CN102908441A - Pain relieving micro-emulsion pharmaceutical composition gel ointment and preparation method thereof - Google Patents
Pain relieving micro-emulsion pharmaceutical composition gel ointment and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a micro-emulsion pharmaceutical composite gel ointment which is free of oil bleeding on surface. Computability of volatile components and water-soluble bases in the gel ointment is improved. As proved by transdermal absorption tests, transdermal absorption of imperatorin in the pharmaceutical composition gel ointment in the micro-emulsion form is improved, and is close to the transdermal absorption degree of ferulic fluid, and synchronously transdermal absorption of different components different in property can be improved by the micro-emulsion form. Besides, as proved by tests of preliminary stability of the micro-emulsion pharmaceutical composition gel ointment in three forms, the micro-emulsion form is favorable for enhancing stability of volatile components in the formula.
Description
Technical field
The present invention relates to a kind of micro-emulsion type gel ointment and preparation method thereof, particularly a kind of micro-emulsion type pharmaceutical composition gel ointment for pain relieving and preparation method thereof.
Background technology
Prior art discloses pain relieving plaster unguentum and preparation technology thereof, the pain relieving plaster unguentum is comprised of Rhizoma Chuanxiong, the Radix Angelicae Dahuricae, Pericarpium Zanthoxyli, Herba Asari, Oleum menthae, Lignum Pini Nodi wet goods, disclose the extraction process of pain relieving plaster unguentum crude drug in 2008 annual master's thesis " preparation technology of pain relieving plaster unguentum and quality standard research ", Rhizoma Chuanxiong, Radix Angelicae Dahuricae percolation extract to get the thick extractum (4gmL of percolate
-1), Pericarpium Zanthoxyli, Herba Asari extraction by steam distillation volatile oil get the thick extractum (4gmL of alcohol deposit fluid simultaneously
-1); prior art also discloses the preparation technology of pain relieving plaster unguentum: NP700 is joined in the glycerol stir; add Rhizoma Chuanxiong-Radix Angelicae Dahuricae extract, Herba Asari-Pericarpium Zanthoxyli water extract and volatile oil; add cross-linking agent after mixing; stir evenly; then evenly coat on the non-woven fabrics, add a cover at last protective layer, namely get medicated adhesive plaster.
Yet, the disclosed pain relieving plaster unguentum of above-mentioned prior art belongs to a kind of Chinese medicine compound gel ointment, this gel ointment generally need to add the Transdermal absorption that volatile oil increases main component in the preparation, this is so that contain a large amount of volatile oil in the prescription, thereby cause the adjuvant such as water-soluble base such as NP-700 in volatile ingredient and the gel ointment between the compatibility poor, the simultaneously general direct adding of volatile ingredient or adopt suitable dissolution with solvents after join in the gel ointment prescription, volatile ingredient stability also exists problem; And containing a large amount of chemical constituents in the general Chinese medicine gel ointment, Transdermal absorption is also asynchronous between the composition of different in kind.
Microemulsion formulation is comprised of surfactant (S), cosurfactant (CoS), oil phase (Oil), water, oil phase and water can dissolve composition of different nature, because of its particle diameter little, prescription contains a large amount of surfactants and cosurfactant, also is a kind of good transdermal administration carrier.In order to solve the existing the problems referred to above of pain relieving plaster unguentum, the employing of microemulsion technology is necessary, but how with this technology effective application in the pain relieving plaster unguentum, how to solve the compatibility of medicine and substrate, rarely have research in the prior art.
Summary of the invention
The object of the invention is to disclose a kind of micro-emulsion type pharmaceutical composition gel ointment for pain relieving, the present invention also aims to disclose the preparation method of this micro-emulsion type pharmaceutical composition gel ointment.
The present invention seeks to be achieved by the following scheme.
The raw material of micro-emulsion type pharmaceutical composition gel ointment of the present invention consists of:
A phase: NP-700 1-3 weight portion, dihydroxyaluminum aminoacetate 0.05-0.12 weight portion, glycerol 8-15 weight portion, polyvinylpolypyrrolidone (PVPP) 0.10-0.50 weight portion;
B phase: tartaric acid 0.05-0.12 weight portion, disodiumedetate (EDTA-Na
2) 0.01-0.04 weight portion, water 2-6 parts by volume;
Microemulsion phase-C phase:
Oil phase Borneolum Syntheticum: 0.10-0.40 weight portion mixed volatilization oil: 0.20-0.80 parts by volume;
Surfactant tween 80: 1.50-3.20 weight portion;
Cosurfactant dehydrated alcohol: 0.80-1.80 weight portion;
Water Rhizoma Chuanxiong, the thick extractum 0.5-2 of Radix Angelicae Dahuricae percolate parts by volume,
Pericarpium Zanthoxyli, the thick extractum 0.5-2 of Herba Asari water extract-alcohol precipitation liquid parts by volume,
Density is 2-6gmL under the room temperature
-1
Wherein, described NP-700 refers to the polyacrylic acid that part is neutralized, and directly buys from market.
The raw material composition of micro-emulsion type pharmaceutical composition gel ointment of the present invention is preferably:
A phase: NP-700 2 weight portions, dihydroxyaluminum aminoacetate 0.08 weight portion, glycerol 12 weight portions, PVPP 0.30 weight portion;
B phase: tartaric acid 0.08 weight portion, EDTA-Na
20.02 weight portion, water 4 parts by volume;
Microemulsion phase-C phase:
Oil phase Borneolum Syntheticum: 0.25 weight portion mixed volatilization oil: 0.50 parts by volume;
Surfactant tween 80: 2.33 weight portions;
Cosurfactant dehydrated alcohol: 1.31 weight portions;
Water Rhizoma Chuanxiong, thick extractum 1 parts by volume of Radix Angelicae Dahuricae percolate,
Pericarpium Zanthoxyli, thick extractum 1 parts by volume of Herba Asari water extract-alcohol precipitation liquid,
Density is 4gmL under the room temperature
-1
The raw material composition of micro-emulsion type pharmaceutical composition gel ointment of the present invention is preferably:
A phase: NP-700 1.5 weight portions, dihydroxyaluminum aminoacetate 0.10 weight portion, glycerol 14 weight portions, PVPP 0.15 weight portion;
B phase: tartaric acid 0.06 weight portion, EDTA-Na
20.03 weight portion, water 5 parts by volume;
Microemulsion phase-C phase:
Oil phase Borneolum Syntheticum: 0.15 weight portion mixed volatilization oil: 0.70 parts by volume;
Surfactant tween 80: 3.03 weight portions;
Cosurfactant dehydrated alcohol: 0.90 weight portion;
Water Rhizoma Chuanxiong, thick extractum 0.6 parts by volume of Radix Angelicae Dahuricae percolate,
Pericarpium Zanthoxyli, thick extractum 1.8 parts by volume of Herba Asari water extract-alcohol precipitation liquid,
Density is 5gmL under the room temperature
-1
The raw material composition of micro-emulsion type pharmaceutical composition gel ointment of the present invention is preferably:
A phase: NP-700 2.5 weight portions, dihydroxyaluminum aminoacetate 0.06 weight portion, glycerol 10 weight portions, PVPP 0.55 weight portion;
B phase: tartaric acid 0.11 weight portion, EDTA-Na
20.02 weight portion, water 3 parts by volume;
Microemulsion phase-C phase:
Oil phase Borneolum Syntheticum: 0.35 weight portion mixed volatilization oil: 0.30 parts by volume;
Surfactant tween 80: 1.63 weight portions;
Cosurfactant dehydrated alcohol: 1.70 weight portions;
Water Rhizoma Chuanxiong, thick extractum 1.8 parts by volume of Radix Angelicae Dahuricae percolate,
Pericarpium Zanthoxyli, thick extractum 0.6 parts by volume of Herba Asari water extract-alcohol precipitation liquid,
Density is 3gmL under the room temperature
-1
The preparation method of micro emulsion gel unguentum of the present invention comprises the steps:
Borneolum Syntheticum is added in the mixed volatilization oil, magnetic agitation adds tween 80, dehydrated alcohol after making fully dissolving, magnetic agitation is even, press accurate Rhizoma Chuanxiong, the thick extractum of Radix Angelicae Dahuricae percolate and Pericarpium Zanthoxyli, the thick extractum of Herba Asari water extract-alcohol precipitation liquid of adding of recipe quantity, after magnetic agitation 10--20 minute, namely get the pharmaceutical composition microemulsion phase again---the C phase; After dihydroxyaluminum aminoacetate is uniformly dispersed with glycerol, add NP-700, Glass rod stirs, add PVPP, continue to stir, add again the C phase, after the stirring, add the B phase, continue to stir after 10--20 minute, coating, room temperature is placed 4h, cover separate paper, can make micro-emulsion type pharmaceutical composition gel ointment of the present invention.
Wherein, above-mentioned mixing time is all preferred 15 minutes.
The pass of above-mentioned weight portion and parts by volume is g/ml or kg/l.
Wherein, Rhizoma Chuanxiong, the thick extractum of Radix Angelicae Dahuricae percolate are prepared from by the following method: get 20 purpose Rhizoma Chuanxiongs, each 80-120 weight portion of angelica root powder, add 20-40 times of weight 80-90% ethanol, soak after 20-40 hour, 0.5-1.5 parts by volume/min percolation extracts; Percolate 40-60 ℃ is concentrated into the thick extractum that is equivalent to crude drug 2-6g/ml, for subsequent use.
Wherein, Rhizoma Chuanxiong, the thick extractum of Radix Angelicae Dahuricae percolate preferably are prepared from by the following method: get 20 purpose Rhizoma Chuanxiongs, each 100 weight portion of angelica root powder, add 30 times of weight, 86% ethanol, soak after 30 hours, 1 parts by volume/min percolation extracts; 50 ℃ of percolates are concentrated into the thick extractum that is equivalent to crude drug 4g/ml, and are for subsequent use.
Wherein, Pericarpium Zanthoxyli, the thick extractum of Herba Asari water extract-alcohol precipitation liquid are prepared from by the following method: get Pericarpium Zanthoxyli 200-300 weight portion, Herba Asari 100-200 weight portion adds the water of 5-12 times of weight, extracts 2-6 hour, namely gets Pericarpium Zanthoxyli, Herba Asari volatile oil; 40-60 ℃ of water extraction liquid is concentrated into and is equivalent to crude drug 0.5-1.5 times of weight, and with 40-80% ethanol precipitation 20-30 hour, alcohol deposit fluid filtration under diminished pressure, filtrate 40-60 ℃ is concentrated into the thick extractum that is equivalent to crude drug 2-6g/mL, for subsequent use.
Wherein, Pericarpium Zanthoxyli, the thick extractum of Herba Asari water extract-alcohol precipitation liquid preferably are prepared from by the following method: get Pericarpium Zanthoxyli 250 weight portions, Herba Asari 150 weight portions add 8 times of weight water, extract 4 hours, namely get Pericarpium Zanthoxyli, Herba Asari volatile oil; 50 ℃ of water extraction liquid are concentrated into and are equivalent to crude drug 1 times of weight, and with 60% ethanol precipitation 24 hours, alcohol deposit fluid filtration under diminished pressure, 50 ℃ of filtrates are concentrated into the thick extractum that is equivalent to crude drug 4g/mL, and are for subsequent use.
The raw material of mixed volatilization oil consists of: Pericarpium Zanthoxyli, Herba Asari volatile oil: 2-4 parts by volume, Oleum menthae: 1-parts by volume, Oleum Terebinthinae: 3-7 parts by volume.
The raw material composition of mixed volatilization oil is preferably: Pericarpium Zanthoxyli, Herba Asari volatile oil: 3 parts by volume, Oleum menthae: 2 parts by volume, Oleum Terebinthinae: 5 parts by volume.
Micro-emulsion type pharmaceutical composition gel ointment of the present invention surface is without " bellding " phenomenon, and the compatibility in volatile ingredient and the gel ointment between the water-soluble base is improved; The Transdermal absorption experimental result shows that the microemulsion form has promoted the Transdermal absorption of pharmaceutical composition gel ointment Imperatorin, makes the Transdermal absorption degree of itself and ferulic acid close, and the microemulsion form can be impelled the synchronous Transdermal absorption of the composition of different in kind; Three kinds of form pharmaceutical composition gel ointment primary stability experimental results show that the microemulsion form is conducive to strengthen the stability of volatile ingredient in the prescription.
Figure of description:
Fig. 1: the investigation of transdermal receiving liquid;
Fig. 2: three kinds of form gel ointment Imperatorin Transdermal absorption curve charts;
Fig. 3: Percutaneous Absorption of Ferulic Acic curve chart in three kinds of form gel ointments;
Fig. 4: micro-emulsion type pain relieving gel ointment imperatorin and Percutaneous Absorption of Ferulic Acic curve chart;
Fig. 5: micelle-type pain relieving gel ointment imperatorin and Percutaneous Absorption of Ferulic Acic curve chart;
Fig. 6: former pain relieving gel ointment imperatorin and Percutaneous Absorption of Ferulic Acic curve chart.
Following experimental example and embodiment are used for further specifying but are not limited to the present invention.
Experimental example 1 and 2 employed instruments, material, animal are distinguished as follows:
1, instrument
Electronic balance (BSA224S Sai Duolisi); Magnetic stirring apparatus (85-2 constant temperature blender with magnetic force); Nanometer particle size analyzer (Malvern) LC-20AT high performance liquid chromatograph (Shimadzu International Trading Company Ltd); TP-3A type ZTY intelligence transdermal tester (Yuhua Instrument Co., Ltd., Gongyi City), Agilent 7890A type gas chromatograph, Agilent 7683B injector, Agilent work station; CX2100 type ultrasonic cleaner (Beijing Medical Equipment Plant)
2, material
Tween 80 (Tween-80 analytical pure, Beijing Yili Fine Chemicals Co., Ltd., lot number 20080929); Arlacel-80 (Span-80 analytical pure, Guangdong. chemical plant, Gansu Province, west, Shantou, lot number 0508312); Dehydrated alcohol, (analytical pure, Beijing Chemical Plant); 1,2-PD (analytical pure, Beijing Chemical Plant); Glycerol (analytical pure, Beijing Chemical Plant); PEG-400 (analytical pure, Tianjin recovery fine chemistry industry institute); Polyoxyethylene castor oil 35 (EL-35) (German BASF AG, lot number 31267875L0); Polyoxyethylene hydrogenated Oleum Ricini 40 (RH-40) (German BASF AG, lot number 45727668E0); Pericarpium Zanthoxyli Herba Asari volatile oil (self-control); Borneolum Syntheticum; Oleum menthae (Jishui County, Jiangxi Province water south prestige despot medicinal oil refinery, lot number 20091230); Oleum Terebinthinae (Shantou Xilong Chemical Factory, lot number 060104), NP-700 (medicinal, American I SP company provides); Dihydroxyaluminum aminoacetate (medicinal, American I SP company provides); Aluminum chloride (Tianjin recovery fine chemistry industry institute); Aluminium hydroxide (Tianjin recovery fine chemistry industry institute); Tartaric acid (Tianjin good fortune chemical reagent factory in morning); EDTA-Na
2(Beijing Chemical Plant), sodium chloride (Beijing Chemical Plant) zinc oxide (the safe chemical reagent company limited in Shen, Tianjin) sodium carboxymethyl cellulose (Beijing Chemical Plant)
3, animal
The ICR mice (20 ± 1.0g), Beijing Vital River Experimental Animals Technology Co., Ltd.'s (licence numbering: SCXK (capital) 2006-0009)
Experimental example 1: the research of micro-emulsion type pharmaceutical composition gel ointment prescription
One, in the micro-emulsion type pharmaceutical composition gel ointment of the present invention gel ointment substrate on the impact of microemulsion
Gel ointment substrate: NP-700, aluminium hydroxide, tartaric acid, aluminum chloride, dihydroxyaluminum aminoacetate, EDTA-Na
2Wherein NP-700 is 50% polyacrylic acid and the polymer of 50% sodium polyacrylate, has preferably water solublity.
At first according to behind the embodiment 1 described method pharmaceutical compositions microemulsion, add respectively the substrate of above-mentioned gel ointment, place stir on the magnetic stirring apparatus after, place a period of time and observe.The results are shown in Table 1.
Table 1 gel ointment substrate is on the impact of microemulsion
By finding out in the table, microemulsion is thick after adding NP-700, is difficult to judge whether to cause the microemulsion breakdown of emulsion; Other substrate do not cause the microemulsion breakdown of emulsion, pharmaceutical composition microemulsion of the present invention can be prepared into gel ointment.
Two, pharmaceutical composition microemulsion of the present invention is on the impact of gel ointment performance
According to the former blank substrate formula preparation of prior art gel ointment, write out a prescription such as following table:
The former blank substrate prescription of table 2 prior art gel ointment
After at first aluminium hydroxide being uniformly dispersed with glycerol, add NP-700, stir, for subsequent use; With tartaric acid, aluminum chloride with 20% dissolve with ethanol after, for subsequent use; To be added to by the C of embodiment 1 preparation A mutually in, rear the addings B phase that stirs stirs, coating is placed under room temperature, the performance of observation gel ointment.
Found that, ooze immediately the cloth phenomenon after the prepared gel ointment coating.Therefore, blank substrate prescription needs further to improve.
Three, the research of micro-emulsion type pharmaceutical composition gel ointment prescription of the present invention
The cloth phenomenon occurs oozing because the pharmaceutical composition microemulsion phase joins in the substrate of prior art gel ointment, it is as follows to analyze reason: the impact of (1) gel ointment prescription mesostroma; (2) impact of preparation temperature; According to the possible cause of analyzing, carry out following a few part experiment.
1, the investigation of preparation temperature
Preparation temperature: 20 ℃, 25 ℃, 30 ℃, 35 ℃
Take by weighing 4 parts of the pharmaceutical composition microemulsion phase of embodiment 1 preparation and above-mentioned two described substrate, prepare gel ointment respectively under above-mentioned 4 temperature, coating is observed and is oozed the cloth phenomenon, the results are shown in Table 3.
Table 3 preparation temperature is investigated the result
The result shows, under above-mentioned 4 preparation temperature conditions, gel ointment all has the cloth of oozing phenomenon, as seen, preparation temperature is not the reason that causes gel ointment to ooze cloth, and the gel ointment viscosity for preparing under above-mentioned 4 temperature and peel strength be obviously difference not, therefore, to the preparation temperature of micro-emulsion type pain relieving gel ointment, do not do special requirement, preparation gets final product under the room temperature.
2, the NP-700 consumption is on the impact of micro-emulsion type pharmaceutical composition gel ointment performance
(1) method: in the constant situation of other substrates quantities of the former basic prescription of above-mentioned two described prior aries, change the consumption of NP-700, test.
(2) experimental design and result see Table 4.
Table 4 different N P-700 consumption experimental program and experimental result table
Experimental result shows, increase along with the NP-700 consumption, viscosity strengthens, and when the NP-700 consumption increased to 4.00g, the cloth phenomenon of oozing of gel ointment alleviated to some extent, viscosity and peel strength are fine, but when the consumption of NP-700 continued to increase, viscosity was strong especially, and peel strength is very poor, consider, change the consumption of NP-700 in the prescription into 4.00g.
3, the glycerol consumption is on the impact of micro-emulsion type pharmaceutical composition gel ointment performance
(1) method: in the constant situation of other substrates quantities of the former basic prescription of above-mentioned two described prior aries, change the consumption of glycerol, test.
(2) experimental design and result see Table 5.
Table 5 different glycerol consumption experimental program and experimental result table
The result shows that along with the increase of glycerol consumption, the mouldability of gel ointment is very poor, and is coalescent agglomerating, chooses it with Glass rod, do not have filament, and viscosity is bad, and coating is poor, and that strengthens that the glycerol consumption do not improve gel ointment oozes the cloth phenomenon.
4, dosage of crosslinking agent is on the impact of micro-emulsion type pharmaceutical composition gel ointment performance
(1) method: in the constant situation of other substrates quantities of the former basic prescription of above-mentioned two described prior aries, change the consumption of cross-linking agent (aluminium hydroxide and aluminum chloride), test.
(2) experimental design and experimental result see Table 6.
The investigation experimental program of table 6 dosage of crosslinking agent and experimental result table
Experimental result shows, along with the increase of dosage of crosslinking agent, that does not improve gel ointment oozes the cloth phenomenon, and strengthens the consumption of cross-linking agent, crosslinked too fast when the preparation gel ointment, is unfavorable for next step coating.
Above-mentioned experiment is investigated the consumption of the main matrix that affects the gel ointment performance, found that problem that gel ointment oozes cloth do not have be improved significantly; If be that medicine is not prepared into the microemulsion form and prepares gel ointment according to former technique, find not occur oozing the cloth phenomenon, gel ointment viscosity, fissility are all better, after inferring that medicine is prepared into microemulsion, contain a large amount of surfactants and cosurfactant, compare with original prescription, addition increases greatly, may surpass the drug loading of blank substrate; Also might be the performance that medicine is prepared into has affected cross-linking agent after the microemulsion form, so that the hydraulic performance decline of gel ointment, thereby the cloth phenomenon has appearred oozing.Therefore, intend improving blank substrate prescription.
5, different blank substrate prescriptions are on the impact of micro-emulsion type pharmaceutical composition gel ointment performance of the present invention
(1) drafting blank substrate writes out a prescription as follows:
A phase: NP-700 2g, dihydroxyaluminum aminoacetate 0.08g, glycerol 12g
B phase: tartaric acid 0.08g, EDTA-Na
20.02g, water 4mL
(2) experimental technique: by above prescription precision weighing, glycerol is added in the beaker of the 50mL that fills dihydroxyaluminum aminoacetate, then add NP-700, stir, be the A phase; Precision takes by weighing tartaric acid and EDTA-Na
2, place the beaker of 50mL to add water 4mL and make its dissolving, be the B phase; Then C phase (by the microemulsion phase of embodiment 1 preparation) join A mutually in, stir, then slowly add the B phase, the limit edged stirs, until after B solution adds, continue to stir 15min with Glass rod, mastic is coated on the back lining materials of 5 * 12cm, room temperature is placed, and whether observe has the cloth of oozing phenomenon.
(3) experimental result, micro-emulsion type pharmaceutical composition gel ointment is when firm coating is complete, the cloth phenomenon does not appear oozing, after continuing again to place a period of time, the slight cloth phenomenon of oozing appears again, but compare with the blank substrate prescription in prior art Central Plains, oozing the cloth phenomenon has had improvement to a certain degree.
Next attempt in the substrate of gel ointment adding suitable adhesion-promoting/thick dose and filler and improve the embossability of substrate, thus improve gel ointment ooze the cloth phenomenon.
6, filler is on the impact of micro-emulsion type pharmaceutical composition gel ointment performance of the present invention
Adopt zinc oxide and Kaolin to investigate.Experimental design sees Table 7.
Table 7 filler is investigated the experimental program table
The result shows, in micro-emulsion type pain relieving gel ointment prescription, add filler after, had a strong impact on the mouldability of micro-emulsion type pain relieving gel ointment, gel ointment can not molding, what add that filler fails to improve gel ointment oozes the cloth phenomenon.
7, thickening agent is on the impact of micro-emulsion type pharmaceutical composition gel ointment performance of the present invention
Thickening agent commonly used in the gel ointment has copolyvidone (PVPP), sodium carboxymethyl cellulose (CMC-Na) etc., and this experiment adopts these two kinds of thickening agents to investigate, and experimental design sees Table 8.
Table 8 thickening agent is investigated the experimental program table
Experimental result shows that behind the adding CMC-Na, micro-emulsion type pain relieving gel ointment still exists and oozes the cloth phenomenon; After in micro-emulsion type pain relieving gel ointment, adding PVPP, the cloth phenomenon does not appear oozing, further study the consumption of PVPP.
8, single factor is investigated the consumption of PVPP
(1) experimental design: keep the consumption of other substrate of the former basic prescription of above-mentioned two described prior aries constant, according to NP-700: PVPP=1: 0.05,1: 0.1,1: 0.15,1: 0.20,1: 0.25 ratio is investigated.Concrete experimental design sees Table 9.
The single factor of table 9 is investigated PVPP consumption experimental program table
(2) evaluation index: fissility, viscosity, whether ooze cloth
Fissility: cover separate paper, can peel off easily with separate paper, not adhesion person: 10 minutes; Be easier to peel off, and not adhesion person: 8 minutes; Can peel off fully, small amount adhesion person is arranged: 6 minutes; Can not peel off fully, a small amount of adhesion person is arranged: 4 minutes; The a large amount of adhesion can not adhesion person: 2 minutes.
Viscosity: skin is subjects, viscosity the greater: 10 minutes; Secondly: 8 minutes; Be bonded at and do not fall the person on the skin: 6 minutes; Viscosity smaller: 4 minutes; Substantially inviscid: 2 minutes.
(3) experimental result sees Table 10.
The single factor method of table 10 is investigated the consumption experimental result table of PVPP
In experimentation, find, cloth is not only oozed in No. 1, No. 2 tests, and fissility is bad, No. 3, No. 4, No. 5 not obviously differences, guaranteeing that gel ointment does not ooze cloth, in the good situation of viscosity, the consumption of PVPP is as far as possible few, comprehensive These parameters result, the addition of PVPP and the ratio of NP-700 be 1: 0.15 o'clock more suitable.
9, respectively be added to the investigation of order
Substrate prescription (NP-700 2.00g, dihydroxyaluminum aminoacetate 0.08g, glycerol 12g, PVPP0.30g according to screening; Tartaric acid 0.08g, EDTA-Na
20.02g; Microemulsion phase), add microemulsion phase in the described prescription ratio of embodiment 1, contrived experiment is determined the addition sequence of each phase.
Method one: glycerol adds NP-700, dihydroxyaluminum aminoacetate is the A phase, and water tartarize, EDTA-Na2 are the B phase, B be added to A mutually in, add again C phase (microemulsion phase).B → A+ microemulsion phase.Phenomenon and result: matrix-forming, performance is general, has microemulsion to separate out after placement a period of time.
Method two: with C phase (microemulsion phase) join A mutually in, for the B phase, again B is added to the A phase after tartaric acid, EDTA-Na2 be dissolved in water.(microemulsion phase → A) → (tartaric acid, EDTA-Na2 → water are B).Phenomenon and result: mastic color homogeneous, separate out without granule; Matrix-forming, viscosity, fissility are all better.
10, the investigation of micro-emulsion type pharmaceutical composition gel ointment drug loading
Substrate prescription (NP-700 2.00g, dihydroxyaluminum aminoacetate 0.08g, glycerol 12g, PVPP0.30g by screening; Tartaric acid 0.08g, EDTA-Na
20.02g; Microemulsion phase) and respectively be added to the form order, progressively increase the volume of microemulsion phase, experimental result sees Table 11.
Definite result of table 11 micro-emulsion type pain relieving gel ointment drug loading
Result: determine that this drug loading of substantially writing out a prescription is the 35.00g crude drug, namely add the 6.7mL microemulsion phase, by experiment as seen, along with increasing of the microemulsion phase volume that adds, the mastic color deepens gradually, the cream amount increases gradually, mastic thickens, when the microemulsion that adds be increased to a certain amount of after, the cloth phenomenon appears oozing in gel ointment, and hydraulic performance decline can not satisfy the requirement of molding.
Four, conclusion
According to above-mentioned experimental result, the prescription that optimizes at last the gel ointment of micro-emulsion type pharmaceutical composition of the present invention is:
A phase: NP-700 2g, dihydroxyaluminum aminoacetate 0.08g, glycerol 12g, PVPP 0.30g
B phase: tartaric acid 0.08g, EDTA-Na
20.02g, water 4mL
C phase: Borneolum Syntheticum 0.25g, mixed volatilization oil 0.50mL, Tween-80 2.33g, dehydrated alcohol 1.31g, the white percolate (4gmL in river
-1), Pericarpium Zanthoxyli Herba Asari extracting solution (4gmL
-1) each 1mL.
Preparation method: at first Borneolum Syntheticum is added in the mixed volatilization oil, magnetic agitation adds Tween-80 after making fully dissolving, the dehydrated alcohol magnetic agitation is even, and precision pipettes the medical material concentrated solution, magnetic agitation (C phase) for subsequent use after 15 minutes; After dihydroxyaluminum aminoacetate is uniformly dispersed with glycerol, add NP-700, Glass rod stirs, add PVPP, continue to stir, add again the C phase, after the stirring, add the B phase, continue to stir after 15 minutes coating, room temperature is placed 4h, cover separate paper, get final product, the gel ointment surface of the micro-emulsion type pharmaceutical composition that makes is without " bellding " phenomenon.
The research of 2: three kinds of form pharmaceutical compositions of experimental example gel ointment Transdermal absorption
One, the preparation of three kinds of form pharmaceutical composition gel ointments
1, the former pharmaceutical composition gel ointment prescription of prior art:
A phase: NP-700 2g, dihydroxyaluminum aminoacetate 0.08g, glycerol 12g, PVPP 0.30g
B phase: tartaric acid 0.08g, EDTA-Na
20.02g, water 4mL
C phase: the white percolate (4gmL in river
-1), Pericarpium Zanthoxyli Herba Asari extracting solution (4gmL
-1) each 1mL
D phase: Borneolum Syntheticum 0.25g, mixed volatilization oil 0.50mL, dehydrated alcohol 2mL
Preparation method: A (NP700, glycerol, dihydroxyaluminum aminoacetate) is stirred rear ultrasonic degas, D (Borneolum Syntheticum, volatile oil) is added to A stirs mutually.Behind C (the thick extractum of the Rhizoma Chuanxiong Radix Angelicae Dahuricae, the thick extractum of Pericarpium Zanthoxyli Herba Asari) phase mix homogeneously, add A and stir mutually with D, the ultrasonic degas bubble.With B (tartaric acid, EDTA-Na
2) behind the phase mixing, add A, D, C phase, to stir to proper viscosity and coat on the non-woven fabrics of 5 * 12cm, room temperature is placed 4h, adds a cover separate paper, gets final product.
2, micro-emulsion type pharmaceutical composition gel ointment prescription of the present invention:
A phase: NP-700 2g, dihydroxyaluminum aminoacetate 0.08g, glycerol 12g, PVPP 0.30g
B phase: tartaric acid 0.08g, EDTA-Na
20.02g, water 4mL
C phase: Borneolum Syntheticum 0.25g, mixed volatilization oil 0.50mL, Tween-80 2.33g, dehydrated alcohol 1.31g, the white percolate (4gmL in river
-1), Pericarpium Zanthoxyli Herba Asari extracting solution (4gmL
-1) each 1mL.
Preparation method: at first Borneolum Syntheticum is added in the mixed volatilization oil, after magnetic agitation made the rear Tween-80 of adding of fully dissolving, dehydrated alcohol, magnetic agitation was even, and precision pipettes each 1mL of medical material concentrated solution, magnetic agitation (C phase) for subsequent use after 15 minutes; After dihydroxyaluminum aminoacetate is uniformly dispersed with glycerol, add NP-700, Glass rod stirs, and adds PVPP, continues to stir, and adds the C phase again, after the stirring, adds the B phase, continue to stir after 15 minutes, and coating, room temperature is placed 4h, covers separate paper, gets final product.
3, micelle-type drug composition gel ointment prescription:
A phase: NP-700 2g, dihydroxyaluminum aminoacetate 0.08g, glycerol 12g, PVPP 0.30g
B phase: tartaric acid 0.08g, EDTA-Na
20.02g, water 4mL
C phase: Borneolum Syntheticum 0.25g, mixed volatilization oil 0.50mL, Tween-80 2.33g, water 2mL, the white percolate (4gmL in river
-1), Pericarpium Zanthoxyli Herba Asari extracting solution (4gmL
-1) each 1mL.
Preparation method: at first Borneolum Syntheticum is added in the mixed volatilization oil, magnetic agitation adds Tween-80 after making fully dissolving, hydromagnetic power stirs, and precision pipettes the medical material concentrated solution, magnetic agitation (C phase) for subsequent use after 15 minutes; After dihydroxyaluminum aminoacetate is uniformly dispersed with glycerol, add NP-700, Glass rod stirs, and adds PVPP, continues to stir, and adds the C phase again, after the stirring, adds the B phase, continue to stir after 15 minutes, and coating, room temperature is placed 4h, covers separate paper, gets final product.
Two, the preparation of rat skin in vitro
Get male mice (body weight 20 ± 1.0g), after the execution, smear immediately depilatory cream (starch: soap powder: Na2S=7: 1: 3, add water furnishing pasty state) depilation, clean with normal saline and clear water, get skin of abdomen, peel off fat deposit, normal saline flushing places refrigerator (20 ℃) to preserve with the valve bag sealing for several times, and is for subsequent use.Take out during test, naturally thaw under the room temperature, and the integrity of visual examination Corium Mus, any breakage can not be arranged.
Three, the investigation of transdermal receiving liquid
Use respectively normal saline (A), 50% ethanol normal saline (B), 30% ethanol normal saline (C), 20% ethanol normal saline (D), 0.5%SDS normal saline (E), 10%PEG-400 normal saline (F), 20%PEG-400 normal saline (G), 30%PEG-400 normal saline (H) to be receiving liquid, getting the gel ointment of same type tests according to " 2.5.2 " lower operation, investigate take imperatorin 24h unit are accumulation transit dose as index, and in experimentation, observe the state of skin.The results are shown in Table 12, Fig. 1.
1, transdermal experiment method
Adopt rectilinear improved Franz diffusing cells method to measure, this diffusion cell is involuted by two tubular glass tubings up and down, and the skin that is sandwiched between glass is divided into up and down two Room with it.Upper chamber is diffuser casing, and lower chamber is receiving chamber, on the right side of receiving chamber one probe tube is arranged, and for sample introduction, sampling and aerofluxus bubble, the reception tank volume is 17mL, and effectively diffusion area is 3.14cm
2, before the experiment skin to be taken out, room temperature is placed 30min, during experiment, receiving chamber is filled it up with receiving liquid, and the mice Pericarpium Arecae is clipped between two Room, horny layer is affixed on gel ointment on the mice Pericarpium Arecae towards diffuser casing, and backing layer is towards diffuser casing, be fixed between two Room, get rid of bubble, the water bath with thermostatic control heating, the temperature precision is controlled at 37 ℃ ± 0.2 ℃, start magnetic stirring apparatus, rotating speed 300rmin
-1, when 24h, the receiving liquid in the receiving chamber is all poured out, with the receiving liquid evaporate to dryness, add methanol constant volume to 5mL, carry out assay according to the lower method of " 2.3.1 " item, according to formula Q (mgcm
-2)=(V * Cn)/A, calculate imperatorin 24h unit are accumulation transit dose Q; In the formula: Cn is the concentration (mgmL that 24h records
-1), V=5mL, A are diffusion cell area (3.14cm
2).
2, experimental result
The investigation of table 12 transdermal receiving liquid
Can be found out by Fig. 1 and table 12, when adopting 30% ethanol normal saline to be receiving liquid, imperatorin 24h accumulation transit dose is maximum, 50% ethanol takes second place, and by the observation to skin, the normal saline that contains PEG-400 is receiving liquid, zest less to skin, but the amount of the imperatorin that records is very little, during research transdermal Uptake kinetics, can not provide sufficient sink conditions; During take the 0.5%SDS normal saline as receiving liquid, skin is dissolved, and SDS is too large to the zest of skin; Although take the normal saline that contains ethanol during as receiving liquid, to exist certain zest from observing in appearance skin, but found through experiments, can obtain good penetration curve and kinetic parameter when adopting the normal saline that contains ethanol to be receiving liquid in conjunction with bibliographical information.Therefore the normal saline solution of selecting 30% ethanol is the penetration kinetics research that receiving liquid is carried out main effective ingredient.
Four, the research of three kinds of form pharmaceutical composition gel ointment Imperatorins, Percutaneous Absorption of Ferulic Acic dynamic characteristic
Adopt improved Franz diffusing cells method to measure, take 30% ethanol normal saline as receiving liquid, getting the gel ointment of three kinds of forms tests according to " 2.5.2 " lower operation, respectively 2,4,6,8,12, the accurate receiving liquid 1mL that draws during 24h, sample introduction is measured, add simultaneously the fresh receiving liquid with volume, because of acceptable solution continuous sampling and the blank acceptable solution of each adding, make measured value little than actual value, the data that recorded by high performance liquid chromatogram are by following various the processing, and draw the transdermal penetration curve, the results are shown in Table 13-18; Fig. 2,3.
Qn＝Cn′*V/W
Cn ' is the actual penetrating concentration (mgmL of t time medicine
-1)
Cn is the mensuration concentration (mgmL of t time medicine
-1)
Qn is accumulative total transdermal percentage rate (%) in the t time
V is acceptable solution cumulative volume (17mL)
W is the content (mg) of three kinds of medicament forms gel ointment Imperatorins, ferulic acid
Table 13 micro emulsion gel unguentum Imperatorin Transdermal absorption result
Table 14 micelle gel ointment Imperatorin Transdermal absorption result
Table 15 original shape gel ointment Imperatorin Transdermal absorption result
Percutaneous Absorption of Ferulic Acic result in the table 16 micro emulsion gel unguentum
Percutaneous Absorption of Ferulic Acic result in the table 17 micelle gel ointment
Percutaneous Absorption of Ferulic Acic result in the table 18 original shape gel ointment
Adopt SAS8.2 respectively three kinds of form pharmaceutical composition gel ointment Imperatorins and ferulic acid 24h accumulation to be carried out statistical procedures through percentage rate, the SNK multiple comparison analyse is the result show, imperatorin 24h accumulation transdermal percentage rate, maximum with micro-emulsion type pharmaceutical composition gel ointment of the present invention, be 52.87%; Significant difference (P＜0.05) is all arranged between micro-emulsion type pharmaceutical composition gel ointment and former pharmaceutical composition gel ointment, the micelle-type gel ointment; Former pharmaceutical composition gel ointment is compared there was no significant difference with the micelle-type gel ointment; Ferulic acid 24h accumulation sees through percentage rate there was no significant difference (P＞0.1) in three kinds of form gel ointments.
The result shows, microemulsion form can promote the to write out a prescription Transdermal absorption of Imperatorin.
Five, imperatorin and Percutaneous Absorption of Ferulic Acic similarity evaluation
Take sampling time point as abscissa, it is the vertical coordinate mapping that imperatorin, ferulic acid 24h accumulation see through percentage rate, and according to formula f
2=50 * lg{1+100 * [1+ (1/n) ∑
n T=1(R
t-T
t)
2]
-0. 5, calculate imperatorin and ferulic acid at the percentile similarity of each sample point accumulation transdermal, usually f
2Value just can conclude that greater than 50 the experiment composition is similar to the release profiles of reference composition, and n counts R the testing time in the formula
tAnd T
tBe respectively at the reference composition of t time point and the average transdermal percentage rate of experiment composition.Experimental result is seen Fig. 4,5,6, table 19,20,21.
Table 19 micro emulsion gel unguentum imperatorin and Percutaneous Absorption of Ferulic Acic similarity evaluation result
Table 20 micelle gel ointment imperatorin and Percutaneous Absorption of Ferulic Acic similarity evaluation result
Table 21 original shape gel ointment imperatorin and Percutaneous Absorption of Ferulic Acic similarity evaluation result
Intuitively observe from the graph, compare with former pharmaceutical composition gel ointment, micelle-type gel ointment, each sample point imperatorin of micro-emulsion type gel ointment of the present invention and the percentile difference of ferulic acid accumulation Transdermal absorption are very little, and imperatorin and ferulic acid are close at each sample point Transdermal absorption percentage rate; The data result that adopts similar factors to calculate shows that micro-emulsion type gel ointment Imperatorin is similar to the percentage comparisons of ferulic acid accumulation Transdermal absorption on the whole, f
2＞50, the similarity of other two kinds of form gel ointment imperatorin and ferulic acid accumulation Transdermal absorption is very poor, f
2All less than 50, the result shows that micro-emulsion type pharmaceutical composition gel ointment of the present invention promotes the Transdermal absorption of imperatorin, and is close with the Percutaneous Absorption of Ferulic Acic percentage rate, so that the Transdermal absorption of two kinds of compositions of different in kind has synchronicity in the prescription.
Six, imperatorin and Percutaneous Absorption of Ferulic Acic penetration kinetics models fitting
Above data are carried out models fitting, for pharmacokinetic studies in its follow-up body provides reference.The results are shown in Table 22-27.
Table 22 micro-emulsion type pharmaceutical composition gel ointment Imperatorin Transdermal absorption models fitting
Table 23 micelle-type drug composition gel ointment Imperatorin Transdermal absorption models fitting
The former pharmaceutical composition gel ointment of table 24 Imperatorin Transdermal absorption models fitting
Percutaneous Absorption of Ferulic Acic models fitting in the table 25 micro-emulsion type pharmaceutical composition gel ointment
Percutaneous Absorption of Ferulic Acic models fitting in the table 26 micelle gel ointment
Percutaneous Absorption of Ferulic Acic models fitting in the former pharmaceutical composition gel ointment of table 27
The result shows that micro-emulsion type pharmaceutical composition gel ointment Imperatorin Transdermal Absorption of the present invention and Monoexponential distribution equation dependency are best, fit equation be ln (1-Q)=-0.0281t-0.0722, r
2=0.9908, ferulic acid Transdermal Absorption and Weibull distribution equation dependency are best, and fit equation is ln (1/ (1-Q))=0.5369lnt-0.2164, r
2=0.9645; Former pharmaceutical composition gel ointment Imperatorin Transdermal Absorption and First-order equation dependency are best, and fit equation is lnQ=0.4920lnt-2.8756, r
2=0.9966, Percutaneous Absorption of Ferulic Acic is also best with the First-order equation dependency, and fit equation is lnQ=0.4831lnt-1.5392, r
2=0.9389; Micelle-type gel ointment Imperatorin Transdermal Absorption and First-order equation dependency are best, and fit equation is lnQ=0.5547lnt-2.9948, r
2=0.9861, ferulic acid Transdermal Absorption and First-order equation dependency are best, and fit equation is lnQ=0.4831lnt-1.5392, r
2=0.9758.
Seven, methyleugenol, content of bornyl alcohol stability study in three kinds of form pharmaceutical composition gel ointments
1, experimental program
(blow-by) placement condition under the open condition: laying temperature: room temperature, standing time: 3 months,
0,1,2, March minute:
Airtight (simulation finished product packing) placement condition: laying temperature: room temperature, standing time: 10 days,
Minute: 0,5,10 days
2, experimental result
Micro emulsion gel unguentum under table 28 open condition
Micelle gel ointment under table 29 open condition
Former gel ointment under table 30 open condition
Micro emulsion gel unguentum under table 31 airtight condition
Micelle gel ointment under table 32 airtight condition
Former gel ointment under table 33 airtight condition
Experimental result shows, under open state and under the dummy packages placement condition, methyleugenol content is compared with former pharmaceutical composition gel ointment in the micro-emulsion type pharmaceutical composition gel ointment of the present invention, the decline degree alleviates to some extent, and the micro-emulsion type gel ointment has certain Stabilization to methyleugenol.
Micro-emulsion type pharmaceutical composition gel ointment under table 34 open condition
Micelle-type drug composition gel ointment under table 35 open condition
Former pharmaceutical composition gel ointment under table 36 open condition
Micro-emulsion type pharmaceutical composition gel ointment under the table 37 dummy packages condition
Micelle-type gel ointment under the table 38 dummy packages condition
Former pharmaceutical composition gel ointment under the table 39 dummy packages condition
Experimental result shows, under open state and under the dummy packages placement condition, content of bornyl alcohol is compared with former pharmaceutical composition gel ointment in the micro-emulsion type pharmaceutical composition gel ointment of the present invention, and the decline degree alleviates to some extent, and the micro-emulsion type gel ointment has certain Stabilization to Borneolum Syntheticum.
Experimental example 3: micro emulsion gel unguentum of the present invention and prior art unguentum drug effect are relatively
Analgesic activity to mice
1, experiment material
The ICR mice (20 ± 10g), Beijing Vital River Experimental Animals Technology Co., Ltd.'s (licence numbering: SCXK (capital) 2006-0009); Micro emulsion gel unguentum of the present invention (preparing by embodiment 1), ZHUANGGU SHEXIANG ZHITONG GAO (Henan Lingrui Pharmacy Stock Co., Ltd, lot number: 100623), Medical adhesive plaster (the sharp hygienic material company limited of Beijing antelope, lot number: 20100929).
2, method and result
(1) on the impact of the white mice threshold of pain due to the hot plate
Mice is divided into five groups at random, positive controls, blank matrix group, micro emulsion gel unguentum group of the present invention, ZHUANGGU SHEXIANG ZHITONG GAO, Medical adhesive plaster group.At first 60 of mices are placed on respectively on the thermometal plate of 55 ± 015 ℃ of temperature, from the mice rear foot touch hot plate to the time till the metapedes of licking as threshold of pain index, the white mice of reaction in 25s is eligible in the threshold of pain, select that the pain sensation is quick on the draw and 50 stable of mices are used for experiment, be divided at random 5 groups, every group 10, measure normal pain threshold 2 times, getting its average is the normal pain threshold of white mice.The threshold of pain changed before and after 24h measured administration after administration.
(2) impact of white mice writhing response due to the Dichlorodiphenyl Acetate
Hot plate method is measured the white mice behind the threshold of pain, the acetic acid of lumbar injection 0.7% again, and injected dose 0.1mL/10g, the writhing number of times of record mice in 15min estimated the analgesic effect of medicine.
(3) experimental result: see Table 40,41.
Table 40 is on the impact of the hot plate induced mice threshold of pain
The impact of table 41 Dichlorodiphenyl Acetate induced mice writhing response
The result: hot plate method and writhing method show that all two kinds of prior art medicament forms of micro emulsion gel unguentum of the present invention and other compare relieving pain and strengthen.
Following embodiment all can realize the described effect of above-mentioned experimental example.
Embodiment 1: micro-emulsion type pharmaceutical composition gel ointment of the present invention
A phase: NP-700 2kg, dihydroxyaluminum aminoacetate 0.08kg, glycerol 12kg, PVPP 0.30kg;
B phase: tartaric acid 0.08kg, EDTA-Na
20.02kg, water 4L;
Microemulsion phase-C phase:
Oil phase Borneolum Syntheticum: 0.25kg mixed volatilization oil: 0.50L;
Surfactant tween 80: 2.33kg;
Cosurfactant dehydrated alcohol: 1.31kg;
Water Rhizoma Chuanxiong, the thick extractum 1L of Radix Angelicae Dahuricae percolate,
Pericarpium Zanthoxyli, the thick extractum 1L of Herba Asari water extract-alcohol precipitation liquid,
Density is 4gmL under the room temperature
-1
Wherein, described NP-700 refers to the polyacrylic acid that part is neutralized, and directly buys from market.
Wherein, Rhizoma Chuanxiong, the thick extractum of Radix Angelicae Dahuricae percolate preferably are prepared from by the following method: get 20 purpose Rhizoma Chuanxiongs, each 100 weight portion of angelica root powder, add 30 times of weight, 86% ethanol, soak after 30 hours, 1 parts by volume/min percolation extracts; 50 ℃ of percolates are concentrated into the thick extractum that is equivalent to crude drug 4g/ml, and are for subsequent use.
Wherein, Pericarpium Zanthoxyli, the thick extractum of Herba Asari water extract-alcohol precipitation liquid preferably are prepared from by the following method: get Pericarpium Zanthoxyli 250 weight portions, Herba Asari 150 weight portions add 8 times of weight water, extract 4 hours, namely get Pericarpium Zanthoxyli, Herba Asari volatile oil; 50 ℃ of water extraction liquid are concentrated into and are equivalent to crude drug 1 times of weight, and with 60% ethanol precipitation 24 hours, alcohol deposit fluid filtration under diminished pressure, 50 ℃ of filtrates are concentrated into the thick extractum that is equivalent to crude drug 4g/mL, and are for subsequent use.
The raw material composition of mixed volatilization oil is preferably: Pericarpium Zanthoxyli, Herba Asari volatile oil: 3 parts by volume, Oleum menthae: 2 parts by volume, Oleum Terebinthinae: 5 parts by volume.
Preparation method comprises the steps:
Borneolum Syntheticum is added in the mixed volatilization oil, magnetic agitation adds tween 80, dehydrated alcohol after making fully dissolving, magnetic agitation is even, press accurate Rhizoma Chuanxiong, the thick extractum of Radix Angelicae Dahuricae percolate and Pericarpium Zanthoxyli, the thick extractum of Herba Asari water extract-alcohol precipitation liquid of adding of recipe quantity, magnetic agitation namely got the pharmaceutical composition microemulsion phase after 15 minutes again---the C phase; After dihydroxyaluminum aminoacetate is uniformly dispersed with glycerol, add NP-700, Glass rod stirs, and adds PVPP, continues to stir, add again the C phase, after the stirring, add the B phase, continue to stir after 15 minutes, coating, room temperature is placed 4h, covers separate paper, can make micro-emulsion type pharmaceutical composition gel ointment of the present invention.
Embodiment 2: micro-emulsion type pharmaceutical composition gel ointment of the present invention
A phase: NP-700 1.5kg, dihydroxyaluminum aminoacetate 0.10kg, glycerol 14kg, PVPP 0.15kg;
B phase: tartaric acid 0.06kg, EDTA-Na
20.03kg, water 5L;
Microemulsion phase-C phase:
Oil phase Borneolum Syntheticum: 0.15kg mixed volatilization oil: 0.70L;
Surfactant tween 80: 3.03kg;
Cosurfactant dehydrated alcohol: 0.90kg;
Water Rhizoma Chuanxiong, the thick extractum 0.6L of Radix Angelicae Dahuricae percolate,
Pericarpium Zanthoxyli, the thick extractum 1.8L of Herba Asari water extract-alcohol precipitation liquid,
Density is 5gmL under the room temperature
-1
Wherein, described NP-700 refers to the polyacrylic acid that part is neutralized, and directly buys from market.
Wherein, Rhizoma Chuanxiong, the thick extractum of Radix Angelicae Dahuricae percolate preferably are prepared from by the following method: get 20 purpose Rhizoma Chuanxiongs, each 100 weight portion of angelica root powder, add 30 times of weight, 86% ethanol, soak after 30 hours, 1 parts by volume/min percolation extracts; 50 ℃ of percolates are concentrated into the thick extractum that is equivalent to crude drug 4g/ml, and are for subsequent use.
Wherein, Pericarpium Zanthoxyli, the thick extractum of Herba Asari water extract-alcohol precipitation liquid preferably are prepared from by the following method: get Pericarpium Zanthoxyli 250 weight portions, Herba Asari 150 weight portions add 8 times of weight water, extract 4 hours, namely get Pericarpium Zanthoxyli, Herba Asari volatile oil; 50 ℃ of water extraction liquid are concentrated into and are equivalent to crude drug 1 times of weight, and with 60% ethanol precipitation 24 hours, alcohol deposit fluid filtration under diminished pressure, 50 ℃ of filtrates are concentrated into the thick extractum that is equivalent to crude drug 4g/mL, and are for subsequent use.
The raw material composition of mixed volatilization oil is preferably: Pericarpium Zanthoxyli, Herba Asari volatile oil: 3 parts by volume, Oleum menthae: 2 parts by volume, Oleum Terebinthinae: 5 parts by volume.
Preparation method comprises the steps:
Borneolum Syntheticum is added in the mixed volatilization oil, magnetic agitation adds tween 80, dehydrated alcohol after making fully dissolving, magnetic agitation is even, press accurate Rhizoma Chuanxiong, the thick extractum of Radix Angelicae Dahuricae percolate and Pericarpium Zanthoxyli, the thick extractum of Herba Asari water extract-alcohol precipitation liquid of adding of recipe quantity, magnetic agitation namely got the pharmaceutical composition microemulsion phase after 15 minutes again---the C phase; After dihydroxyaluminum aminoacetate is uniformly dispersed with glycerol, add NP-700, Glass rod stirs, and adds PVPP, continues to stir, add again the C phase, after the stirring, add the B phase, continue to stir after 15 minutes, coating, room temperature is placed 4h, covers separate paper, can make micro-emulsion type pharmaceutical composition gel ointment of the present invention.
Embodiment 3: micro-emulsion type pharmaceutical composition gel ointment of the present invention
A phase: NP-700 2.5kg, dihydroxyaluminum aminoacetate 0.06kg, glycerol 10kg, PVPP 0.55kg;
B phase: tartaric acid 0.11kg, EDTA-Na
20.02kg, water 3L;
Microemulsion phase-C phase:
Oil phase Borneolum Syntheticum: 0.35kg mixed volatilization oil: 0.30L;
Surfactant tween 80: 1.63kg;
Cosurfactant dehydrated alcohol: 1.70kg;
Water Rhizoma Chuanxiong, the thick extractum 1.8L of Radix Angelicae Dahuricae percolate,
Pericarpium Zanthoxyli, the thick extractum 0.6L of Herba Asari water extract-alcohol precipitation liquid,
Density is 3gmL under the room temperature
-1
Wherein, described NP-700 refers to the polyacrylic acid that part is neutralized, and directly buys from market.
Wherein, Rhizoma Chuanxiong, the thick extractum of Radix Angelicae Dahuricae percolate preferably are prepared from by the following method: get 20 purpose Rhizoma Chuanxiongs, each 100 weight portion of angelica root powder, add 30 times of weight, 86% ethanol, soak after 30 hours, 1 parts by volume/min percolation extracts; 50 ℃ of percolates are concentrated into the thick extractum that is equivalent to crude drug 4g/ml, and are for subsequent use.
Wherein, Pericarpium Zanthoxyli, the thick extractum of Herba Asari water extract-alcohol precipitation liquid preferably are prepared from by the following method: get Pericarpium Zanthoxyli 250 weight portions, Herba Asari 150 weight portions add 8 times of weight water, extract 4 hours, namely get Pericarpium Zanthoxyli, Herba Asari volatile oil; 50 ℃ of water extraction liquid are concentrated into and are equivalent to crude drug 1 times of weight, and with 60% ethanol precipitation 24 hours, alcohol deposit fluid filtration under diminished pressure, 50 ℃ of filtrates are concentrated into the thick extractum that is equivalent to crude drug 4g/mL, and are for subsequent use.
The raw material composition of mixed volatilization oil is preferably: Pericarpium Zanthoxyli, Herba Asari volatile oil: 3 parts by volume, Oleum menthae: 2 parts by volume, Oleum Terebinthinae: 5 parts by volume.
Preparation method comprises the steps:
Borneolum Syntheticum is added in the mixed volatilization oil, magnetic agitation adds tween 80, dehydrated alcohol after making fully dissolving, magnetic agitation is even, press accurate Rhizoma Chuanxiong, the thick extractum of Radix Angelicae Dahuricae percolate and Pericarpium Zanthoxyli, the thick extractum of Herba Asari water extract-alcohol precipitation liquid of adding of recipe quantity, magnetic agitation namely got the pharmaceutical composition microemulsion phase after 15 minutes again---the C phase; After dihydroxyaluminum aminoacetate is uniformly dispersed with glycerol, add NP-700, Glass rod stirs, and adds PVPP, continues to stir, add again the C phase, after the stirring, add the B phase, continue to stir after 15 minutes, coating, room temperature is placed 4h, covers separate paper, can make micro-emulsion type pharmaceutical composition gel ointment of the present invention.
Claims (10)
1. micro-emulsion type pharmaceutical composition gel ointment is characterized in that the raw material of this gel ointment consists of:
A phase: NP-700 1-3 weight portion, dihydroxyaluminum aminoacetate 0.05-0.12 weight portion, glycerol 8-15 weight portion, PVPP 0.10-0.50 weight portion;
B phase: tartaric acid 0.05-0.12 weight portion, EDTA-Na
20.01-0.04 weight portion, water 2-6 parts by volume;
Microemulsion phase-C phase:
Oil phase Borneolum Syntheticum: 0.10-0.40 weight portion mixed volatilization oil: 0.20-0.80 parts by volume;
Surfactant tween 80: 1.50-3.20 weight portion;
Cosurfactant dehydrated alcohol: 0.80-1.80 weight portion;
Water Rhizoma Chuanxiong, the thick extractum 0.5-2 of Radix Angelicae Dahuricae percolate parts by volume,
Pericarpium Zanthoxyli, the thick extractum 0.5-2 of Herba Asari water extract-alcohol precipitation liquid parts by volume,
Density is 2-6gmL under the room temperature
-1
2. gel ointment as claimed in claim 1 is characterized in that the raw material of this gel ointment consists of:
A phase: NP-700 2 weight portions, dihydroxyaluminum aminoacetate 0.08 weight portion, glycerol 12 weight portions, PVPP 0.30 weight portion;
B phase: tartaric acid 0.08 weight portion, EDTA-Na
20.02 weight portion, water 4 parts by volume;
Microemulsion phase-C phase:
Oil phase Borneolum Syntheticum: 0.25 weight portion mixed volatilization oil: 0.50 parts by volume;
Surfactant tween 80: 2.33 weight portions;
Cosurfactant dehydrated alcohol: 1.31 weight portions;
Water Rhizoma Chuanxiong, thick extractum 1 parts by volume of Radix Angelicae Dahuricae percolate,
Pericarpium Zanthoxyli, thick extractum 1 parts by volume of Herba Asari water extract-alcohol precipitation liquid,
Density is 4gmL under the room temperature
-1
Or
A phase: NP-700 1.5 weight portions, dihydroxyaluminum aminoacetate 0.10 weight portion, glycerol 14 weight portions, PVPP 0.15 weight portion;
B phase: tartaric acid 0.06 weight portion, EDTA-Na
20.03 weight portion, water 5 parts by volume;
Microemulsion phase-C phase:
Oil phase Borneolum Syntheticum: 0.15 weight portion mixed volatilization oil: 0.70 parts by volume;
Surfactant tween 80: 3.03 weight portions;
Cosurfactant dehydrated alcohol: 0.90 weight portion;
Water Rhizoma Chuanxiong, thick extractum 0.6 parts by volume of Radix Angelicae Dahuricae percolate,
Pericarpium Zanthoxyli, thick extractum 1.8 parts by volume of Herba Asari water extract-alcohol precipitation liquid,
Density is 5gmL under the room temperature
-1
Or
A phase: NP-700 2.5 weight portions, dihydroxyaluminum aminoacetate 0.06 weight portion, glycerol 10 weight portions, PVPP 0.55 weight portion;
B phase: tartaric acid 0.11 weight portion, EDTA-Na
20.02 weight portion, water 3 parts by volume;
Microemulsion phase-C phase:
Oil phase Borneolum Syntheticum: 0.35 weight portion mixed volatilization oil: 0.30 parts by volume;
Surfactant tween 80: 1.63 weight portions;
Cosurfactant dehydrated alcohol: 1.70 weight portions;
Water Rhizoma Chuanxiong, thick extractum 1.8 parts by volume of Radix Angelicae Dahuricae percolate,
Pericarpium Zanthoxyli, thick extractum 0.6 parts by volume of Herba Asari water extract-alcohol precipitation liquid,
Density is 3gmL under the room temperature
-1
3. such as the arbitrary described gel ointment of claim 1-2, it is characterized in that wherein said Rhizoma Chuanxiong, the thick extractum of Radix Angelicae Dahuricae percolate are prepared from by the following method: get 20 purpose Rhizoma Chuanxiongs, each 80-120 weight portion of angelica root powder, add 20-40 times of weight 80-90% ethanol, soak after 20-40 hour, 0.5-1.5 parts by volume/min percolation extracts; Percolate 40-60 ℃ is concentrated into the thick extractum that is equivalent to crude drug 2-6g/ml, for subsequent use.
4. gel ointment as claimed in claim 3, it is characterized in that wherein said Rhizoma Chuanxiong, the thick extractum of Radix Angelicae Dahuricae percolate are prepared from by the following method: get 20 purpose Rhizoma Chuanxiongs, each 100 weight portion of angelica root powder, add 30 times of weight, 86% ethanol, soak after 30 hours, 1 parts by volume/min percolation extracts; 50 ℃ of percolates are concentrated into the thick extractum that is equivalent to crude drug 4g/ml, and are for subsequent use.
5. such as the arbitrary described gel ointment of claim 1-2, it is characterized in that wherein said Pericarpium Zanthoxyli, the thick extractum of Herba Asari water extract-alcohol precipitation liquid are prepared from by the following method: get Pericarpium Zanthoxyli 200-300 weight portion, Herba Asari 100-200 weight portion, the water that adds the 5-12 times of weight, extracted 2-6 hour, and namely got Pericarpium Zanthoxyli, Herba Asari volatile oil; 40-60 ℃ of water extraction liquid is concentrated into and is equivalent to crude drug 0.5-1.5 times of weight, and with 40-80% ethanol precipitation 20-30 hour, alcohol deposit fluid filtration under diminished pressure, filtrate 40-60 ℃ is concentrated into the thick extractum that is equivalent to crude drug 2-6g/mL, for subsequent use.
6. gel ointment as claimed in claim 5 is characterized in that wherein wherein saidly, and Pericarpium Zanthoxyli, the thick extractum of Herba Asari water extract-alcohol precipitation liquid are prepared from by the following method: get Pericarpium Zanthoxyli 250 weight portions, Herba Asari 150 weight portions, add 8 times of weight water, extracted 4 hours, namely get Pericarpium Zanthoxyli, Herba Asari volatile oil; 50 ℃ of water extraction liquid are concentrated into and are equivalent to crude drug 1 times of weight, and with 60% ethanol precipitation 24 hours, alcohol deposit fluid filtration under diminished pressure, 50 ℃ of filtrates are concentrated into the thick extractum that is equivalent to crude drug 4g/mL, and are for subsequent use.
7. such as the arbitrary described gel ointment of claim 1-2, it is characterized in that the raw material of wherein said mixed volatilization oil consists of: Pericarpium Zanthoxyli, Herba Asari volatile oil: 2-4 parts by volume, Oleum menthae: 1-parts by volume, Oleum Terebinthinae: 3-7 parts by volume.
8. gel ointment as claimed in claim 7 is characterized in that the raw material of wherein said mixed volatilization oil consists of: Pericarpium Zanthoxyli, Herba Asari volatile oil: 3 parts by volume, Oleum menthae: 2 parts by volume, Oleum Terebinthinae: 5 parts by volume.
9. such as the preparation method of the arbitrary described gel ointment of claim 1-8, it is characterized in that the method comprises the steps:
Borneolum Syntheticum is added in the mixed volatilization oil, magnetic agitation adds tween 80, dehydrated alcohol after making fully dissolving, magnetic agitation is even, press accurate Rhizoma Chuanxiong, the thick extractum of Radix Angelicae Dahuricae percolate and Pericarpium Zanthoxyli, the thick extractum of Herba Asari water extract-alcohol precipitation liquid of adding of recipe quantity, after magnetic agitation 10--20 minute, namely get the pharmaceutical composition microemulsion phase again---the C phase; After dihydroxyaluminum aminoacetate is uniformly dispersed with glycerol, add NP-700, Glass rod stirs, add PVPP, continue to stir, add again the C phase, after the stirring, add the B phase, continue to stir after 10--20 minute, coating, room temperature is placed 4h, cover separate paper, can make micro-emulsion type pharmaceutical composition gel ointment of the present invention.
10. the preparation method of gel mastic as claimed in claim 9 is characterized in that wherein said mixing time is 15 minutes.
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| CN102908441B (en) | 2014-07-16 |
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