Calcipotriol non-aqueous gelTechnical field
The present invention relates to the part of Calcipotriol with non-aqueous skin preparation, and its curative effect is high, and toxicity is low, stable, and can guideOr strengthen transmission of the active medicine to skin, so as to obtain higher therapeutic index.The invention further relates to manufacture and using above-mentionedThe method of composition.
Technical background
Calcipotriol is highly soluble in 96% alcohol, but be largely insoluble in water (practically to light and heat-sensitiveInsoluble in water, freely soluble inethanol (96 per cent), slightly soluble inMethylene chloride.It is sensitive to heat and light.EP5.3), existing ointment kind listing,Such as trade name Daivonex, its concentration is 0.005% (w/w), suitable for psoriasis vulgaris (psoriasis).However, Ka BoTriol molecular weight is 413 (no hydrates), and molecule is relatively bigger than normal, and penetration is relatively relatively low, and the ointment formulation permeance property needsFurther improve.In addition, ointment formulation is not usually homogeneous system, viscosity is excessive, too greasy, quilt when being not easy to apply exhibition or apply exhibitionThe instrument such as the finger or cotton swab amount of siphoning away is too many etc., and the advantage without gel preparation, such as more preferable Release Performance, non-greasy are easyCleaning, can add propellant, using convenient etc..Calcipotriol structural formula is as follows：
Solid fat plasmid has been made in Chinese patent CN102342914A in Calcipotriol.However, Calcipotriol is made admittedlyAfter body fat plasmid, particle radii will significantly increase, and fat-soluble further increase, perhaps be advantageous to improve oozing for skin lipid layerThoroughly, but it is unfavorable for the infiltration to skin " water quality layer ", so as to influence the speed that it is particularly shifted to skin to focus on the wholeDegree, so as to influence its skin bioavilability.In addition, Calcipotriol adds aqueous carrier after solid lipid nano granule is made, systemAgent stability may be affected, and such as particle coalescence, precipitate.Furthermore solid fat plasmid nanoscale preparation technology is complicated,Technique poor reproducibility, do not possess technology and condition caused by big industry at this stage, it is difficult to which practicality is promoted.
Obviously, such as performance such as Release Performance, stability, drug transdermal performance of the Calcipotriol preparation in above-mentioned technology needsIt is further to improve.
Therefore, a kind of more preferable Calcipotriol preparation of performance is needed in reality.
The content of the invention
It is an object of the invention to provide a kind of more preferable Calcipotriol preparation of performance, more say and be just to provide under one kindRow performance section or the Calcipotriol preparation all improved, it is desirable to which improved part or all of improvement performance includes but is not limited to：Release Performance, stability, drug transdermal performance, security, clinical practice effect or therapeutic index, system homogeneity or single-phaseProperty.
Based on above-mentioned purpose, the invention provides a kind of composition for localized delivery Calcipotriol, said composition bagContain：
(a) content is no more than 1wt% Calcipotriol,
(b) ethanol,
(c) propane diols,
(d) oleic acid,
(e) hydroxypropyl cellulose,
(f) glycerine,
(g) content is 0-5wt% water, and above content is in terms of composition total weight.
Another aspect of the present invention provides the animal localized delivery Calcipotriol such as the mammal treated to needs or people patientMethod.Methods described includes administering locally to animal above-mentioned composition.
The composition of the present invention uses non-aqueous system, more preferably uses (non-aqueous) homogeneous system, and the system has higherStability (such as relative to hydrogel or emulsifiable paste or ointment, has a higher chemical stability, main ingredient is not degradable；It is and/or higherBiological stability, easy bacteria-developing mildew, is not easy corruption；And/or higher physical stability, it is not easy to be separated) and it is higherApplication effects.
The present invention composition it is substantially anhydrous, still, composition may contain combination water a certain amount of with each component or itsHis moisture, 96% ethanol as solvent is such as added, wherein containing about 4 water.Generally, the water in the present composition is total less than compositionThe 5wt% of weight, preferably less than the 2wt% of composition total weight, the more preferably 1wt% less than composition total weight.
The composition of the present invention includes (i) oleic acid, (ii) ethanol, (iii) propane diols and (iv) using promoting osmosis systemHydroxypropyl cellulose.This promotion osmosis system of the present invention increases percutaneous and topical remedy transmission and reduces skin irritatin,It is horizontal high so as to can reach drug delivery, but do not cause unacceptable skin adverse reaction.
Ethanol, propane diols are in the present invention except also doubling as solvent as penetration enhancers.Specifically, propane diols makees hydroxypropyl fibreTie up the solvent of element.Ethanol (or micro water is used in combination) makees the solvent and/or hydroxypropyl cellulose of medicine.The combination of the present inventionThing includes ethanol about 1%-60% (w/w), preferably containing alcohol about 1%-40% (w/w), more preferably about 5%-30% (w/w), mostGood 5%-25% (w/w)；Comprising propane diols about 5%-60% (w/w), preferably about 10%-50% (w/w), it is more preferably about10%-40% (w/w), optimal 15%-35% (w/w).
Oleic acid makees film fluidizing reagent or penetration enhancers in the composition of the present invention.Oleic acid (oleic acid) is unitaryUnrighted acid.Oleic acid can largely mitigate to stimulate caused by other permeation enhancers.It is worth people it is noted that by oleic acidIt is added in the composition of the present invention, can not only significantly improves main ingredient Calcipotriol Transdermal absorption, and can also significantly reduceSkin irritatin caused by these preparations.Surprisingly, oleic acid shares with gelling agent hydroxypropyl cellulose and stimulation alleviant glycerine,Generate skin irritatin surprisingly low preparation.The amount of oleic acid in the composition is about 0.1%-10% (w/w), preferably about0.1%-5% (w/w).
Hydroxy propyl cellulose makees gelling agent or thickener in the present invention.Preparation ratio containing the gelling agent is free of gelling agentOr the Formulation Skin excitant containing other gelling agents is low.Experiment shows, makes system keep promoting local and warp comprising the gelling agentSkin drug delivery ability, and mitigate part or applied dermally with excitant.This is the discovery that what is highly paid attention to, becauseIt is known that can cause comprising lower alcohol allergic, to firmly believe the solvent for being unsuitable for the compound for being applied to skin in the past.Surprisingly, contain the gelling agent and oleic acid ratio contains oleyl alcohol or other film fluidizing reagents or penetration enhancers and other gelling agentsPreparation excitant it is low.The amount of the gelling agent is about 0.1%-10% (w/w) in composition, it is preferable that the glue in compositionThe amount of solidifying agent is about 0.5%-5% (w/w).More preferably, the amount of the gelling agent is about 1%-3% (w/w) in composition.
Glycerine makees NMF in the present invention and makees stimulation palliative.The amount about 5- of the glycerine gelling agent in the composition60wt%, preferably from about 5-50wt%, about 10-40wt% are more preferable, and about 15-40wt% is best.
The present invention can also be including but not limited to the alcohol identical or different with alcohols penetration enhancers, and it is non-aqueous that this kind of alcohol makees auxiliaryCarrier, including it is not limited to isobutanol and isopropanol etc..
The other compositions that the present composition can include include but is not limited to：Surfactant (lubricant), appearance investigationAgent, pH adjusting agent, supplementary thickener, pigment, spices, stabilizer (such as antioxidant, chelating agent, UV stabilizer), sun-screening agent, withAnd propellant, or more described in any combination.
Suitable for surfactant (lubricant) the particularly preferably oleyl alcohol ethers of PEG-2 ∽ 6 of the present invention, the oleyl alcohol ethers of PEG-2 ∽ 6Promote or improve more significantly infiltration enhancing, appearance investigation and the lubrication of oleic acid, in addition with the effect for improving stability.The amount about 0-10wt% of the oleyl alcohol ethers of EG-2 ∽ 6 gelling agent in the composition, preferably from about 0.1-6wt%, about 0.5-3wt% are moreIt is good.
Suitable for the present invention pH adjusting agent for example malic acid, lactic acid, citric acid, ethanedioic acid, benzoic acid, ascorbic acid,Or more described in any combination, etc..
Suitable for antioxidant such as propylgallate, ascorbic acid, ascorbyl palmitate, the butyl of the present inventionChange the tocopherol of hydroxyanisol (BHA), Yoshinox BHT (BHT), vitamin E or such as alpha tocopherol, or more described inAny combination, etc..
The content of each component is exactly the amount for being enough to realize the component function in the present composition.For example, penetration enhancersAmount typically i.e. infiltration enhancing effective dose.It is preferred that using composition gross weight as 100 parts, composition (a) containing component CalcipotriolsContent about 0.00001-1.0wt% (preferably from about 0.0001-0.5wt%, about 0.001-0.1wt% are more preferable, about 0.001-0.01wt% is best), containing about 1-60wt% components (b) ethanol, (preferably from about 1-40wt%, about 5-30wt% are more preferable, about 5-25wt% is best), containing about 5-60wt% components (c) propane diols, (preferably from about 10-50wt%, about 10-40wt% are more preferable, about 15-35wt% is best), the amount of the oleic acid of (d) containing component in the composition is about 0.1%-10% (w/w) (preferably about 0.1%-5%(w/w)), (preferably from about 0.5-5wt%, about 1-3wt% are more preferable, about 1- by the hydroxypropyl celluloses of (e) containing component about 0.1-10wt%2wt% is best), (preferably from about 5-50wt%, about 10-40wt% are more preferable, about 15-40wt% by the glycerine of (f) containing component about 5-60wt%It is best), the content about 0-5wt% (preferably from about 0-2wt%, about 0-1wt% are best) of component (g) water, containing surfactant (lubricationAgent), penetration enhancers, appearance investigation agent, about 0-10wt% (the preferably from about 0-6wt%, about 0- respectively such as stabilizer or sun-screening agent3wt% is more preferable), containing pH adjusting agent about 0-2wt% altogether, containing antioxidant about 0-2wt%, containing pigment, spices, supplementary thickener pointNot about 0-5wt%, the nonaqueous carrier containing auxiliary, (preferably from about 0-60wt%, about 0-50wt% are more by about 0-80wt% respectively for propellantGood, about 0-40wt% is best).
Can be in a primary tank by ethanol (or micro water being used in combination, such as 96% ethanol), propane diols (infiltration enhancingAgent/solvent), glycerine, oleic acid or and auxiliary nonaqueous carrier etc. it is well mixed, be prepared into the composition of the present invention；Then medicine is addedThing and gelling agent or thickener, it is well mixed.Or hydroxypropyl cellulose is dissolved with propane diols, (or it is used in combination micro- with ethanolThe water of amount, such as 96% ethanol) dissolving medicine Calcipotriol, the two is mixed to even with glycerine, oleic acid.Surface-active is added if necessaryAgent, penetration enhancers, lubricant, appearance investigation agent, pH adjusting agent, supplementary thickener, pigment, spices, stabilizer, sun-screening agent,Propellant etc., it is well mixed.Then, final product is packed.
Industrial applicibility
Composition of the present invention has following partly or entirely excellent compared with conventional related composition or preparationGesture：
1), more preferable Release Performance, more preferable bioavilability；
2), more preferable stability, system homogeneity or single phase property can more muchly be kept；
3), more preferable drug transdermal performance, more preferable using effect；
4), more preferable security, lower excitant.
5), higher therapeutic index.
Preferred embodiment
The following examples explanation present invention, but do not limit the present invention.If not otherwise indicated, all contents are all based on combiningThe percentage of thing gross weight.
Embodiment 1
Reference examples 1
Main ingredient Calcipotriol, glycerine, Ascorbyl Palmitate, oleic acid and hydroxypropyl cellulose dosage (propane diols,96% ethanol is cancelled, and is added without) it is same as Example 1, Calcipotriol is made of the method in Chinese patent CN102342914ASolid lipid nano granule, then add in hydroxy propyl cellulose hydrogel, add glycerine, Ascorbyl Palmitate, oilAcid, full dose 100wt% finally is supplied with water, mixed.
Embodiment 2
Reference examples 2-1
Reference examples 2-2
Reference examples 2-3
Ointment, trade name Daivonex are listed using Calcipotriol.
Embodiment 3
Reference examples 3
Main ingredient Calcipotriol, hydroxypropyl cellulose, glycerine, PEG-4 oleyl alcohol ether and Alpha tocopherol dosages (the third twoAlcohol, 96% ethanol and oleic acid are cancelled, and are added without) it is same as Example 3, Calcipotriol is with Chinese patent CN102342914ASolid fat plasmid has been made in method, then add hydroxy propyl cellulose hydrogel in, add glycerine, PEG-4 oleyl alcohol ether,Alpha tocopherol, full dose 100wt% finally is supplied with water, mixed.
Embodiment 4
Reference examples 4
Ointment, trade name Daivonex are listed using Calcipotriol.
Embodiment 5
Reference examples 5-1
Reference examples 5-2
Main ingredient Calcipotriol, glycerine, hydroxypropyl cellulose and PEG-2 oleyl alcohol ethers dosage (propane diols, 96% ethanol and oleic acidCancel, be added without) it is same as Example 1, solid fat has been made with the method in Chinese patent CN102342914A in CalcipotriolPlasmid, then add in hydroxy propyl cellulose hydrogel, add glycerine, finally supply full dose 100wt% with water, mix.
Embodiment 6
Reference examples 6-1
Reference examples 6-2
Ointment, trade name Daivonex are listed using Calcipotriol.
Test case 1：Treat the clinical test of plaque psoriasis
The plaque psoriasis patient of 1.2 age of clinical data 60 stable diseases more than 18 years old, it is random to be selected in patientIt is divided into Calcipotriol embodiment group, Calcipotriol reference examples group, each group is 30.Non- system used MethodsThe cases enrolled within 8 weeksTretinoin medicines, glucocorticoid and immunodepressant；Psoralen long wave ultraviolet (PU-VA) was not used in 4 weeks；2 weeksUltraviolet B radiation (UVB) and other local treatments were inside not used.
Embodiment and its reference examples appropriate amount of drug are uniformly applied to or are sprayed on affected part by 1.2 administrated methods, are gently massaged, sooner or laterEach medication 1 time, the course for the treatment of 12 weeks.
1.3 follow-up observations start follow-up 1 time weekly in 2 weeks in the treatment of 8 weeks by a definite date, later every follow-up in 2 weeks 1 time.Every timeUpper limbs, lower limb or a certain position of trunk for selecting same target infringement are the object of observation.According to skin lesion scope, erythema, the scales of skin that peel off, scabiesItch and carry out Illness severity (PASI) scoring with the light and heavy degree of sign, and the scoring before and after comparison therapy is treated with evaluatingEffect.Scoring declines 97%~100% and cured for recovery from illness or substantially；It is effective to decline 60%~96%；Decline 25%~59% be effective；Decline less than 25% or rise person is invalid.Basic cure rate=(curing number of cases/Eligibility number substantially)× 100%, total effective rate=[number of cases+effective number of cases is cured substantially)/Eligibility number] × 100%.
1.4 safety evaluatios record adverse reaction relevant with medicine in the whole course for the treatment of.
Because of adverse reaction stopped treatment person, if the course for the treatment of, less than 8 weeks, the case is not counted in therapeutic evaluation case, but is included in peaceFull property evaluation case.
1.5 statistical methods are examined using t, χ2Examine.
2 results
PASI scores in the course for the treatment of between 2.1 two groups of Clinical efficacy comparisons, and the basic cure rate of embodiment group and total effective rate are equalHigher than its reference examples group, clinical effect is more preferable, the results are shown in Table 1：
The embodiment group of table 1 and the efficient comparison of reference examples group (n, %)
In the Clinical observation of 8 weeks, the adverse reactions such as part is red, itches occur for all embodiment groups for 2.2 adverse reactionsSituation is suitable.
Reference examples group occur local red, the adverse reaction situation such as itch also between five quite.Part adverse reaction truth is as follows：
2 groups of embodiment has 3 the adverse reactions such as part is red, itches occur；1 disappeared after 4 weeks, and another 2 alleviated after 2 weeks, 3 weeksAfter disappear.The irritation such as erythema locally occurs for reference examples 2 group 4, itched, and 2 disappeared after 2 weeks, and 2 disappeared after 4 weeks.
3 groups of embodiment has 4 the adverse reactions such as part is red, itches occur；2 disappeared after 4 weeks, and another 2 alleviated after 2 weeks, 3 weeksAfter disappear.The irritation such as erythema locally occurs for reference examples 3 group 5, itched, and 1 disappeared after 2 weeks, and 2 disappeared after 3 weeks, 24 weeksAfter disappear.
As a result show, embodiment is suitable with its reference examples excitant.
Test case 2：Guiding and enhancing measure of the medicine to skin transmission
The diffusion research of Franz ponds is carried out on people's corpse skin with embodiment and its reference examples, determines the skin biology of medicineAvailability, it the results are shown in Table 2：
Measurement result of the medicine of table 2 to skin transmission
The long and shows that the composition of embodiment realizes orientation transmission of the medicine to skin, compared with reference examples, passesThe medicine for being delivered to epidermis and intradermal target location is more.Number it was demonstrated that example composition is more preferable to the directionality of skin transmission,Pharmacological activity is higher.Moreover, example composition is obviously less through infiltration of the skin to acceptable solution, therefore clinically completeBody toxicity is relatively low.By contrast, reference examples (particularly listing reference examples) composition makes relatively relatively large number of Medicated PermeationInto acceptable solution, this may show as the systemic effect of bad clinical toxicity.
Test case 3：Composition stability test
Accelerated stability test is carried out to embodiment and its reference examples, composition stability is evaluated with outward appearance change, is tiedFruit is shown in Table 3：
3 40 DEG C of constant temperature storage test results of table
25 DEG C of room temperature storage results：
Embodiment and the room temperature storage 2 years of 25 DEG C of reference examples, during which divide 3,6,12,18,24 months observation cosmetic variations, measure masterMedicine content and relevant material.Wherein, embodiment and commercially available reference examples outward appearance, the measure situation of change such as drug content and relevant materialEssentially identical, no significant difference with 40 DEG C of constant temperature storage test results.Outward appearance, measure main ingredient contain from the non-listing reference examples 6-12 monthsAmount and relevant material etc. substantially change, and its situation and 40 DEG C of constant temperature storage test results are essentially identical, more seriously, 1-Bacterium change or corruption occurs in it between March.
Result above shows that example composition stability is with being better than reference examples.
Special instruction, reference examples 2-1 can be used as embodiments of the invention 7, and its reference examples is reference examples 2-3；Reference examples 5-1Embodiments of the invention 8 are can be used as, its reference examples is reference examples 5-2.
The clinical test results and medicine of comprehensive analysis treatment plaque psoriasis are to the test of skin transmission, as a result tableIt is bright：
1st, add the embodiment of oleic acid relative to be not added with the reference examples of oleic acid its medicines to ooze rate higher, have higherBioavilability, higher effect or therapeutic index；
2nd, the embodiment of the oleyl alcohol ether of PEG-2~6 is added relative to the embodiment or control for being not added with the oleyl alcohol ether of PEG-2~6Example, its medicine oozed that rate is higher, had a higher bioavilability, higher effect or therapeutic index, the oleyl alcohol of PEG-2~6Ether has significant infiltration humidification, has synergy with oleic acid.
It is attached：Bibliography
Each patent, publication, patent application and test method following in text has been incorporated herein by reference：
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