CN104906042B - It is a kind of to treat novel skin drug-delivery preparation of acute and closed soft tissue injury and preparation method thereof - Google Patents
It is a kind of to treat novel skin drug-delivery preparation of acute and closed soft tissue injury and preparation method thereof Download PDFInfo
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- CN104906042B CN104906042B CN201510281253.5A CN201510281253A CN104906042B CN 104906042 B CN104906042 B CN 104906042B CN 201510281253 A CN201510281253 A CN 201510281253A CN 104906042 B CN104906042 B CN 104906042B
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- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 238000009527 percussion Methods 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 229940067626 phosphatidylinositols Drugs 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- SRLOHQKOADWDBV-NRONOFSHSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] 2-(2-methoxyethoxycarbonylamino)ethyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCCCC SRLOHQKOADWDBV-NRONOFSHSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000002522 swelling effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
It is a kind of to treat novel skin drug-delivery preparation of acute and closed soft tissue injury and preparation method thereof, belong to pharmaceutical technology field.Said preparation is composed of the following components in parts by weight：60 120 parts of arasaponin, 20 150 parts of phosphatidase 1,12 20 parts of cholesterol, 40 80 parts of limonene citral Mixed chaotic sequences, 2.5 parts of vitamin E2,10,000 15000 parts of buffer solution.The arasaponin carrier of the present invention is applied directly to affected part when in use, with effects such as good promoting blood circulation, anti-inflammatory and improvement hemorheology, has good treatment and repair to acute and closed soft tissue injury, hence it is evident that shorten its treatment cycle.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of novel skin for treating acute and closed soft tissue injury
Drug-delivery preparation and preparation method thereof.
Background technology
Acute soft tissue injury means that body is acted on by external or inherent different Risk Factors, causes kinetic system
A series of acute contusion that system, the tissue outside the following bone of skin occur or (and) lacerated wound, including muscle, ligament, manadesma,
The tissues such as tendon, synovial membrane, fat, capsular ligament and peripheral nerve, the acute injury of the different situations of blood vessel.It can be divided into out again
Putting property is damaged and the major class of closed injury two：Wherein open injury clinically has preferable treatment means；And closed
Damage is more common compared with open injury, including joint, ligament sprain with muscle, the pulling of tendon, fracture, these are damaged
Communicated without breach with the external world, therefore the medicine of lesions position is dense after oral medication or common external preparation external preparation for skin in the treatment
Degree is all very low, it is difficult to obtain preferable curative effect.
Carrier（Transfersomes, TFS）Also known as flexible lipidosome, is a kind of new cutaneous penetration carrier, mainly into
It is divided into phosphatide and edge activator（Such as sodium taurocholate, deoxysodium cholate）, the morphotropism with height can efficient tranmittance itself
The skin duct of small several times and reach cutaneous penetration purpose.
Pseudo-ginseng is panax araliaceae plant（Panax notoginseng (Burk.) F.H.Chen）Dry root and root
Stem, is the stagnant key medicine swollen and ache of card and traumatic injury, the stasis of blood that the traditional Chinese medical science is conventionally used to the various bleedings in inside and outside.Arasaponin (Panax
Notoginseng saponins, PNS) it is its main active component, clinically PNS is widely used in soft tissue injury, fracture
Healing, osteoarticular injury and the recovery of limb function etc..But, current PNS commercial dosage forms are main with oral Preparation
And based on intravenous preparation, this is not preferable method of administration for the treatment of body part soft tissue injury.
Therefore PNS is made into carrier percutaneous drug administration preparation can improve valid density of the PNS in lesions position, improved
Its bioavilability, new method is provided for the clinical treatment of acute and closed soft tissue injury.
The content of the invention
The purpose of the present invention is to treat the new of acute and closed soft tissue injury there is provided a kind of for the not enough of existing preparation
Type percutaneous drug delivery preparation, to improve drug bioavailability, shortens treatment cycle, and reduce the toxic side effect of medicine；The present invention
Another object be provide prepare above-mentioned novel skin drug-delivery preparation method.
Described a kind of novel skin drug-delivery preparation for treating acute and closed soft tissue injury, it is characterised in that by following
The composition composition of parts by weight：
60-120 parts of arasaponin, 20-150 parts of phosphatidase 1,12-20 parts of cholesterol, limonene-citral mixed volatilization
10000-15000 parts of oily 40-80 parts, -2.5 parts of vitamin E2, buffer solution, described limonene-citral Mixed chaotic sequences by
Limonene and citral are according to weight ratio 1:4~4:1 mixes, and preferably limonene-citral Mixed chaotic sequences are by lemon
Alkene and citral are according to weight ratio 4:1 mixes, and described buffer solution is phosphate buffer solution.
Described a kind of novel skin drug-delivery preparation for treating acute and closed soft tissue injury, it is characterised in that by following
The composition composition of parts by weight：
80-110 parts of arasaponin, 20-140 parts of phosphatidase 1,14-16 parts of cholesterol, limonene-citral mixed volatilization
10000-12000 parts of oily 60-80 parts, -2.3 parts of vitamin E2, buffer solution.
Described a kind of novel skin drug-delivery preparation for treating acute and closed soft tissue injury, it is characterised in that by following
The composition composition of parts by weight：
100 parts of arasaponin, 20 parts of phosphatidase 1,15 parts of cholesterol, limonene -80 parts of citral Mixed chaotic sequences, dimension life
Plain E2 parts, 10000 parts of buffer solution.
Described a kind of novel skin drug-delivery preparation for treating acute and closed soft tissue injury, it is characterised in that described
Phosphate buffer solution be 1/15 mol/L potassium dihydrogen phosphates and 1/15 mol/L disodium phosphate solns by volume
53.4:The mixed liquor of 46.6 mixing.
A kind of preparation method of described novel skin drug-delivery preparation for treating acute and closed soft tissue injury, its feature
It is to comprise the following steps that：
1）Weigh arasaponin, phosphatide, cholesterol, limonene-citral Mixed chaotic sequences and the vitamin of formula ratio
E, is dissolved in organic solvent, is well mixed, is transferred in eggplant-shape bottle, and decompression rotation boils off organic solvent, obtains dry film；
2）With buffer solution hydration step 1）Obtained dry film, shaking, makes the complete aquation of lipid film, then with supersonic cell powder
Broken instrument carries out ultrasonication processing；
3）Sample after above-mentioned ultrasonication is handled is placed after 2~3 h, is placed in liposome mini-extruder extrusion instrument,
100 nm polycarbonate membranes are squeezed through under 0.25 MPa, 50 nm polycarbonate membranes are squeezed through under 0.49 MPa, treatment are produced acute
The novel skin drug-delivery preparation of closed soft tissue injury.
A kind of preparation method of described novel skin drug-delivery preparation for treating acute and closed soft tissue injury, its feature
It is described step 1）Middle organic solvent is in methanol, n-butanol, isopropanol, acetone, acetonitrile, n-hexane and dichloromethane
One or more kinds of mixed liquors, preferably methanol dichloromethane by volume 3:The mixed liquor of 4 mixing.
A kind of preparation method of described novel skin drug-delivery preparation for treating acute and closed soft tissue injury, its feature
It is described step 1）The addition of middle organic solvent and the scope of the weight part ratio of phosphatide are 200~417：1, be preferably
292:1。
A kind of preparation method of described novel skin drug-delivery preparation for treating acute and closed soft tissue injury, its feature
It is described step 1）Middle 45 DEG C of decompression rotary distillation condition, 50 r/min.
A kind of preparation method of described novel skin drug-delivery preparation for treating acute and closed soft tissue injury, its feature
It is described step 1）Middle 25 DEG C of ultrasonication treatment conditions temperature, the W of power 16 continues 5 s, is repeated 6 times every time.
A kind of preparation method of described novel skin drug-delivery preparation for treating acute and closed soft tissue injury, its feature
It is described step 2）Middle phosphate buffer solution is 1/15 mol/L potassium dihydrogen phosphates and 1/15 mol/L phosphoric acid hydrogen
Two sodium solutions by volume 53.4:The mixed liquor of 46.6 mixing.
Arasaponin is the effective ingredient in Chinese for extracting from Chinese medicine pseudo-ginseng in the present invention, meets NF 2010 and marks
Standard, commercially available product, manufacturer such as Yunnan plant Pharm Pur GmbH still, is not restricted to this company.
As the phosphatide for forming carrier in the present invention, natural phospholipid and synthetic phospholipid can be used.Natural phospholipid
Including phosphatidyl-ethanolamine, phosphatidyl glycerol, phosphatidylserine, phosphatidylinositols, egg yolk lecithin, hydrogenation yolk lecithin
Fat, EPG, yolk phospholipid acyl serine, PI, soybean lecithin, hydrogenated soy phosphatidyl choline,
Hydrolecithin, EPG, lecithin acyl serine and lecithin acyl inositol etc..Synthetic phospholipid is dioleoyl phospholipid acyl
Choline, DSPC, DPPC, DMPC, two lauroyl phosphatidyls
Choline, DSPG, DPPG, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two lauroyl phosphatide
Acyl glycerine and polyglycol derivatization phospholipid such as PEG-DSPE 2000（DSPE-
mPEG2000）；Two soft ester acyl courage phosphatide-polyethylene glycol 2000s（DPPG-mPEG2000）；HSPC-poly- second
Glycol 2000（HSPC-mPEG2000）；DOPC-polyethylene glycol 2000（DOPC-mPEG2000）Deng.
The present inventor has found that commercially available PC contents are particularly suitable as base for 60%~95% soybean lecithin by research
Plinth phosphatide membrane material encapsulates active pharmaceutical ingredient, so as to form the carrier of high-quality, the PC contents of preferably soya lecithin are 70%
~80%.
In the present invention cholesterol play a part of adjust membrane fluidity, can improve bimolecular lamellar lipid membrane stability and
The envelop rate of medicine.Cholesterol used meets the standard of pharmacopeia 2010.
Lived in the present invention from limonene-citral Mixed chaotic sequences as edge activator using volatile oil as edge
Agent greatly improves formed carrier security relative to other surfaces activating agent class edge activator, so that suffering from
The longer use this product of person is possibly realized.
The present inventor has found that both ratios can be 1 in limonene-citral Mixed chaotic sequences by research:4~4:1
（W/W）Scope, when Mixed chaotic sequences ratio be 4:When 1, the Chinese and Western medicine compound transmission body elasticity formed is optimal, and skin oozes
Permeability is optimal.
Vitamin E prevents phosphatide to be oxidized as antioxidant in the present invention.
Research finds that the present invention passes through arasaponin, phosphatide, cholesterol, limonene-citral Mixed chaotic sequences and dimension
Raw element E rational proportions, can be made arasaponin carrier best in quality, its envelop rate with have good stability, toxicity is low,
Bioavilability is high, determined curative effect.
The feed postition of Mixed chaotic sequences can use following three kinds of methods in the present invention：Together add, be made with phosphatide etc.
Dry film；Other compositions in addition to volatile oil are added finally by the method for vortex mixed and waved by the scattered obtained liposome of film
Hair oil；Volatile oil is dissolved in after a small amount of ethanol, so it is miscible with hydrating fluid, finally with gained mixed liquor aquation lipid dry film.Knot
Fruit shows, volatile oil and phosphatide etc., which are together added, is made that prepared by dry film enter'ss carrier is elastic and envelop rate is more excellent.
Arasaponin carrier best in quality can be made by the method for the present invention, wherein transmission body elasticity is larger,
Entrapment efficiency is high, and stability is high, and particle diameter is suitable and is evenly distributed, and bioavilability is high, determined curative effect.
Research finds that the particle diameter of carrier has considerable influence to its skin targeting, particle diameter is smaller, and medicine is in skin
Hold-up is bigger；In addition, excellent elasticity is also to improve the essential condition of carrier percutaneous abilities.It is prepared by the method for the present invention
Arasaponin transmission body elasticity it is good, particle diameter is small and is evenly distributed, and this is it target site osmotic efficiency is high, bioavilability
One of the reason for height, determined curative effect.
Function is with curing mainly：The effects such as with promoting blood circulation, anti-inflammatory and improvement blood microcirculation, it is used as a variety of diseases such as soft tissue injury
The externally applied drug of disease, has good curative effect particularly with acute and closed soft tissue injury.
Usage and consumption：Externally applied drug, according to damaged area size, takes appropriate amount of drug to be applied directly to affected part, use as far as possible
Medicine position is in non-closed state, daily 2-3 times.
Note：Skin injury or ulcer person use with caution.
Storage：It is closed, put and preserved at shady and cool, lucifuge.
The present invention arasaponin carrier be applied directly to affected part when in use, with good promoting blood circulation, anti-inflammatory and
Improve the effect such as hemorheology, have good treatment and repair to acute and closed soft tissue injury, hence it is evident that shorten it
Treatment cycle.
Brief description of the drawings
Fig. 1 is influence figure of the arasaponin carrier to rat model tectology；
In figure：Normal group（A）；After the h of modeling 24（B）；PNS carrier test groups（C）；Positive control green grass or young crops roc ointment
Group（D）；XUESAITONG JIAONANG group（E）；XUESAITONG ZHUSHEYE group（F）；Model control group（G）.
Embodiment
In order to help those skilled in the art that the present invention is more completely understood, Binding experiment data describe this hair in detail
Bright embodiment.But cited embodiment does not limit the right of the present invention in any way.
Described in the embodiment of the present invention and arasaponin carrier particle diameter and particle diameter distribution, form, envelop rate, bullet
The evaluation method of the indexs such as property is as follows：
1. particles size and distribution evaluation method
Take above-mentioned arasaponin carrier distilled water suitably to dilute, the particle diameter of carrier is determined using laser particle analyzer
And its distribution situation.
2. morphologic observation
Take above-mentioned arasaponin carrier appropriate, be diluted with water, drip on copper mesh, with 1% Salkowski's solution negative staining, filter
Paper draws excess stain liquid, and transmission electron microscope observation is used after drying.
3. the assay method of envelop rate
It is measured using centrifugal ultrafiltration method.Carrier sample to be measured is taken, is shaken up, a small amount of progress light microscope sight is taken
Examine, confirm that being wherein free of precision after drug crystallization measures 200 μ L, is placed in ultra-filtration centrifuge tube（The molecular cut off of milipore filter is
100000 Da）, carry out refrigerated centrifuge（RCF：14000 g, temperature：4 ℃）, all outer aqueous phases are collected, conjunction is transferred to
In the measuring bottle of fit product, with mobile phase constant volume, shake up, with ginsenoside Rg in arasaponin1, ginsenoside Rb1For index,
Determined with HPLC methods and transmit each index components content in external aqueous phase, in addition, determining each index in carrier sample with HPLC methods
Component content, is calculated as follows envelop rate：
EE=（W
S
-W
EA
）/W
S
×100%
In formulaEEFor envelop rate；W S For ginsenoside Rg in sampling amount1Or ginsenoside Rb1Content (mg)；W EA For outer water
Ginsenoside Rg in phase1Or ginsenoside Rb1Content (mg).
4. the assay method of elasticity
Precision measures 10 mL carriers, is placed in liposome mini-extruder extrusion instrument, squeezes through 50 nm polycarbonate membranes, and pressure is 0.49
MPa, by sample, all the extrusion time used is designated as its elasticity.（This law bibliography：Zaafarany G. M. E., Avad
G. A. S., Holayel S. M. et al. Role of egde activators and surface charge in
developing ultradeformable vesicles with enhanced skin delivery [J]. Int J
Pharm, 2010,397(1-2):164-172.）
Embodiment 1
Arasaponin carrier is made up of following parts by weight ingredient：
100 parts of arasaponin
120 parts of soybean lecithin
15 parts of cholesterol
Limonene-citral Mixed chaotic sequences (4:1, W/W) 80 parts
2 parts of vitamin E
0000 part of phosphate buffer 1
The specification of main constituents and source：Arasaponin（Meet the standard of NF 2010）, Yunnan plant medicine
Thing Co., Ltd；Soybean lecithin（PC contents are 80%, injection stage）, Shanghai Taiwei Pharmaceutical Co., Ltd.；Cholesterol（Meet state
Family's standard of pharmacopeia 2010）, Nanjing Xinbai Pharmaceutical Co；Limonene, citral（Meet the standard of NF 2010）Ji'an
The oily Co., Ltd of the poly- roc natural perfume material in city；Vitamin E（Meet the standard of NF 2010）Zhejiang NHU Company Ltd；
Phosphate buffer solution be 1/15 mol/L potassium dihydrogen phosphates and 1/15 mol/L disodium phosphate solns by volume
53.4:The mixed liquor of 46.6 mixing.
The preparation method of arasaponin carrier is：
Prepared using film dispersion method, this method comprises the following steps：
(a) arasaponin, soybean lecithin, cholesterol, the limonene-citral Mixed chaotic sequences of formula ratio are weighed
And vitamin E, it is dissolved in organic solvent（Organic solvent is methanol dichloromethane by volume 3:The mixed liquor of 4 mixing）In, it is organic
The parts by weight of solvent and the weight part ratio of phosphatide are 292:1, it is well mixed, is transferred in eggplant-shape bottle, decompression rotation boils off organic
Solvent, 45 DEG C of decompression rotary distillation condition, 50 r/min, obtains dry film.
(b) dry film obtained with phosphate buffer hydration step (a), shaking makes the complete aquation of lipid film, then with super
Sound wave cell pulverization instrument carries out ultrasonication processing.
(c) above-mentioned ultrasonication is handled, 25 DEG C of ultrasonication treatment conditions temperature, the W of power 16 continues 5 every time
S, is repeated 6 times, and the sample after ultrasonication processing is placed after 2~3 h, is placed in liposome mini-extruder extrusion instrument, in 0.25 MPa
Under squeeze through 100 nm polycarbonate membranes, 50 nm polycarbonate membranes are squeezed through under 0.49 MPa, carrier suspension is produced.
Testing result：The average grain diameter of above-mentioned arasaponin carrier is（123.60 ± 0.36）Nm, ginsenoside
Rg1, ginsenoside Rb1Envelop rate be respectively（82.42 ± 0.69）% and（94.40 ± 0.74）%, elasticity is（2.74 ±
0.32）min.
Embodiment 2
Arasaponin carrier is made up of following parts by weight ingredient：
120 parts of arasaponin
150 parts of soybean lecithin
17 parts of cholesterol
Limonene-citral Mixed chaotic sequences (1:1, W/W) 60 parts
2.5 parts of vitamin E
5000 parts of phosphate buffer 1
The specification of main constituents and source：Arasaponin（Meet the standard of NF 2010）, Yunnan plant medicine
Thing Co., Ltd；Soybean lecithin（PC contents are 75%, injection stage）, German Lipoid companies；Cholesterol（Meet NF
2010 standards）, Nanjing Xinbai Pharmaceutical Co；Limonene, citral（Meet the standard of NF 2010）The poly- roc of Ji'an City
Natural perfume material oil Co., Ltd；Vitamin E（Meet the standard of NF 2010）Zhejiang NHU Company Ltd；Phosphate
Cushioning liquid is 1/15 mol/L potassium dihydrogen phosphates and 1/15 mol/L disodium phosphate solns by volume 53.4:46.6
The mixed liquor of mixing.
The preparation method of arasaponin carrier is：
Prepared using film dispersion method, this method comprises the following steps：
(a) arasaponin, soybean lecithin, cholesterol, the limonene-citral Mixed chaotic sequences of formula ratio are weighed
And vitamin E, it is dissolved in organic solvent（Organic solvent is methanol, n-butanol, isopropanol, acetone, acetonitrile, n-hexane and dichloro
Mixed liquor more than one or both of methane）In, the parts by weight of organic solvent and the weight part ratio of phosphatide are 200:1, mix
Close uniform, be transferred in eggplant-shape bottle, decompression rotation boils off organic solvent, obtains dry film.
(b) dry film obtained with phosphate buffer hydration step (a), shaking makes the complete aquation of lipid film, then with super
Sound wave cell pulverization instrument carries out ultrasonication processing.
(c) sample after above-mentioned ultrasonication is handled is placed after 2~3 h, is placed in liposome mini-extruder extrusion instrument,
100 nm polycarbonate membranes are squeezed through under 0.25 MPa, 50 nm polycarbonate membranes are squeezed through under 0.49 MPa, carrier is produced and mixes
Suspension.
Testing result：The average grain diameter of above-mentioned arasaponin carrier is（136.23 ± 1.18）Nm, ginsenoside
Rg1, ginsenoside Rb1Envelop rate be respectively（81.06 ± 1.09）% and（92.84 ± 0.94）%, elasticity is（3.54 ±
0.57）min.
Embodiment 3
Arasaponin carrier is made up of following parts by weight ingredient：
60 parts of arasaponin
120 parts of soybean lecithin
12 parts of cholesterol
Limonene-citral Mixed chaotic sequences (1:4, W/W) 40 parts
2 parts of vitamin E
0000 part of phosphate buffer 1
The specification of main constituents and source：Arasaponin（Meet the standard of NF 2010）, Yunnan plant medicine
Thing Co., Ltd；Soybean lecithin（PC contents are 95%, injection stage）, Shanghai Taiwei Pharmaceutical Co., Ltd.；Cholesterol（Meet state
Family's standard of pharmacopeia 2010）, Nanjing Xinbai Pharmaceutical Co；Limonene, citral（Meet the standard of NF 2010）Ji'an
The oily Co., Ltd of the poly- roc natural perfume material in city；Vitamin E（Meet the standard of NF 2010）Zhejiang NHU Company Ltd；
Phosphate buffer solution be 1/15 mol/L potassium dihydrogen phosphates and 1/15 mol/L disodium phosphate solns by volume
53.4:The mixed liquor of 46.6 mixing.
The preparation method of arasaponin carrier is：
Prepared using film dispersion method, this method comprises the following steps：
(a) arasaponin, soybean lecithin, cholesterol, the limonene-citral Mixed chaotic sequences of formula ratio are weighed
And vitamin E, it is dissolved in organic solvent, is well mixed, is transferred in eggplant-shape bottle, decompression rotation boils off organic solvent, is done
Film.
(b) dry film obtained with phosphate buffer hydration step (a), shaking makes the complete aquation of lipid film, then with super
Sound wave cell pulverization instrument carries out ultrasonication processing.
(c) sample after above-mentioned ultrasonication is handled is placed after 2~3 h, is placed in liposome mini-extruder extrusion instrument,
100 nm polycarbonate membranes are squeezed through under 0.25 MPa, 50 nm polycarbonate membranes are squeezed through under 0.49 MPa, carrier is produced and mixes
Suspension.
Testing result：The average grain diameter of above-mentioned arasaponin carrier is（134.20±0.60）Nm, ginsenoside
Rg1, ginsenoside Rb1Envelop rate be respectively（82.52±1.45）% and（92.92 ± 2.01）%, elasticity is（5.02±
1.06）min.
Present invention treatment acute and closed soft tissue injury experimental study
1. materials and methods
1.1 medicineArasaponin carrier：By arasaponin, cholesterol, soybean lecithin, vitamin E, in
Medicine volatile oil, phosphate buffer composition, pharmacodynamics investigation is carried out from the sample obtained by embodiment 1.Content of dispersion：10 mg/
ML, is provided by Zhejiang University of Traditional Chinese Medicine's Chinese medicine preparation laboratory.Blue or green roc ointment：It is main by whin, sub- rheum officinale, Aconitum Szechenyianum Gay, scold
Composition such as sub (stoning), by XiZang QiZheng Tibetan pharmaceuticals Co., Ltd, Chinese medicines quasi-word Z54020140.
1.2 models are set up carries out modeling using quantification gravity punch method（This law bibliography：Ma Yinan closeds
Soft tissue injury modeling method and research of problems [J] contemporary Chinese medical journals, 2014,24 (3): 20-
23.）.24 h before modeling, the hair of rat right lower extremity calf is sloughed with shaver.Before experiment, the mL/ of intraperitoneal injection 3
kg-12% yellow Jackets are set up rat acute soft tissue by rat anesthesia, using homemade weight freely falling body percussion device and damaged
Wound model.Concrete operation method is：The g of metal weight 160 guided by a metal guide rod, under 140 cm eminence is vertical
Fall, to being hit on the outside of rat right lower extremity gastrocnemius, cause the cm of area about 42Size has the urgency of obvious subcutaneous hemorrhage and swelling
Property soft tissue injury model.In experimentation, it is to avoid the breakage of rat skin and fracture.Through visually observing after modeling, injury region
Obvious tumefaction, ecchymosis and muscle color are substantially deepened, and illustrate modeling success.
The successful rat of modeling is randomly divided into five groups, the respectively total soap of model control group, pseudo-ginseng by 1.3 packets with administration
Glycosides carrier percutaneous dosing group（Test group）, blue or green roc ointment group, XUESAITONG ZHUSHEYE group and XUESAITONG JIAONANG group, separately setting one group just
Normal control group, every group 20.In starting administration after the h of experimental animal modeling 24, model control group is given necessarily with Normal group
Physiological saline is measured, blue or green roc ointment group gives 0.2 g/cm2Blue or green roc ointment, test group gives optimal prescription by 1.4 mL/kg/d
Carrier（By arasaponin clinical oral administration lowest dose level, as obtained by being converted dose,equivalent coefficient）, XUESAITONG ZHUSHEYE group
XUESAITONG ZHUSHEYE is given by 0.36 ml/kg/d（By XUESAITONG ZHUSHEYE clinical administration dosage, rolled over by dose,equivalent coefficient
Calculate gained）, XUESAITONG JIAONANG group gives XUESAITONG JIAONANG by 27 mg/kg/d（By XUESAITONG JIAONANG clinical administration dosage, pass through
Dose,equivalent coefficient conversion gained）.Test group is administered with non-closed state（It is taken twice daily, the d of successive administration 5）；Model pair
Wrapped up according to group, Normal group and blue or green roc ointment group with gauze（Dressing daily 1 time, the d of successive administration 5）；XUESAITONG ZHUSHEYE
The daily intramuscular administration of group 2 times, the d of successive administration 5；XUESAITONG JIAONANG group, takes water-soluble with physiology salt after the medicine of specified quantitative in capsule
Daily gastric infusion 3 times, successive administration 5 days after solution.
1.4 damage disease index observation observations daily hinder limb subcutaneous extvavasated blood, muscle swelling and the change of muscle color simultaneously
Scored, standards of grading：Ecchymoma（3 points of damaged tissues part volume bulk meter, a small amount of 2 points of point-like meter, no hemostasis person meter
1 point）；Muscle swelling（Impaired 3 points of part muscle obvious tumefaction meter, slightly 2 points of swelling meter, no struttuer count 1 point）；Muscle color
（Impaired part muscle is in dark violet 3 points of color depth meter, and kermesinus is shallow to count 2 points, and color and luster normally counts 1 point）.
1.5 Determination of Blood Rheology take partial rat at random in each group after administration 3 d and 5 d, in rat abdomen cardinal vein
The mL of venous blood about 5 is gathered, EDTA anti-freezings carry out Determination of Blood Rheology using blood rheological instrument.Rat after blood sampling is collected
It is middle to put to death.
1.6 Histomorphologicals take partial rat at random in each group after 5 d of administration, put to death, separate lesion center group
Knit, extract the tissue block of suitable size.The tissue block of taking-up is fixed with neutral buffered formalin solution, paraffin section is made,
HE is dyed, in light Microscopic observation wound local organization form and the wet face state of inflammatory cell.
1.7 statistical methods are represented so determining numerical value with means standard deviation, using SPSS17.0 softwares to all numbers
According to progress one-way analysis of variance.
2. result
2.1 arasaponin carriers damage the influence of disease index score to rat model
Germicidal efficacy is found, test group, positive controls, XUESAITONG JIAONANG group and Xuesaitong injection group after 1 d is administered
Damage of Rats disease situation has different degrees of improvement, and model group rats are then not improved；Test group and sun after 2 d is administered
Property control rats damage disease index substantially reduce, XUESAITONG JIAONANG group and Xuesaitong injection group Damage of Rats disease index
It is slightly decreased, model group declines limited；Test group and positive controls rat after 3 d is administered and is visible by naked eyes damage disease substantially
Wait, XUESAITONG JIAONANG group, Xuesaitong injection group and model group rats are still suffered from different degrees of subcutaneous without obvious foot swelling
Extravasated blood and muscle discoloration；XUESAITONG JIAONANG group after 5 d, Xuesaitong injection group and model group rats are administered substantially without naked eyes
Visible damage disease.Statistical result is shown in Table 1.
The different observation group's damage disease indexes of table 1 compare
Compared with model group, * P<0.05, * * P< 0.01；Compared with normal group, ▲ P<0.05, ▲ ▲ P<
0.01；Compared with XUESAITONG JIAONANG group, △ P<0.05, △ △ P< 0.01；Compared with XUESAITONG ZHUSHEYE group, ＆ P<
0.05 , ＆＆ P< 0.01；
Note：After administration 1 day, n=20；After administration 2 days, n=20；After administration 3 days, n=20；After administration 5 days, n=
10
Influence of the 2.2 arasaponin carriers to rat model hemorheology
Result of the test shows that the WBV and plasma viscosity of test group and positive controls all decline bright after being administered 3 days
Aobvious, XUESAITONG JIAONANG group and the decline of XUESAITONG ZHUSHEYE group are limited, and model group is not improved；Test group and sun after being administered 5 days
The WBV and plasma viscosity of property control group are all close to Normal group, XUESAITONG JIAONANG group, XUESAITONG ZHUSHEYE group and mould
Type group is still higher.Statistical result is shown in Table 2.
The different observation group's hemorheology of table 2（mPa·s）Compare
Compared with model group, * P<0.05, * * P< 0.01；Compared with normal group, ▲ P<0.05, ▲ ▲ P<
0.01；Compared with XUESAITONG JIAONANG group, △ P<0.05, △ △ P< 0.01；Compared with XUESAITONG ZHUSHEYE group, ＆ P<
0.05 , ＆＆P< 0.01；Note：n = 10
Influence of the 2.3 arasaponin carriers to rat model tectology
Normal group muscle fibre form is more consistent, and myocyte is in spindle shape, and endochylema enriches, no pathological change（See Fig. 1
A）；Visible muscle fibre deformation after the h of modeling 24, or even dialysis, and with oedema, bleeding, a large amount of cell infiltrations, local organization
Degeneration necrosis（See Fig. 1 B）.It is administered after 5 d, test group and hemostasis, oedema in positive controls muscle fibre swelling, muscular tissue, goes out
Blood stove disappears substantially, and blood vessel hyperplasia, collagen fiber hyperplasia recover substantially compared with normal structure（See Fig. 1 C, D）；" Xuesaitong Injection "
The visible part muscle fibre swelling that Capsules group, XUESAITONG ZHUSHEYE group and model control group have, the visible leucocyte diffusivity having
Infiltration, recovery effects are not good（See Fig. 1 E, F, G）.
3. conclusion
Arasaponin transmission physical efficiency significantly reduce the damage disease index of rat model, hence it is evident that improve its blood it is highly concentrated,
Viscous, poly-, solidifying state, also has good repair to its Pathomorphologic.The present invention is to soft group of rat acute closed
Knitting damage has definite therapeutic effect.
Clinical data
Basic document：Acute and closed soft tissue injury 200, wherein male 126, women 74, age are observed altogether
For 17-35 Sui.
Case selection：All tissue and surroundings such as muscle, ligament, manadesma, tendon, synovial membrane as caused by wound strain exopathogen
Nerve, the acute closed property injured patient of blood vessel can include.
Administrated method and the course for the treatment of：The medicine of Example 1 is applied to affected part in right amount, is in non-close using medicine position as far as possible
State, it is daily 2-3 times.Treatment observes curative effect after 10 days.
Curative effect judging standard：
1st, fully recover：Local pain, swelling and the dermal ecchymosis disappear after medication, and movable function recovers normal.
2nd, it is effective：Local pain mitigates significantly after medication, and swelling and the dermal ecchymosis disappear substantially, and movable function is substantially extensive
It is multiple.
3rd, effectively：Local pain mitigates after medication, and swelling and the dermal ecchymosis have disappeared, and movable function has recovered.
4th, it is invalid：Local pain, swelling and the dermal ecchymosis do not have change after medication.
As a result：Recovery from illness 142, effective 36, effective 15, invalid 7.Obvious effective rate 89.0%, total effective rate 96.5%.
All patients are showed no obvious adverse reaction.
Claims (13)
1. a kind of novel skin drug-delivery preparation for treating acute and closed soft tissue injury, it is characterised in that by following parts by weight
Composition is constituted：
60-120 parts of arasaponin, 20-150 parts of phosphatidase 1,12-20 parts of cholesterol, limonene-citral Mixed chaotic sequences 40-
80 parts, -2.5 parts of vitamin E2,10000-15000 parts of buffer solution, described limonene-citral Mixed chaotic sequences are by limonene
With citral according to weight ratio 1:4~4:1 mixes, and described buffer solution is phosphate buffer solution.
2. a kind of novel skin drug-delivery preparation for treating acute and closed soft tissue injury as claimed in claim 1, its feature
It is described limonene-citral Mixed chaotic sequences by limonene and citral according to weight ratio 4:1 mixes.
3. a kind of novel skin drug-delivery preparation for treating acute and closed soft tissue injury as claimed in claim 1, its feature
It is to be composed of the following components in parts by weight：
80-110 parts of arasaponin, 20-140 parts of phosphatidase 1,14-16 parts of cholesterol, limonene-citral Mixed chaotic sequences 60-
80 parts, -2.3 parts of vitamin E2,10000-12000 parts of buffer solution.
4. a kind of novel skin drug-delivery preparation for treating acute and closed soft tissue injury as claimed in claim 1, its feature
It is to be composed of the following components in parts by weight：
100 parts of arasaponin, 20 parts of phosphatidase 1,15 parts of cholesterol, limonene -80 parts of citral Mixed chaotic sequences, vitamin E2
Part, 10000 parts of buffer solution.
5. a kind of novel skin drug-delivery preparation for treating acute and closed soft tissue injury as described in claim 1,2,3 or 4,
It is characterized in that described phosphate buffer solution is 1/15 mol/L potassium dihydrogen phosphates and 1/15 mol/L phosphoric acid hydrogen two
Sodium solution by volume 53.4:The mixed liquor of 46.6 mixing.
6. a kind of novel skin administration system for treating acute and closed soft tissue injury as described in claim 1,2,3,4 or 5
The preparation method of agent, it is characterised in that comprise the following steps that：
1）Arasaponin, phosphatide, cholesterol, limonene-citral Mixed chaotic sequences and the vitamin E of formula ratio are weighed, it is molten
In organic solvent, it is well mixed, is transferred in eggplant-shape bottle, decompression rotation boils off organic solvent, obtains dry film；
2）With buffer solution hydration step 1）Obtained dry film, shaking, makes the complete aquation of lipid film, then with Ultrasonic cell smash
Carry out ultrasonication processing；
3）Sample after above-mentioned ultrasonication is handled is placed after 2~3 h, is placed in liposome mini-extruder extrusion instrument, 0.25
100 nm polycarbonate membranes are squeezed through under MPa, 50 nm polycarbonate membranes are squeezed through under 0.49 MPa, treatment are produced acute closed
The novel skin drug-delivery preparation of property soft tissue injury.
7. a kind of preparation side for the novel skin drug-delivery preparation for treating acute and closed soft tissue injury as claimed in claim 6
Method, it is characterised in that described step 1）Middle organic solvent is methanol, n-butanol, isopropanol, acetone, acetonitrile, n-hexane and two
Mixed liquor more than one or both of chloromethanes.
8. a kind of preparation side for the novel skin drug-delivery preparation for treating acute and closed soft tissue injury as claimed in claim 6
Method, it is characterised in that described step 1）Middle organic solvent is methanol dichloromethane by volume 3:The mixed liquor of 4 mixing.
9. a kind of preparation side for the novel skin drug-delivery preparation for treating acute and closed soft tissue injury as claimed in claim 6
Method, it is characterised in that described step 1）The addition of middle organic solvent and the scope of the weight part ratio of phosphatide are 200~417：
1。
10. a kind of preparation for the novel skin drug-delivery preparation for treating acute and closed soft tissue injury as claimed in claim 6
Method, it is characterised in that described step 1）The addition of middle organic solvent and the scope of the weight part ratio of phosphatide are 292:1.
11. a kind of preparation for the novel skin drug-delivery preparation for treating acute and closed soft tissue injury as claimed in claim 6
Method, it is characterised in that described step 1）Middle 45 DEG C of decompression rotary distillation condition, 50 r/min.
12. a kind of preparation for the novel skin drug-delivery preparation for treating acute and closed soft tissue injury as claimed in claim 6
Method, it is characterised in that described step 1）Middle 25 DEG C of ultrasonication treatment conditions temperature, power 16W, lasting 5s, is repeated every time
6 times.
13. a kind of preparation for the novel skin drug-delivery preparation for treating acute and closed soft tissue injury as claimed in claim 6
Method, it is characterised in that described step 2）Middle phosphate buffer solution is 1/15 mol/L potassium dihydrogen phosphates and 1/15
Mol/L disodium phosphate solns by volume 53.4:The mixed liquor of 46.6 mixing.
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| WO2024057304A1 (en) * | 2022-09-12 | 2024-03-21 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Compositions for dermal/transdermal delivery and cosmetic use |
| CN116392442A (en) * | 2023-04-06 | 2023-07-07 | 浙江中医药大学 | Skin administration preparation prepared by microfluid and having coexistence of lipid vesicles and micelles and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1491658A (en) * | 2003-09-05 | 2004-04-28 | 云南植物药业有限公司 | Notiginseng total saponin liposome and its preparation |
| CN1543974A (en) * | 2003-11-19 | 2004-11-10 | 复旦大学 | Notoginsen triterpenes liposome and prepartion thereof |
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2015
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1491658A (en) * | 2003-09-05 | 2004-04-28 | 云南植物药业有限公司 | Notiginseng total saponin liposome and its preparation |
| CN1543974A (en) * | 2003-11-19 | 2004-11-10 | 复旦大学 | Notoginsen triterpenes liposome and prepartion thereof |
Non-Patent Citations (3)
| Title |
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| 三七总皂昔复方脂质体凝胶剂的制备及皮肤给药研究;徐白等;《中国临床药学杂志》;20071231;第16卷(第3期);第144-148页 * |
| 三七总皂苷脂质体微丸的制备;李娜等;《中国实验方剂学杂志》;20130930;第19卷(第18期);第35-38页 * |
| 离体皮肤渗透法测定三七总皂苷传递体经皮吸收特性;方蓉等;《中草药》;20150228;第46卷(第4期);第513-519页 * |
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