CN103340823A - Formulation of paeonol proniosomes and preparing method thereof - Google Patents
Formulation of paeonol proniosomes and preparing method thereof Download PDFInfo
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Abstract
The invention discloses a formulation of paeonol proniosomes and a preparing method thereof. The preparing method comprises the steps: firstly, dissolving 3 to 6 parts of paeonol, 64 to 145 parts of a non-ionic surfactant, 64 to 145 parts of lecithin and 7 to 13 parts of cholesterol into 1 to 3 parts of an organic phase, capping and sealing, and heating in a water bath to dissolve all the ingredients completely; and then adding 1-3 parts of an aqueous solution, heating in the water bath again to form a clear solution, and cooling to the room temperature to obtain the paeonol proniosomes. The paeonol proniosomes are in a semi-solid gel state, can be recombined to form non-ionic surfactant niosomes after hydration, provide a effective method for solving the problems of easy aggregation and easy fusion of niosomes and leakage of drugs in a solution state and a storage process of the non-ionic surfactant noisomes, have obvious superiorities in transportation, storage and use, are suitable for industrial production, and are used as quite promising novel carriers. The paeonol proniosomes can be directly applied to skins, and also can be prepared into a gel agent, an ointment, a patch and other transdermal drug delivery formulations.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly non-ionic precursor preparation and preparation method thereof before a kind of novel medicament carrier paeonol.
Background technology:
Paeonol is the main active of ranunculaceae peony (Paeonia suffruticosa Andr.) root bark and asclepiadaceae plant Radix Cynanchi Paniculati Pycnostelma Paniculatum (Bunge) K.Schu herb, has calmness, hypnosis, analgesic, analgesia, antiinflammatory, antiallergic and multiple pharmacologically active such as antibiotic.Be used for the treatment of rheumatalgia, stomachache and other pain, eczema, allergic dermatitis etc. clinically, all have better curative effect.The paeonol percutaneous dosing is used for treatment of diseases such as eczema, allergic dermatitis, has overcome shortcomings such as easily recurrence after traditional hormone medicine drug withdrawal, side effect are big; Discovered in recent years that paeonol can suppress the active and melanic generation of tryrosinase in the melanocyte, had therapeutical effect preferably to mottle, skin pruritus, psoriasis etc.But because its poorly water-soluble, fusing point is low, volatile and shortcoming such as poor stability, has limited its use and curative effect.
The existing dosage form of paeonol percutaneous drug delivery mainly is ointment at present, development along with preparation technique, in order to overcome the poorly water-soluble of paeonol own, volatile, stable bad shortcoming, w/o/w type emulsion type gel the beta-cyclodextrin inclusion compound technology appearred in recent years,, phosphatide complexes, the dosage form that liposome etc. are new, but all exist poor stability, drug loading is little, shortcomings such as yield is low are not easy to suitability for industrialized production.
Preceding non-ionic precursor (proniosomes) is a kind of a kind of novel medicament depot dosage form behind liposome, nonionic surfactant vesicle (niosome), it is to be the utricule that adjuvant is made with the non-ionic surface active agent, and hydration can produce the aqueous dispersion of nonionic surfactant vesicle before using.It is applied in the transdermal delivery system, have following advantage: 1. raw material is easy to get, price is cheap, good stability, be easy to suitability for industrialized production; 2. non-ionic surface active agent molecule two ends possess hydrophilic property and lipotropy can be sealed amphipathic medicine and nontoxic; 3. with drug encapsulation in nonionic surfactant vesicle, delayed drug release, can improve drug bioavailability; 4. improve effectively that liposome, nonionic surfactant vesicle niosome vesicle in storage process are easily assembled, problem such as fusion and medicine leakage, and have a clear superiority at transportation, storage, user's mask.
According to paeonol therapeutical effect characteristics, it is prepared into the external transdermal drug-delivery preparation, more can reach the effect for the treatment of disease.But exist problems such as local drug concentration is difficult for reaching, dosage is big, curative effect is not obvious during the common external preparation percutaneous dosing of paeonol.Non-ionic precursor percutaneous dosing before adopting, can be on skin voluntarily hydration form nonionic surfactant vesicle.Has following advantage: can solve 1. that the paeonol crude drug is volatile, stability is bad, be insoluble in problem such as water; 2. behind the percutaneous dosing, can form drug depot at local skin, slowly discharge medicine, keep stabilised blood concentration in the body, play efficient, long-acting; 3. provide exemplary role for preceding non-ionic precursor technology in the suitability research of Chinese medicine.
Summary of the invention
The object of the present invention is to provide the preceding non-ionic precursor preparation of a kind of paeonol, it is semi-solid state, has solved the stability problem in the storage of paeonol nonionic surfactant vesicle and the transportation.
Another object of the present invention provides the preparation method of the preceding non-ionic precursor preparation of above-mentioned a kind of paeonol.
For achieving the above object, the invention provides following technical scheme: non-ionic precursor preparation before a kind of paeonol, it is characterized in that: calculate by weight, prescription comprises following component: 3～6 parts of paeonol, 64～145 parts of non-ionic surface active agents, 64～145 parts in lecithin, 7～13 parts in cholesterol, organic facies 1-3 part, water 1-3 part.
Described non-ionic surface active agent is selected from one or both mixing among Span-20, Span-40, Span-60, Span-80, Span-85, Tween-20, Tween-60, Tween-80, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, sucrose stearate s-3, sucrose stearate s-7, sucrose stearate s-11, the sucrose stearate s-15.
Described lecithin is selected from one or both mixing in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, the hydrolecithin.
Described organic facies is dehydrated alcohol, propanol, isopropyl alcohol or butanols.
Described water is selected from phosphate buffered saline(PBS), hydration glycerol or distilled water.
The preparation method of non-ionic precursor preparation before the above-mentioned paeonol, it is characterized in that may further comprise the steps: (1) is dissolved in organic facies with paeonol, non-ionic surface active agent, lecithin, cholesterol, seals, and heating in water bath to all the components dissolves fully; (2) add aqueous phase solution, heating in water bath is cooled to room temperature to forming clear solutions again, namely gets the preceding non-ionic precursor of paeonol.
Water bath heating temperature in the described step (1) is 60-70 ℃.
Water bath heating temperature in the described step (2) is 60-70 ℃.
Non-ionic precursor is a kind of semi-solid gel state before of the present invention, can recombinate after the hydration and form nonionic surfactant vesicle, easily assemble for solving in non-ionic precursor surfactant vesicle solution state and the storage process vesicle, problems such as fusion and medicine leakage provide an efficient ways, and at transportation, storage, user's mask remarkable advantages is arranged, being applicable to suitability for industrialized production, is a kind of novel carriers extremely likely.The present invention with paeonol before non-ionic precursor further make ointment, compare with the common ointment of paeonol.Show through the nude mice isolated experiment, non-ionic precursor and ointment thereof before the paeonol of the present invention, the ability that sees through keratodermatitis is all stronger, be significantly higher than the common ointment of paeonol, and drug treating time can continue 12h.Pharmacokinetics experiment shows before the paeonol behind the non-ionic precursor ointment percutaneous dosing that medicine more accumulates in the skin histology liquid and less being distributed in the systemic blood, compare with common ointment, no matter be in subcutaneous tissue liquid or the blood, its mean residence time is all longer, eliminate slowly in the body, played certain slow release, long-acting; And behind the common ointment percutaneous dosing of paeonol, medicine more concentrates in the blood, and no matter is that the elimination of paeonol in subcutaneous tissue liquid or the blood is all very fast, and mean residence time is shorter.
Non-ionic precursor can directly apply on the skin before the paeonol of the present invention, also can be prepared into various transdermal administration dosage forms such as gel, ointment, patch.
Description of drawings
Fig. 1 is the form photo of the nonionic surfactant vesicle that non-ionic precursor forms after aquation before the paeonol of the embodiment of the invention 16 gained;
Fig. 2 is the particle size distribution figure of the nonionic surfactant vesicle that non-ionic precursor forms after aquation before the paeonol of the embodiment of the invention 16 gained;
Fig. 3 is the accumulation Transdermal absorption amount-time diagram of the preceding non-ionic precursor of the paeonol of the embodiment of the invention 16 gained and ointment and common ointment.
Fig. 4 is non-ionic precursor ointment and common ointment paeonol concentration-time curve in the blood after the rat abdomen administration before the paeonol of the embodiment of the invention 16 gained.
Fig. 5 is non-ionic precursor ointment and common ointment paeonol concentration-time curve in the skin histology liquid after the rat abdomen administration before the paeonol of the embodiment of the invention 16 gained.
The specific embodiment
The present invention is non-ionic precursor preparation before a kind of paeonol, calculate by weight, prescription comprises following component: 3～6 parts of paeonol, 64～145 parts of non-ionic surface active agents, 64～145 parts in lecithin, 7～13 parts in cholesterol, organic facies 1-3 part, water 1-3 part.
Paeonol is principal agent in the prescription; Non-ionic surface active agent is selected from one or both mixing among Span-20, Span-40, Span-60, Span-80, Span-85, polysorbate-20, polysorbate-60, Polyoxyethylene Sorbitan Monooleate, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, sucrose stearate s-3, sucrose stearate s-7, sucrose stearate s-11, the sucrose stearate s-15 as coating material; Lecithin, cholesterol are membrane stabilizer, and wherein lecithin can be selected from one or both mixing in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, the hydrolecithin; Organic facies is dehydrated alcohol, propanol, isopropyl alcohol or butanols.Water can be selected phosphate buffered saline(PBS) liquid, hydration glycerol or the distilled water of different pH value, most preferably the phosphate buffered saline(PBS) of pH7.4 according to the character of medicine.
The present invention mainly adopts the gel phase partition method to prepare the preceding non-ionic precursor of paeonol, concrete preparation method may further comprise the steps: (1) is dissolved in organic facies with paeonol, non-ionic surface active agent, lecithin, cholesterol, seal, heating in water bath to all the components dissolves fully; (2) add aqueous phase solution, heating in water bath is cooled to room temperature to forming clear solutions again, namely gets the preceding non-ionic precursor of paeonol.Water bath heating temperature in step (1), the step (2) is preferably 60-70 ℃.
Because water is limited the quantity of, the preceding non-ionic precursor that the present invention makes is thickness character, after it is dissolved in water, can disperse or reconstitute paeonol nonionic surfactant vesicle suspension that granularity and form and employing additive method obtain does not have the vesicle of significant difference, and the envelop rate of paeonol is higher.
Below the present invention is further elaborated by specific embodiment, but the present invention is not limited to this specific examples.
3 parts of paeonol, Span-6090 part, 90 parts of soybean lecithins, cholesterol are dissolved in 1 part of dehydrated alcohol for 10 parts, seal, 60 ℃ of heating in water bath to all the components dissolve fully, 1 part of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
5 parts of paeonol, Span-6064 part, 64 parts of soybean lecithins, cholesterol are dissolved in 1 part of propanol for 7 parts, seal, 65 ℃ of heating in water bath dissolve fully until all the components, add 1% hydration glycerol towards 1 part of saline solution, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
Embodiment 3
5 parts of paeonol, Span-6064 part, 64 parts of soybean lecithins, cholesterol are dissolved in 2 parts of isopropyl alcohols for 13 parts, seal, 65 ℃ of heating in water bath dissolve fully until all the components, add 2 parts of distilled water, heating in water bath takes out to forming clear solutions again, the room temperature cooling, namely.
5 parts of paeonol, Span-6064 part, 116 parts of soybean lecithins, cholesterol are dissolved in 3 parts of butanols for 7 parts, seal, 70 ℃ of heating in water bath dissolve fully until all the components, 2 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
Embodiment 5
5 parts of paeonol, Span-6064 part, 116 parts of soybean lecithins, cholesterol are dissolved in 3 parts of dehydrated alcohol for 13 parts, seal, 65 ℃ of heating in water bath dissolve fully until all the components, 1 part of the phosphate buffered saline(PBS) of adding pH6.8, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
5 parts of paeonol, Span-60116 part, 64 parts of soybean lecithins, cholesterol are dissolved in 2 parts of dehydrated alcohol for 7 parts, seal, 67 ℃ of heating in water bath dissolve fully until all the components, 2 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
Embodiment 7
6 parts of paeonol, Span-60116 part, 64 parts of soybean lecithins, cholesterol are dissolved in 1.5 parts of dehydrated alcohol for 13 parts, seal, 65 ℃ of heating in water bath dissolve fully until all the components, 1 part of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
6 parts of paeonol, Span-6090 part, 90 parts of soybean lecithins, cholesterol are dissolved in 3 parts of dehydrated alcohol for 5 parts, seal, 65 ℃ of heating in water bath dissolve fully until all the components, 2 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
Embodiment 9
5 parts of paeonol, Span-6090 part, 90 parts of soybean lecithins, cholesterol are dissolved in 2 parts of dehydrated alcohol for 15 parts, seal, 60 ℃ of heating in water bath 5min, dissolve 1 part of the phosphate buffered saline(PBS) of adding pH7.4, the about 2min of heating in water bath more fully until all the components, form clear solutions, take out, the room temperature cooling, namely.
5 parts of paeonol, Span-6090 part, 45 parts of soybean lecithins, cholesterol are dissolved in 3 parts of dehydrated alcohol for 10 parts, seal, 68 ℃ of heating in water bath dissolve fully until all the components, 3 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
Embodiment 11
5 parts of paeonol, Span-6090 part, 135 parts of soybean lecithins, cholesterol are dissolved in 3 parts of dehydrated alcohol for 10 parts, seal, 70 ℃ of heating in water bath dissolve fully until all the components, 2 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
5 parts of paeonol, Span-6045 part, 90 parts of soybean lecithins, cholesterol are dissolved in 2 parts of dehydrated alcohol for 10 parts, seal, 65 ℃ of heating in water bath dissolve fully until all the components, 3 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
Embodiment 13
5 parts of paeonol, Span-60135 part, 90 parts of soybean lecithins, cholesterol are dissolved in 3 parts of dehydrated alcohol for 10 parts, seal, 65 heating in water bath dissolve fully until all the components, 2 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
Embodiment 14
4 parts of paeonol, Span-6090 part, 90 parts of soybean lecithins, cholesterol are dissolved in 2.5 parts of dehydrated alcohol for 10 parts, seal, 68 ℃ of heating in water bath dissolve fully until all the components, 1.5 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
Embodiment 15
4 parts of paeonol, Span-6075 part, 108 parts of soybean lecithins, cholesterol are dissolved in 1.5 parts of dehydrated alcohol for 8 parts, seal, 60 ℃ of heating in water bath dissolve fully until all the components, 1.5 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
Embodiment 16
5 parts of paeonol, Span-6080 part, 108 parts of soybean lecithins, cholesterol are dissolved in 1.5 parts of dehydrated alcohol for 8 parts, seal, 65 ℃ of heating in water bath dissolve fully until all the components, 1 part of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
Embodiment 17
6 parts of paeonol, Span-2090 part, 90 parts of soybean lecithins, cholesterol are dissolved in 3 parts of dehydrated alcohol for 5 parts, seal, 60 ℃ of heating in water bath dissolve fully until all the components, 2 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath is to forming clear solutions again, take out, the room temperature cooling, namely.
Embodiment 18
5 parts of paeonol, Span-80100 part, 108 parts of soybean lecithins, cholesterol are dissolved in 2 parts of dehydrated alcohol for 10 parts, seal, 62 ℃ of heating in water bath dissolve fully until all the components, 1 part of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath forms clear solutions approximately again, take out, the room temperature cooling, namely.
Embodiment 19
5 parts of paeonol, polysorbate-2090 part, 90 parts of soybean lecithins, cholesterol are dissolved in 1.5 parts of dehydrated alcohol for 10 parts, seal, 65 ℃ of heating in water bath dissolve fully until all the components, 2 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath forms clear solutions approximately again, take out, the room temperature cooling, namely.
5 parts of paeonol, polysorbate-6090 part, 90 parts of soybean lecithins, cholesterol are dissolved in 2 parts of dehydrated alcohol for 10 parts, seal, 66 ℃ of heating in water bath dissolve fully until all the components, 2 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath forms clear solutions approximately again, take out, the room temperature cooling, namely.
Embodiment 21
5 parts of paeonol, 90 parts of Polyoxyethylene Sorbitan Monooleates, 90 parts of soybean lecithins, cholesterol are dissolved in 3 parts of dehydrated alcohol for 10 parts, seal, 65 ℃ of heating in water bath dissolve fully until all the components, 1 part of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath forms clear solutions approximately again, take out, the room temperature cooling, namely.
Embodiment 22
5 parts of paeonol, polysorbate-6090 part, 90 parts of Ovum Gallus domesticus Flavus lecithins, cholesterol are dissolved in 1 part of dehydrated alcohol for 10 parts, seal, 70 ℃ of heating in water bath dissolve fully until all the components, 2 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath forms clear solutions approximately again, take out, the room temperature cooling, namely.
Embodiment 23
5 parts of paeonol, 90 parts of polyoxyethylene fatty acid esters, 90 parts of Ovum Gallus domesticus Flavus lecithins, cholesterol are dissolved in 3 parts of dehydrated alcohol for 10 parts, seal, 60 ℃ of heating in water bath dissolve fully until all the components, 1 part of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath forms clear solutions approximately again, take out, the room temperature cooling, namely.
Embodiment 24
5 parts of paeonol, 90 parts of polyoxyethylene aliphatic alcohol ethers, 90 parts of Ovum Gallus domesticus Flavus lecithins, cholesterol are dissolved in 2 parts of dehydrated alcohol for 10 parts, seal, 67 ℃ of heating in water bath dissolve fully until all the components, 1 part of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath forms clear solutions approximately again, take out, the room temperature cooling, namely.
Embodiment 25
5 parts of paeonol, sucrose stearate s-390 part, 90 parts of Ovum Gallus domesticus Flavus lecithins, cholesterol are dissolved in 3 parts of dehydrated alcohol for 10 parts, seal, 68 ℃ of heating in water bath dissolve fully until all the components, 1.5 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath forms clear solutions approximately again, take out, the room temperature cooling, namely.
Embodiment 26
5 parts of paeonol, sucrose stearate s-790 part, 90 parts of Ovum Gallus domesticus Flavus lecithins, cholesterol are dissolved in 2.5 parts of dehydrated alcohol for 10 parts, seal, 70 ℃ of heating in water bath dissolve fully until all the components, 2 parts of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath forms clear solutions approximately again, take out, the room temperature cooling, namely.
Embodiment 27
5 parts of paeonol, sucrose stearate s-1190 part, 90 parts of Ovum Gallus domesticus Flavus lecithins, cholesterol are dissolved in 2 parts of dehydrated alcohol for 10 parts, seal, 60 ℃ of heating in water bath dissolve fully until all the components, 1 part of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath forms clear solutions approximately again, take out, the room temperature cooling, namely.
Embodiment 28
5 parts of paeonol, sucrose stearate s-1590 part, 90 parts of Ovum Gallus domesticus Flavus lecithins, cholesterol are dissolved in 3 parts of dehydrated alcohol for 10 parts, seal, 70 ℃ of heating in water bath dissolve fully until all the components, 1 part of the phosphate buffered saline(PBS) of adding pH7.4, heating in water bath forms clear solutions approximately again, take out, the room temperature cooling, namely.
Be research of the present invention example with embodiment 1-20, further set forth advantage of the present invention by following experiment.
(1) the preceding non-ionic precursor of paeonol is to the envelop rate of paeonol
Get the preceding non-ionic precursor 0.2g of paeonol, add the phosphate buffered saline(PBS) 10ml of pH7.4, ultrasonic dissolution.Get 1ml in 14000rpm, 4 ℃ of centrifugal 40min, the accurate supernatant of drawing adds methanol and is diluted in the 5ml volumetric flask, adopts the high effective liquid chromatography for measuring paeonol content, calculates the paeonol envelop rate according to following formula.Getting its envelop rate is 12.73～66.45%.Concrete data see Table 1.
Wherein, EE% is envelop rate, and Ct and Cr are respectively the amount of free medicine in the total amount that adds medicine and the vesicle.
(2) form and the particle size distribution of the non-ionic precursor vesicle of rebuilding after the non-ionic precursor hydration before the paeonol
Get non-ionic precursor before the paeonol, add aqueous dispersion after, be 7.022～14.298 μ m with its mean diameter of H-3000N type sem observation, size is even, as Fig. 1, table 1.Measure its particle size distribution value with Ma Erwen laser light scattering particle size determination instrument, the particle size distribution value of mensuration is 0.75～3.78, as Fig. 2.The paeonol non-ionic precursor retention volume height of its formation, particle size distribution is more even, and is reliable and stable, can further be prepared into the preparation that is used for the treatment of diseases such as eczema according to clinical needs.
(3) non-ionic precursor soft paste sturdy the testing of passing through inside before the paeonol, (serve as that research routine with embodiment 16).
The nude mice cervical vertebra is put to death, and carefully peels off skin, rejects subcutaneous fat; The skin that takes off carries out the transdermal test immediately.With normal saline as acceptable solution and place the good Franz diffusion cell of preheating (the transdermal area is 3.14cm
2, receiving chamber's volume is 15ml, 37 ± 1 ℃ of whole experiment constant temperature, 300 ± 10r/min stirs).The nude mice skin of having handled well is fixed between the receiving chamber and supply chamber that has added stirrer.Non-ionic precursor ointment is on Corium Mus before adding homemade paeonol unguentum, the preceding non-ionic precursor of paeonol and paeonol, cover preservative film, respectively at 0.5,1,2,4,6,8,10, the 12h 1ml that from acceptable solution, takes a sample, replenish the normal saline of equal volume simultaneously in accepting the pond.The sample that obtains is measured content with HPLC.The results are shown in Table 2, Fig. 3.
By the result as can be known, the steady-state permeation speed of non-ionic precursor and ointment thereof, common ointment is respectively (10.327 μ gcm before the paeonol
-2H
-1, 7.826 μ gcm
-2H
-1, 5.967 μ gcm
-2H
-1), unit are accumulation transdermal penetration amount Q is respectively (125.54 ± 8.87 μ gcm
-2, 96.20 ± 5.87 μ gcm
-2, 75.83 ± 18.42 μ gcm
-2), show that the preceding non-ionic precursor of paeonol and ointment transdermal penetration ability thereof all are higher than the common ointment of paeonol.
(4) pharmacokinetics of the common ointment of non-ionic precursor ointment machin experiment before the paeonol, (serve as that research routine with embodiment 16).
Get the Wistar rat, weigh, adopt 10% chloral hydrate lumbar injection to make its anesthesia (0.35ml/100g), first after the injection, every half of 1.5h injection initial dose to keep the narcotism of rat.Sodium sulfide alcoholic solution with 8% loses hair or feathers to its abdominal part, it is lain on the back be fixed on the Mus plate, will tear pipe box and live puncture needle, implants subcutaneously, extracts puncture needle out, tears pipe and stays subcutaneous.Be inducted into subcutaneously from tearing tube opening the concentric annular probe, tear and tear pipe, probe is namely implanted subcutaneous, with medical adhesive tape stationary probe position.In this simultaneously, cut off an otch that is about 1cm with eye scissors at the right cervical region of rat, passivity is separated jugular vein, bundle closes its proximal part, to tear pipe with puncture needle and be inducted into blood vessel, with above-mentioned same method probe is inducted into blood vessel, with stitching thread probe and vein is connect again and prick fixingly, get a cotton balls that dips in normal saline and cover the surgical wound position.Smear non-ionic precursor ointment and each 1g of common ointment thereof before the paeonol respectively at rat abdomen, adopt glass administrator (administration area 3.14cm
2) be sealingly fastened in rat abdomen.Adopt normal saline as perfusate, perfusion rate is 5 μ lml
-1, collect once every 20min, collect 12h altogether.Adopt high-efficient liquid phase technique to measure the content of collecting paeonol in the liquid.The results are shown in Table 3,4, Fig. 4,5.
As shown in Table 3, the pharmacokinetic parameter in the preceding non-ionic precursor ointment blood of paeonol is as (t
1/2, MRT, T
Max) obviously greater than common ointment, and AUC value, C
MaxOn the contrary, show preceding non-ionic precursor ointment less the entering in the blood of paeonol behind the rat abdomen percutaneous drug delivery of paeonol, but its elimination in vivo is slower, mean residence time is also longer, and the drug level fluctuation is little.Can enter in the blood for a long time, stably after the preceding non-ionic precursor ointment percutaneous dosing of paeonol is described, have certain slow releasing function.And the medicine in the common ointment more concentrates in the blood, but eliminates comparatively fast in the body, and mean residence time is shorter.
As shown in Table 4, before the paeonol in the non-ionic precursor ointment subcutaneous tissue liquid every pharmacokinetic parameters all greater than common ointment.Show before the paeonol that behind the non-ionic precursor ointment percutaneous dosing, paeonol more accumulates in the subcutaneous tissue liquid, medicine reach the peak concentration height, mean residence time is long, eliminates slowly in the body, can keep 10h, has played certain slow release, long-acting.And behind the common ointment percutaneous dosing of paeonol, the short period reaches peak value, but eliminates in the body soon, and the persistent period is short, only can keep 6h.
The envelop rate of table 1 embodiment 1-16 and size, particle diameter score value
Paeonol unit are accumulation Transdermal absorption amount in each preparation of table 2 different time points
The pharmacokinetic parameters of paeonol in non-ionic precursor ointment and the common ointment blood of paeonol before table 3 paeonol
* P＜0.05 has significant difference
The pharmacokinetic parameters of paeonol in non-ionic precursor ointment and the common ointment subcutaneous tissue liquid before table 4 paeonol
* P＜0.01, * P＜0.05 has significant difference
Claims (8)
1. non-ionic precursor preparation before the paeonol, it is characterized in that: calculate by weight, prescription comprises following component: 3～6 parts of paeonol, 64～145 parts of non-ionic surface active agents, 64～145 parts in lecithin, 7～13 parts in cholesterol, organic facies 1-3 part, water 1-3 part.
2. non-ionic precursor preparation before a kind of paeonol according to claim 1, it is characterized in that: described non-ionic surface active agent is selected from one or both mixing among Span-20, Span-40, Span-60, Span-80, Span-85, polysorbate-20, polysorbate-60, Polyoxyethylene Sorbitan Monooleate, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, sucrose stearate s-3, sucrose stearate s-7, sucrose stearate s-11, the sucrose stearate s-15.
3. non-ionic precursor preparation before a kind of paeonol according to claim 1, it is characterized in that: described lecithin is selected from one or both mixing in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, the hydrolecithin.
4. non-ionic precursor preparation before a kind of paeonol according to claim 1, it is characterized in that: described organic facies is dehydrated alcohol, propanol, isopropyl alcohol or butanols.
5. non-ionic precursor preparation before a kind of paeonol according to claim 1, it is characterized in that: described water is selected from phosphate buffered saline(PBS), hydration glycerol or distilled water.
6. the preparation method of non-ionic precursor preparation before the described paeonol of arbitrary claim among the claim 1-5, it is characterized in that may further comprise the steps: (1) is dissolved in organic facies with paeonol, non-ionic surface active agent, lecithin, cholesterol, seal, heating in water bath to all the components dissolves fully; (2) add aqueous phase solution, heating in water bath is cooled to room temperature to forming clear solutions again, namely gets the preceding non-ionic precursor of paeonol.
7. the preparation method of non-ionic precursor preparation before a kind of paeonol according to claim 6, it is characterized in that: the water bath heating temperature in the described step (1) is 60-70 ℃.
8. the preparation method of non-ionic precursor preparation before a kind of paeonol according to claim 6, it is characterized in that: the water bath heating temperature in the described step (2) is 60-70 ℃.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105687136A (en) * | 2014-11-26 | 2016-06-22 | 安徽中医药大学 | PEGylated paeonol nonionic surfactant vesicle and preparation method thereof |
| CN105748436A (en) * | 2014-12-15 | 2016-07-13 | 安徽中医药大学 | Paeonol niosome emulsifiable paste for external use and preparation method thereof |
| CN110123739A (en) * | 2019-05-14 | 2019-08-16 | 扬子江药业集团江苏紫龙药业有限公司 | Non-ionic precursor gel preparation and preparation method thereof before a kind of Rupatadine fumarate |
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| CN102697705A (en) * | 2012-01-18 | 2012-10-03 | 广东药学院 | Liposome gel preparation and preparation method and application thereof |
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| CN102697705A (en) * | 2012-01-18 | 2012-10-03 | 广东药学院 | Liposome gel preparation and preparation method and application thereof |
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| 江晓等: "前非离子体的研究进展"", 《中国实验方剂学杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105687136A (en) * | 2014-11-26 | 2016-06-22 | 安徽中医药大学 | PEGylated paeonol nonionic surfactant vesicle and preparation method thereof |
| CN105748436A (en) * | 2014-12-15 | 2016-07-13 | 安徽中医药大学 | Paeonol niosome emulsifiable paste for external use and preparation method thereof |
| CN105748436B (en) * | 2014-12-15 | 2020-09-25 | 安徽中医药大学 | Paeonol vesicle cream for external use and preparation method thereof |
| CN110123739A (en) * | 2019-05-14 | 2019-08-16 | 扬子江药业集团江苏紫龙药业有限公司 | Non-ionic precursor gel preparation and preparation method thereof before a kind of Rupatadine fumarate |
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