CN102935063A - Acetyl dithranol paste and preparation method thereof - Google Patents
Acetyl dithranol paste and preparation method thereof Download PDFInfo
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Abstract
The invention discloses acetyl dithranol paste and a preparation method thereof. The acetyl dithranol paste comprises, by mass, 0.12-1.20% of acetyl dithranol with the grain diameter from 10 mu m to 80 mu m and 98.80-99.88% of white Vaseline. The preparation method comprises steps of grinding the acetyl dithranol until the grain diameter is in a range from 10 mu m to 80 mum; heating and melting the white Vaseline, filtering the white Vaseline when the white Vaseline is hot, removing impurities, heating the white Vaseline at the temperature from 145 DEG C to 155 DEG C, preserving the temperature for 1-2 hours, conducting sterilization and removing water; and grinding and mixing a little white Vaseline and smashed acetyl dithranol when the temperature of the white Vaseline lowers to the range from 45 DEG C to 55 DEG C, adding the mixture to a residual substrate, stirring evenly for 15-30 minutes, mixing the main medicine and the substrate evenly, cooling, conducting solidification and obtaining the acetyl dithranol paste. The acetyl dithranol paste is uniform and smooth. The acetyl dithranol paste can be applied to the skin easily and the medicine is easy to absorb. Compared with acetyl dithranol paste in the market, the acetyl dithranol paste has identical curative effect and little side effect.
Description
Technical field
The present invention relates to a kind of acetyl Anthra-Derm and preparation method thereof.
Background technology
Psoriasis (psoriasis) is a kind of immune-mediated dermatosis of common chronic inflammation, can involve skin, mucosa, first, joint, it is between twenty and fifty that the patient mostly is, characteristics with the recurrence of being easy to, course of disease length, have a strong impact on patient's life, work and social activity, even discriminated against, caused moral injury.The white psoriasis prevalence in Europe is 2% left and right, and the prevalence of the U.S. is 4.6%.China's investigation in 1984 finds that psoriatic prevalence is 0.123%.Along with various factorss such as urbanization process quickening, environmental pollution, social competition's aggravations, Chinese psoriatic prevalence increases year by year.According to Shanxi province Taiyuan city, Xichang City, Sichuan Province, Hebei province's Langfang City, Henan Province's Jiaozuo City, Zibo City, Shandong Province and Inner Mongolia Autonomous Region Hailar City Epidemiologic Study of Psoriasis result demonstration in totally six different geographical cities in 2010, it was 0.47% that current psoriatic prevalence has increased.Estimate that the existing disease patient of current China psoriasis has surpassed 3,000,000 people, because this disease is the irregular hereditary of polygenes excited by inside and outside triggering factors on the basis of genetic background, present stage radical cure primary disease is difficult.Therefore inquire into safe and effectively, prolonged application has no side effect and is cheap, the medicine easy to use particular importance that just seems.
The study hotspot for the treatment of psoriasis is biological preparation both at home and abroad at present, although such medicine is effective, expensive, annual medical expense each patient is over 10,000 yuan.In psoriatic all polytherapies, the medicine for external use treatment is one of most important treatment means, for most of patients, selecting properly and use medicine for external use can make the state of an illness be effectively controlled and even alleviate, and regrettably still lack at present a kind of desirable external used medicine.Existing anti-psoriasis medicine for external use mainly comprises following a few class: glucocorticoid, vitamin D-derivatives, tar class, tretinoin and dithranol.Although said medicine is effective, have following shortcoming: the glucocorticoid external can cause the local skin atrophy, telangiectasis, folliculitis etc., and large-area applications also may cause systemic Absorption and produce the system side effect, even makes state of an illness aggravation; The tar class causes the patient and is difficult to accept because its intrinsic abnormal flavour and greasy dirt can not get effectively overcoming; Vitamin D-derivatives is domestic still can not be produced, dependence on import, and expensive being difficult to promotes; Tretinoin medicines has obvious stimulation and photosensitization.
Dithranol (Dithranol) has another name called anthraline (Anthralin), dithranol, trade name Se Genuolin (Cignolin), chemical name 1,8-dihydroxy-9-anthrone, for the anthracyclinone derivatives of synthetic, being used for the treatment of psoriasis has had the history of 92 years.It is effective that at first Balmanno Squire in 1876 reports that chrysophanic acid (Chrysopha-nic acid) ointment is used for the treatment of psoriasis, chrysophanic acid, from the goa contained in Brazilian araroba timber (Goa powder), confirms that the effective ingredient in goa is Purified Goa powder (Chrysarobin) later.Galewsky in 1916 etc. have synthesized dithranol for psoriatic treatment.Dithranol is strong reductant, has by the synthetic inhibition of minimizing DNA epidermal cell proliferation, induces the epithelial cell differentiation, makes the performances such as Some Related Enzymes in skin lesion recovers normally, anti-inflammatory treat psoriatic effects
[1].
Dithranol is unstable, in the dark gets final product autoxidation, at daylight, ultraviolet radiation, be exposed to the speed that can obviously accelerate oxidation under air, high temperature, alkaline environment.Main oxidation product is 1,8-istizin, dithranol dimer and anthraquinone dimer.1,8-istizin is still unstable, can be further oxided.Through more senior dimerization and multimerization, it is stable and soluble that the dithranol derivant becomes.In the middle of it, product is considered to have anti-psoriasis activity as dithranol anion, dithranol free radical and oxygen-cent red radical, is also the reason of zest erythema simultaneously
[2].
Dithranol plays a role the strongest at epidermis, external dithranol white vaseline ointment is in psoriatic lesion after 60 minutes, and the overwhelming majority 1,8-istizin and a small amount of dithranol dimer and dithranol are gathered in the psoriatic lesion epidermis.Erythema occurred after the normal skin contact after 48～72 hours, and can continue 1 week, some individuality or high doses applied, just there will be erythema in 24 hours, within 48 hours, occur infiltrating, and this acute reaction is relevant with the release of inflammatory mediator.Studies confirm that, alkali phosphatase is the affected labelling of inflammatory process blood capillary, is also the most effective labelling of dithranol inflammatory reaction.Antihistaminic or NSAID (non-steroidal anti-inflammatory drug) can not change the inflammatory reaction of dithranol.Its media type caused inflammation still awaits illustrating.The absorbance that the dithranol percutaneous enters blood is very low, mainly with the form of oxidation product, from urine, discharges
[2-3].
Since the 1980s, domestic and international many scholars have carried out the research of finding the dithranol derivant, find that 10-butyryl dithranol does not have the side effect of obvious chafe and dyeing, basic research shows that 10-butyryl dithranol has the effect similar to dithranol, but also there is no up till now the report of 10-butyryl dithranol preparation as the new drug listing, illustrate that its curative effect awaits checking.Theoretically, dithranol derivant side chain is longer, and chemical constitution is more stable, and zest is less, but curative effect is less.The synthetic less dithranol derivant of side chain of research has actual meaning
[4-5].
It is the synthetic 10-acetyl dithranol of raw material that dithranol, chloroacetic chloride are take in domestic packway inscription etc. in 1984
[6], application mass spectral analysis (MS), infrared spectrum analysis (IR) reach
1The H nuclear magnetic resonance spectroscopy (the hydrogen spectrum,
1HMR), determined its structural formula
[7]The curative effect of selecting ointment dosage form and having observed 10-acetyl dithranol, find that 10-acetyl Anthra-Derm curative effect is similar to the Anthra-Derm effect, but the untoward reaction of stimulation and dyeing obviously reduces
[8].But, above-mentioned ointment is only the curative effect difference of having investigated merely raw material, do not investigate for various raw material and the adjuvant factors that affect the ointment drug effect, therefore provide the acetyl Anthra-Derm agent that a kind of bioavailability is high, clinical efficacy is definite, side effect is little to have great importance.
List of references:
[1] Zhang Furen. the anti-psoriasis mechanism of anthraline and the progress of clinical practice thereof. foreign medical science dermatological fascicle, 1989,15 (5): 261-264.
[2]Mustakallio?KK.Irritation，staining?and?antipsoriatic?activity?of?10-acyl?analogues?ofanthralin.Br?J?Dermatol，1981，105(Suppl?20)：23-27.
[3]Mustakallio?KK.Irritation?and?staining?by?dithranol(anthralin)and?related?compounds：I.Estimation?with?chamber?testing?and?contact?thermography.Acta?Derm?Venereol?Suppl(Stockh).1979，59(85)：125-132.
[4]Mustakallio?KK.Irritation?and?staining?by?dithranol(anthralin)and?related?compounds：II.Structure?activity?relationships?among?10-meso-substituted?acyl?analogues.Acta?DermVenereol.1980；60(2)：169-171.
[5]Wiegrebe?W，Muller?K.Treatment?of?psoriasis?with?anthrones-chemical?principles，biochemical?aspects，and?approaches?to?the?design?of?novel?derivatives.SkinPharmccol，1995，8(1)：1-24.
[6] packway inscription, Wang Li jasmine .10-10-acetylanthralin synthetic. medical industry, 1984,15 (10): 4-6.
[7] packway inscription, Wang Lili, chromatography and the stability study thereof of the flourish .10-10-acetylanthralin in river and anthraline. medical industry, 1987,18 (1): 13-15.
[8] Shao Changgeng, the packway inscription, Wang Lili, wait the research relatively of the anti-psoriasis curative effect of .10-10-acetylanthralin ointment and anthralin Ointment. clinical department of dermatologry magazine, 1984,13 (6): 12-13.
Summary of the invention
The purpose of this invention is to provide a kind of acetyl Anthra-Derm agent and preparation method thereof.
Acetyl Anthra-Derm provided by the present invention agent, be comprised of the raw material of following quality percentage composition: acetyl dithranol 0.12-1.20% and white vaseline 98.80-99.88%; The particle diameter of described acetyl dithranol is 10-80 μ m.
The agent of described acetyl Anthra-Derm specifically can be divided into three kinds of specifications: acetyl dithranol content 0.12%, 0.6%, 1.2%.
Prepare the method for above-mentioned acetyl Anthra-Derm agent, comprise the steps:
1) get the acetyl dithranol and be crushed to particle diameter and be 10-80 μ m, standby;
2) get after the white vaseline heating and melting and filter while hot, remove impurity; And then be heated to 145-155 ℃ of insulation and within 1-2 hour, carry out sterilizing and remove moisture, standby;
3) treat that the white vaseline temperature is down to 45-55 ℃, get acetyl dithranol quality 5-20 described white vaseline (substrate) doubly and step 1) principal agent (acetyl dithranol) mixed grinding after pulverizing, then join in remaining substrate, homogenizing stirs 15～30 minutes, make principal agent mix homogeneously and be cooled to substrate and solidify, obtain the agent of acetyl Anthra-Derm.
Described method also comprises acetyl Anthra-Derm agent content is checked; The step of fill, packing, full inspection.
Acetyl Anthra-Derm provided by the invention agent is oil ointment.The acetyl dithranol is principal agent, and white vaseline is oil adjuvant, is applied on skin and can forms the closure oil film, promotes the skin hydration effect, and epidermis is had to softening and protective effect; This type of substrate is not corrupt, easy bacteria-developing not, and prescription is simple, and technological process is simple, and cost is low.
Pharmacodynamic study shows, acetyl Anthra-Derm low dose group (0.15%) prepared by the present invention, middle dosage group (0.3%), (0.6%) three dosage group of high dose group all are formed with significant facilitation to granular layer in the mouse tail scale, the scale digital display work of granular layer are arranged more than the blank group.The effect that the acetyl Anthra-Derm forms granular layer strengthens with the increase of dosage.The acetyl Anthra-Derm can make keratinization of epidermis entirely not transfer to normally.0.03%, 0.06%, 0.12% group of acetyl dithranol wax bar has inhibitory action to mouse vagina epithelial cell mitosis, and strengthens with the increase inhibitory action of dosage.0.12% acetyl dithranol wax bar has therapeutical effect to the paraplasm of epidermis cell.SD rat and miniature pig acetyl Anthra-Derm single-dose toxicity test result show: animal is showed no obvious general toxic reaction, and administration place skin is visible minimal irritation all, and zest can take a turn for the better voluntarily or recover.SD rat and miniature pig percutaneous give the acetyl Anthra-Derm 90 days repetitively administered toxicity tests, dyeing in various degree occurs, with matched group, compare, and each administration treated animal indices is showed no significant difference.
In sum, its curative effect of acetyl Anthra-Derm prepared by the present invention is not less than Anthra-Derm, and zest and dyeing side effect are lighter, good market prospects.This acetyl Anthra-Derm is even, and exquisiteness is easy to coat skin, is easy to the absorption of medicine; Steady quality, technological operation is simple and easy to do.Compare therapeutic equivalence, relieving side effects with listing medicine acetyl Anthra-Derm.
The accompanying drawing explanation
The production technological process that Fig. 1 is acetyl Anthra-Derm provided by the invention.
Fig. 2 is 24h after the last administration in embodiment 6: substrate matched group outward appearance sign and medication local circumstance.
Fig. 3 is 24h:100 order administration group outward appearance sign and medication local circumstance after the last administration in embodiment 6.
Fig. 4 is 24h:180 order administration group outward appearance sign and medication local circumstance after the last administration in embodiment 6.
Fig. 5 is 24h after the last administration in embodiment 6: the obvious stimulation reactions such as the local visible redness of superfine powder administration group medication, hemorrhage incrustation.
Fig. 6 is that in embodiment 6, administration finishes: 100 order administration groups and substrate matched group clip root of the tail are relatively.
Fig. 7 is that in embodiment 6, administration finishes: 180 order administration groups and substrate matched group clip root of the tail are relatively.
Fig. 8 is that in embodiment 6, administration finishes: superfine powder administration group has obvious variation than substrate matched group clip root of the tail.
The specific embodiment
Below by specific embodiment, the present invention will be described, but the present invention is not limited thereto.
Experimental technique described in following embodiment, if no special instructions, be conventional method; Described reagent and material, if no special instructions, all can obtain from commercial channels.
Embodiment 1, acetyl dithranol dosage form selection foundation
1 adjuvant compatibility test
Because of acetyl dithranol 10 acetyl derivatives that are dithranol; both molecular structures are approximate, and seemingly, the mechanism of action is also basic identical for the physicochemical property comparing class; the preparation of the dithranol that version pharmacopeia in 2010 is recorded is Anthra-Derm, tentatively determines that the preparation of acetyl dithranol is ointment.Ointment has the dissimilar ointment such as grease type ointment, emulsifiable paste, water-soluble ointment gel.For determining the dosage form of acetyl dithranol, selected relevant to ointment 15 kinds of adjuvants and additive to carry out compatibility test.
1.1 the kind of adjuvant and additive:
Adjuvant has: vaseline (in vain), hard paraffin, liquid paraffin, lanoline, dimethicone, stearic acid, octadecanol, glyceryl monostearate, glycerol, propylene glycol;
Additive has: Tween 80, triethanolamine, sodium lauryl sulphate, ethyl hydroxybenzoate, BHT.
1.2 principal agent mixes with adjuvant and additive
Larger for supplementary product consumption, pressing the high standard 1.2% of acetyl Anthra-Derm calculates, can be in principal agent: the ratio of adjuvant=1: 50 be mixed, i.e. vaseline (in vain), hard paraffin, liquid paraffin, lanoline, dimethicone, stearic acid, octadecanol, glyceryl monostearate, glycerol, propylene glycol, tween 80 and sodium lauryl sulphate etc.; Consumption is less, can be in principal agent: the ratio of adjuvant=1: 1 is mixed, i.e. triethanolamine, ethyl hydroxybenzoate and BHT.
1.3 observation condition and result
After above-mentioned sample mix, be placed in beaker, uncovered room temperature is placed 10 days, the variation of the appearance color that detects by an unaided eye.
The results are shown in Table 1
Table 1 adjuvant compatibility test result
The acetyl dithranol is in most adjuvants and unstable, and only stable in the hydrocarbon base of oils substrate and dimethicone, substrate is containing functional group or few containing functional group; Its surperficial color of sample after placing is always dark than the color of inner sample, illustrates that light, air and airborne moisture can accelerate sample and change.
The preliminary comparison of 2 different dosage forms is determined with dosage form
Because the preliminary definite preparation of acetyl dithranol is ointment.Ointment has the dissimilar ointment such as grease type ointment, emulsifiable paste, water-soluble ointment gel.For determining the dosage form of acetyl dithranol, prepared the ointment dosage form of three kinds of acetyl dithranol, i.e. grease type ointment, oil-in-water type emulsifiable paste and water-soluable gel, and carried out corresponding investigation.
2.1 the preparation of acetyl Anthra-Derm:
Get it filled and use white vaseline 100g, 150 ℃ of heating are carried out sterilizing in 1 hour and remove moisture, treat that the white vaseline temperature is down to approximately 50 ℃, the substrate that takes a morsel (10g) and principal agent 0.5g mixed grinding, then join in remaining substrate, stirs, make principal agent mix homogeneously with substrate and, to solidifying, obtain.
2.2 the preparation of acetyl Dritho-Creme:
Prescription forms
Preparation method:
The oil phase preparation: get white vaseline, octadecanol, liquid paraffin, heat fused, be incubated 90 ℃.
Water preparation: get sodium lauryl sulphate, anhydrous sodium sulfite, ethyl hydroxybenzoate, glycerol and be added to the water, be stirred to dissolve, solution heats and is incubated 90 ℃.
The oil phase temperature keeps 90 ℃, and water is slowly added in oil phase, fully stirs into cream type substrate.When temperature is down to 50 ℃, the substrate that takes a morsel and principal agent mixed grinding, then join in remaining substrate, stirs, and principal agent is mixed homogeneously with substrate, obtains.
2.3 the preparation of acetyl dithranol gel:
Prescription forms:
Preparation method:
Get Acritamer 940 and add appropriate purified water placement 24hr, abundant swelling, after acetyl dithranol and salicylic acid fine powder are added to appropriate glycerol and grind well, add in the substrate that swelling is good, stir, add ethyl hydroxybenzoate alcoholic solution and Vitamin C aqueous acid, finally with triethanolamine, regulate pH value between 6～7, add purified water to full dose, stir evenly, obtain.
2.4 observation condition and result
Above-mentioned three kinds of ointment formulation samples evenly are divided into two parts, respectively are placed in beaker, and a sealing lucifuge room temperature is placed, and another part of uncovered room temperature placed, the variation of 0 hour, 12 hours, the 36 hours appearance colors that detect by an unaided eye.The results are shown in Table 2.
Three kinds of ointment formulations of table 2 are placed result of the test
Determining of 3 dosage forms
Adjuvant compatibility test explanation acetyl dithranol is in most adjuvants and unstable, only stable in the hydrocarbon base of oils substrate and dimethicone; The visual examination explanation that three kinds of ointment dosage forms of trial-production are preliminary through 36 hours, only significant change does not occur in grease type ointment outward appearance.
The acetyl dithranol is from the stability aspect, that grease type ointment is best suited for, also be unique selectable dosage form; Simultaneously, this type of substrate penetration capacity a little less than, be beneficial to medicine and bring into play drug action in part; And this type of substrate is applied on skin can form the closure oil film, promote the skin hydration effect, epidermis is had to softening and protective effect; Finally, this type of substrate is not corrupt, easy bacteria-developing not, and prescription is simple, and technological process is simple, and cost is low.Therefore, select the dosage form of grease type ointment as the acetyl dithranol.
Its surperficial color of sample after placing is always dark than the color of inner sample, illustrates that light, air and airborne moisture can accelerate sample and change.Should select protection against the tide, the good packaging material of shading performance when considering the packing of sample.
Embodiment 2, acetyl Anthra-Derm are selected the specification foundation
Anthra-Derm is recorded by Chinese Pharmacopoeia 2010 editions, and three kinds of specifications are arranged, and is respectively 0.1%, 0.5% and 1%.10 acetyl derivatives that the acetyl dithranol is dithranol, both molecular structures are approximate, the mechanism of action is identical, the specification of the anthralin Ointment recorded according to pharmacopeia, by etc. molar concentration calculate three kinds of specifications that obtain this product, be respectively 0.12%, 0.6% and 1.2%.
The impact of temperature on the ointment granularity prepared in embodiment 3, investigation
The ointment of oil-soluble substrate mainly adopts polishing and two kinds of preparation methoies of fusion method, but the applicable laboratory of polishing etc. prepares sample on a small quantity, and a large amount of preparations of commercial production adopt fusion method often: the fusing substrate of first heating, uniform temperature to be reduced to, add medicine, cooling getting final product stirs again.But, may dissolve more medicine when temperature is higher, stir after cooling and can separate out crystal not of uniform size, affect uniformity and the drug effect of ointment.Therefore, different preparation temperature is examined or check the impact of ointment granularity.
The preparation of 1 sample
Prescription forms
Acetyl dithranol 1.2g
White vaseline 98.8g
Make 100g
Sterilizing and dewatered medicinal white vaseline 98.8g are carried out in the 150 ℃ of heating of learning from else's experience in 1 hour, get altogether four parts, treat that temperature is down to respectively 70 ℃, 60 ℃, 50 ℃, 40 ℃, get crude drug 1.2g and join in substrate, stir, grind, make principal agent mix homogeneously with substrate and, to solidifying, obtain.
2 ointment smear microscopys
The preparation of slide: the drying of the 95% ethanol defat of learning from else's experience, clean, without the new glass sheet of greasy dirt, no marking, indicate sample number into spectrum on slide.A slide is smeared a duplicate samples, and every slide is only used once.
Method of direct smear: get the ointment sample appropriate, evenly smear the rectangle ointment film into about 2 * 4cm in the slide front, thickness is moderate.Each sample is coated with 3 slides, then under microscope, carries out microscopy, the results are shown in Table 3.
The different read tablet results (10 times of eyepiece * 20 times object lens) of table 3 ointment smear microscopy
Conclusion: sample prepared by four kinds of different temperatures has carried out respectively the microscopy test, and result shows that the ointment sample particle of preparation below 60 ℃ is all random, all is less than 80 μ m, and without crystalline polamer; Although the ointment sample particle of 70 ℃ of preparations all is less than 80 μ m, bar-shaped crystallization occurred, and crystalline polamer is arranged.Illustrate when temperature is higher that preparing ointment can cause crystallize, should below 60 ℃, prepare ointment, in conjunction with reality, can select 50 ℃ to prepare the ointment sample.
The impact on ointment of embodiment 4, examination antiseptic and antioxidant
The additive that ointment is commonly used mainly contains antiseptic and antioxidant.For the acetyl Anthra-Derm, can consider not adding preservative agent, reason has 6: 1. the acetyl Anthra-Derm be take hydrocarbons as substrate, and character is extremely stable, does not occur corrupt and becomes sour, not easy bacteria-developing; 2. in technique, vaseline is heated to 150 ℃ of insulations 1 hour, not only sterilizing but also dewater; 3. principal agent is not moisture, and qualified through microbial limit control; 4. listing take its salts ointment that vaseline is substrate, sulphur ointment etc. all containing antiseptic; 5. antiseptic likely produces certain zest.6. antiseptic may exert an influence to the stability of principal agent.
Antioxidant commonly used has three kinds: chelating agen, reducing agent and antioxidant.Characteristics in conjunction with ointment, we select antioxidant BHA (BHA) more commonly used that polarity is less and propyl gallate (PG) and reducing agent vitamin C (Vc) to prepare ointment as antioxidant jointly to carry out the influence factor with the ointment that does not add antioxidant and examine or check test, determined whether to add antioxidant and added which kind of antioxidant.
The preparation of 1 sample
Prescription 1 forms
Acetyl dithranol 1.2g
White vaseline 198.8g
Make 200g
Separately get the culture dish of six dried and clean, the ointment sample that each impouring 25g left and right makes, to carry out influence factor's test.
Get the flat weighing bottle (dried and clean) of two accurately weighed weight, each respectively adds the ointment sample of about 1g, accurately weighed again, to be drawn wet weight increment test.
Prescription 2 forms
Acetyl dithranol 1.2g
BHA 0.04g
White vaseline 198.8g
Make 200g
The packing that makes the ointment sample is the same.
Prescription 3 forms
Acetyl dithranol 1.2g
Propyl gallate 0.2g
White vaseline 198.6g
Make 200g
The packing that makes the ointment sample is the same.
Prescription 4 forms
Acetyl dithranol 1.2g
Vitamin C 0.2g
White vaseline 198.6g
Make 200g
The packing that makes the ointment sample is the same.
2 influence factor's tests
By prescription 1, write out a prescription 2, write out a prescription 3,4 each two culture dishs that fill the ointment sample of writing out a prescription are placed in respectively high temperature (40 ℃) (annotates: because of placement under 60 ℃ of conditions more than 2 hours, ointment melt and all become liquid, therefore temperature is reduced to 40 ℃ carries out), place 10 days under illumination (4500lx), high humidity (RH92.5%) condition, in the 5th day and sampling in the 10th day, the situation of change of the character of sample for reference, uniformity, related substance and content, the results are shown in Table 4.
Influence factor's result of the test of four kinds of prescriptions of table 4
3 conclusions
Sample prepared by four kinds of formulation and technology conditions is being placed and is being carried out influence factor's test in 10 days respectively under high temperature (40 ℃), illumination (4500lx), high humidity (RH92.5%) condition, and result shows:
(1) four kind of sample prepared by preparation process condition does not have notable difference, the index of investigating without significant change, be basicly stable;
(2) although the examination the sample related substance and drug content without significant change, the sample of placing under hot conditions is all thinner; Certain variation has all appearred in the sample appearance of placing under illumination condition, the sample ointment skin color of prescription one and prescription four is slightly dark, the sample ointment skin color of prescription two and prescription three is darker, may be BHA (BHA) and propyl gallate (PG) the incidence rate variation with this understanding added; Have no obvious variation under super-humid conditions.Point out that this preparation should seal, shading, preserve better in cool dark place.
(3) compare and have no obvious advantage due to the prescription two, three, four that adds antioxidant and the prescription one that do not add antioxidant; Add prescription two, the three sample surfaces colors of antioxidant obviously to deepen simultaneously, four vitamin Cs (Vc) of writing out a prescription are water-soluble substances, brought certain difficulty to the preparation technology of ointment, therefore tentatively think not add antioxidant and be advisable, finally the influence factor's result of the test with the band packing decides.
Embodiment 5, the contacting metal vessel impact on ointment
Ointment is in actual production, comprise pulverizing, the substrate of raw material processing, stirring homogeneous and last fill all may contacting metal equipment, thereby infiltrate more or less metal ion, whether the metal ion of infiltrating can exert an influence to ointment is investigate.Following technique one adopts glass material to prepare ointment as far as possible, and technique two adopts stainless steel to prepare ointment as far as possible.Whether the metal ion that may bring into the examination stainless steel equipment affects the stability of ointment.
The preparation of 1 sample
Prescription forms
Acetyl dithranol 1.2g
White vaseline 198.8g
Make 200g
Technique one: the preparation of acetyl Anthra-Derm: with aforementioned method.Vessel used all adopt glass material, comprise sample disintegrating apparatus (mortar), heating disinfection vessel (beaker), mixing plant (glass material stirring rod) etc., the sample finally made, with being distributed in culture dish under " the impact examination on ointment of embodiment 4 antiseptic and antioxidant " item, carries out influence factor's examination.
Technique two: the preparation of acetyl Anthra-Derm: with aforementioned method.Vessel used adopt stainless steel as far as possible, sample disintegrating apparatus rustless steel Universalpulverizer, heating disinfection vessel rustless steel steel bowl, mixing plant rustless steel stirring rod; Simultaneously, actual in conjunction with producing, the acetyl Anthra-Derm configured is placed in to stainless steel cup and under 50 ℃ of conditions, is incubated 24 hours, take out, stir, the sample made, with being distributed in culture dish under " the impact examination on ointment of embodiment 4 antiseptic and antioxidant " item, carries out influence factor's examination.
2 influence factor's tests
Technique one and technique two each two culture dishs that fill the ointment sample are placed in respectively to high temperature (40 ℃) (notes: because placing more than 2 hours under 60 ℃ of conditions, ointment melt and all become liquid, therefore temperature is reduced to 40 ℃ carries out), place 10 days under illumination (4500lx), high humidity (RH92.5%) condition, in the 5th day and sampling in the 10th day, the situation of change of the character of sample for reference, uniformity, related substance and content, the results are shown in Table 5.
The influence factor result of the test of table 5 contacting metal vessel to ointment
3 conclusions
Ointment sample prepared by two kinds of preparation process conditions has carried out respectively influence factor's test, result shows that sample prepared by two kinds of preparation process conditions does not have notable difference, illustrate that it is feasible that vessel with stainless steel prepare ointment, the index of investigating without significant change, be basicly stable; Simultaneously, although all change not quite with the sample related substance of examining or check under terms of packing and drug content, the ointment sample skin color under illumination condition is slightly dark, and it is greatly that related substance changes relative with drug content, illustrate that this product should seal, shading, preserve in cool dark place.
The research of embodiment 6, acetyl Anthra-Derm Raw powder degree
According to the preparation specification of preliminary formulation, tentatively manufactured experimently the preparation of three kinds of specifications.The preparation of three kinds of specifications all can detect the granule of crude drug under the microscope, illustrates that the preparation of three kinds of specifications is suspension type.The acetyl dithranol is almost insoluble in Vaseline basis, mainly with particle state, is dispersed in substrate greatly, forms suspension type ointment.
The crude drug granularity may make a significant impact bioavailability and clinical efficacy, also may affect the content uniformity of preparation simultaneously.Theoretically, the crude drug particle diameter is excessive, and the drug molecule that has directly contacted drug action with patient skin will reduce, and curative effect reduces; The crude drug granularity is less, possible bioavailability and clinical efficacy are better, the content uniformity of preparation is better, and still, the crude drug particle diameter is too little, one side will increase greatly with the drug molecule that patient skin has directly contacted drug action, because this medicine has certain zest, whether toxic and side effects also can increase, on the other hand, the processing cost of raw material also can increase, and also is unfavorable for workman's labor protection.The problems referred to above are single can't make a choice from preparation examination index, therefore, has adopted Integral animal experiment to investigate the impact of crude drug different-grain diameter on drug action, for the formulation of this product preparation raw material powder degree provides foundation.
Pharmacopeia must not stipulate and detected the particle that is greater than 180 μ m, this test and Selection the ointment for preparing of corase particles that conforms with that pharmacopeia requires, raw material, all by 100 mesh sieves, can not pass through 120 mesh sieves, the ointment particle of preparation is at 150 μ m.
The particle that existing conventional machinery technology can reach generally adopts micronizing, this test and Selection Ultra-Micro Grinding Equipment prepared superfine powder ointment, the ointment particle of preparation is below 10 μ m.
Ointment-80 μ the m of the third particle between the above-mentioned two kinds of ointment of Jie has been selected in this test simultaneously, and raw material, all by 180 mesh sieves, can not pass through 200 mesh sieves.
1 Shandong University of non-clinical study mechanism new drug evaluation center
1: 180 order acetyl Anthra-Derm of test sample, yellow ointment
Numbering: TSB100413-1
Preparation: getting the 1g particle diameter is 180 purpose acetyl dithranol raw materials, adds the white vaseline substrate 99g of thermal dehydration, stirs, and obtains.The content that HPLC records the acetyl Anthra-Derm is 99.48%.
Test sample 2:100 order acetyl Anthra-Derm, yellow ointment
Numbering: TSB100413-2
Preparation: get 1g 100 purpose acetyl dithranol raw materials, add the white vaseline substrate 99g of thermal dehydration, stir, obtain.It is 99.31% that HPLC records acetyl Anthra-Derm content
Test sample 3: superfine powder acetyl Anthra-Derm, yellow ointment
Numbering: TSB100413-3
By Jinan Billionpowder Tech& Eng Co., Ltd on behalf of preparation: get 5g acetyl dithranol raw material, add the white vaseline substrate 495g of thermal dehydration, with WZJ6-TBI, carry out micronizing, obtain.It is 99.03% that HPLC records acetyl Anthra-Derm content
Substrate reference substance: vaseline, simple ointment, numbering: TSB100413-4
Above-mentioned sample provides by Pharmaceutical Research Inst. of Shandong Prov. Medical Science Academy, preservation condition: room temperature is airtight, site of storage: the test sample chamber.
2 laboratory animals and feeding and management
Laboratory animal: title: KM mice, grade: clean level, quantity: 50 (formal test is chosen 40), age in week: 6 week age, sex: ♀ ♂ half and half, body weight: 20～23g, source: Shandong University's Experimental Animal Center, production licence number: SCXK (Shandong) 20090001.
Feeding and management: temperature: 20～26 ℃, relative humidity: 40～70%, illumination: 150～300Lux, feedstuff: maintain the Mus material, Shandong University's Experimental Animal Center provides, drinking water for animals: tap water, freely drink and get.
3 animal grouping and administrations
The animal grouping: get healthy 40 KM mices, adaptability is raised 5 days, by body weight, is divided at random 4 groups, is respectively: substrate matched group, 180 order administration groups, 100 order administration groups, superfine powder administration group.Every group 10, ♀ ♂ half and half.
Administration: afterbody is smeared.Substrate matched group: vaseline.180 order administration groups: 180 order 10-acetyl Anthra-Derms.100 order administration groups: 100 order 10-acetyl Anthra-Derms.Superfine powder administration group: superfine powder 10-acetyl Anthra-Derm.Administration volume: 1.5g/, administration frequency: every day 1 time, successive administration 14d.
Be subject to the impact of this product physicochemical property and Mus tail surface area, can't realize the larger dose administration.
4 test methods
Adaptability is raised and is finished, and chooses 40 of afterbody not damaged mices, and is divided at random 4 groups by body weight.Closely continue (1h) after first administration and observe animal whole body and medication local response situation; Thereafter before each administration with warm water (take imperceptible scalding one's hand as standard) cleaning Mus tail, then use rechallenge after dry aseptic emery cloth wiping, and guarantee that as far as possible administration is even.During administration, observe animal general signs and medicine-feeding part situation every day; 24h after the last administration finishes, dislocation method is put to death mice, and clip root of the tail section carries out routine pathology to its epidermis and learns inspection, in 100 scales of counting Mus tail epidermis, has granular layer to form number.
5 data statistics processing methods
All data mean with x ± s, apply SPSS11.0 software and carry out the t check.
6 results
6.1 general signs
Respectively organize the mice general signs during administration good, show no obvious abnormalities variation.
6.2 administration part
The 3rd day visible red and swollen significantly irritant reaction symptom of superfine powder medication group mice administration, administration hemorrhage and incrustation in the 6th day, extend sx↑ in time, and this symptom continues to administration always and finishes, and with the substrate matched group, obvious variation is relatively arranged.All the other two administration groups have no the irritant reaction symptom, with the substrate matched group, relatively without obvious, change.The results are shown in accompanying drawing 2 to 8.
6.3 pathological examination
Each medication group successive administration is after 14 days, the granular cell layer of embarking on journey continuously as seen under light microscopic between the scale epidermis between adjacent hair follicle, 180 orders and ultrafine preparation technique 10-acetyl Anthra-Derm granular layer scale number have significant difference (P<0.01) than the substrate matched group, and all the other show no obvious abnormalities.The results are shown in Table 6.
The impact that table 6 different-grain diameter 10 acetyl Anthra-Derms form mouse tail scale granular layer
Annotate:
*P<0.01, compare with the substrate matched group.
7 discuss
Psoriasis is clinical common chronic, recurrent, inflammatory skin disease, is one of whole world department of dermatologry field primary study and disease preventing and treating.This disease cause of disease is unclear, and at present treatment is main mainly with the part medication of suiting the medicine to the illness.Its animal model kind is also more, and commonly used have Mus tail squamous epithelial cancer, female Mus vagina epithelium, the transplanting of nude mice skin lesion, mutant mouse and a transgenic mouse etc.Due to Mus tail squamous epithelial cancer, method is simple, has been widely used in and prepared Animal Models of Psoriasis at present.
Result of study finds, the formation of the promotion Mus tail granular layer that the acetyl Anthra-Derm prepared under 100 orders, 180 orders preparation process different from superfine powder all can be in various degree infers that this product should have some improvement or therapeutical effect treating aspect psoriasis.Statistical analysis is visible, 180 orders and ultrafine preparation technique can obviously increase the quantity that granular layer forms, with the substrate matched group, significant significant difference (P<0.01) is relatively arranged, 100 order preparation process, than substrate matched group no difference of science of statistics, show that 180 orders and ultrafine preparation technique are obvious than 100 order action effects.But can cause the significantly stimulation such as mouse tail redness, hemorrhage incrustation after the administration of ultrafine preparation technique, advise further optimizing or rejecting this technique.
Comprehensive above information is visible: 100 orders promote, increase the formation of Mus tail granular layer or form number not obvious, 180 orders and superfine powder can obviously promote the formation of granular layer and increase Mus tail granular layer quantity of formation, but superfine powder can cause that mouse tail is red and swollen, the obvious irritant reaction symptom of hemorrhage incrustation.Infer that 180 order preparation process are better than 100 order preparation process and are better than ultrafine preparation technique.
8 conclusions
Under this experimental condition, 100 orders, 180 orders and superfine powder acetyl Anthra-Derm all can form number to mouse tail scale granule and exert an influence, 180 orders, ultrafine preparation process acts successful, and ultrafine preparation technique has obvious stimulation to mice.Prompting, in three kinds of preparation process, 180 order preparation process are better than 100 orders and superfine powder.
The preparation of embodiment 7, acetyl Anthra-Derm
1 preparation prescription
1.1 specification: the specification of this product is 0.12%, 0.6% and 1.2% 3 kind of specification
1.2 prescription forms
Acetyl dithranol 24g (120g or 240g)
White vaseline adds to 20000g
Make 1000
2 preparation process and flow process
2.1 preparation process
2.1.1 get the acetyl dithranol, cross 180 mesh sieves after pulverizing, standby;
2.1.2 filter while hot with fine cloth or No. seven copper wire sieves after getting the white vaseline heating and melting, remove impurity.And then be heated to 150 ℃ and within 1 hour, carry out sterilizing and remove moisture, standby;
2.1.3 treat that the white vaseline temperature is down to approximately 50 ℃, the substrate that takes a morsel and principal agent mixed grinding, then join in remaining substrate, homogenizing stirs 15～30 minutes, and principal agent is mixed homogeneously with substrate;
2.1.4 semi-finished product content checks;
2.1.5 fill, packing, full inspection, warehouse-in.
Claims (6)
1. acetyl Anthra-Derm agent, be comprised of the raw material of following quality percentage composition: acetyl dithranol 0.12-1.20% and white vaseline 98.80-99.88%; The particle diameter of described acetyl dithranol is 10-80 μ m.
2. acetyl Anthra-Derm according to claim 1 agent is characterized in that: the agent of described acetyl Anthra-Derm is comprised of the raw material of following quality percentage composition: acetyl dithranol 0.12% and white vaseline 99.88%.
3. acetyl Anthra-Derm according to claim 1 agent is characterized in that: the agent of described acetyl Anthra-Derm is comprised of the raw material of following quality percentage composition: acetyl dithranol 0.60% and white vaseline 99.40%.
4. acetyl Anthra-Derm according to claim 1 agent is characterized in that: the agent of described acetyl Anthra-Derm is comprised of the raw material of following quality percentage composition: acetyl dithranol 1.20% and white vaseline 98.80%.
5. prepare the method for the described acetyl Anthra-Derm of any one agent in claim 1-4, comprise the steps:
1) acetyl dithranol raw material pulverizing to the particle diameter of getting described quality percentage composition is 10-80 μ m, standby;
2) filter while hot after getting the white vaseline heating and melting of described quality percentage composition, remove impurity; And then be heated to 145-155 ℃ of insulation and within 1-2 hour, carry out sterilizing and remove moisture, standby;
3) when the white vaseline temperature is down to 45-55 ℃, get acetyl dithranol quality 5-20 described white vaseline and step 1 doubly) acetyl dithranol mixed grinding after the pulverizing that obtains, then join in the residue white vaseline, homogenizing stirs 15～30 minutes, make the acetyl dithranol mix homogeneously and be cooled to white vaseline and solidify, obtain the agent of acetyl Anthra-Derm.
6. method according to claim 5, it is characterized in that: described method also comprises that the content inspection is carried out in agent to the acetyl Anthra-Derm; The step of fill, packing, full inspection.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103932978A (en) * | 2014-04-16 | 2014-07-23 | 白玲强 | Anthralin ointment and preparation process thereof |
| CN104398472A (en) * | 2014-12-04 | 2015-03-11 | 山东省皮肤病性病防治研究所 | Dithranol oiling agent and preparation process thereof |
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| CN103932978A (en) * | 2014-04-16 | 2014-07-23 | 白玲强 | Anthralin ointment and preparation process thereof |
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