CN102552916B - New uses of sodium salicylate - Google Patents
New uses of sodium salicylate Download PDFInfo
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- CN102552916B CN102552916B CN201010581178.1A CN201010581178A CN102552916B CN 102552916 B CN102552916 B CN 102552916B CN 201010581178 A CN201010581178 A CN 201010581178A CN 102552916 B CN102552916 B CN 102552916B
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- sodium salicylate
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- streptokinase
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- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 title claims abstract description 31
- 229960004025 sodium salicylate Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 51
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- 229960005202 streptokinase Drugs 0.000 claims abstract description 36
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- 208000014617 hemorrhoid Diseases 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 28
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- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 1
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- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了水杨酸钠的新用途，为将水杨酸钠作为外用制剂中促渗剂的用途，所述外用制剂为以重组链激酶为主要药效成分的治疗痔类疾病的外用制剂。本发明还进一步公开了一种治疗痔类疾病的外用制剂，其主药成分是浓度为80000IU—180000IU/g的重组链激酶，外用制剂还含有重量百分比含量为0.01—3%的水杨酸钠作为促渗剂。本发明采用水杨酸钠作为促渗剂制备的重组链激酶软膏，透皮效果佳，制备的外用制剂可用于治疗痔类疾病。The invention discloses a new use of sodium salicylate, which is the use of sodium salicylate as a penetration enhancer in an external preparation, and the external preparation is an external preparation for treating hemorrhoid diseases with recombinant streptokinase as the main medicinal component . The present invention further discloses an external preparation for treating hemorrhoids, the main ingredient of which is recombinant streptokinase with a concentration of 80,000IU-180,000IU/g, and the external preparation also contains sodium salicylate in an amount of 0.01-3% by weight as a penetration enhancer. The recombinant streptokinase ointment prepared by using sodium salicylate as a penetration enhancer has good transdermal effect, and the prepared external preparation can be used for treating hemorrhoid diseases.
Description
Technical field
The present invention relates to biotechnology and field of medical applications, be specifically related to sodium salicylate as purposes and the related application of penetrating agent in recombined streptokinase external preparation.
Background technology
Sodium salicylate is as a kind of conventional antipyretic-antalgic and non_steroidal anti_inflammatory drug, and its mechanism of action is similar to aspirin, by suppressing cyclooxygenase, reduces the synthetic of prostaglandin, plays antiinflammatory, rheumatism and antipyretic effect.Its antiinflammatory anti rheumatism action is similar to aspirin, but antipyretic, analgesic activity a little less than.
Recombined streptokinase is a kind of protein medicaments that adopts recombinant DNA technology to prepare, its mechanism of action is with 1: 1 mole ratio, to be combined into complex with plasminogen, then Plasminogen activation is become to fibrinolysin, the hydrolysis of fibrinolysin catalysis thrombosis main matrix fibrin, thereby effectively, thrombus specifically, reach the effect for the treatment of thrombotic disease.Current clinical use dosage form is lyophilized injectable powder, for revascularizations such as acute myocardial infarction, deep venous thrombosis, there is no the relevant report of its percutaneous dosing.
Hemorrhoid are one of the most common diseases that affect health of people and quality of life, are also one of recial diseases that in world wide, sickness rate is the highest, and the annual about amplitude with 16% of the sickness rate of China rises in recent years.At present, more than 90% hemorrhoid adopt non-operative treatment to treat conventionally.The medicament categories that is used for the treatment of hemorrhoid is more, and chemosynthesis class medicine mostly is peroral dosage form and easily causes the generation of Systemic reaction; Chinese medicine class suppository or ointment untoward reaction are light, mainly by heat-clearing and toxic substances removing, hemostasia and promoting granulation, reach the effect of reducing swelling and alleviating pain, but due to the course for the treatment of is long and drug withdrawal after easily repeatedly, and cause patient must long-term prescription can be effective; And suppository still has the inconvenience such as the discomfort of use, administration time limitation, and Comparatively speaking, the external preparation such as ointment or membrane are more easily accepted by patient.
Summary of the invention
The object of the invention is to overcome defect of the prior art, a kind of new purposes and related application of sodium salicylate is provided.
First the present invention discloses the purposes of sodium salicylate as penetrating agent in external preparation, and described external preparation is for take the external preparation of the treatment hemorrhoid class disease that recombined streptokinase is main pharmacodynamics composition.
Wherein, recombined streptokinase system is by the colibacillus of high efficient expression streptokinase genes, makes purity > 95% (HPLC method, electrophoresis method) through fermentation, after separated and highly purified.
Described hemorrhoid class disease refer under human body rectum end mucosa and anal canal skin under venous plexus there is expansion and the formed soft vein of flexing group, comprising internal hemorrhoid, external hemorrhoid, mixed hemorrhoid, is a kind of chronic disease of the vein group of the venous plexus generation varicose of anal orifice and rectal intestine bottom and anal mucosa and one or more softnesses of forming.
Further, the content of described sodium salicylate in external preparation is 0.01-3%, preferably 0.1-2.5%.
The present invention also further discloses a kind of external preparation for the treatment of hemorrhoid class disease, and its principal agent composition is that concentration is the recombined streptokinase of 80000IU-180000IU/g, preferably 100000IU-150000IU/g.Described external preparation also contain weight percent content be the sodium salicylate of 0.01-3% as penetrating agent, preferred 0.1-2.5%.
Described external preparation can be for percutaneous drug administration preparation or through tract mucosa delivery preparation, and further, described external preparation is ointment or suppository.
Because recombined streptokinase albumen exists molecular weight large, easy inactivation, easily degraded, be difficult for the defects such as transdermal penetration, preparation external preparation is in stability, permeability, the aspects such as absorbance are difficult for reaching requirement, after deliberation, the accessory formula of optimizing is by octadecanol, monoglyceride, vaseline, liquid Paraffin, glycerol, span, sodium salicylate and ethyl hydroxybenzoate are jointly as adjuvant, wherein, sodium salicylate is as penetrating agent, the external preparation of this optimization of C/C composites is in stability, permeability, absorbance aspect all does well, and local irritation, the adverse reaction rates such as anaphylaxis are extremely low.
As one of preferred version, the external preparation for the treatment of hemorrhoid class disease of the present invention is percutaneous dosing ointment, its principal agent composition is that concentration is the recombined streptokinase of 100000IU-150000IU/g, and described ointment comprises the adjuvant component gross weight of ointment (take be benchmark) of following weight percentage:
Octadecanol 5-20%
Monoglyceride 3-15%
Vaseline 2-20%
Liquid Paraffin 2-10%
Glycerol 5-10%
Span 0.5-2%
Ethyl hydroxybenzoate 0.05-0.5%
Sodium salicylate 0.1-2.5%.
Water for injection surplus
The preparation method of ointment of the present invention is:
1) by recipe quantity, take sterilized octadecanol, monoglyceride, vaseline, liquid Paraffin, span, ethyl hydroxybenzoate, heating makes complete melting, stirs evenly, and the decontamination that sieves, as decentralized photo I;
2) separately get a container, take sterilized glycerol, sodium salicylate and water for injection and mix, heating in water bath dissolves, and sieves, as decentralized photo II.
3) then, temperature is controlled to 70-80 ℃, adopts the method for vacuum homogenizing, make 1), 2) biphase mix and the particle diameter of emulsifying and microgranule is controlled at 200nm-3 μ m;
4) recombined streptokinase is carried out, after protein protection, through degerming, process;
5) by above-mentioned steps 3) emulsion that obtains is while continuing to stir and be cooled to 30-35 ℃, adds step 4) in treated principal agent composition recombined streptokinase, it is mixed, continuation is stirred and is naturally cooled to room temperature and obtains product.
The particle diameter of the ointment microgranule that above preparation method obtains is superfine, is easy to transdermal, improves absorbance; And in the present invention, used the penetrating agent sodium salicylate that is more suitable for recombined streptokinase, the concentration that makes principal agent arrive site of action improves greatly, and drug effect significantly strengthens.
As two of preferred version, the external preparation for the treatment of hemorrhoid class disease of the present invention is suppository, its principal agent composition is that concentration is the recombined streptokinase of 100000IU-150000IU/g, also comprises the adjuvant component gross weight of suppository (take be benchmark) of following weight percentage in described suppository:
Hydrogenation cocos nucifera oil glycerol mixed ester 75-95%
Span 0.5-2.0%
Ethyl hydroxybenzoate 0.05-0.5%
Sodium salicylate 0.1-2.5%
Water for injection surplus
The preparation method of suppository of the present invention is:
1) by recipe quantity, take sterilized hydrogenation cocos nucifera oil glycerol mixed ester, span, ethyl hydroxybenzoate, heating makes complete melting, stir evenly, and the decontamination that sieves, standby.
2) sodium salicylate is dissolved in to water for injection, after heating in water bath dissolves, this solution is added to above-mentioned 1) in mixture in, stir evenly.
3) recombined streptokinase is carried out, after protein protection, through degerming, process;
4) by above-mentioned steps 2) mixture that obtains is while continuing to stir and be cooled to 30-35 ℃, add step 3) in treated principal agent composition recombined streptokinase, stirring mixes it, is then filled in suppository mould, makes it naturally cool to room temperature and obtains product.
The recombined streptokinase that external preparation of the present invention adopts technique for gene engineering to prepare is raw material, through adding suitable penetrating agent, makes and absorbs the significant external preparation of good efficacy, and percutaneous or mucosa delivery are for the treatment of hemorrhoid class disease.
In the present invention, inventor applies recombined streptokinase ointment prepared by different penetrating agents and has carried out transdermal penetration test, and with do not add penetrating agent and carry out comparative study.Result shows, the recombined streptokinase ointment that adopts sodium salicylate to prepare as penetrating agent, and transdermal effect is best.
Ointment of the present invention, coats hemorrhoid surface by part, and through drug osmotic, the orientable blood stasis that acts on, makes that thromboembolism, hematoma melt, pain relief, has advantages of short treating period, evident in efficacy, untoward reaction rate is low.Owing to having adopted the method for vacuum homogenizing; make the microgranule of this ointment very tiny; and adopt protein protective agent to carry out pretreated recombined streptokinase; more stable in preparation; under the synergism of penetrating agent sodium salicylate; transdermal barrier very easily, through site of action, brings into play good drug effect.
Suppository of the present invention, by cavity/canal drug administration, under body normal body temperature, can soften rapidly melting, or be dissolved in juice, discharges medicine gradually and produces therapeutical effect, the treatment of the internal hemorrhoid of being more convenient for and mixed hemorrhoid.
The specific embodiment
Below enumerate specific embodiment further to set forth the present invention, should be understood that example is not for limiting the scope of the invention.
Embodiment 1 mice Transdermal absorption experimental study
Get healthy male mice in kunming, body weight 20-25g, its disconnected neck is put to death, with shears, the hair of abdominal part is cut off, and use scraper scraping, take off skin of abdomen, remove subcutaneous tissue and fat, check Corium Mus integrity (must not have any breakage), with normal saline, clean, be laid on aluminium foil, under-20 ℃ of conditions, save backup.
Adopt two-chamber osmotic disperser, isolated skin stratum corneum side upwards, is fixed between two Room.In receiving chamber, add appropriate protein stabilized buffer, with the speed of 300 revs/min, carry out magnetic agitation, a side connects updip pipeline, makes can supplement receiving liquid after sampling.In diffuser casing, add 1 * 10
5iU recombined streptokinase and different penetrating agents (in Table 1), evenly coat skin surface.Whole device is placed in 33 ℃ of waters bath with thermostatic control, and respectively at the 1st, 2,3,4,6,8h samples 3ml from receiving chamber, and supplementary equivalent is preheated to the buffer of 33 ℃, and sample is carried out to determining the protein quantity.Result demonstration, while adopting sodium salicylate as penetrating agent, recombined streptokinase transdermal penetration effect is best.
The percutaneous accumulation transit dose (mg/ml) of table 1 different formulations
The positive control drug effect research of embodiment 2 mice auricle swellings
Get 48 of regular grade Kunming mouses, every group 12, male and female half and half, be divided at random three test group, be respectively recombined streptokinase and add three kinds of different penetrating agents and normal saline group (negative control), get dimethylbenzene 0.05ml be evenly applied to the left ear of mice before and after two sides cause inflammation, after 0.5h, the mice of each test group, cause and on scorching auricle, evenly coat respectively equivalent recombined streptokinase and three kinds of different penetrating agents, penetrating agent concentration is with embodiment 1 (in Table 2), negative control group is coated normal saline, after 2 hours, mice cervical vertebra is put to death from disconnected, along auricle baseline, cut left and right ears, with 9mm card punch, at same position, take off an auricle respectively, on electronic balance, weigh, calculating two auricle weight differences is swelling, inhibitory rate of intumesce=(the average swelling of the average swelling-administration of normal saline group group)/average swelling * 100% of normal saline group
Result demonstration, recombined streptokinase adds that three test group of different penetrating agents all have detumescence effect, wherein, the improvement of the swelling degree of sodium salicylate group is obviously better than other test group.
The detumescence effect of table 2 different formulations
| Formula | Formula A | Formula B | Formula C | Negative control group |
| Penetrating agent | Sodium salicylate | Azone | Menthol | / |
| Inhibitory rate of intumesce | 1.84±0.21 | 1.70±0.24 | 1.35±0.22 | 0 |
The preparation of embodiment 3 recombined streptokinase ointments
According to the form below formula is prepared ointment
Preparation technology:
1) by recipe quantity, take sterilized octadecanol, monoglyceride, vaseline, liquid Paraffin, span, ethyl hydroxybenzoate, heating makes complete melting, stirs evenly, and the decontamination that sieves, as decentralized photo I;
2) separately get a container, take sterilized glycerol and sodium salicylate and mix, heating in water bath, sieves, as decentralized photo II.
3) then, temperature is controlled to 70-80 ℃, adopts the method for vacuum homogenizing, make 1), 2) biphase mix and the particle diameter of emulsifying and microgranule is controlled at 200nm-3 μ m;
4) recombined streptokinase is carried out, after protein protection, through degerming, process;
5) by the above-mentioned the 3rd) in emulsion while continuing to stir and to be cooled to 30-35 ℃, add the 4th) the treated principal agent composition of Xiang Zhongyi, it is mixed, continuation stirs and naturally cools to room temperature and get final product.
The pharmacodynamic study of pedal swelling model due to embodiment 4 rat carrageenans
Get 40 of rats, body weight 130-150g, is divided into 5 groups at random, and 10 every group, male and female half and half, give four kinds of preparations (prescription A, B, C, D) in embodiment 33 times in the coating of right back sufficient sole of the foot portion respectively, every minor tick 5 minutes.After last administration, measure each Mus foot sole of the foot thickness, then in its right back sufficient plantar subcutaneous injection 1% carrageenin 0.1ml/ only, cause after inflammation respectively within 1,2,3,4 hour, surveying sufficient sole of the foot thickness, swelling=(cause scorching metapedes sole of the foot thickness-cause scorching front foot sole of the foot thickness).
Result shows, four kinds of preparations all can on Carrageenan due to rat paw edema have inhibitory action, but the swelling degree of prescription A group (sodium salicylate group) is improved and is obviously better than other test group.
The drug effect comparison of table 3 different formulations
The preparation of embodiment 5 recombined streptokinase ointments
According to following table, adopt the method preparation ointment of embodiment 3
The preparation of embodiment 6 recombined streptokinase suppositorys
According to following table formula preparation suppository
The preparation method of suppository of the present invention is:
1) by recipe quantity, take sterilized hydrogenation cocos nucifera oil glycerol mixed ester, span, ethyl hydroxybenzoate, heating makes complete melting, stir evenly, and the decontamination that sieves, standby.
2) sodium salicylate is dissolved in to water for injection, after heating in water bath dissolves, this solution is added to above-mentioned 1) in mixture in, stir evenly.
3) recombined streptokinase is carried out, after protein protection, through degerming, process;
4) by above-mentioned steps 2) mixture that obtains is while continuing to stir and be cooled to 30-35 ℃, add step 3) in treated principal agent composition recombined streptokinase, stirring mixes it, is then filled in suppository mould, makes it naturally cool to room temperature and obtains product.
The pharmacodynamic study of embodiment 7 rat Oleum Tiglii anus swelling models
Get 50 of rats, body weight 200-250g, is divided into 5 groups at random, and 10 every group, male and female half and half, insert rat anus by Oleum Tiglii mixed liquor, keep somewhere certain hour, then in causing scorching rear different time, observes, to determine the most preferably parameters of living model.Through mixed liquor consumption, cotton balls inserts the anus retention time, the different condition screenings such as age in rat week, confirm that most preferably condition is as follows: the proportioning of Oleum Tiglii mixed liquor is, distilled water: pyridine: ether: 6% Oleum Tiglii=1: 4: 5: 10, consumption is 0.16ml, infiltrate 10 seconds of rat anal, 6 week age of inserting after cotton balls with ether light anaesthesia, after 6 hours, crissum swelling is obvious, histological observation is visible, tissue edema, serous coat also significantly swelling around under mucosa, normal mucosa wrinkle wall disappears, mucomembranous epithelial cell activity decreased, vasodilation under mucosa, and there are leukocyte and fibrin to infiltrate.
Adopt after above living model modeling, give respectively four kinds of preparations in embodiment 6 (prescription E, F, G, H), using blank substrate as negative control simultaneously.Before administration, after administration, within 1,2,4,6,8,10,12,24 hour, survey the diameter of whole anus surrounding tissue swelling, get the average of its length two diameters as the index of measured swelling degree, compare with blank substrate matched group.
Result demonstration, four kinds of preparations all can have significant inhibitory action (P < 0.05) to rat crissum swelling due to Oleum Tiglii, but the improvement of the swelling degree of prescription E group (sodium salicylate group) is obviously better than other test group.
The preparation of embodiment 8 recombined streptokinase suppositorys
According to following table, adopt the method preparation suppository of embodiment 6
Claims (4)
1. sodium salicylate is as the purposes of penetrating agent in external preparation, and described external preparation, for take the external preparation of the treatment hemorrhoid class disease that recombined streptokinase is main pharmacodynamics composition, is characterized in that, described external preparation is percutaneous drug administration preparation.
2. the purposes of sodium salicylate as claimed in claim 1, is characterized in that described external preparation is ointment.
3. an external preparation for the treatment of hemorrhoid class disease, it is characterized in that, described external preparation is percutaneous dosing ointment, and its principal agent composition is that concentration is the recombined streptokinase of 100000IU-150000IU/g, and described ointment comprises the adjuvant component of following weight percentage:
4. external preparation as claimed in claim 3, is characterized in that, described percutaneous dosing ointment adopts the method comprising the following steps to make:
1) by formula, take sterilized octadecanol, monoglyceride, vaseline, liquid Paraffin, span, ethyl hydroxybenzoate, heating makes complete melting, stirs evenly, and the decontamination that sieves, as decentralized photo I;
2) separately get a container, take sterilized glycerol, sodium salicylate and water for injection and mix, heating in water bath dissolves, and sieves, as decentralized photo II;
3) then, temperature is controlled to 70-80 ℃, adopts the method for vacuum homogenizing, make I, the biphase particle diameter that mixes also emulsifying and microgranule of II is controlled at 200nm-3 μ m;
4) recombined streptokinase is carried out, after protein protection, through degerming, process;
5) by above-mentioned steps 3) emulsion that obtains is while continuing stir and be cooled to 30-35 ℃, adds step 4) in treated principal agent composition recombined streptokinase, it is mixed, continue to stir and naturally cool to room temperature acquisition product.
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| Title |
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| 王洪钟等.皮肤渗透促进剂－氮卓酮及其同系物合成的研究.《日用化学工业》.1991,(第6期),第9-13页. * |
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