CN104958257A - Cryptotanshinone skin cutin liposomal preparation and preparing method thereof - Google Patents
Cryptotanshinone skin cutin liposomal preparation and preparing method thereof Download PDFInfo
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Abstract
The invention discloses a cryptotanshinone skin cutin liposomal preparation and a preparing method thereof. According to a formula, cryptotanshinone, lectin and cholesterol are dissolved in an organic phase, ceramide is dissolved in a water phase, preheating is allowed on a magnetic stirrer, the obtained organic phase is slowly dropped into the water phase, in which the ceramide is dissolved during magnetic stirring, and continuous stirring is performed to volatize the organic phase and transferred to a brown glass bottle for preservation. The cryptotanshinone skin cutin liposomal preparation has the advantages that the speed of the cryptotanshinone to permeate the skin can be evidently increased, and quantity of the preparation enters general circulation can be decreased at the premise of improving local effect; by preparation by means of organic solvent injection, the problems such that the cryptotanshinone is poor in water solubility and unstable are evidently improved, the speed of the cryptotanshinone to permeate through the cuticle can be increased, and a higher quantity of the preparation retains on the skin; the preparation can be prepared into various transdermal drugs, such as gels, ointments and plasters; the preparation is more widely applicable in the field of pharmaceuticals and cosmetics.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly a kind of novel pharmaceutical carrier cryptotanshinone skin keratin lipoid preparation and preparation method thereof.
Background technology:
Cryptotanshinone (Cryptotanshinone, CTS) has very strong representational component in labiate fat soluble ingredient of red sage root.In external curing dermatosis, it all embodies stronger activity improving in microcirculation, resolution, reparation skin lesion etc.At present, the external patent medicine of cryptotanshinone is contained on the market mainly based on Acne treatment, such as TANSHINONES ointment, kecuocryptone ointment, kecuocryptone gel etc.Using clinically with cryptotanshinone is the struvite and pustular acne Be very effective of red sage formulation treatment of effective ingredient, and zoopery display is nontoxic non-stimulated.The chemical composition that total tanshinone is separated proves through extracorporeal bacteria inhibitor test, and the bacteriostatic activity of cryptotanshinone is the strongest, and content is higher.But in the research progress of cryptotanshinone, its some characteristics manifested gradually greatly limit its application in product forms, such as poorly water-soluble, see that light easily decomposes, to liver drug enzyme, there is inducing action etc.Therefore, for traditional, the unification of cryptotanshinone preparation formulation on market and the characteristic of medicine itself, modern medicines novel form and a kind of dermal topical application novel form strengthening cryptotanshinone stability of new technology development is utilized to have great importance.
Skin keratin lipoid has another name called ceramide liposome (Cerasomes, CS), belongs to the novel delivery system of liposome developed recently, primarily of the composition such as ceramide (Ceramide), cholesterol of polarity close to keratodermatitis.Saturated lipid such as ceramide, cholesterol and free fatty etc. together form cuticular permeability barrier, can the exchange of effective barrier material.The phospholipid bilayer of skin keratin lipoid is made up of class Stratum corneum lipids, wherein ceramide is as one of the important component of keratodermatitis, there is moisturizing, maintain the physiological functions such as skin barrier, antiallergic, defying age, cell death inducing, there is potential medical applications and be worth.Liposome, as pharmaceutical carrier, makes drug accumulation in target site, improves the effect of curative effect and reduction untoward reaction.The combination of ceramide and liposome, improves the ability of liposome dissolving horny layer penetration cell on the one hand; Other drug or active component can be encapsulated on the other hand, improve its stability and biocompatibility, medicine is more stably discharged in corresponding tissue.
Summary of the invention
The object of the present invention is to provide a kind of cryptotanshinone skin keratin lipoid preparation, it is suspension state, and the drug effect persistent period is long, and percutaneous rate is fast, and bioavailability effectively improves.
Another object of the present invention is to provide the preparation method of above-mentioned cryptotanshinone skin keratin lipoid preparation.
For achieving the above object, the invention provides following technical scheme: a kind of cryptotanshinone skin keratin lipoid preparation, it is characterized in that: calculate by weight, formula comprises following component: cryptotanshinone 0.5 ~ 7 part, ceramide 30 ~ 100 part, 20 ~ 125 parts, lecithin, 10 ~ 200 parts, cholesterol, organic facies 800 ~ 5000 parts, aqueous phase 2000 ~ 12500 parts.
Described ceramide is water solublity ceramide.
Described lecithin is selected from one or both mixing in soybean lecithin, hydrolecithin, Ovum Gallus domesticus Flavus lecithin.
Described organic facies is selected from dehydrated alcohol or ether.
Described aqueous phase is selected from distilled water, or the phosphate buffered saline(PBS) of pH7.4 or pH5.8.
The preparation method of above-mentioned cryptotanshinone skin keratin lipoid preparation, is characterized in that comprising the following steps: cryptotanshinone, lecithin, cholesterol are dissolved in organic facies by (1); (2) ceramide is dissolved in aqueous phase, and is placed in preheating on magnetic stirring apparatus; (3) while magnetic agitation, step (1) gained organic facies slowly instilled and be dissolved with in the aqueous phase of ceramide, Keep agitation makes organic facies volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Being preheated to temperature in described step (2) is 30-70 DEG C.
Magnetic agitation speed in described step (3) is 200-600rpm, and mixing time is 2-4h.
In described step (3), organic facies syringe slowly instills in aqueous phase.
In described step (3), in Keep agitation process, temperature remains within the scope of 30-70 DEG C.
Cryptotanshinone is prepared into skin keratin lipoid preparation and is used for the treatment of acne, overcome the drawback of the large shortcoming of classical hormonal class drug side effect and compound Chinese medicinal preparation complicated component, the more important thing is, constituent due to skin keratin lipoid close with horny layer and more easily and horny layer mutually merge, thus the speed of cryptotanshinone skin permeation can be significantly improved.And skin keratin lipoid as fat-soluble medicine carrier time, increase local effect while, can also reduce medicine enter body circulation amount.Thus one, the existence of ceramide makes preparation be combined with illing skin horny layer better, improves the bioavailability of cryptotanshinone at local skin.On the other hand, compared with other topical novel forms, cryptotanshinone skin keratin lipoid also has the advantage of its uniqueness, such as, wherein do not add the surfactant needed in microemulsion preparation process and cosurfactant, decreases the zest etc. of preparation to skin.
Cryptotanshinone skin keratin lipoid preparation prepared by the present invention's organic solvent injection method, significantly improves the performances such as cryptotanshinone poorly water-soluble, instability, can improve cryptotanshinone through cuticular infiltration rate, increases the skin hold-up of medicine.And show in body pharmacokinetic studies, compared with cryptotanshinone ordinary gel, giving cryptotanshinone skin keratin lipoid gel and can significantly improve the local biologic availability of skin, reducing side effect, and during the sustained release of 12h, chien shih medicine can be remained valid concentration for a long time at skin.Cryptotanshinone skin keratin lipoid of the present invention can be prepared into the various transdermal administration such as gel, ointment, patch, can expand cryptotanshinone further in application that is medical and cosmetic field.
Accompanying drawing explanation
Fig. 1 is the form of cryptotanshinone skin keratin lipoid under transmission electron microscope prepared by the embodiment of the present invention 1;
Fig. 2 is the permeation test in vitro result of cryptotanshinone skin keratin lipoid preparation prepared by the embodiment of the present invention 1 and cryptotanshinone ordinary preparation, wherein: CTS-CS gel-cryptotanshinone skin keratin lipoid gel; CTS gel-cryptotanshinone ordinary gel;
Fig. 3 is the skin hold-up result of the test of cryptotanshinone skin keratin lipoid preparation and cryptotanshinone ordinary preparation, wherein: CTS-CS gel-cryptotanshinone skin keratin lipoid gel; CTS gel-cryptotanshinone ordinary gel;
Fig. 4 is the drug level result of variations that cryptotanshinone skin keratin lipoid preparation and cryptotanshinone ordinary preparation are applied to after rat skin in the subcutaneous rat tissue fluid of microdialysis sample detecting different time points and blood, wherein: CTS-CSgel-cryptotanshinone skin keratin lipoid gel; CTS gel-cryptotanshinone ordinary gel.
Detailed description of the invention
The present invention is a kind of preparation method of cryptotanshinone skin keratin lipoid, calculate by weight, formula comprises following component: cryptotanshinone 0.5 ~ 7 part, ceramide 30 ~ 100 part, 20 ~ 125 parts, lecithin, 10 ~ 200 parts, cholesterol, organic facies 800 ~ 5000 parts, aqueous phase 2000 ~ 12500 parts.In formula, cryptotanshinone is principal agent; Lecithin, ceramide as filmogen, wherein lecithin preferably in soybean lecithin, hydrolecithin, Ovum Gallus domesticus Flavus lecithin one or both mixing; Cholesterol is membrane stabilizer, regulates the mobility of film; Organic facies is selected from dehydrated alcohol or ether; Ceramide is water solublity ceramide; Aqueous phase according to pharmaceutical properties, can select phosphate buffered saline(PBS) or the distilled water of different pH value.
The present invention mainly adopts organic solvent injection method to prepare cryptotanshinone skin keratin lipoid, concrete preparation method comprises the following steps: cryptotanshinone, lecithin, cholesterol are dissolved in a small amount of organic facies by (1): ceramide is dissolved in aqueous phase by (2), and be placed on magnetic stirring apparatus and be preheated to prescription temperature, preferred temperature is 30-70 DEG C; (3) while magnetic agitation, slowly instilled in aqueous phase by above-mentioned organic facies syringe, the constant temperature maintaining step (2) stirs and organic facies is volatilized, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.In step (3), preferred magnetic agitation speed is 200-600rpm, and mixing time is 2-4h.
Below by way of specific embodiment, the present invention is further elaborated, but the present invention is not limited to this specific examples.
Embodiment 1
Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 50 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 2
Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 50 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 3
Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 50 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 2h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 4
Cryptotanshinone 5mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 50 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 5
Cryptotanshinone 2.5mg, soybean lecithin 0.1g, cholesterol 0.05g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 60 DEG C; Keep temperature, keep magnetic agitation speed to be 400rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 4h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 6
Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 60 DEG C; Keep temperature, keep magnetic agitation speed to be 400rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 7
Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 60 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 8
Cryptotanshinone 1mg, soybean lecithin 0.1g, cholesterol 0.05g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 40 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 9
Cryptotanshinone 1mg, soybean lecithin 0.05g, cholesterol 0.017g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 60 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 10
Cryptotanshinone 1mg, soybean lecithin 0.08g, cholesterol 0.017g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 40 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 11
Cryptotanshinone 2.5mg, soybean lecithin 0.1g, cholesterol 0.05g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 40 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 12
Cryptotanshinone 1mg, soybean lecithin 0.1g, cholesterol 0.05g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.05g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 60 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 13
Cryptotanshinone 2.5mg, soybean lecithin 0.1g, cholesterol 0.017g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.08g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 60 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 14
Cryptotanshinone 2.5mg, soybean lecithin 0.1g, cholesterol 0.017g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.1g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 40 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 15
Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 30 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 16
Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.16g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 50 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 17
Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 70 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 18
Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.013g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 50 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 19
Cryptotanshinone 0.8mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 50 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 20
Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 5mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mLpH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 50 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 4h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 21
Cryptotanshinone 1mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL dehydrated alcohol and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mL pH5.8 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 50 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 22
Cryptotanshinone 1mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL ether and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mL pH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 50 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ether volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 23
Cryptotanshinone 1mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL ether and obtain organic facies; Ceramide 0.03g is dissolved in 10mL distilled water and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 60 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Embodiment 24
Cryptotanshinone 1mg, Ovum Gallus domesticus Flavus lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL ether and obtain organic facies; Ceramide 0.03g is dissolved in the phosphate buffered saline(PBS) of 10mL pH7.4 and obtains aqueous phase, and be placed on magnetic stirring apparatus and be preheated to 60 DEG C; Keep temperature, keep magnetic agitation speed to be 600rpm, slowly instilled in aqueous phase by organic facies syringe, Keep agitation 3h makes ethanol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
Experiment and interpretation of result
The cryptotanshinone skin keratin lipoid that Example 1 obtains carries out following experiment and sets forth advantage of the present invention further.
(1) entrapment efficiency determination of cryptotanshinone in cryptotanshinone skin keratin lipoid
Get cryptotanshinone skin keratin lipoid 1mL, put in 10mL volumetric flask, the PBS solution adding corresponding pH is diluted to scale, and ultrasonic 10min, shakes up.Precision measures 1mL, and in 14000rpm, 4 DEG C of centrifugal 10min, take out, Aspirate supernatant, puts in 5mL volumetric flask, adds dissolve with methanol and is settled to scale, adopts the content of high effective liquid chromatography for measuring cryptotanshinone.According to following formulae discovery entrapment efficiency.Obtaining its envelop rate is 15.47 ~ 67.20%.Experimental result is in table 1.
Wherein, EE% is envelop rate, Ct and Cr is respectively and adds medicine total amount and free drug amount.
(2) morphological observation of cryptotanshinone skin keratin lipoid and particle size distribution measuring
Adopt Zetasizer 3000HS type current potential Particle Size Analyzer to measure the size of cryptotanshinone skin keratin lipoid and distribution, dispersant is distilled water, laser wavelength 633nm, temperature 25 DEG C, and dispersant refractive index is 1.33.Obtain the coefficient of dispersion (σ) to represent the uniformity of particle size distribution.The coefficient of dispersion measured is 0.23 ~ 0.66, distributes very even.It is 50 ~ 150 μm by its mean diameter of H-7650 transmission electron microscope observation.Figure 1 shows that the cryptotanshinone skin keratin lipoid of embodiment 1 gained.Experimental result is shown in Fig. 1, table 1.
The envelop rate of table 1 embodiment 1-24 and coefficient of dispersion result
(3) cryptotanshinone skin keratin lipoid gel percutaneous penetration (with embodiment 1 for research example)
The preparation of cryptotanshinone skin keratin lipoid gel and cryptotanshinone ordinary gel: carbomer 2g, propylene glycol 15g, glycerol 20g are added water in right amount, slowly stirs on magnetic stirring apparatus, and soak 5h, fully swelling substrate.By cryptotanshinone skin keratin lipoid 10mL obtained for 1. embodiment 1, wherein cryptotanshinone concentration is 0.1mgmL
-1; 2. 0.1mgmL
-1cryptotanshinone alcoholic solution 10mL, add anhydrous sodium sulfate 0.2g, sodium hydroxide 0.2g incorporate in substrate, finally add water to 100g and stir evenly, obtain cryptotanshinone skin keratin lipoid gel and cryptotanshinone ordinary gel respectively.
Isolated rat penetrating absorption: nude mice cervical vertebra is put to death, and carefully peels off skin, rejects subcutaneous fat; The skin taken off carries out penetrating absorption immediately.Normal saline is placed in preheated Franz diffusion cell as acceptable solution (transdermal area is 3.14cm
2, receiving chamber's volume is 15ml, whole experimentation constant temperature 32 ± 1 DEG C, and 300 ± 10r/min stirs).Processed good rat skin is fixed on add stirrer in advance between receiving chamber and supply chamber, and guarantee in receiving liquid and there is no bubble between receiving chamber and skin contact.Add cryptotanshinone skin keratin lipoid gel or cryptotanshinone ordinary gel 1g in supply chamber, need ensure fully to contact with skin surface, in addition in order to prevent the moisture in preparation from evaporating, supply chamber opening part must cover with preservative film, in addition because cryptotanshinone is shown in that light easily decomposes, therefore also need with masking foil, supply chamber to be covered completely again.After everything is ready, in 0.5,1,1.5,2,3,4,5,6,7,8,9,10,11,12h samples 1mL from receiving liquid, supplements the receiving liquid of same volume simultaneously.The sample obtained measures content with HPLC after microporous filter membrane filters.The results are shown in Figure 2.
This experiment contrasts cryptotanshinone skin keratin lipoid gel and cryptotanshinone ordinary gel, and from result, the former unit are Percutaneous permeability is significantly higher than the latter, up to 45.26 ± 3.53 μ gcm
-2, and in 12h sustained release, there is stable percutaneous rate; The infiltration rate of cryptotanshinone ordinary gel is 4.0968 ± 0.29 μ gh
-1cm
-2; The infiltration rate of cryptotanshinone skin keratin lipoid gel is 3.0550 ± 0.36 μ gh
-1cm
-2.There were significant differences for the infiltration rate of two groups, and namely skin keratin lipoid group is apparently higher than common group.
Skin of rat hold-up is tested: skin hold-up test operation is with " in vitro penetrating absorption ", after starting respectively at percutaneous penetration 4,8,12,24h takes off rat skin, with the gel that distilled water cleaning skin removed is residual, skin is shredded homogenate 5min in the homogenizer being placed on and 5mL methanol is housed, centrifugal 30min (10000rmin
-1) after get supernatant HPLC and measure the content of cryptotanshinone.
This experiment adopts cryptotanshinone ordinary gel to compare, and result display cryptotanshinone skin keratin lipoid gel is compared with the skin hold-up of cryptotanshinone gel, and between group, effect and group internal effect all have significant difference, and between there is not interaction.Skin hold-up result shows, the skin hold-up of cryptotanshinone skin keratin lipoid gel group all higher than paeonol unguentum group, especially 4,12h time, skin hold-up difference has significance (P=0.000,0.021).The results are shown in Table 2, Fig. 3.
The hold-up result of table 2 skin Chinese medicine
Note: CTS-CS gel-cryptotanshinone skin keratin lipoid gel; CTS gel-cryptotanshinone ordinary gel
Rat experiments in vivo is studied: experiments in vivo adopts microdialysis to study.Experimental selection 10% chloral hydrate solution carries out intraperitoneal injection of anesthesia (0.35mL/100g) to rat, is lain on the back fixing after rat holonarcosis, cuts the careful hair removing rat abdomen with the electronic hair that pushes away of animal.By the insertion skin corium (accuracy of probe inserted position can be guaranteed after repeating) that cover has the guiding pin of tearing pipe careful, extract guiding pin, Y type microdialysis probe is inserted along tearing pipe the position needing in skin corium to sample, then will tear pipe and tear taking-up, use tissue glue's stationary probe.Meanwhile, rat neck hair is rejected, the otch of a 3cm is cut off at rat right neck, blunt separation jugular vein, with stitching thread ligation distal end, use the same method by probe in right atrium direction implantation jugular vein, and with stitching thread, probe and jugular vein ligation are fixed in case anti-avulsion falls, then cover rat neck operative site with the gauze being moistened with normal saline.Probe perfusion rate keeps 2 μ Lmin
-1, perfusate is cryptotanshinone normal saline (containing 20%PEG-400) solution.The half of first dosage is injected to maintain the narcotism of rat every 1.5h first after injection.On the skin of abdominal part sampling sites, smear 1g cryptotanshinone skin keratin lipoid gel or cryptotanshinone ordinary gel after balance 1h, at once start to collect dialysis solution with plastic cement receiving flask, interval is 30min, collects 12h altogether.The dialysis solution HPLC method gathered carries out the mensuration of medicament contg, draws pharmaceutical concentration-time curve figure.The results are shown in Table 3, Fig. 4.
Table 3 microdialysis detects the drug level change in different time points rat dermal layer tissue liquid and blood
Note: CTS-CS gel-cryptotanshinone skin keratin lipoid gel; CTS gel-cryptotanshinone ordinary gel; t
1/2for the half-life; T
maxfor peak time; C
maxfor peak concentration; AUC is area under the drug-time curve.
Carry out statistical analysis to the pharmacokinetic parameters of cryptotanshinone skin keratin lipoid gel and cryptotanshinone ordinary gel, the peak time of cryptotanshinone skin keratin lipoid gel group is smaller than cryptotanshinone ordinary gel, consistent with the result of percutaneous penetration; But and the medicine elimination time is obviously longer, the former blood drug level is starkly lower than the latter.Result shows, cryptotanshinone skin keratin lipoid gel medicine can be made to be distributed in more quickly in skin and the time of staying longer, namely the former has stable drug level, show that cryptotanshinone skin keratin lipoid gel may define drug depot at keratodermatitis, discharge cryptotanshinone lentamente, result shows that drug distribution amount in cryptotanshinone skin keratin lipoid preparation skin corium is apparently higher than the latter, improve the local biologic availability of medicine at skin, therefore skin keratin lipoid preparation has very strong advantage for the treatment of local skin disease.
Claims (10)
1. a cryptotanshinone skin keratin lipoid preparation, it is characterized in that: calculate by weight, formula comprises following component: cryptotanshinone 0.5 ~ 7 part, ceramide 30 ~ 100 part, 20 ~ 125 parts, lecithin, 10 ~ 200 parts, cholesterol, organic facies 800 ~ 5000 parts, aqueous phase 2000 ~ 12500 parts.
2. cryptotanshinone skin keratin lipoid preparation according to claim 1, is characterized in that: described ceramide is water solublity ceramide.
3. cryptotanshinone skin keratin lipoid preparation according to claim 1, is characterized in that: described lecithin is selected from one or both mixing in soybean lecithin, hydrolecithin, Ovum Gallus domesticus Flavus lecithin.
4. cryptotanshinone skin keratin lipoid preparation according to claim 1, is characterized in that: described organic facies is selected from dehydrated alcohol or ether.
5. cryptotanshinone skin keratin lipoid preparation according to claim 1, is characterized in that: described aqueous phase is selected from distilled water, or the phosphate buffered saline(PBS) of pH7.4 or pH5.8.
6. the preparation method of cryptotanshinone skin keratin lipoid preparation described in claim 1-5, is characterized in that comprising the following steps: cryptotanshinone, lecithin, cholesterol are dissolved in organic facies by (1); (2) ceramide is dissolved in aqueous phase, and is placed in preheating on magnetic stirring apparatus; (3) while magnetic agitation, step (1) gained organic facies slowly instilled and be dissolved with in the aqueous phase of ceramide, Keep agitation makes organic facies volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and preserves and get final product.
7. the preparation method of cryptotanshinone skin keratin lipoid preparation according to claim 6, is characterized in that: being preheated to temperature in described step (2) is 30-70 DEG C.
8. the preparation method of cryptotanshinone skin keratin lipoid preparation according to claim 6, it is characterized in that: the magnetic agitation speed in described step (3) is 200-600rpm, mixing time is 2-4h.
9. the preparation method of cryptotanshinone skin keratin lipoid preparation according to claim 6, is characterized in that: in described step (3), organic facies syringe slowly instills in aqueous phase.
10. the preparation method of cryptotanshinone skin keratin lipoid preparation according to claim 6, is characterized in that: in described step (3), in Keep agitation process, temperature remains within the scope of 30-70 DEG C.
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