CN104958257B - A kind of Cryptotanshinone skin keratin lipoid body preparation and preparation method thereof - Google Patents
A kind of Cryptotanshinone skin keratin lipoid body preparation and preparation method thereof Download PDFInfo
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- CN104958257B CN104958257B CN201510334608.2A CN201510334608A CN104958257B CN 104958257 B CN104958257 B CN 104958257B CN 201510334608 A CN201510334608 A CN 201510334608A CN 104958257 B CN104958257 B CN 104958257B
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Abstract
The invention discloses a kind of Cryptotanshinone skin keratin lipoid body preparations and preparation method thereof, Cryptotanshinone, lecithin, cholesterol are dissolved in organic phase by formula, ceramide is dissolved in water phase, it is placed on magnetic stirring apparatus and preheats, while magnetic agitation, gained organic phase is slowly dropped into the water phase dissolved with ceramide, lasting stirring makes organic phase volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.The method can significantly improve the rates of Cryptotanshinone skin permeation, while increasing local effect, can also reduce the amount that drug enters body circulation.The present invention is prepared with organic solvent injection method, significantly improves the performances such as Cryptotanshinone poorly water-soluble, unstable, be can be improved the infiltration rate that Cryptotanshinone penetrates cuticula, is increased the skin hold-up of drug.The present invention can be prepared into the various transdermal administrations such as gelling agent, ointment, patch, application of the energy further expansion Cryptotanshinone in medicine and cosmetic field.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, especially a kind of novel pharmaceutical carrier Cryptotanshinone skin keratin lipoid
Preparation and preparation method thereof.
Background technique:
Cryptotanshinone (Cryptotanshinone, CTS) is that have very strong generation in Lamiaceae plant fat soluble ingredient of red sage root
The component of table.In terms of external curing skin disease, it is embodied in terms of improving microcirculation, resolution, repairing
Stronger activity out.Currently, the external application patent medicine containing Cryptotanshinone is mainly to treat based on acne on the market, such as tanshinone is soft
Cream, kecuocryptone ointment, kecuocryptone gel etc..It clinically uses scorching using Cryptotanshinone as the treatment of the red sage formulation of effective component
Disease property and acne pustulosa significant effect, and zoopery show it is nontoxic non-stimulated.The chemical component warp of total-tanshinone separation
Extracorporeal bacteria inhibitor test proves that the bacteriostatic activity of Cryptotanshinone is most strong, and content is higher.However in the research progress of Cryptotanshinone
In, some characteristics gradually shown greatly limit its application in product forms, such as poorly water-soluble, it is light-exposed easily point
Solution has inducing action etc. to liver drug enzyme.Therefore, for the traditional of Cryptotanshinone preparation formulation in the market, unification and
The characteristic of drug itself utilizes a kind of local skin for enhancing Cryptotanshinone stability of modern medicines novel form and new technology development
Administration novel form has great importance.
Skin keratin lipoid also known as ceramide liposome (Cerasomes, CS), belong to the new of liposome developed recently
Type delivery system is mainly made of polarity close to the ceramide (Ceramide) of keratoderma, cholesterol etc..It is saturated lipid
The permeability barrier that such as ceramide, cholesterol and free fatty acid together form cuticula, can effectively barrier material friendship
It changes.The phospholipid bilayer of skin keratin lipoid is made of class Stratum corneum lipids, and wherein ceramide is as keratoderma
One of important component, there is moisturizing, maintain skin barrier, antiallergy, anti-aging, physiological functions, the tool such as induce cell apoptosis
There are potential medical applications to be worth.For liposome as pharmaceutical carrier, having makes drug accumulation in target area, improves curative effect and reduces not
The effect of good reaction.On the one hand the combination of ceramide and liposome improves liposome dissolving cuticula and penetrating cell
Ability；On the other hand other drugs or active constituent can be encapsulated, improves its stability and biocompatibility, allows medicament to more
It is steadily discharged into corresponding tissue.
Summary of the invention
The purpose of the present invention is to provide a kind of Cryptotanshinone skin keratin lipoid body preparations, are suspension state, medicine
Object acting duration is long, and percutaneous rate is fast, and bioavilability effectively improves.
It is a further object to provide the preparation methods of above-mentioned Cryptotanshinone skin keratin lipoid body preparation.
In order to achieve the above objectives, the invention provides the following technical scheme: a kind of Cryptotanshinone skin keratin lipoid body preparation,
It is characterized by: calculate by weight, formula includes following components: 0.5~7 part of Cryptotanshinone, 0~100 part of Cer NP,
20~125 parts of lecithin, 10~200 parts of cholesterol, 800~5000 parts of organic phase, 2000~12500 parts of water phase.
The ceramide is water-soluble ceramide.
The lecithin is mixed selected from one or both of soybean lecithin, hydrolecithin, egg yolk lecithin.
The organic phase is selected from dehydrated alcohol or ether.
The water phase is selected from distilled water or the phosphate buffered saline solution of pH7.4 or pH5.8.
The preparation method of above-mentioned Cryptotanshinone skin keratin lipoid body preparation, it is characterised in that the following steps are included: (1) will
Cryptotanshinone, lecithin, cholesterol are dissolved in organic phase；(2) ceramide is dissolved in water phase, is placed in magnetic stirring apparatus
Upper preheating；(3) while magnetic agitation, organic phase obtained by step (1) is slowly dropped into the water phase dissolved with ceramide,
Lasting stirring makes organic phase volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
It is 30-70 DEG C that temperature is preheated in the step (2).
Magnetic stirring speed in the step (3) is 200-600rpm, mixing time 2-4h.
In the step (3), organic phase is slowly dropped into water phase with syringe.
In the step (3), continues temperature in whipping process and be maintained within the scope of 30-70 DEG C.
Cryptotanshinone is prepared into skin keratin lipoid body preparation to be used to treat acne, overcomes classical hormonal class drug pair
The drawbacks of acting on big disadvantage and compound Chinese medicinal preparation complicated component, it is often more important that, due to the group of skin keratin lipoid
It is close with cuticula at ingredient and be easier to mutually merge with cuticula, so as to significantly improve the speed of Cryptotanshinone skin permeation
Rate.And skin keratin lipoid as fat-soluble medicine carrier when, while increasing local effect, can also reduce drug into
Enter the amount of body circulation.Thus one, the presence of ceramide improves preparation preferably in conjunction with illing skin cuticula,
Bioavilability of the Cryptotanshinone in local skin.On the other hand, compared with other local administration novel forms, Cryptotanshinone skin
Cutin lipoid also has its unique advantage, such as does not add the surfactant needed in micro emulsion preparation process wherein and help table
Face activating agent reduces preparation to the irritation etc. of skin.
Cryptotanshinone skin keratin lipoid body preparation prepared by present invention organic solvent injection method, significantly improves hidden pellet
Join the performances such as ketone poorly water-soluble, unstable, can be improved the infiltration rate that Cryptotanshinone penetrates cuticula, increase the skin of drug
Hold-up.And show compared with Cryptotanshinone ordinary gel in body pharmacokinetic studies, giving Cryptotanshinone skin keratin lipoid
Body gel can significantly improve the local biologic availability of skin, reduce side effect, and the sustained release time of 12h allows medicament to
Effective concentration is kept for a long time in skin.Cryptotanshinone skin keratin lipoid of the invention can be prepared into gelling agent, ointment, patch
The various transdermal administrations such as agent, application of the energy further expansion Cryptotanshinone in medicine and cosmetic field.
Detailed description of the invention
Fig. 1 is form of the Cryptotanshinone skin keratin lipoid under transmission electron microscope prepared by the embodiment of the present invention 1；
Fig. 2 is that Cryptotanshinone skin keratin lipoid body preparation prepared by the embodiment of the present invention 1 is commonly made with Cryptotanshinone
The in vitro transdermal test result of agent, in which: CTS-CS gel-Cryptotanshinone skin keratin lipoid gel；CTS gel-hidden
Tanshinone ordinary gel；
Fig. 3 is the skin hold-up test knot of Cryptotanshinone skin keratin lipoid body preparation and Cryptotanshinone ordinary preparation
Fruit, in which: CTS-CS gel-Cryptotanshinone skin keratin lipoid gel；CTS gel-Cryptotanshinone ordinary gel；
Fig. 4 is Cryptotanshinone skin keratin lipoid body preparation and Cryptotanshinone ordinary preparation applied to micro- after rat skin
Analyse the drug concentration change result in sample detecting different time points subcutaneous rat tissue fluid and blood, in which: CTS-CS
Gel-Cryptotanshinone skin keratin lipoid gel；CTS gel-Cryptotanshinone ordinary gel.
Specific embodiment
The present invention is a kind of preparation method of Cryptotanshinone skin keratin lipoid, is calculated by weight, formula include with
Lower component: 0.5~7 part of Cryptotanshinone, 20~125 parts of lecithin, 10~200 parts of cholesterol, has 0~100 part of Cer NP
800~5000 parts of machine phase, 2000~12500 parts of water phase.Cryptotanshinone is main ingredient in formula；Lecithin, ceramide be used as at
Membrane material, wherein lecithin preferably is selected from the mixing of one or both of soybean lecithin, hydrolecithin, egg yolk lecithin；Gallbladder
Sterol is membrane stabilizer, the mobility of adjusting film；Organic phase is selected from dehydrated alcohol or ether；Ceramide is water-soluble nerve acyl
Amine；Water phase can select the phosphate buffered saline solution or distilled water of different pH value according to pharmaceutical properties.
The present invention mainly uses organic solvent injection method to prepare Cryptotanshinone skin keratin lipoid, specific preparation method packet
Include following steps: (1) Cryptotanshinone, lecithin, cholesterol being dissolved in a small amount of organic phase: ceramide is dissolved in water by (2)
Xiang Zhong is placed on magnetic stirring apparatus and is preheated to prescription temperature, and preferred temperature is 30-70 DEG C；(3) in the same of magnetic agitation
When, above-mentioned organic phase is slowly dropped into water phase with syringe, maintains the constant temperature stirring of step (2) that organic phase is made to volatilize,
It is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.Preferred magnetic stirring speed is 200-600rpm in step (3), 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 thereto specific examples.
Embodiment 1
By Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g is dissolved in 3mL dehydrated alcohol is had
Machine phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic agitation
50 DEG C are preheated on device；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 2
By Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g is dissolved in 3mL dehydrated alcohol is had
Machine phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic agitation
50 DEG C are preheated on device；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 3
By Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g is dissolved in 3mL dehydrated alcohol is had
Machine phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic agitation
50 DEG C are preheated on device；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 2h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 4
Cryptotanshinone 5mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL dehydrated alcohol obtain it is organic
Phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic stirring apparatus
On be preheated to 50 DEG C；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 5
Cryptotanshinone 2.5mg, soybean lecithin 0.1g, cholesterol 0.05g are dissolved in 3mL dehydrated alcohol obtain it is organic
Phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic stirring apparatus
On be preheated to 60 DEG C；Temperature is kept, holding magnetic stirring speed is 400rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 4h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 6
By Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g is dissolved in 3mL dehydrated alcohol is had
Machine phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic agitation
60 DEG C are preheated on device；Temperature is kept, holding magnetic stirring speed is 400rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 7
By Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g is dissolved in 3mL dehydrated alcohol is had
Machine phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic agitation
60 DEG C are preheated on device；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 8
Cryptotanshinone 1mg, soybean lecithin 0.1g, cholesterol 0.05g are dissolved in 3mL dehydrated alcohol obtain it is organic
Phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic stirring apparatus
On be preheated to 40 DEG C；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 9
Cryptotanshinone 1mg, soybean lecithin 0.05g, cholesterol 0.017g are dissolved in 3mL dehydrated alcohol obtain it is organic
Phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic stirring apparatus
On be preheated to 60 DEG C；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 10
Cryptotanshinone 1mg, soybean lecithin 0.08g, cholesterol 0.017g are dissolved in 3mL dehydrated alcohol obtain it is organic
Phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic stirring apparatus
On be preheated to 40 DEG C；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 11
Cryptotanshinone 2.5mg, soybean lecithin 0.1g, cholesterol 0.05g are dissolved in 3mL dehydrated alcohol obtain it is organic
Phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic stirring apparatus
On be preheated to 40 DEG C；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 12
Cryptotanshinone 1mg, soybean lecithin 0.1g, cholesterol 0.05g are dissolved in 3mL dehydrated alcohol obtain it is organic
Phase；Ceramide 0.05g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic stirring apparatus
On be preheated to 60 DEG C；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 13
By Cryptotanshinone 2.5mg, soybean lecithin 0.1g, cholesterol 0.017g is dissolved in 3mL dehydrated alcohol is had
Machine phase；Ceramide 0.08g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic agitation
60 DEG C are preheated on device；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 14
By Cryptotanshinone 2.5mg, soybean lecithin 0.1g, cholesterol 0.017g is dissolved in 3mL dehydrated alcohol is had
Machine phase；Ceramide 0.1g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic stirring apparatus
On be preheated to 40 DEG C；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 15
By Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g is dissolved in 3mL dehydrated alcohol is had
Machine phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic agitation
30 DEG C are preheated on device；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 16
Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.16g are dissolved in 3mL dehydrated alcohol obtain it is organic
Phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic stirring apparatus
On be preheated to 50 DEG C；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 17
By Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g is dissolved in 3mL dehydrated alcohol is had
Machine phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic agitation
70 DEG C are preheated on device；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 18
By Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.013g is dissolved in 3mL dehydrated alcohol is had
Machine phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic agitation
50 DEG C are preheated on device；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 19
By Cryptotanshinone 0.8mg, soybean lecithin 0.1g, cholesterol 0.025g is dissolved in 3mL dehydrated alcohol is had
Machine phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic agitation
50 DEG C are preheated on device；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 20
By Cryptotanshinone 1.5mg, soybean lecithin 0.1g, cholesterol 0.025g is dissolved in 5mL dehydrated alcohol is had
Machine phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mLpH7.4 and obtains water phase, is placed in magnetic agitation
50 DEG C are preheated on device；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 4h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 21
Cryptotanshinone 1mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL dehydrated alcohol obtain it is organic
Phase；Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mL pH5.8 and obtains water phase, is placed in magnetic stirring apparatus
On be preheated to 50 DEG C；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe
In, persistently stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 22
Cryptotanshinone 1mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL ether and obtain organic phase；It will
Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mL pH7.4 and obtains water phase, is placed on magnetic stirring apparatus pre-
Heat is to 50 DEG C；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe, is held
Continuous stirring 3h makes ether volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 23
Cryptotanshinone 1mg, soybean lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL ether and obtain organic phase；It will
Ceramide 0.03g is dissolved in 10mL distilled water and obtains water phase, is placed on magnetic stirring apparatus and is preheated to 60 DEG C；Keep temperature
Degree, holding magnetic stirring speed are 600rpm, and organic phase is slowly dropped into water phase with syringe, and persistently stirring 3h waves ethyl alcohol
Hair, is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Embodiment 24
Cryptotanshinone 1mg, egg yolk lecithin 0.1g, cholesterol 0.025g are dissolved in 3mL ether and obtain organic phase；It will
Ceramide 0.03g is dissolved in the phosphate buffered saline solution of 10mL pH7.4 and obtains water phase, is placed on magnetic stirring apparatus pre-
Heat is to 60 DEG C；Temperature is kept, holding magnetic stirring speed is 600rpm, and organic phase is slowly dropped into water phase with syringe, is held
Continuous stirring 3h makes ethyl alcohol volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
Experiment and interpretation of result
Cryptotanshinone skin keratin lipoid made from Example 1 carries out following experiment and comes what the present invention is further explained
Advantage.
(1) in Cryptotanshinone skin keratin lipoid Cryptotanshinone entrapment efficiency determination
Cryptotanshinone skin keratin lipoid 1mL is taken, sets in 10mL volumetric flask, the PBS solution of corresponding pH is added to be diluted to quarter
Degree, ultrasonic 10min shake up.Precision measures 1mL, in 14000rpm, 4 DEG C of centrifugation 10min, takes out, Aspirate supernatant, sets 5mL appearance
In measuring bottle, adds methanol to dissolve and be settled to scale, using the content of high effective liquid chromatography for measuring Cryptotanshinone.According to following public affairs
Formula calculates entrapment efficiency.Obtaining its encapsulation rate is 15.47~67.20%.Experimental result is shown in Table 1.
Wherein, EE% is encapsulation rate, and Ct and Cr are respectively that drug total amount and free drug amount is added.
(2) morphological observation and particle size distribution measuring of Cryptotanshinone skin keratin lipoid
It is big using partial size of the Zetasizer 3000HS type current potential Particle Size Analyzer to Cryptotanshinone skin keratin lipoid
Small and distribution is measured, and dispersing agent is distilled water, laser wavelength 633nm, 25 DEG C of temperature, and dispersing agent refractive index is 1.33.?
The uniformity of particle diameter distribution is indicated to the coefficient of dispersion (σ).The coefficient of dispersion of measurement is 0.23~0.66, is distributed visibly homogeneous.
It is 50~150 μm with its average grain diameter of H-7650 transmission electron microscope observation.Fig. 1 show the resulting hidden Radix Salviae Miltiorrhizae of embodiment 1
Ketone skin keratin lipoid.Experimental result is shown in Fig. 1, tables 1.
The encapsulation rate and coefficient of dispersion result of 1 embodiment 1-24 of table
(3) Cryptotanshinone skin keratin lipoid gel percutaneous penetration (being research example with embodiment 1)
The preparation of Cryptotanshinone skin keratin lipoid gel and Cryptotanshinone ordinary gel: by carbomer 2g, propylene glycol
15g, glycerol 20g add appropriate amount of water, uniform in being slowly stirred on magnetic stirring apparatus, and impregnate 5h, are sufficiently swollen to obtain matrix.It will be 1. real
Cryptotanshinone skin keratin lipoid 10mL made from example 1 is applied, wherein Cryptotanshinone concentration is 0.1mgmL-1；②0.1mg·
mL-1Cryptotanshinone ethanol solution 10mL, add anhydrous sodium sulfate 0.2g, sodium hydroxide 0.2g incorporate matrix in, finally add water to
100g is simultaneously stirred evenly, and respectively obtains Cryptotanshinone skin keratin lipoid gel and Cryptotanshinone ordinary gel.
Isolated rat penetrating absorption: nude mice cervical vertebra is put to death, and carefully removes skin, rejects subcutaneous fat；The skin removed is vertical
Carry out penetrating absorption.Physiological saline is placed in the Franz diffusion cell being preheated to (transdermal area is as acceptable solution
3.14cm2, receiving building volume is 15ml, and 32 ± 1 DEG C of whole experiment process constant temperature, 300 ± 10r/min is stirred).It will be processed good
Rat skin be fixed between the receiving chamber and supply chamber for being previously added stirrer, and ensure in receiving liquid and receiving chamber and skin
There is no bubble between skin contact surface.Cryptotanshinone skin keratin lipoid gel or Cryptotanshinone ordinary gel 1g is added in supply
Interior need to guarantee to come into full contact with skin surface, in addition to preventing the moisture in preparation from evaporating, supply chamber opening must use guarantor
Fresh film covering, additionally, due to the light-exposed easy decomposition of Cryptotanshinone, therefore also needs that supply chamber is completely covered with masking foil again.All are just
After thread, 1mL is sampled from receiving liquid in 0.5,1,1.5,2,3,4,5,6,7,8,9,10,11,12h, while supplementing same volume
Receiving liquid.Obtained sample measures content with HPLC after miillpore filter filters.As a result see Fig. 2.
This experiment compares Cryptotanshinone skin keratin lipoid gel and Cryptotanshinone ordinary gel, can by result
Know, the former unit area Percutaneous permeability is significantly higher than the latter, up to 45.26 ± 3.53 μ gcm-2, and continue in 12h
Release has stable percutaneous rate；The infiltration rate of Cryptotanshinone ordinary gel is 4.0968 ± 0.29 μ gh-1·cm-2；
The infiltration rate of Cryptotanshinone skin keratin lipoid gel is 3.0550 ± 0.36 μ gh-1·cm-2.Two groups of infiltration rate
There were significant differences, i.e., skin keratin lipoid group is apparently higher than common group.
The test of skin of rat hold-up: skin hold-up test operation is with " in vitro penetrating absorption ", respectively at external
Transdermal experiment start after 4,8,12, remove rat skin for 24 hours, the remaining gel of skin removed, skin is cut wash with distilled water
Broken be placed in the homogenizer equipped with 5mL methanol is homogenized 5min, is centrifuged 30min (10000rmin-1) after take supernatant HPLC
Measure the content of Cryptotanshinone.
This experiment is compared using Cryptotanshinone ordinary gel, as the result is shown Cryptotanshinone skin keratin lipoid gel and
The skin hold-up of Cryptotanshinone gel is compared, and effect and group internal effect have a significant difference between group, and between there is no hand over
Mutual effect.Skin hold-up is the results show that the skin hold-up of Cryptotanshinone skin keratin lipoid gel group is above the root bark of tree peony
Phenol ointment group, especially in 4,12h, skin hold-up difference has conspicuousness (P=0.000,0.021).It the results are shown in Table 2,
Fig. 3.
The hold-up result of drug in 2 skin of table
Note: CTS-CS gel-Cryptotanshinone skin keratin lipoid gel；CTS gel-Cryptotanshinone ordinary gel
The research of rat experiments in vivo: experiments in vivo is studied using microdialysis.10% chloraldurate solution of experimental selection
To carry out intraperitoneal injection of anesthesia (0.35mL/100g) to rat, fixation of being lain on the back after rat holonarcosis is pushed away with animal is electronic
Hair cuts the hair of careful removal rat abdomen.By the careful insertion skin corium of the guidance needle for being cased with tearing pipe (after repeating
May insure the accuracy of probe inserted position), guidance needle is extracted, Y type microdialysis probe is inserted into skin corium along tearing pipe
Then tearing pipe is torn taking-up, fixes probe with tissue glue by the interior position for needing to sample.At the same time, by rat neck hair
Hair is rejected, and cuts off the notch of a 3cm in rat right neck, and blunt separation jugular vein ligatures distal end with suture, with same
Probe is implanted into jugular vein by the method for sample to atrium dextrum direction, and is fixed against probe and jugular vein ligation with suture
It falls off, is then covered on rat neck operative site with the gauze for being moistened with physiological saline.Probe perfusion rate keeps 2 μ Lmin-1, perfusate is Cryptotanshinone physiological saline (containing 20%PEG-400) solution.First dosage is injected every 1.5h after injecting for the first time
Half is to maintain the narcosis of rat.1g Cryptotanshinone skin keratin is smeared on the skin of abdomen sampling sites after balancing 1h
Lipoid gel or Cryptotanshinone ordinary gel start to collect dialyzate with plastic cement receiving flask, time interval 30min at once,
12h is collected altogether.Dialyzate collected carries out the measurement of medicament contg with HPLC method, draws pharmaceutical concentration-time curve figure.Knot
Fruit is shown in Table 3, Fig. 4.
3 microdialysis of table detects the drug concentration 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；
t1/2For half-life period；TmaxFor peak time；CmaxFor peak concentration；AUC is area under the drug-time curve.
Statistical is carried out to the pharmacokinetic parameters of Cryptotanshinone skin keratin lipoid gel and Cryptotanshinone ordinary gel
Analysis, the peak time of Cryptotanshinone skin keratin lipoid gel group are smaller than Cryptotanshinone ordinary gel, with transdermal test in vitro reality
The result tested is consistent；And drug eliminates the time but it is significantly longer, the former blood concentration is significantly lower than the latter.The results show that
Cryptotanshinone skin keratin lipoid gel can make that drug is distributed in more quickly in skin and the residence time is longer, i.e., the former
With stable drug concentration, show that Cryptotanshinone skin keratin lipoid gel may form drug storage in keratoderma
Library slowly discharges Cryptotanshinone, the results showed that the drug distribution amount in Cryptotanshinone skin keratin lipoid body preparation skin corium
It is apparently higher than the latter, improves drug in the local biologic availability of skin, therefore skin keratin lipoid body preparation is used for skin
The treatment of localized diseases has very strong advantage.
Claims (9)
1. a kind of Cryptotanshinone skin keratin lipoid body preparation, it is characterised in that: calculate by weight, formula includes with the following group
Point: 0.5~7 part of Cryptotanshinone, water-soluble 0~100 part of Cer NP, 20~125 parts of lecithin, 10~200 parts of cholesterol,
800~5000 parts of organic phase, 2000~12500 parts of water phase；
Cryptotanshinone, lecithin, cholesterol are dissolved in organic phase when preparation；Water-soluble ceramide is dissolved in water phase, and
It is placed on magnetic stirring apparatus and preheats；Then organic phase is slowly dropped into water phase, lasting stirring makes organic phase volatilize to obtain the final product.
2. Cryptotanshinone skin keratin lipoid body preparation according to claim 1, it is characterised in that: the lecithin choosing
It is mixed from one or both of soybean lecithin, hydrolecithin, egg yolk lecithin.
3. Cryptotanshinone skin keratin lipoid body preparation according to claim 1, it is characterised in that: the organic phase choosing
From dehydrated alcohol or ether.
4. Cryptotanshinone skin keratin lipoid body preparation according to claim 1, it is characterised in that: the water phase is selected from
The phosphate buffered saline solution of distilled water or pH7.4 or pH5.8.
5. the preparation method of any one of the claim 1-4 Cryptotanshinone skin keratin lipoid body preparation, it is characterised in that packet
It includes following steps: (1) Cryptotanshinone, lecithin, cholesterol being dissolved in organic phase；(2) ceramide is dissolved in water phase,
It is placed on magnetic stirring apparatus and preheats；(3) while magnetic agitation, organic phase obtained by step (1) is slowly dropped into and is dissolved with
In the water phase of ceramide, lasting stirring makes organic phase volatilize, and is transferred in Brown Glass Brown glass bottles and jars only and saves to obtain the final product.
6. the preparation method of Cryptotanshinone skin keratin lipoid body preparation according to claim 5, it is characterised in that: the step
Suddenly it is 30-70 DEG C that temperature is preheated in (2).
7. the preparation method of Cryptotanshinone skin keratin lipoid body preparation according to claim 5, it is characterised in that: the step
Suddenly the magnetic stirring speed in (3) is 200-600rpm, mixing time 2-4h.
8. the preparation method of Cryptotanshinone skin keratin lipoid body preparation according to claim 5, it is characterised in that: the step
Suddenly in (3), organic phase is slowly dropped into water phase with syringe.
9. the preparation method of Cryptotanshinone skin keratin lipoid body preparation according to claim 5, it is characterised in that: the step
Suddenly in (3), continue temperature in whipping process and be maintained within the scope of 30-70 DEG C.
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Effective date of registration: 20210119 Address after: No.7, Fengshan 3rd road, Changlong Industrial Zone, Sijiu Town, Taishan City, Jiangmen City, Guangdong Province 529222 Patentee after: Taishan Lifeng Investment Co.,Ltd. Address before: 510515 No. 1023-1063 Shatainan Road, Baiyun District, Guangzhou City, Guangdong Province Patentee before: SOUTHERN MEDICAL University |