CN100337650C - Liquid medicine composition for external-applied anti-inflammation and antipruritic - Google Patents
Liquid medicine composition for external-applied anti-inflammation and antipruritic Download PDFInfo
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Abstract
The present invention discloses an externally-applied liquid medicine composition for eliminating inflammation and itching. The composition comprises a medicinal effect substance and an auxiliary material for medicinal use, wherein the medicinal effect substance is composed of paeonol and clove oil, and the auxiliary material for medicinal use comprises a composite solvent for medicinal use. The composite solvent for medicinal use, to which the present invention relates to, can obviously increase the speed at which the paeonol passes through strata cornea and the passing quantity, and obviously increase the stored quantity of the paeonol in active tissues of skin (an active epidermis layer and a dermis layer) so that the main medicinal effect substance can quickly and persistently take the medicinal effect.
Description
Invention field the present invention relates to a kind of composition of liquid medicine that contains paeonol, Oleum Caryophylli, said composition is a dermatologic, but anti-inflammatory anti-itch, be used for various dermatopathies such as eczema, dermatitis, skin pruritus, mosquito bedbug bite redness, allergic rhinitis and anti-curing cold are also had certain effect.
Background technology art paeonol (Paeonol; Pae) be the main active of Chinese medicine Cortex Moutan (root bark of Paeoniaceae plant Paeonia suffruticosa Paeonia suffruticosa) and Radix Cynanchi Paniculati (herb of Asclepiadaceae plant Radix Cynanchi Paniculati Cynanchum paniculatum), have effects (P2369 is rolled up in " Chinese medicine modern study and application " the 3rd) such as protection cardiac muscle, blood pressure lowering, analgesia, calmness, analgesic, antibiotic, antiallergic action.Put down in writing according to the Li Shizhen (1518-1593 A.D.) Compendium of Material Medica: Cortex Moutan is hot to loose, hardship can be let out, cold can be clear, red complexion branchs of dehematizing, the property of fragrant Mus is arranged, go into liver and gall heart kidney three warmers blood system, can shy the diffusing blood of blood, disease such as all blood system wind heat stasis of bloods are stagnant.Clinical practice shows, the notion of Heat Syndrome of TCM except with modern medicine in nonspecific inflammation have the substantial connection, also have intrinsic the contact with some allergic disease.Animal experiment shows that (75-150mg/kg * 5d ip) significantly suppresses the reaction of Cavia porcellus Forssman cutaneous vasculitis, the reverse skin allergy of rat, rat active and the swollen account of the passive Arthus type foot sole of the foot, 50-200mgkgd to paeonol
-1(ip) to sheep red blood cell, the inductive mice delayed of bovine serum albumin pedal swelling, to 2, the mice contact dermatitis that the 4-dinitrofluorobenzene causes all has obvious suppression effect (Wu Guanzhong, Hang Bingqian, Hang Jingxia, etc. the anti-allergy action of paeonol. the journal 1990:21:103-106. of China Medicine University).Other has document to show, paeonol at external 1: 15000 concentration solution to escherichia coli, bacillus subtilis, 1: 2000 pair of staphylococcus aureus has obvious inhibitory action, to influenza virus and common pathogenic dermatophytes also have inhibitory action (king bathes life. herbal pharmacology and application. Beijing: the People's Health Publisher, 1983:903).
Oleum Caryophylli is the volatile oil that extracts in the dry flower of plant clove of myrtaceae, mainly contains eugenol (Eugenol), acetyleugenol, β-caryophyllene (β-Caryophyllene), humulene (Humulene), benzaldehyde and chavicol (Chavicol) etc. in the oil.The volatile oil of Folium Caryophylli oil for from Folium Caryophylli, proposing, Oleum Caryophylli similar to the composition of Folium Caryophylli oil (" contemporary Chinese research and the application " first volume).Eugenol is one of main effective ingredient in Oleum Caryophylli and the Folium Caryophylli oil.There is the report Flos Caryophylli can suppress the growth of staphylococcus and tubercule bacillus, Oleum Caryophylli and eugenol are under finite concentration, in the internal energy growth that stops Brucella fully of test tube, Trichophyton concentricunm, haemophilus, bordetella pertussis and part fungus are also had inhibitory action, and this class bacterium has no drug resistance to Oleum Caryophylli and eugenol; Oleum Caryophylli also has effects (" Chinese medicine modern study and the application " first volume) such as anthelmintic, calmness, analgesia, local anesthesia.And Oleum Caryophylli itself also can promote the Transdermal absorption of other medicines as transdermal enhancer.
Liu Chunhai, Yang Yonghua etc. are in " grieved tincture concentration of alcohol is to the influence of paeonol Transdermal absorption " (the 23rd the 10th phase of volume of " Chinese patent medicine " calendar year 2001), described by recipe quantity Chinese crude drugs such as Folium Hibisci Mutabilis, Radix Cynanchi Paniculati have been carried out percolation by preparation technology, percolate is transferred to different pure content respectively with ethanol, with the paeonol content is to investigate index, adopts external diffusion cell method that the accumulation infiltration capacity of paeonol is carried out than effect.But only investigated the transdermal total amount of medicine in the literary composition, the memory space that really plays the medicine of antipruritic effect in the skin has not been investigated.
Ma Yunshu, Zhao Haoru etc. are in " the transdermal test in vitro preliminary study of paeonol and phosphatide complexes thereof " (" Yunnan Chinese medicine magazine " 1999 the 20th the 4th phases of volume), studied the transdermal test in vitro process of paeonol and phosphatide complexes thereof, the transit dose of paeonol through whole bark detected.Its paeonol is unit are transmitance (μ g/mgcm in 50% alcoholic solution
2) identical substantially with test data of the present invention, be starkly lower than the transmitance of paeonol in double solvents among the present invention.And this piece document does not see through horny layer, skin corium or skin storage capacity etc. to medicine and furthers investigate.
Song Yuhua, Du Guangyan etc. in " influence of the azone of variable concentrations peaceful nasal drop Transdermal absorption " (" PLA's Acta Pharmaceutica Sinica " 1999 the 5th phase the 15th volume) to nose, investigated the variable concentrations azone as transdermal enhancer to the paeonol transit dose in this nasal drop and the influence of transmission rates.Because the peaceful nasal drop of nose is a nasal mucosa medicine administration, therefore there be not the related data of paeonol in each layer of skin cumulant.
Application number is in " adhesive plaster for alleviating pain and detumescence " patent of 95111515.6, to be that paeonol and pharmaceutical carrier are made the agent of external rubber patch, and is not mentioned in the test of animal isolated skin Transdermal absorption, the seeing through of effective ingredient, absorption and distribution situation.
Mimura K, Baba S. is at " research that the experimental animal tracer method absorbs the paeonol percutaneous " (Radioisotopes.1983 Jan; 32 (1): 7-12.), paeonol is made hydrophilic mastic spread on the base cloth, be attached to back part of animal skin, adopt the C14 labelling method to carry out metabolism research in the urine of rabbit, pig, Mus.Distribution and the metabolism situation of not mentioned medicine in skin in the test.
Zhou Meihua etc. have studied the permeability of isoeugenol through the mice isolated skin in " the stripped Transdermal absorption research of isoeugenol ", but do not see the report of relevant eugenol Transdermal absorption aspect.
The preparation that contains paeonol that retrieves at present has Paeonal injection liquid (Shanghai first first pharmaceutical factory of biochemical Pharma Inc., the accurate word (1995) of medicine is defended No. 001063 in Shanghai), paeonol unguentum, paeonol tablet and other compound preparation.Paeonal injection liquid has antiinflammation, is used for rheumatoid arthritis, has clinically confirmed that curative effect is better.Paeonol unguentum (paeonol frost) (standard No. WS3-B-1900-95) is used for various dermatopathies such as various eczemas, dermatitis, skin pruritus, mosquito bedbug bite redness clinically, and allergic rhinitis and anti-curing cold are also had certain effect.Contain paeonol 0.5g, Oleum Caryophylli 0.07ml in the paeonol unguentum of every 10g,, have the anti-inflammatory anti-itch effect as antiallergic agent.Every of paeonol sheet contains paeonol 40mg, is analgesic, is used for the anti-inflammatory analgetic of rheumatoid arthritis clinically.Do not find the external use liquid pharmaceutical composition that paeonol and Oleum Caryophylli and suitable pharmaceutically acceptable auxiliaries are made by retrieval, do not find the research record of this respect yet.
The external preparation that contains paeonol and Oleum Caryophylli has only a kind of dosage form of ointment (cream) at present.In use, need smear by finger or other instruments, both inconvenient, also unhygienic; During the large tracts of land administration, be difficult to accomplish to smear evenly, dosage is inaccurate, easily causes the waste of medicine; And easy pollution clothes, not easy cleaning; During the summer administration, viscosity is big, and the patient is reluctant to accept.It should be noted that especially the release of active medicine in substrate is slow in the ointment, thereby cause onset slow, had a strong impact on the performance of curative effect of medication.
Administration for convenience heightens the effect of a treatment, and the present invention has prepared composition of liquid medicine.Horny layer is the rate-limiting factor of Transdermal absorption, and skin pruritus is because the free nerve endings network of corium and epidermis intersection is upset, and relevant with the release of histamine and albumen and peptide matters.The present invention is surprised to find by test, this composition of liquid medicine can improve speed and the transit dose that main pharmacodynamics material paeonol sees through keratodermatitis greatly, and can increase its medicine reserves at skin activity tissue (active epidermis and skin corium), greatly shorten the drug effect time, improved curative effect
Summary of the invention the present invention relates to the antipruritic composition of liquid medicine of a kind of externally applied anti-inflammation, and this pharmaceutical composition comprises paeonol, Oleum Caryophylli and pharmaceutically acceptable auxiliaries.Wherein contain paeonol 0.1%～50%, Oleum Caryophylli 0.01%～20%, pharmaceutically acceptable auxiliaries 40%～98% by weight; Be preferably paeonol 0.5%～30%, Oleum Caryophylli 0.05%～10%, pharmaceutically acceptable auxiliaries 65%～97%; More excellent is paeonol 1%～10%, Oleum Caryophylli 0.1%～5%, pharmaceutically acceptable auxiliaries 85%～96%; Optimum is paeonol 5%, Oleum Caryophylli 0.72%, pharmaceutically acceptable auxiliaries 94.28%;
Pharmaceutically acceptable double solvents is any two or more the combination in the alcohols solvent, or any two or more the combination in the fatty acid ester kind solvent, or any two or more the combination in alcohols solvent and the fatty acid ester kind solvent.Alcohols solvent is lower alcohol, polyhydric alcohol, preferred alcohol, propylene glycol, Macrogol 200, PEG400, more preferably ethanol, propylene glycol, Macrogol 200; The fatty acid ester kind solvent is the isopropyl alcohol fatty acid ester, preferred isopropyl myristate, isopropyl palmitate, more preferably isopropyl myristate.
The Transdermal absorption treatment of medicine can be divided into topical therapeutic and whole body therapeutic, and the key of topical therapeutic is that medicine must see through epidermal area arrival diseased region, and keeps certain hour.Whether topical therapeutic is effective, depends on that can medicine as soon as possible see through whether long enough of horny layer and the retention time of medicine in skin activity tissue (active epidermis and skin corium), and whether memory space is abundant.
The present invention selects the series prescription by testing sieve, given full play to the itching-relieving action of paeonol, Oleum Caryophylli, can either (promptly shrink local blood capillary by physical action is antipruritic at epidermal area, reduce histamine to discharge and antipruritic), can infiltrate skin soon again, combine with protein such as the histamine that causes pruritus or peptide class, destroy its effect and antipruritic.Simultaneously, medicine has reached higher local concentration and can continue the regular hour (being the storage storehouse effect of skin) at local skin, has brought into play curative effect fully.The present invention makes liquid preparation for external application with paeonol, Flos Caryophylli wet goods effective substance, preferred appropriate drug adjuvant, thereby improved the transit dose and the transmission rates of effective substance greatly, also improved their storage capacities in skin activity tissue (active epidermis and skin corium) simultaneously.
The present invention makes the external use liquid pharmaceutical composition with paeonol, Oleum Caryophylli and pharmaceutically acceptable auxiliaries, has effectively overcome the shortcoming of ointment, and has had the following advantages: 1) easy to use, be coated in skin surface, but just homodisperse of medicine.2) the liquid preparation production technology is simple, realizes commercial production easily.3) medicine is uniformly dispersed in solution, and quality is controlled easily.
In order to make the best antipruritic effect of external use liquid pharmaceutical composition performance of the present invention, the present invention has selected double solvents for use.Double solvents involved in the present invention can make paeonol see through horny layer as early as possible, enter skin activity tissue (active epidermis, skin corium), and medicine is stored in the skin activity tissue, thereby reach antipruritic fast, continue the itching relieving effect, and then fundamentally solved the defective that liquid preparation for external application is difficult to lasting produce effects.
The present invention has the following advantages: after (1) local application, can increase the hydration of cuticular humidifying and skin, make the easier horny layer that sees through of medicine; (2) improved effective substance at the in-house content of skin activity, the whole body that reduces medicine absorbs, thereby avoids the toxic and side effects of medicine.
The invention provides a kind of liquid preparation that can bring into play drug effect fast, lastingly that contains paeonol, Oleum Caryophylli, and see through experiment and skin " storage storehouse effect " experiment confirm by horny layer: the liquid preparation that is provided has better transdermal effect and significant skin " storage storehouse effect " than prior art paeonol unguentum.
Preparation technology of the present invention is: get paeonol, Oleum Caryophylli, add an amount of stirring and evenly mixing of solvent, whether all solubilizer observes dissolving to capacity again.Whether left standstill 24 hours, observing has crystallization to separate out.
The density of Oleum Caryophylli is 1.03g/ml after measured.Add in test Oleum Caryophylli and add, select for use pipet, adjustable micropipettor or microsyringe to pipette according to different volumes according to volume.
The specific embodiment for investigate paeonol in different solvents the transdermal situation, the present invention has designed horny layer and has seen through experiment, skin depot experiment.
1. horny layer sees through experiment:
In the invention process, we have adopted classical transdermal experiment method, and promptly Franz diffusion cell method has been measured the percutaneous rate that effective substance in the pharmaceutical composition of different formulations enters keratodermatitis.By this experiment, mainly investigate the transdermal speed of effective ingredient paeonol.
Selected skin is dry Periostracum Serpentis, soaks 30min with normal saline, experimentizes after washing repeatedly with distilled water.Select the Franz diffusion cell for use, Periostracum Serpentis is fixed in reception bottleneck (diameter is 1.5cm), make to receive liquid with 30% ethanol normal saline.The medicinal liquid for preparing is applied to the Periostracum Serpentis surface, and the dosage of each sample is for containing paeonol 1mg.Respectively 5,15,30,60,120,180,240,300, the 360min sampling, each sampling 0.5ml, and in time additional fresh reception liquid, measure the drug level of each time point with the HPLC method, calculate accumulation transit dose (Q), accumulation transmitance, stable state transmission rates J, accumulation transit dose (Q) and the Q-t equation of time (t), and calculate lag time (tL).
Comparative example 1
Paeonol 5g
Oleum Caryophylli 0.7ml
Ethanol (70%) adds to 100g
Preparation technology: get paeonol and add an amount of dissolving of ethanol (70%), add Oleum Caryophylli and stir evenly, add ethanol (70%) extremely quantitatively.Mixing promptly.
Comparative example 2
Paeonol 5g
Oleum Caryophylli 0.7ml
Macrogol 200 adds to 100g
Preparation technology: get paeonol and add Polyethylene Glycol 200 and dissolve in right amount, add Oleum Caryophylli and stir evenly, add Macrogol 200 to quantitatively.Mixing promptly.
Comparative example 3
Paeonol 5g
Oleum Caryophylli 0.7ml
Propylene glycol adds to 100g
Preparation technology: get paeonol and add propylene glycol and dissolve in right amount, add Oleum Caryophylli and stir evenly, add propylene glycol to quantitatively.Mixing promptly.
Comparative example 4
Paeonol 5g
Oleum Caryophylli 0.7ml
Isopropyl myristate adds to 100g
Preparation technology: get paeonol and add isopropyl myristate and dissolve in right amount, add Oleum Caryophylli and stir evenly, add isopropyl myristate to quantitatively.Mixing promptly.
Embodiment 1
Paeonol 0.1g
Oleum Caryophylli 0.01ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (50%): Macrogol 200=1: 2
Embodiment 2
Paeonol 0.5g
Oleum Caryophylli 0.05ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (60%): Macrogol 200=1: 1
Embodiment 3
Paeonol 1g
Oleum Caryophylli 0.1ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (70%): PEG400=1: 1
Embodiment 4
Paeonol 10g
Oleum Caryophylli 5ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): PEG400=1: 1
Embodiment 5
Paeonol 30g
Oleum Caryophylli 10ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): Macrogol 200=2: 1
Embodiment 6
Paeonol 30g
Oleum Caryophylli 20ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): Macrogol 200=2: 1
Embodiment 7
Paeonol 40g
Oleum Caryophylli 10ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): Macrogol 200=3: 1
Embodiment 8
Paeonol 5g
Oleum Caryophylli 0.7ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): isopropyl palmitate=1: 1
Embodiment 9
Paeonol 5g
Oleum Caryophylli 0.7ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): propylene glycol: isopropyl palmitate=10: 4: 6
Embodiment 10
Paeonol 5g
Oleum Caryophylli 0.7ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): Macrogol 200: isopropyl palmitate=10: 4: 5
Comparative example 5
Paeonol 60g
Oleum Caryophylli 10ml
Mixed solvent adds to 100g
Preparation technology: get paeonol, Oleum Caryophylli stirs evenly, and adds mixed solvent and stirs, and can't dissolve fully.
Annotate: mixed solvent ethanol (95%): Macrogol 200=3: 1
Embodiment 11
Paeonol 5g
Oleum Caryophylli 0.7ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): Macrogol 200=1: 1
Embodiment 12
Paeonol 5g
Oleum Caryophylli 0.7ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): propylene glycol=1: 1
Embodiment 13
Paeonol 5g
Oleum Caryophylli 0.7ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): isopropyl myristate=1: 1
Embodiment 14
Paeonol 5g
Oleum Caryophylli 0.7ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent propylene glycol: Macrogol 200=1: 1
Embodiment 15
Paeonol 5g
Oleum Caryophylli 0.7ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): propylene glycol: isopropyl myristate=10: 3: 3
Embodiment 16
Paeonol 5g
Oleum Caryophylli 0.7ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): Macrogol 200: isopropyl myristate=10: 3: 3
Embodiment 17
Paeonol 5g
Oleum Caryophylli 0.7ml
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli and stir evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): Macrogol 200: propylene glycol=1: 1: 1
Comparative example 6
Paeonol 5g
Oleum Caryophylli 0.7ml
Stearic acid 11g
Potassium carbonate 0.9g
Glyceryl monostearate 2.5g
Triethanolamine 0.3ml
Glycerol 10g
Water 72g
Preparation technology: get stearic acid, potassium carbonate, glyceryl monostearate, triethanolamine, glycerol, water and make ointment base, be heated to 70 ℃, add paeonol, Oleum Caryophylli mixing promptly.
Table 1 different formulations solvent is to the influence of paeonol transdermal penetration
| Experimental group | Accumulation transit dose (ug) | ||||||||
| 5min | 10min | 30min | 60min | 120min | 180min | 240min | 300min | 360min | |
| Comparative example 1 comparative example 2 comparative examples 3 comparative examples 4 comparative examples 6 embodiment 11 embodiment 12 embodiment 13 | 11.358 3.657 4.638 2.367 0.378 9.627 3.019 2.452 | 16.945 6.564 7.926 9.622 1.048 7.157 9.647 8.621 | 58.957 17.451 24.451 36.294 6.944 46.381 27.428 27.625 | 116.429 68.627 75.628 97.186 27.249 106.428 98.635 54.754 | 327.958 196.294 204.629 308.186 68.154 307.241 267.816 206.627 | 428.675 356.354 367.294 472.915 150.549 547.354 455.776 402.007 | 445.641 496.461 485.621 523.673 299.427 592.648 557.927 521.104 | 465.648 608.315 576.128 559.634 427.915 613.188 589.648 540.216 | 481.649 657.364 624.354 583.416 527.643 641.082 612.754 559.637 |
| Embodiment 14 embodiment 15 embodiment 16 embodiment 17 | 3.267 3.637 3.371 4.952 | 5.649 6.145 7.625 7.291 | 24.925 48.314 56.349 48.318 | 57.645 144.361 126.765 96.312 | 209.672 347.012 317.624 301.249 | 395.815 631.485 608.427 523.152 | 486.426 672.406 687.945 548.974 | 522.345 712.076 716.318 574.165 | 536.957 752.364 746.957 584.627 |
| Experimental group | Prescription | Accumulation transmitance (%) | The Q-T equation | Stable state percutaneous rate J (ug/cm 2·h) | Time lag t L(h) |
| Comparative example 1 comparative example 2 comparative examples 3 comparative examples 4 comparative examples 6 embodiment 11 embodiment 12 embodiment 13 embodiment 14 embodiment 15 embodiment 16 embodiment 17 | EtOH (70%) PEG200 PG IPM ointment 95%EtOH: PEG200 (1: 1) 95%EtOH: PG (1: 1) 95%EtOH: IPM (1: 1) PG: PEG200 (1: 1) 95%EtOH: PG: IPM (10: 3: 3) 95%EtOH: PEG200: IPM (10: 3: 3) 95%EtOH: PG: PEG200 (1: 1: 1) | 48.16 65.74 62.44 58.34 52.76 64.11 61.28 55.96 53.70 75.24 74.70 58.46 | Q＝156.12t-21.23 Q＝144.36t-81.46 Q＝145.83t-75.82 Q＝187.86t-82.97 Q＝61.65t-43.32 Q＝220.46t-120.59 Q＝178.57t-83.07 Q＝173.63t-126.12 Q＝169.01t-117.13 Q＝243.56t-112.84 Q＝240.83t-130.72 Q＝213.42t-119.94 | 156.12 144.36 145.83 187.86 61.65 220.46 178.57 173.63 169.01 223.56 240.83 213.42 | 0.14 0.56 0.51 0.44 0.70 0.55 0.47 0.73 0.70 0.46 0.54 0.56 |
By table 1 data as can be seen, comparative example 6 (paeonol unguentum) transdermal speed is the slowest, and transit dose only is 68.154 μ g during 120min, well below liquid preparation.The present invention changes paeonol unguentum into liquid preparation, has significantly improved the horny layer infiltration rate of paeonol, shortens lag time, has also increased paeonol epidermis transit dose simultaneously.
Comparative example 1 (solvent is 70% ethanol) beginning transmission rates is very fast, but the accumulation transit dose is less in 360min, and the transit dose when 360min only is 481.649 μ g, and transmitance is 272.70 μ g/mg.cm
2Ma Yunshu, Zhao Haoru etc. are 2455.0 μ g/cm at " the transdermal test in vitro preliminary study of paeonol and phosphatide complexes thereof " (" Yunnan Chinese medicine magazine " 1999 the 20th the 4th phases of volume) paeonol (solvent is 50%EtOH) 360min transit dose
2, transmitance is 245.50 μ g/mg.cm
2The transmitance of paeonol is identical substantially.By table 1 as can be seen, the transit dose of paeonol in double solvents of the present invention is apparently higher than the transit dose in ethanol.Because single alcohol solvent is volatile, though can guide drugs comparatively fast see through skin, final transdermal total amount is lower.Comparative example 2 (solvent is a Macrogol 200) and comparative example 3 (solvent is a propylene glycol), the beginning transmission rates is slower, but (growth of 240min～360min) see through is very fast the time in later stage.The transmission rates of this explanation Macrogol 200 and propylene glycol is slow, but sees through longer duration.This is all can form the medicine film because Macrogol 200 and propylene glycol are sprayed on the skin, forms a drug-reservoir at skin surface, and medicine can slow release come out from bank.Two or more solvent can remedy the deficiency of single solvent mutually, and mixed solvent obviously is better than single solvent aspect transdermal effect.
2. skin storage storehouse experiment:
Because the site of action of main pharmacodynamics material paeonol is the viable skin layer of skin in this pharmaceutical composition, promptly active epidermis and skin corium, so the amount retained of paeonol in active mass becomes positive correlation with drug effect.Classical Franz diffusion cell method is also selected in experiment for use, and main purpose is to investigate the influence of different solvents to paeonol memory space in the skin activity skin layer.
Assay method:
Select 18～22g male ICR mouse (Beijing Vital River Experimental Animals Technology Co., Ltd. provides) for use, put to death.Shave hair, get skin of abdomen, remove subcutaneous tissue.Select the Franz diffusion cell for use, skin is fixed on the reception bottleneck, 30% ethanol normal saline is housed in the receiving bottle.The medicinal liquid for preparing is applied on the skin, and dosage is 1mg by paeonol.Respectively at the skin surface medicinal liquid being washed repeatedly with acceptable solution when 10min, 30min, 60min, 120min after the administration, and paste horny layer repeatedly 25～30 times, promptly can be considered until the pressure sensitive adhesive tape surface clean horny layer is glued with pressure sensitive adhesive tape.To glue cuticular skin and shred, and use Potter-Elvehjem Tissue Grinders homogenate, and add 95% ethanol, and extract paeonol in the active mass, centrifugal 10min gets supernatant.So operation is three times, merges supernatant, carries out content detection of paeonol in the skin corium with the HPLC method.
Table 2 different solvents is organized the memory space influence to paeonol at skin activity
| min | Comparative example 6 (μ g) | Comparative example 1 (μ g) | Comparative example 2 (μ g) | Comparative example 3 (μ g) | Comparative example 4 (μ g) | Embodiment 11 (μ g) |
| 10 | 0.916 | 12.429 | 7.327 | 5.342 | 7.465 | 5.318 |
| 30 | 6.019 | 31.058 | 10.04 | 13.229 | 17.291 | 27.655 |
| 60 | 15.042 | 75.124 | 54.066 | 57.298 | 68.246 | 87.684 |
| 120 | 22.319 | 108.324 | 118.318 | 126.327 | 127.326 | 144.329 |
| min | Embodiment 12 (μ g) | Embodiment 13 (μ g) | Embodiment 14 (μ g) | Embodiment 15 (μ g) | Embodiment 16 (μ g) | Embodiment 17 (μ g) |
| 10 | 7.445 | 6.188 | 4.625 | 5.657 | 5.654 | 5.645 |
| 30 | 24.184 | 26.627 | 28.629 | 46.348 | 36.342 | 31.215 |
| 60 | 67.253 | 50.328 | 54.467 | 101.572 | 89.528 | 59.546 |
| 120 | 132.764 | 134.846 | 122.407 | 173.648 | 166.981 | 154.915 |
As can be seen from Table 2,2 hours memory space minimums in the skin activity tissue of comparative example 6 (paeonol unguentum) can not reach antipruritic effect preferably.The present invention changes paeonol unguentum into liquid preparation, has significantly improved in 2 hours paeonol in the memory space of skin activity tissue.Comprehensive 4 time points, paeonol is higher in the memory space of 10min, 30min in the comparative example 1, but at the low memory of 120min, reason may be because ethanol itself promptly has the good transdermal effect, so when beginning is higher at the medicament contg of skin activity tissue; After long-time the placement, because the speed that alcoholic acid volatilization makes paeonol see through horny layer and skin corium slows down the low memory of paeonol in the skin activity tissue when causing 120min.Comparative example 2, comparative example 3, comparative example 4 be not because solvent has volatility, so the memory space in the skin activity tissue is lower when beginning, but accumulation skin Chinese medicine reserves are then apparently higher than comparative example 1.The present invention has adopted pharmaceutically acceptable double solvents, has improved the memory space of each time point of paeonol in the skin activity tissue, has obtained beyond thought result.Confirm that the double solvents that the present invention adopts can improve the memory space of paeonol in the skin activity tissue.
Some adjuvants have also been added in the present invention, as transdermal enhancer, essence etc.Penetration enhancer can infiltrate horny layer, reduces the order that the iuntercellular lipid is arranged; Slough the passage that the iuntercellular lipid forms; Increase the horny layer water content; Reduce the phase rate of transformation of horny layer lipid.The adding of transdermal enhancer can improve the speed that paeonol enters the skin activity tissue by horny layer, can improve paeonol in the in-house memory space of skin activity simultaneously.Be paeonol transdermal situation behind the mensuration adding penetration enhancer, we have carried out horny layer and have seen through test and skin depot test.Experimental implementation is the same.The results are shown in Table 3, table 4.
Embodiment 18
Paeonol 5g
Oleum Caryophylli 0.7ml
Azone 1g
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli, azone stirs evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): propylene glycol: isopropyl myristate=10: 3: 3
Embodiment 19
Paeonol 5g
Oleum Caryophylli 0.7ml
Azone 2.5g
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli, azone stirs evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): propylene glycol: isopropyl myristate=10: 3: 3
Comparative example 7
Paeonol 5g
Oleum Caryophylli 0.7ml
Azone 5g
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli, azone stirs evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): propylene glycol: isopropyl myristate=10: 3: 3
Embodiment 20
Paeonol 5g
Oleum Caryophylli 0.7ml
Isopropyl alcohol 5g
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli, isopropyl alcohol stirs evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): propylene glycol: isopropyl myristate=10: 3: 3
Embodiment 21
Paeonol 5g
Oleum Caryophylli 0.7ml
Azone 1g
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli, azone stirs evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): Macrogol 200: isopropyl myristate=10: 3: 3
Embodiment 22
Paeonol 5g
Oleum Caryophylli 0.7ml
Oleic acid 5g
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli, oleic acid stirs evenly, add mixed solvent to quantitatively.Mixing promptly.
Annotate: mixed solvent ethanol (95%): Macrogol 200: isopropyl myristate=10: 3: 3
Embodiment 23
Paeonol 5g
Oleum Caryophylli 0.7ml
Azone 1g
Essence 0.5g
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli, azone, essence and stir evenly, add mixed solvent to quantitatively.Mixing promptly.Abnormal smells from the patient fragrance.
Annotate: mixed solvent ethanol (95%): propylene glycol: isopropyl myristate=10: 3: 3
Comparative example 8
Paeonol 5g
Oleum Caryophylli 0.7ml
Azone 1g
Essence 1g
Mixed solvent adds to 100g
Preparation technology: get paeonol and add mixed solvent and dissolve in right amount, add Oleum Caryophylli, azone, essence and stir evenly, add mixed solvent to quantitatively.Mixing promptly.Abnormal smells from the patient is too strong.
Annotate: mixed solvent ethanol (95%): propylene glycol: isopropyl myristate=10: 3: 3
The different penetration enhancer of table 3 are to the influence of paeonol transdermal penetration
| Experimental group | Accumulation transit dose (ug) | ||||||||
| 5min | 15min | 30min | 60min | 120min | 180min | 240min | 300min | 360min | |
| Comparative example 7 embodiment 18 embodiment 19 embodiment 20 embodiment 21 embodiment 22 | 5.216 13.507 8.513 7.625 8.327 6.342 | 19.685 46.544 34.983 28.641 28.643 37.124 | 27.943 79.641 64.337 58.649 56.523 68.876 | 46.545 162.095 146.868 126.545 127.114 117.542 | 207.643 374.183 371.645 307.643 308.471 311.297 | 404.985 644.167 638.326 604.985 544.615 524.942 | 594.726 715.367 705.421 694.726 648.637 653.883 | 609.624 774.853 756.312 709.624 727.425 732.514 | 636.842 804.216 779.883 736.842 784.234 755.227 |
| Experimental group | Prescription | Accumulation transmitance (%) | The Q-T equation | Stable state percutaneous rate J (ug/cm2h) | Time lag t (h) |
| Comparative example 7 embodiment 18 embodiment 19 embodiment 20 embodiment 21 embodiment 22 | 5.0% azone, 1.0% azone, 2.5% azone, 5% isopropyl alcohol, 1.0% azone, 5% oleic acid | 63.68 80.42 77.99 73.68 78.42 75.52 | Q＝184.19t-147.00 Q＝241.04t-88.59 Q＝245.73t-105.85 Q＝239.22t-132.05 Q＝180.07t-42.97 Q＝182.27t-53.75 | 184.19 241.04 245.73 239.22 180.07 182.27 | 0.80 0.37 0.43 0.55 0.24 0.29 |
Table 4 transdermal enhancer is organized the influence of memory space at skin activity to paeonol
| min | Embodiment 18 (μ g) | Embodiment 19 (μ g) | Comparative example 7 (μ g) | Embodiment 20 (μ g) | Embodiment 21 (μ g) | Embodiment 22 (μ g) |
| 10 30 60 120 | 14.268 57.683 104.672 209.467 | 12.852 49.513 92.224 187.699 | 4.832 12.231 54.213 101.664 | 12.642 41.523 86.613 168.256 | 11.437 43.428 97.642 188.542 | 7.824 39.856 84.715 167.219 |
By table 3, table 4 as can be seen, add the skin transmission rates that penetration enhancer (as azone, oleic acid, isopropyl alcohol etc.) can improve paeonol, shorten lag time, improve the memory space of paeonol in the skin activity tissue.By embodiment as can be known, 1%～2.5% azone, 5% oleic acid, 5% isopropyl alcohol all have short saturating effect to the transdermal of paeonol, and 5% azone then has inhibitory action to the transdermal effect of paeonol.Can add azone (addition is not higher than 5%), oleic acid, isopropyl alcohol in the present invention as penetration enhancer.
External preparation for skin medicine as the treatment local patholoic change, the present invention is by reasonably prescription design, improve the effective substance paeonol greatly and seen through cuticular speed, and its reserves in skin have been increased, improve local drug concentration, reduce the whole body absorption, reach the purpose that strengthens its curative effect, and reduce the toxic and side effects that may occur.
Claims (8)
1. externally applied anti-inflammation itching relieving composition of liquid medicine, this composition of liquid medicine comprises effective substance and pharmaceutically acceptable auxiliaries, it is characterized in that: described effective substance is by paeonol, Oleum Caryophylli is formed, this composition of liquid medicine contains paeonol 0.1%～50% by weight percentage, Oleum Caryophylli 0.01%～20%, pharmaceutically acceptable auxiliaries 40%～98%, described pharmaceutically acceptable auxiliaries is to comprise pharmaceutically acceptable double solvents, this pharmaceutically acceptable double solvents is any two or more the combination in the alcohols solvent, or any two or more the combination in the fatty acid ester kind solvent, or any two or more the combination in alcohols solvent and the fatty acid ester kind solvent.
2. composition of liquid medicine according to claim 1 is characterized in that: this composition of liquid medicine contains paeonol 0.5%～30%, Oleum Caryophylli 0.05%～10%, pharmaceutically acceptable auxiliaries 65%～97% by weight percentage.
3. composition of liquid medicine according to claim 1 is characterized in that: this composition of liquid medicine contains paeonol 1%～10%, Oleum Caryophylli 0.1%～5%, pharmaceutically acceptable auxiliaries 85%～96% by weight percentage.
4. composition of liquid medicine according to claim 1 is characterized in that: this composition of liquid medicine contains paeonol 5%, Oleum Caryophylli 0.72%, pharmaceutically acceptable auxiliaries 94.28% by weight percentage.
5. composition of liquid medicine according to claim 1 is characterized in that: alcohols solvent is lower alcohol, polyhydric alcohol in the described pharmaceutically acceptable double solvents; The fatty acid ester kind solvent is the isopropyl alcohol fatty acid ester.
6. composition of liquid medicine according to claim 1 is characterized in that: alcohols solvent is ethanol, propylene glycol, Macrogol 200, PEG400 in the described pharmaceutically acceptable double solvents; The fatty acid ester kind solvent is isopropyl myristate, isopropyl palmitate.
7. composition of liquid medicine according to claim 1 is characterized in that: alcohols solvent is ethanol, propylene glycol, Macrogol 200 in the described pharmaceutically acceptable double solvents; The fatty acid ester kind solvent is an isopropyl myristate.
8. according to claim 6 or 7 described composition of liquid medicine, it is characterized in that: wherein concentration of ethanol is 50%～100%.
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| CN102793759B (en) * | 2012-07-25 | 2015-01-07 | 青岛文创科技有限公司 | Medicinal composition for treating vagina inflammatory diseases in gestation period |
| KR101568306B1 (en) | 2013-08-09 | 2015-11-11 | 주식회사 엘지생활건강 | Composition for skin moisturizing comprising paeonol |
| CN103705420B (en) * | 2013-12-30 | 2015-10-28 | 青蛙王子(中国)日化有限公司 | A kind of mosquito bite detumescence essence for children and preparation method thereof |
| EP3281626B1 (en) * | 2015-04-06 | 2023-08-23 | LG Household & Health Care Ltd. | Soluble microneedle for delivering poorly-soluble drug |
| CN105477088A (en) * | 2016-01-26 | 2016-04-13 | 陕西中医药大学 | Pure traditional Chinese medicine ointment for treating skin diseases and application thereof |
| CN110193041A (en) * | 2019-07-11 | 2019-09-03 | 江西中医药大学 | Treat essential oil composition of eczema and preparation method thereof, application method and application |
| CN115645464B (en) * | 2022-11-11 | 2024-04-12 | 广州中医药大学(广州中医药研究院) | Traditional Chinese medicine composition for treating atherosclerosis and fatty liver and application thereof |
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| Title |
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| 两种含丁香油制剂的体外溶出度测定 张纯等，北京针灸骨伤学院学报，第8卷第1期 2001 * |
| 丹皮酚软膏含量测定方法的修订 薛玉梅等，中成药，第17卷第5期 1995 * |
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