anti-cancer drug clathrate compound and preparation method |
| CN105193836A (en) * | 2015-09-11 | 2015-12-30 | 陶烈晖 | Method of supplementing nucleotide and preparation for external use |
| CN105396140A (en) * | 2015-12-02 | 2016-03-16 | 浙江医药高等专科学校 | Anti-tumor immunotherapy nano-drug delivery system and construction method thereof |
| CN107281499A (en) * | 2017-07-25 | 2017-10-24 | 广东省药品检验所（广东省药品质量研究所、广东省口岸药品检验所） | A kind of method for improving pharmaceutic adjuvant beta cyclodextrin inclusion characteristic |
| CN108403617A (en) * | 2018-02-24 | 2018-08-17 | 中山大学 | Triamcinolone acetonide solubility micropin and preparation method thereof |
| CN109589303A (en) * | 2019-02-19 | 2019-04-09 | 广东海洋大学 | A kind of preparation method of hydrocortisone cyclodextrin inclusion compound ointment |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8383663B2 (en) | 2010-07-19 | 2013-02-26 | Supratek Pharma Inc. | Bendamustine anionic-catioinic cyclopolysaccharide compositions |
| WO2012127277A3 (en) * | 2010-07-19 | 2013-03-14 | Supratek Pharma, Inc. | Bendamustine anionic-catioinic cyclopolysaccharide compositions |
| CN104922693A (en) * | 2015-06-19 | 2015-09-23 | 南开大学 | Anionic-type cyclodextrin and anti-cancer drug clathrate compound and preparation method |
| CN105193836A (en) * | 2015-09-11 | 2015-12-30 | 陶烈晖 | Method of supplementing nucleotide and preparation for external use |
| CN105396140A (en) * | 2015-12-02 | 2016-03-16 | 浙江医药高等专科学校 | Anti-tumor immunotherapy nano-drug delivery system and construction method thereof |
| CN105396140B (en) * | 2015-12-02 | 2019-07-02 | 浙江医药高等专科学校 | Anti-tumor immunotherapy administration nano-drug administration system and its construction method |
| CN107281499A (en) * | 2017-07-25 | 2017-10-24 | 广东省药品检验所（广东省药品质量研究所、广东省口岸药品检验所） | A kind of method for improving pharmaceutic adjuvant beta cyclodextrin inclusion characteristic |
| CN107281499B (en) * | 2017-07-25 | 2020-12-01 | 广东省药品检验所（广东省药品质量研究所、广东省口岸药品检验所） | Method for improving beta-cyclodextrin inclusion performance of pharmaceutic adjuvant |
| CN108403617A (en) * | 2018-02-24 | 2018-08-17 | 中山大学 | Triamcinolone acetonide solubility micropin and preparation method thereof |
| CN109589303A (en) * | 2019-02-19 | 2019-04-09 | 广东海洋大学 | A kind of preparation method of hydrocortisone cyclodextrin inclusion compound ointment |
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