CN1284524C - Application of solid liposome nanoparticle for preparing pharmaceutical used for ion leading-in trandermal therapy - Google Patents
Application of solid liposome nanoparticle for preparing pharmaceutical used for ion leading-in trandermal therapy Download PDFInfo
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Abstract
The present invention relates to application of solid lipid nanoparticles for preparing medicines used for cutaneous penetration administration through iontophoresis technology. In the present invention, the cutaneous penetration quantity and the penetration rate of the cutaneous penetration administration medicine of the medicine carrying solid lipid nanoparticles through iontophoresis technology are obviously higher than those of the medicine carrying solid lipid nanoparticles through non-iontophoresis technology and common medicine cutaneous penetration preparations so as to overcome the defects that the cutaneous penetration administration of the nonionic medicine through iontophoresis technology can not easily achieve the effect of effective cutaneous penetration and the cutaneous penetration effect of the medicine is difficult to enhance since the solid lipid nanoparticles are directly used for cutaneous penetration administration; the electrified nanoparticles can be used for administration in a local orientation mode under the action of an electric field through iontophoresis technology; the local treatment effect of the medicine in focal positions is displayed without changing the original pharmacological effect of the medicine so as to prevent the medicine from generating toxic effect and side effect on the system of the whole body and avoid medicine damage and stimulation on skin simultaneously. The present invention can be used for treating disease symptoms in bones, joints, soft tissues and skin.
Description
Technical field
The present invention relates to solid lipid nanoparticle is used for the medicine of iontophoresis transdermal administration in preparation application.
Background technology
Iontophoresis technology (iontophoresis) is to utilize electric current that medicine ion is imported skin via positioning of electrode, enter local organization or sanguimotor a kind of bio-physical method, its 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 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.In recent years studies show that, 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 flooding mechanism, significantly improve the transdermal penetration speed and the transdermal penetration amount of medicine, and safe, controlled, developing into a kind of important means of drug transdermal administration.
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.
Solid lipid nanoparticle (Solid lipid nanoparticle, SLN) be a class novel nano drug-loading system that is developing in recent years, natural or the synthetic lipid materials that it is low with toxicity such as fatty acid, fatty glycerides, can degrade and have good biocompatibility in the body is a carrier, with drug encapsulation or be adsorbed in the lipoid carrier and make the medicine carrying solid micelle that particle diameter is 50～1000nm.Because the high-melting-point lipid that solid lipid nanoparticle is selected for use (as the satisfied fatty acid and the glyceride thereof of long carbochain) at room temperature is solid usually, therefore both possessed polymer nanoparticle physical stability height, drug loading height, can control medicine release, have good advantages such as targeting, have the liposome good biocompatibility again, be convenient to advantage such as large-scale production.Solid lipid nanoparticle mainly is suitable for lipophilic drugs, hydrophilic medicament can be made by methods such as esterifications also that refabrication is the medicine carrying solid lipid nanoparticle after the fat-soluble strong prodrug.
When solid lipid nanoparticle is used for intravenous injection, because intravenous injection requires the solid lipid nanoparticle particle diameter definitely will have many difficulties in application in safety range; The peroral dosage form of solid lipid nanoparticle also has many problems to need to solve in application owing to be subjected to the influence of food and the influence that the harmonization of the stomach pancreatin is degraded to solid lipid nanoparticle.Discover that solid lipid nanoparticle is that small solid micelle can stick to skin surface formation thin film, and skin is had closure function, promotes the hydration of skin, makes keratodermatitis swelling loose, improves the penetrance of medicine to skin.Simultaneously, the lipid materials with good biocompatibility is that carrier can be avoided damage and the zest of medicine life-time service to skin.But solid lipid nanoparticle is directly used in transdermal administration, and is limited to the transdermal penetration effect that improves medicine.
Summary of the invention
The object of the present invention is to provide solid lipid nanoparticle to be used for the application of the medicine of iontophoresis transdermal administration in preparation, adopt the solid lipid nanoparticle drug-loading system to be used for the iontophoresis transdermal administration, its transdermal penetration is effective, to skin zero damage and stimulation, all right topical reduces the general toxic and side effects of medicine, the medicine ion importing transdermal administration of the at present a large amount of nonionics (or degree of dissociation is little) of solution is difficult to reach effective transdermal effect and solid lipid nanoparticle is directly used in transdermal administration to improving the limited defective of transdermal penetration effect of medicine, can be used for bone, the joint, the treatment for diseases of soft tissue and skin.
For achieving the above object, technical scheme provided by the invention is: solid lipid nanoparticle is used for the application of the medicine of iontophoresis transdermal administration in preparation.
Consisting of of the solid lipid nanoparticle of above-mentioned medicine carrying: active pharmaceutical ingredient 0.01～5.0wt%, lipoid medicine carrying body 0.5～40wt%, surfactant 0.5～20%wt%, surplus is a water.
Above-mentioned lipoid medicine carrying body can be any one or two kinds of above mixture in the mono fatty acid glyceride, bis-fatty acid glyceride, triglyceride of fatty acid such as stearic acid, mountain Yu acid, Palmic acid, myristic acid, lauric acid, behenic acid and above-mentioned fatty acid.
Above-mentioned surfactant can be any one or two kinds of above mixture in lecithin and Polyethylene Glycol, Polyethylene Glycol mono fatty acid ester, polyoxyethylene-polyoxypropylene copolymer, Polysorbate, cholate, glycocholate, cholyltaurine salt, the alevaire.
The present invention can be prepared into the medicine carrying solid lipid nanoparticle water dispersant, gel or the ointment that is used for the iontophoresis transdermal administration.
Above-mentioned active medicine comprises anti-fungal infection class medicine such as bifonazole, griseofulvin, clotrimazole, econazole, miconazole, Terbinafine, fluconazol, itraconazole, voriconazole, nystatin, ketoconazole, amphotericin B etc.; Glucocorticoid medicine such as hydrocortisone, hydrocortisone acetate, prednisolone acetate, prednisolone acetate, triamcinolone acetonide acetate, dexamethasone acetate, acetic acid fluorine hydroxyl cortisone, fluocinonide, betamethasone etc.; NSAID (non-steroidal anti-inflammatory drug) such as salicylic acid, aspirin, Phenylbutazone, ibuprofen, ketoprofen, naproxen, indomethacin, piroxicam, meloxicam, benzydamine, timegadine, tiaramide, nimesulide; Natural drug active component such as colchicine, triptolide, danshensu, TANSHINONES, sinomenine, ferulic acid, muscone etc.
The preparation method of the solid lipid nanoparticle of above-mentioned medicine carrying comprises:
(1) fusion-even method of high pressure breast and fusion-ultrasonic dispersion:
With solid-state lipid materials heat fused, add medicine again, form the melt liquid of pastille, surfactant is dissolved in the water with the melt liquid equality of temperature, again melt liquid is added in the entry, with the rotating speed of 2000～5000rpm melt liquid is dispersed in the water with high-shear emulsion machine simultaneously, forms colostrum.
Colostrum high pressure breast under the temperature of 5～15 ℃ of the fusing points that is higher than lipid materials is even, the even pressure 200～1800bar of breast, the even cycle-index of breast 3～8 times.Behind newborn even the finishing, be chilled to the solid lipid nanoparticle that room temperature promptly obtains medicine carrying.
Or with colostrum supersound process under the temperature of 5～15 ℃ of the fusing points that is higher than lipid materials, ultrasonic power is 200～1000W, ultrasonic time 10～30min.Behind ultrasonic the finishing, be chilled to the water dispersant that room temperature promptly gets the solid lipid nanoparticle of medicine carrying.
(2) thin film-even method of high pressure breast and thin film-ultrasonic dispersion
Medicine and lipid materials are dissolved in the organic solvent, and getting drug level is the solution of 0.05～0.50mg/ml.Used organic solvent can be alkane solvents such as cyclohexane extraction, normal hexane, also can be the mixed solvent of ethyl acetate, acetone and ethanol or acetone and methanol.Place the inherent water bath with thermostatic control decompression of container rotary evaporation to remove organic solvent above-mentioned solution, promptly obtain attached to the lipid membrane on the chamber wall.It is dry until removing organic solvent fully to place vacuum desiccator to place in the container that is loaded with lipid membrane.
Other gets surfactant, and the heated and stirred formation water that is dissolved in the water joins water in the above-mentioned thin film, and the heating rotation is until forming uniform colostrum.
Colostrum is carried out the even or supersound process of high pressure breast, and method is the same, is chilled to the water dispersant that room temperature gets the solid lipid nanoparticle of medicine carrying.
(3) microemulsion method
With the lipid materials heat fused, add medicine, surfactant and water again, make the O/W type microemulsion of appearance transparent.Under stirring condition, microemulsion is scattered in 10～40 times the cold water (～2 ℃), can forms the water dispersant of solid lipid nanoparticle.
The particle size range of the solid lipid nanoparticle nanoparticle of method for preparing is 50～1000nm, and polydispersity index (particle size distribution evaluating) is 0.05～0.4; Surface Zeta potential absolute value scope is 10～70mV.Above parameter adopts the multi-functional granularity of Zetapals/potentiometer to measure.
The medicine carrying solid lipid nanoparticle water dispersant of method for preparing can be directly used in the iontophoresis transdermal administration, also can be prepared into exterior-applied formulations such as gel, ointment and be used for the iontophoresis transdermal administration.The preparation method of gel and ointment is seen " pharmaceutics " (Bi Dianzhou chief editor, People's Health Publisher: 369～382).
Clinical practice and studies show that the curative effect of medicine not merely depends on medicine itself, also closely related with the physical state of pharmaceutical preparation, physicochemical property etc., therefore changing the physical state of medicine and physicochemical property etc. is a kind of effective means of new drug development.After medicine was by the nanoparticle parcel, nanoparticle had the surface charging characteristic in solution, with the index of Zeta potential as its surface charging character of reflection and size.The surface charging characteristic of combining nano grain and chemical modification, with medication preparation is the medicine carrying solid lipid nanoparticle that can be used for the iontophoresis transdermal administration, make the medicine carrying solid lipid nanoparticle that has surface charge that is enclosed with active ingredient medicine under electric field action, move and carry medicine transdermal horny layer and enter subcutaneous tissue, thus the transdermal penetration speed and the transdermal penetration amount of raising medicine.And make the electric field action of charged nanoparticle realize down local orientation's administration by the iontophoresis technology, on the basis that does not change the original pharmacological effect of medicine, the performance medicine avoids medicine to produce toxic and side effects in the whole body system in the topical therapeutic effect of lesions position.Simultaneously, can reduce damage and the zest of medicine itself after being had the solid lipid nanoparticle parcel that the natural or synthetic lipid materials of good biocompatibility makes by medicine to skin.
Anti-fungal infection class medicine such as bifonazole, griseofulvin, clotrimazole, econazole, miconazole, Terbinafine, fluconazol, itraconazole, voriconazole, nystatin, ketoconazole or amphotericin B etc. are usually used in treating cutaneous fungal infection, but this class drug oral poor effect, and easily cause the general toxic and side effects.Adopt percutaneous drug delivery can reduce this type of medicine whole body and absorb the toxic and side effects that causes, but conventional percutaneous drug delivery mode or dosage form transdermal effect are bad.
Glucocorticoid medicine such as hydrocortisone, cortisone acetate, prednisolone acetate, prednisolone acetate, triamcinolone acetonide acetate, dexamethasone acetate, acetic acid fluorine hydroxyl cortisone, fluocinonide, betamethasone etc. adopt topical, osteoarthritis, rheumatic arthritis, gouty arthritis, scapulohumeral periarthritis, tenosynovitis and acute muscle injury etc. there are antiinflammatory, analgesic effect, also can be used for the treatment of various skin diseases such as neurodermatitis, seborrheic dermatitis, psoriasis, chronic eczema.But the clinical long-term extensive application of glucocorticoid medicine can cause many untoward reaction, as because of lipid metabolism with water and salt metabolic disturbance causes hemo-hyperadrenocorticism syndrome, digestive system complication, cardiovascular complications and amyotrophy, wound healing slow etc.Therefore adopt medicine carrying solid lipid nanoparticle iontophoresis transdermal administration not only can reduce glucocorticoid medicine for above-mentioned disease, also be expected to reduce general topical simultaneously and can't effectively arrive lesions position and cause side reaction (as amyotrophy or be absorbed enter systemic blood Circulation etc.) because of circulation absorbs the whole body toxic and side effects that is produced.We have carried out the preparation and the research of iontophoresis transdermal administration of the medicine carrying solid lipid nanoparticle of glucocorticoid medicine.
NSAID (non-steroidal anti-inflammatory drug) such as salicylic acid, aspirin, Phenylbutazone, ibuprofen, ketoprofen, naproxen, indomethacin, piroxicam, meloxicam, benzydamine, timegadine, tiaramide, nimesulide etc. are oral can anti-inflammatory and antalgic, but these medicines are taken in a large number for a long time and can be produced as digestive tract ulcer and reaction such as hemorrhage, or dysfunctions such as kidney, bone marrow.
Natural drug active component such as colchicine, triptolide, danshensu, TANSHINONES, sinomenine, ferulic acid, muscone etc. have multiple pharmacologically actives such as anti-inflammation, but its preparation capable of permeating skin transdermal effect is poor.
The invention provides the application of medicine carrying solid lipid nanoparticle in the iontophoresis transdermal administration of said medicine for this reason.
As the transdermal administration system, adopt two Room iontophoresis diffusion cells to carry out the test of isolated rat skin transdermal the medicine carrying solid lipid nano-particle preparation, the action thing skin irritation test of going forward side by side to investigate the iontophoresis transdermal penetration effect of this nano medicament carrying system.
Iontophoresis transdermal experiment method:
Adopt two Room iontophoresis diffusion cell (diffusion area 0.785cm
2, Supply House, receiving chamber volume are 4.0ml), Supply House is placed pharmaceutical preparation, inserts negative electrode, and the ethanol-normal saline of placement 20% inserts anelectrode as acceptable solution in the receiving chamber.Isolated rat skin is sandwiched between two Room, and stratum corneum side is to Supply House, keeps constant speed to stir and 32 ℃ constant temperature water bath.2,4,6,8,10,12h takes out whole acceptable solutions at interval respectively, replenishes the equal-volume acceptable solution simultaneously.Adopt the HPLC method to measure the wherein content of active medicine.
The transdermal administration group is respectively: commercially available positive drug matched group (being applied to rat skin, not added electric field); Medicine carrying solid lipid nano-particle preparation group (not added electric field, passive diffusion)); Medicine carrying solid lipid nanoparticle group (iontophoresis).
Utilize the HPLC method to measure the concentration of different time acceptable solution Chinese medicine, according to receiving chamber 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.
Animal skin stimulation test method:
The adult healthy rabbit is divided into 3 groups (6 every group), male and female half and half, body weight 2kg at random.In to before being tried thing 24h back part of animal spinal column diamond wool being taken off, the depilation area is about body surface area 10%.Being tried thing is: commercially available positive drug matched group; The blank solid lipid nanoparticle group of medicine carrying not; Medicine carrying solid lipid nano-particle preparation group.To be tried thing and be applied to and tried the thing district, be administered once every day, continuous 15 days, observes and smear position skin situations such as not damaged and irritative response are arranged.
The present invention adopts the solid lipid nanoparticle drug-loading system to be used for the iontophoresis transdermal administration, application result shows that iontophoresis medicine carrying solid lipid nanoparticle transdermal administration drug transdermal infiltration capacity and infiltration rate are significantly higher than medicine carrying solid lipid nanoparticle nonionic and import (P＜0.01) and marketed drugs contrast (P＜0.01 or P＜0.05), transdermal administration is difficult to reach effective transdermal effect and solid lipid nanoparticle is directly used in transdermal administration to improving the limited defective of transdermal penetration effect of medicine thereby the medicine ion that has solved at present a large amount of nonionics (or degree of dissociation is little) imports, make the electric field action of charged nanoparticle realize local orientation's administration down by the iontophoresis technology, on the basis that does not change the original pharmacological effect of medicine, the performance medicine avoids medicine to produce toxic and side effects in the whole body system in the topical therapeutic effect of lesions position.Simultaneously, avoided damage and the zest of class medicines such as glucocorticoid after being had the solid lipid nanoparticle parcel that the natural or synthetic lipid materials of good biocompatibility makes by medicine to skin.The present invention can be used for the treatment for diseases of bone, joint, soft tissue and skin.
The specific embodiment
The preparation of blank solid lipid nanoparticle gel
Prescription is stearic acid 1.0wt%, lecithin 0.5wt%, and Polyethylene Glycol mono fatty acid ester 2.6wt% and 0.4wt% sodium cholate, surplus is a water.Adopt fusion-ultrasonic method to make blank solid lipid nanoparticle water dispersant, according to gel preparation method " pharmaceutics " (Bi Dianzhou chief editor, People's Health Publisher: 381-382) make blank solid lipid nanoparticle gel.This blank solid lipid nanoparticle mean diameter of writing out a prescription is 107nm, and polydispersity index is 0.159, and surperficial Zeta potential absolute value mainly is to provide sample for reference for later experiment for the preparation of the blank solid lipid nanoparticle gel of 31.6mV.
Embodiment 1: the preparation of triamcinolone acetonide acetate solid lipid nanoparticle gel and the application in the iontophoresis transdermal administration thereof
Triamcinolone acetonide acetate is white in color or the off-white color crystalline powder, and no stink is soluble in chloroform, slightly is dissolved in acetone, is slightly soluble in ethanol, is insoluble in water.Diseases such as clinical treatment osteoarthritis, gouty arthritis, rheumatic arthritis and prolapse of lumbar intervertebral disc, cervical spondylosis often adopt treatment meanss such as articular cavity or canalis spinalis suspensoid at present, the administration poor compliance, especially spinal injection operation easier height, danger are greatly, prohibited at present, this method is as the first-line treatment method of treatment spinal canal stenosis disease before this.And local intramuscular injection absorbs slowly, and onset needs a few hours, and effect can keep for 2 thoughtful 3 weeks, and systemic side effects is big.Common ointment transdermal effect is limited, and life-time service has damaging action to skin.In order to improve its transdermal penetration performance, reduce the damage of exterior-applied formulation to skin, the present invention has prepared triamcinolone acetonide acetate solid lipid nanoparticle gel, and carried out the iontophoresis transdermal administration: write out a prescription to getting triamcinolone acetonide acetate crude drug 0.05wt%, glyceryl monostearate 0.5wt%, lecithin 0.3wt%, sodium glycocholate 0.2wt%, surplus is a water.Adopt aforesaid thin film-ultrasonic dispersion to be prepared into the medicine carrying solid lipid nanoparticle, according to gel preparation method " pharmaceutics " (Bi Dianzhou chief editor, People's Health Publisher: 381～382) make triamcinolone acetonide acetate solid lipid nanoparticle gel.Wherein the solid lipid nanoparticle mean diameter is 123nm, and polydispersity index is 0.193, and nanoparticle surface Zeta potential absolute value is 47.9mV.
The test of iontophoresis transdermal: Percutaneously administrable preparation is respectively, the aching and limp cream of commercially available 0.05wt% triamcinolone acetonide acetate (being applied to rat skin, not added electric field); Above-mentioned 0.05wt% triamcinolone acetonide acetate solid lipid nanoparticle gel (not added electric field, passive diffusion); Above-mentioned 0.05% triamcinolone acetonide acetate solid lipid nanoparticle gel (iontophoresis).
The different preparation transdermal experiment of table 1 result (n=5)
| Group | 12h unit are accumulation drug osmotic amount (μ gcm -2) | Drug transdermal infiltration rate (μ gcm -2·h -1) |
| The above-mentioned 0.05% Triamcinolone Acetonide Acetate Solid body lipid nano particle gel (ion importing) of control group 0.05% Triamcinolone Acetonide Acetate Solid body lipid nano particle gel (not added electric field, passive diffusion) | 82.5±8.9 137.3±13.6 366.8±33.1 | 3.41±0.54 5.78±0.63 12.52±1.76 |
Experimental result shows that iontophoresis medicine carrying solid lipid nanoparticle group drug transdermal infiltration capacity and infiltration rate are significantly higher than nonionic importing group (P＜0.01) and marketed drugs matched group (P＜0.01).
The result is as follows for the animal skin stimulation test:
The different preparation animal skin of table 2 stimulation test result
| Group | The skin experiment result |
| Blank solid lipid nanoparticle group medicine carrying solid lipid nanoparticle group matched group | Skin does not have significant change skin and does not have significant change skin surface blackout, dry, atrophy |
Experimental result shows that triamcinolone acetonide acetate solid lipid nanoparticle gel does not have significant change at the animal skin surfaces life-time service, and matched group ointment is then because glucocorticoid medicine causes skin surface blackout, dry, atrophy to the damage of skin.
Embodiment 2: the preparation of dexamethasone acetate solid lipid nanoparticle ointment and the application in the iontophoresis transdermal administration thereof
Dexamethasone acetate is the glucocorticosteroid hormonal medicaments, and clinical practice is very extensive.This medicine is molten at acetone, methanol, ethanol part omitted, and almost insoluble in the water, the oral administration systemic side effects is bigger.Adopt transdermal administration can reduce side effect.Common ointment transdermal effect is limited, and life-time service has damaging action to skin.
The present invention has prepared dexamethasone acetate solid lipid nanoparticle ointment, and has carried out the iontophoresis transdermal administration:
Prescription is dexamethasone acetate crude drug 1.5wt%, (both weight ratios are stearic acid: 1～3: 1) amount to 5.5wt%, lecithin 3.0wt%, Polyethylene Glycol mono fatty acid ester 10.0wt% with glyceryl tristearate mixing lipid, alevaire 0.8wt%, surplus is a water.Adopt aforesaid thin film-even method of high pressure breast to be prepared into the medicine carrying solid lipid nanoparticle, according to coagulating ointment preparation method " pharmaceutics " (Bi Dianzhou chief editor, People's Health Publisher: 369-379) make dexamethasone solid lipid nanoparticle ointment.
This prescription solid lipid nanoparticle mean diameter is 239nm, and polydispersity index is 0.255, and nanoparticle surface Zeta potential absolute value is 29.4mV.
Carried out the test of iontophoresis transdermal, Percutaneously administrable preparation is respectively: commercially available 1.5wt% dexamethasone acetate ointment (being applied to rat skin, not added electric field); Above-mentioned 1.5wt% dexamethasone acetate solid lipid nanoparticle ointment (not added electric field, passive diffusion); Above-mentioned 1.5wt% dexamethasone acetate solid lipid nanoparticle ointment (iontophoresis).
The different preparation transdermal experiment of table 3 result (n=5)
| Group | 12h unit are accumulation drug osmotic amount (μ gcm -2) | Drug transdermal infiltration rate (μ gcm -2·h -1) |
| Control group 1.5% Dexamethasone Acetate-loaded Solid Lipid Nanoparticles ointment (not added electric field, passive diffusion) above-mentioned 1.5% Dexamethasone Acetate-loaded Solid Lipid Nanoparticles ointment (ion importing) | 202.5±21.6 164.9±19.5 571.2±85.3 | 8.65±0.74 6.30±0.63 51.23±2.31 |
Experimental result shows that iontophoresis medicine carrying solid lipid nanoparticle group drug transdermal infiltration capacity and infiltration rate are significantly higher than nonionic importing group (P＜0.01) and marketed drugs matched group (P＜0.01).
The result is as follows for the animal skin stimulation test.
The different preparation animal skin of table 4 stimulation test result
| Group | The skin experiment result |
| Blank solid lipid nanoparticle group medicine carrying solid lipid nanoparticle group matched group | Skin does not have significant change skin and does not have significant change skin surface blackout, dry, atrophy |
Experimental result shows that dexamethasone acetate solid lipid nanoparticle gel does not have significant change at the animal skin surfaces life-time service, and matched group ointment is then because glucocorticoid medicine causes skin surface blackout, dry, atrophy to the damage of skin.
Embodiment 3: the preparation of ketoconazole solid lipid nanoparticle ointment and the application in the iontophoresis transdermal administration thereof
Ketoconazole is water insoluble, is dissolved in hot ethanol, is the imidazoles antifungal agent, and the pathogenic bacterium of whole body and superficial mycosis are all had antibacterial activity, is widely used in multiple epidermis and systemic fungal infection.But its exterior-applied formulation (ointment) transdermal effect is limited, and peroral dosage form is long to the deep fungal infection curative effect, onset is slow, and this medical instrument has the cell membrane of inhibition ergosterol biosynthesis simultaneously, causes the side effect of serious hormonal system obstacle.
The present invention has prepared ketoconazole solid lipid nanoparticle ointment, has carried out the iontophoresis transdermal administration, observes the ketoconazole solid lipid nanoparticle can significantly improve medicine under iontophoresis transdermal penetration amount.
Prescription is ketoconazole crude drug 2.5wt%, and the mixing lipid of myristic acid, lauric acid and glyceride thereof amounts to 35.0wt%, lecithin 5.0wt%, and Polysorbate 12.0wt%, sodium cholate 2.0wt%, surplus is a water.Adopt aforesaid fusion-even method of high pressure breast to be prepared into the medicine carrying solid lipid nanoparticle, according to ointment preparation method " pharmaceutics " (Bi Dianzhou chief editor, People's Health Publisher: 369～379) make ketoconazole solid lipid nanoparticle ointment.The solid lipid nanoparticle mean diameter that this prescription makes is 563nm, and polydispersity index is 0.394, and nanoparticle surface Zeta potential absolute value is 41.9mV.
Carried out the test of iontophoresis transdermal, Percutaneously administrable preparation is respectively: commercially available ketoconazole ointment (being applied to rat skin, not added electric field); Above-mentioned 2.5% ketoconazole solid lipid nanoparticle coagulates ointment (not added electric field, passive diffusion); Above-mentioned 2.5% ketoconazole solid lipid nanoparticle ointment (iontophoresis).
The different preparation transdermal experiment of table 5 result (n=5)
| Group | 12h unit are accumulation drug osmotic amount (μ gcm -2) | Drug transdermal infiltration rate (μ gcm -2·h -1) |
| Matched group 2.5% ketoconazole solid lipid nanoparticle ointment (not added electric field, passive diffusion) 2.5% ketoconazole solid lipid nanoparticle ointment (iontophoresis) | 57.9±4.3 61.2±4.6 192.5±16.7 | 2.67±0.24 2.34±0.29 7.62±1.01 |
Experimental result shows that iontophoresis medicine carrying solid lipid nanoparticle group drug transdermal infiltration capacity and infiltration rate are apparently higher than nonionic importing group (P＜0.01) and marketed drugs matched group (P＜0.01).
Embodiment 4: the preparation of griseofulvin solid lipid nanoparticle ointment and the application in the iontophoresis transdermal administration thereof
Griseofulvin is a fat-soluble medicine, and oral this medicine blood drug level variation is big, is subject to influence of various factors.Externally-applied soft ointment is mainly used in skin, the hair that treatment Microsporon, Epidermophyton and trichophyton etc. cause and refers to that (toe) first infects.
The present invention has prepared griseofulvin solid lipid nanoparticle ointment, has carried out the iontophoresis transdermal administration.
Prescription is griseofulvin crude drug 4.5wt%, and the mixing lipid of behenic acid and glyceride thereof amounts to 28.0wt%, lecithin 5.0wt%, and polyoxyethylene-polyoxypropylene copolymer 1 0.0wt%, cholyltaurine salt sodium 2.0wt%, surplus is a water.Adopt aforesaid thin film-even method of high pressure breast to be prepared into the medicine carrying solid lipid nanoparticle, according to coagulating ointment preparation method " pharmaceutics " (Bi Dianzhou chief editor, People's Health Publisher: 369～379) make griseofulvin solid lipid nanoparticle ointment.The solid lipid nanoparticle mean diameter that this prescription makes is 875nm, and polydispersity index is 0.323.Nanoparticle surface Zeta potential absolute value is 33.5mV.
Carried out the test of iontophoresis transdermal, Percutaneously administrable preparation is respectively: commercially available griseofulvin ointment (being applied to rat skin, not added electric field); Above-mentioned 4.5% griseofulvin solid lipid nanoparticle coagulates ointment (not added electric field, passive diffusion); Above-mentioned 4.5% griseofulvin solid lipid nanoparticle ointment (iontophoresis).
The different preparation transdermal experiment of table 6 result (n=5)
| Group | 12h unit are accumulation drug osmotic amount (μ gcm -2) | Drug transdermal infiltration rate (μ gcm -2·h -1) |
| Control group 4.5% griseofulvin solid lipid nano granule ointment (not added electric field, passive diffusion) 4.5% griseofulvin solid lipid nano granule ointment (ion importing) | 106.5±8.9 77.3±5.6 167.3±31.8 | 4.54±0.58 5.78±0.63 12.72±1.64 |
Experimental result shows that iontophoresis medicine carrying solid lipid nanoparticle group drug transdermal infiltration capacity and infiltration rate are significantly higher than nonionic importing group (P＜0.01) and marketed drugs matched group (P＜0.05).
Embodiment 5: the preparation of ibuprofen solid lipid nanoparticle water dispersant and the application in the iontophoresis transdermal administration thereof
Ibuprofen is a kind of common NSAID (non-steroidal anti-inflammatory drug), be mainly used in the treatment of osteoarthritis, rheumatic arthritis, gout etc. clinically, but have 5～15% patient gastrointestinal side effect to occur behind the oral administration approximately, as upper abdomen pain, feel sick, ulcer, hemorrhage etc.Ibuprofen is made Percutaneously administrable preparation, then can avoid gastrointestinal side effect.
The present invention has prepared ibuprofen solid lipid nanoparticle water dispersant, has carried out the iontophoresis transdermal administration.
Prescription is ibuprofen crude drug 2.0wt%, and stearic acid and glyceryl tristearate amount to 5.5wt%, lecithin 3.0wt%, and Polyethylene Glycol mono fatty acid ester 10.0wt%, sodium cholate 1.0wt%, surplus is a water.Adopt aforesaid thin film-even method of high pressure breast to be prepared into the medicine carrying solid lipid nanoparticle, according to gel preparation method " pharmaceutics " (Bi Dianzhou chief editor, the People's Health Publisher: 381-382) making this prescription solid lipid nanoparticle mean diameter of ibuprofen solid lipid nanoparticle gel is 198nm, and polydispersity index is 0.223.Nanoparticle surface Zeta potential absolute value is 47.2mV.
Carried out the test of iontophoresis transdermal, Percutaneously administrable preparation is respectively: commercially available ibuprofen ointment (being applied to rat skin, not added electric field); Above-mentioned 2.0% ibuprofen solid lipid nanoparticle water dispersant (not added electric field, passive diffusion); Above-mentioned 2.0% ibuprofen solid lipid nanoparticle water dispersant (iontophoresis).
The different preparation transdermal experiment of table 7 result (n=5)
| Group | 12h unit are accumulation drug osmotic amount (μ gcm -2) | Drug transdermal infiltration rate (μ gcm -2·h -1) |
| Control group 2.0% brufen solid lipid nano granule water dispersant (not added electric field, passive diffusion) 2.0% brufen solid lipid nano granule water dispersant (ion importing) | 93.7±5.2 287.9±21.8 1706.3±101.8 | 4.37±0.39 35.08±4.60 182.72±15.73 |
Experimental result shows that iontophoresis medicine carrying solid lipid nanoparticle group drug transdermal infiltration capacity and infiltration rate are significantly higher than nonionic importing group (P＜0.01) and marketed drugs matched group (P＜0.01).
Embodiment 6: the preparation of triptolide solid lipid nanoparticle gel and the application in the iontophoresis transdermal administration thereof
Triptolide is to separate the diterpenic lactone that obtains from Celastraceae Thunder God Calamus Radix Tripterygii Wilfordii, Tripterygium hypoglaucum and Tripterygium Forretii Dicls, Tripterygium regelii Spragus et Takeda etc.It is one of main effective ingredient in the Radix Tripterygii Wilfordii.Because the physiologically active of Radix Tripterygii Wilfordii is strong, has significant antiinflammatory, antitumor, antifertility and immunosuppressive action, can be used for treating more than 50 sick kinds such as rheumatoid arthritis, lupus erythematosus, dermatosis, kidney disease clinically.But its toxicity is stronger, and its clinical adverse mainly occurs in digestive system, urinary system, reproductive system, cardiovascular system, bone marrow and blood system.Can also cause edema, blood sugar increasing, therefore diplopia etc. have limited clinical practice.
The present invention has prepared triptolide solid lipid nanoparticle gel and has carried out the iontophoresis transdermal administration, reaches the general toxic and side effects that topical reduces medicine with expectation.
Prescription is triptolide crude drug 1.0wt%, the mixture of stearic acid, glyceryl monostearate, glyceryl tristearate amounts to 5.0wt%, lecithin 1.5wt%, polyoxyethylene-polyoxypropylene copolymer 1 0.50wt%, alevaire 0.8wt%, surplus is a water.Adopt aforesaid fusion-even method of high pressure breast to be prepared into the medicine carrying solid lipid nanoparticle, according to gel preparation method " pharmaceutics " (Bi Dianzhou chief editor, People's Health Publisher: 381-382) make triptolide solid lipid nanoparticle gel.
It is 285nm that this prescription makes the solid lipid nanoparticle mean diameter, and polydispersity index is 0.313.Nanoparticle surface Zeta potential absolute value is 27.6mV.
Carried out the test of iontophoresis transdermal, Percutaneously administrable preparation is respectively: commercially available Radix Tripterygii Wilfordii patch (being applied to rat skin, not added electric field); Above-mentioned 1.0% triptolide solid lipid nanoparticle coagulates ointment (not added electric field, passive diffusion); Above-mentioned 1.0% triptolide solid lipid nanoparticle ointment (iontophoresis).
The different preparation transdermal experiment of table 1 result (n=5)
| Group | 12h unit are accumulation drug osmotic amount (μ gcm -2) | Drug transdermal infiltration rate (μ gcm -2·h -1) |
| Control group 1.0% triptolide solid lipid nano granule gel (not added electric field, passive diffusion) 1.0% triptolide solid lipid nano granule gel (ion importing) | 101.7±4.8 45.9±3.6 132.4±5.4 | 6.76±0.62 2.43±0.25 7.92±0.71 |
Experimental result shows that iontophoresis medicine carrying solid lipid nanoparticle group drug transdermal infiltration capacity and infiltration rate are significantly higher than nonionic importing group (P＜0.01) and marketed drugs matched group (P＜0.05).
Claims (4)
1. solid lipid nanoparticle is used for the application of the medicine of iontophoresis transdermal administration in preparation; Consisting of of above-mentioned solid lipid nanoparticle: active pharmaceutical ingredient 0.01～5.0wt%, lipoid medicine carrying body 0.5～40wt%, surfactant 0.5～20wt%, surplus is a water; Wherein, above-mentioned active medicine is anti-fungal infection class medicine ketoconazole or griseofulvin, or glucocorticoid medicine dexamethasone acetate or triamcinolone acetonide acetate, or the NSAID (non-steroidal anti-inflammatory drug) ibuprofen, or natural drug active component triptolide.
2. purposes according to claim 1 is characterized in that: above-mentioned lipoid medicine carrying body is any one or two kinds of above mixture in the mono fatty acid glyceride, bis-fatty acid glyceride, triglyceride of stearic acid, mountain Yu acid, Palmic acid, myristic acid, lauric acid, behenic acid and above-mentioned fatty acid.
3. purposes according to claim 1 and 2 is characterized in that: above-mentioned surfactant is any one or two kinds of above mixture in lecithin and Polyethylene Glycol, Polyethylene Glycol mono fatty acid ester, polyoxyethylene-polyoxypropylene copolymer, Polysorbate, cholate, glycocholate, cholyltaurine salt, the alevaire.
4. purposes according to claim 1 and 2 is characterized in that: the medicine carrying solid lipid nanoparticle is prepared into water dispersant, gel or the ointment that is used for the iontophoresis transdermal administration.
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| CN100386080C (en) * | 2005-12-01 | 2008-05-07 | 西安交通大学 | Tetrandrine solid lipide nano particle and its preparing method |
| CN102793674B (en) * | 2011-05-26 | 2014-11-26 | 澳门科技大学 | Triptolide solid lipid nanoparticle as well as preparation method and application thereof |
| CN102342914A (en) * | 2011-10-07 | 2012-02-08 | 南昌大学 | Calcipotriol solid lipid nanoparticle and preparation method of same |
| CN102600079B (en) * | 2012-03-19 | 2013-11-13 | 吉林大学 | Nystatin flexible liposome as well as gel and preparation method of nystatin flexible liposome |
| CN103622935B (en) * | 2013-11-26 | 2015-10-28 | 福建省医学科学研究院 | The preparation method of Radix Tripterygii Wilfordii lactone alcohol nano-film coating agent |
| CN105816428B (en) * | 2016-04-29 | 2018-10-23 | 福建省医学科学研究院 | A kind of triptolide nano liposomes and preparation method thereof |
| CN107441492A (en) * | 2016-05-30 | 2017-12-08 | 复旦大学 | The medical composition and its use of Cyclooxygenase-2 Inhibitor and Nano medication delivery system |
| CN107811969B (en) * | 2016-09-14 | 2021-09-03 | 阿赖耶识（上海）生物技术有限公司 | High-stability non-vesicular nanoparticles and application thereof in treating fungal infection |
| CN108324945B (en) * | 2017-01-19 | 2020-09-08 | 首都医科大学附属北京妇产医院 | Inhibitor for inhibiting nano-drug particles from penetrating placenta barrier |
| CN109265658B (en) * | 2018-07-24 | 2021-09-28 | 中山大学 | Drug-loaded nanoparticle based on ferulic acid polymer and preparation method and application thereof |
| CN109602706A (en) * | 2019-01-21 | 2019-04-12 | 陕西中医药大学 | A kind of ferulic acid nano structured lipid carrier and preparation method thereof |
| CN111904932B (en) * | 2019-05-08 | 2023-06-20 | 北京德立福瑞医药科技有限公司 | Micelle preparation containing glucocorticoid and preparation method thereof |
| CN114831939B (en) * | 2021-01-30 | 2024-06-07 | 南京星银药业集团有限公司 | Triamcinolone acetonide acetate composition spray and preparation method thereof |
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