CN103622974B - A kind of compound suppository containing mesalazine and N-acetylcystein and preparation method thereof - Google Patents
A kind of compound suppository containing mesalazine and N-acetylcystein and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of micronized mesalazine and N-acetylcystein is compound suppository of effective ingredient and preparation method thereof, compound suppository of the present invention belongs to composition for rectal administration, be mainly used in the relevant disease for the treatment of ulcerative colitis and indication, oral administration weak curative effect, shortcoming that side effect is large can be overcome, and can the pharmaceutically-active persistent period be improved, for medical personnel and patient provide better treatment means.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of micronized mesalazine and N-acetylcystein is compound suppository of effective ingredient and preparation method thereof.
Background technology
Inflammatory bowel (Inflammatoryboweldisease, IBD) be mainly divided into Crohn disease (Crohn ' sDisease, and ulcerative colitis (UlcerativeColitis CD), UC) two classes, the two symptom having some common: stomachache, vomiting, diarrhoea, hemafecia or some relevant diseases such as to lose weight.
UC is a kind of nonspecific colonic inflammatory disease, and unknown etiology as yet may be a kind of autoimmune disease, the state of an illness generally with light, moderate is common.It is characterized by that diarrhoea is discharged along with mucus and blood, angina abdominis and mucosa irritation and edema be attended by ulcer speckle.Suffer from chronic UC thus the risk that the people affecting whole colon suffers from colon cancer increases.In addition, when medical therapy lost efficacy, may the required affected intestinal of excision.
Mesalazine (5-aminosalicylic acid) (5-ASA) is the common drug for the treatment of UC, it is by suppressing the activity of platelet activating factor and suppressing colonic mucosa fatty acid oxidation, inhibitory action is played to the generation of medium leukotriene (LTB4) and prostaglandin (PGE2) and release, thus improves colonic mucosa inflammation.This medicine is applicable to gently, moderate patient or severe patient be through glucocorticoid treatment existing effect alleviation person.The UC patient being confined to rectum for pathological changes clinically recommends rectum to give mesalazine treatment, and rectally overcomes oral administration weak curative effect, shortcoming that side effect is large, and can improve the pharmaceutically-active persistent period.
N-acetylcystein (NAC) is a kind of mucolytic, because the sulfydryl (-SH) in its chemical constitution can make the bond fission of mucinous pair of sulfur (-S-S-), mucin is decomposed, thus reduces mucus viscosity, mucus is easily discharged.For decomposing the mucus that colonal mucosa phlegmasia produces in the combination of this compound recipe, to increase human body comfort.NAC or a kind of antioxidant simultaneously, regulates the metabolic activity of cell, and the damage of prevention DNA, works in coordination with inflammation-inhibiting with mesalazine and react.
Domestic marketed products is main mainly with Mesalazine table.Because mesalazine is local gastrointestinal activity medicine, this medicine of low dosage can be selected can overcome oral administration weak curative effect, shortcoming that side effect is large by rectally, and can improve the pharmaceutically-active persistent period.
CN102970971A discloses a kind of preparation method improving the mesalazine rectal suppository of comfort level, it is characterized in that the preferable amount of mesalazine is 1450mg-1550mg, drug loading is 41%-43%, calculate according to this scope, suppository should at about 3.75g, the suppository volume that it is prepared into is excessive, and comfort is not strong.In addition, the substrate used in this patent is oiliness or lipid substrate, although mesalazine indissoluble in water, is use fat-soluble substrate entirely, also and be unfavorable for the release of this product.Increasing comfort in its this patent is can reduce the viscosity realization of molten mixture by the tap density of increase mesalazine.Although the comfort level of mesalamine suppository can be made preparation method to strengthen to some extent, can not from the sense of discomfort changed in fact because the mucus of esoenteritis generation brings.
This preparation method can not improve comfort level from mechanism.
CN103230375A discloses a kind of mesalazine drop pill, can avoid conventional tablet because of disintegration longer, dissolution rate with the factor such as lower, but can not avoid oral administration weak curative effect, shortcoming that side effect is large.CN102784154A discloses a kind of preparation method of Mesalazine table, have employed nanotechnology, enteric technology and compaction of pellet technology, increases it and discharge in intestinal, improves curative effect.But the preparation equipment needed for it is more, manufacturing process is complicated, and is oral administration, and weak curative effect, side effect is large.
CN103211780A and CN1568954A is all the positioning release medicine micropills disclosing a kind of mesalazine, is oral administration, does not have rectally city to discharge rapidly.
Summary of the invention
The invention provides a kind of compound suppository be made up of mesalazine and N-acetylcystein, it is advantageous that and improve availability by after mesalazine micronization, and be combined with N-acetylcystein and can improve comfort, increase antioxygen anti-radical action, improve antiinflammatory action, be prepared into suppository, avoid oral administration weak curative effect, shortcoming that side effect is large.
Another object of the present invention there is provided the preparation method of the compound suppository of a kind of mesalazine and N-acetylcystein composition.
1. first calculate the amount of required principal agent and substrate by the gauge of bolt mould used, the substrate of recipe quantity is heated in water-bath and dissolves (temperature is determined according to substrate fusing point).
2. mesalazine being carried out micronization, to cross 300 mesh sieves for subsequent use.All the other solid-state adjuvants all cross 80 mesh sieves.
3. the mesalazine of recipe quantity and N-acetylcystein to be added in the substrate of dissolving and to mix, medicaments uniformity is dispersed in substrate.
4. impouring while hot cools and scribbles to slightly overflowing die orifice for degree in the bolt mould of lubricant, to be cooled solidify after, to prune spilling part with cutter, release suppository, dry, to obtain final product.
The present invention provides a kind of preparation method of effective increase mesalazine dissolution simultaneously, and we adopt micronization technology and use solubilizing agent to increase mesalazine dissolution in vivo, thus improves its bioavailability in vivo.
The technique that we prepare compound suppository can repeat, operation feasible, and can industrialization produce.The ratio folk prescription mesalamine suppository better effects if of the mesalazine obtained by the present invention and the compound suppository of N-acetylcystein is shown according to zoopery.
In a word, the present invention and domestic existing medicine are in contrast, the Mesalazine table changing folk prescription is the mesalazine of compound recipe-N-acetylcystein compound suppository, and has the beneficial effect of following several aspect compared with the mesalamine suppository mentioned with CN102970971A:
1. increase human body comfort.N-acetylcystein this compound recipe combination in for decompose colonal mucosa phlegmasia produce mucus, to increase human body comfort.
2. collaborative enhancing antioxygen, antiinflammatory action.The fibrogenic factors such as transforming growth factor (TGF-β 1), tumor necrosis factor (TNF-α), interleukin are suppressed thus inflammation-inhibiting reaction by stoping the activation of NF-κ B path.
3. avoid oral administration weak curative effect, shortcoming that side effect is large.
4. can improve the release of medicine after mesalazine being carried out micronization, increase its utilization rate.
5. use is fat-soluble combines mutually with water-soluble base, can increase the release of two kinds of medicines, increase operation rate.
The present invention is by the following technical solutions:
Containing the compound suppository of mesalazine and N-acetylcystein, the drug regimen of unit dose comprises micronized mesalazine 200mg ~ 1000mg, N-acetylcystein 50mg ~ 250mg.
The weight ratio of carrier composition shared by mesostroma is: 50-90; Weight ratio shared by solubilizing agent is: 2-15; Weight ratio shared by absorption enhancer is: 0.5-3; Plasticizer weight ratio is: 1-3; Lubricant: 0.5-3.
The substrate of described suppository is selected from PEG400, Macrogol 4000, glycerol, gelatin, polyoxyethylene 40, one or more of poloxamer; The combination of preferred PEG400 and poloxamer.Described solubilizing agent be selected from polyglycerol monooleate, HS15, polyoxyethylene (hydrogenation) Oleum Ricini condensation substance, sucrose ester, sodium lauryl sulphate, tween one or more.Described absorption enhancer be selected from polyethyleneglycol glyceride, EDTA and salt thereof, citric acid and salt, cholic acid and salt thereof, (Asia) oleic acid and salt thereof, Mentholum, beta-schardinger dextrin-one or more.Described plasticizer be selected from tween 85, fatty glyceride, Oleum Ricini, glycerol or propylene glycol one or more.Described lubricant is selected from the lubricant that the green soap of greasing base, glycerol and ethanol are made, and for the liquid Paraffin of hydrophilic matrix, vegetable oil one or more.
According to the feature of above-mentioned adjuvant, we control preparation technology, and with the size of mesalazine, melt and become the time limit, dissolution rate screens matrix species, consumption and technique as the index of prescription and craft screening.Have employed following experimental program:
Experimental program 1: mesalazine size is on the impact of dissolution rate: according to embodiment 1 technique, select 60 orders, 100 orders, 200 orders, 300 object mesalazines, prepare four parts of different samples, and be that the scheme that the mesalazine of 700g/L prepares mesalamine suppository according to CN102970971A embodiment 1 prepares sample five in conjunction with the tap density that CN102970971A provides, the assay method of the dissolution rate provided according to CN102970971A and Chinese Pharmacopoeia " version in 2010 ": at 37 DEG C in the phosphate-buffered salt of the 0.2M of pH7.5, the stirring paddle rotary speed of 125rmp, at its content of different time points sampling and measuring under the condition of use sedimentation indigo plant.
Mesalazine Dissolution experiments result (%)
| Time (min) | 5 | 10 | 15 | 30 | 45 | 60 |
| 60 orders | 13.25 | 19.52 | 23.44 | 29.67 | 34.61 | 42.37 |
| 100 orders | 15.87 | 22.36 | 28.98 | 35.53 | 45.67 | 62.38 |
| 200 orders | 23.35 | 33.46 | 48.29 | 62.59 | 70.44 | 84.38 |
| 300 orders | 25.01 | 37.04 | 53.89 | 80.53 | 87.43 | 94.55 |
| Sample five | 26.35 | 35.46 | 48.29 | 72.59 | 83.44 | 89.38 |
Result shows that mesalazine of the present invention carries out micronized process in advance and makes its method crossing 300 mesh sieves have raising clearly to its dissolution, can be good at reaching necessary requirement, and be that the result of extraction of the mesalazine of 700g/L is good than the bulk density described in CN102970971A patent.
Embodiment 2: the selection of substrate: substrate is that the crucial adjuvant becoming time limit and drug release is melted in impact, and for this reason, we screen substrate.Because of principal agent mesalazine slightly soluble in water, and N-acetylcystein is water soluble drug, and these two kinds of medicines can effectively discharge therefore to select substrate to ensure, and not frangibility, the not melting when body temperature, but can be quickly dissolved in body secretes liquid after filling in rectum.Melt the detection method becoming the time limit and see version " Chinese Pharmacopoeia " annex XB in 2010.The assay method of dissolution is shown in the method in experimental program 1, and final sampling measures at 60min.We conducted following screening:
Can see according to result, the suppository obtained by the combination of PEG400 and poloxamer melts that to become the time limit the shortest, and the release of mesalazine and N-acetylcystein is all the highest, therefore preferably their combination as substrate.
Specific embodiment:
The following example is used for describing the present invention further, but it is not any restriction to scope of the present invention.
Embodiment 1: one of compound suppository of mesalazine and N-acetylcystein and preparation method thereof (recipe quantity: 1000)
Mei Lasha piperazine 200g
N-acetylcystein 1000g
PEG400 500g
Gelatin 100g
Sodium lauryl sulphate 50g
EDTA20g
Propylene glycol 20g
Liquid paraffin 20g
Preparation method: mesalazine being carried out micronization, to cross 300 mesh sieves for subsequent use.All the other solid-state adjuvants all cross 80 mesh sieves.
The PEG400 of recipe quantity and gelatin are heated in water-bath and dissolves, then recipe quantity mesalazine and N-acetylcystein to be added in the substrate of dissolving and to mix, medicaments uniformity is made to be dispersed in substrate, then impouring while hot cools and scribbles in the bolt mould of sodium lauryl sulphate, EDTA, propylene glycol, liquid paraffin to slightly overflowing die orifice for degree, to be cooled solidify after, to prune spilling part with cutter, release suppository, dry, obtain water solublity medicated bougie.
Embodiment 2: two (recipe quantities: 1000) of compound suppository of mesalazine and N-acetylcystein and preparation method thereof
Mei Lasha piperazine 400g
N-acetylcystein 8000g
Polyoxyethylene 40600g
Glycerol 100g
Polyglycerol monooleate 100g
Citric acid 30g
Oleum Ricini 10g
Green soap 30g
Preparation method: mesalazine being carried out micronization, to cross 300 mesh sieves for subsequent use.All the other solid-state adjuvants all cross 80 mesh sieves.
The polyoxyethylene 40 of recipe quantity and glycerol are heated in water-bath and dissolves, then recipe quantity mesalazine and N-acetylcystein to be added in the substrate of dissolving and to mix, medicaments uniformity is made to be dispersed in substrate, then impouring while hot cools and scribbles in the bolt mould of polyglycerol monooleate, citric acid, Oleum Ricini, green soap to slightly overflowing die orifice for degree, to be cooled solidify after, to prune spilling part with cutter, release suppository, dry, obtain water solublity medicated bougie.
Embodiment 3: three (recipe quantities: 1000) of compound suppository of mesalazine and N-acetylcystein and preparation method thereof
Mei Lasha piperazine 600g
N-acetylcystein 6000g
Macrogol 4000 500g
PEG400 300g
Polyoxyethylene (hydrogenation) Oleum Ricini 130g
Linoleic acid 5g
Fatty glyceride 30g
Vegetable oil 30g
Preparation method: mesalazine being carried out micronization, to cross 300 mesh sieves for subsequent use.All the other solid-state adjuvants all cross 80 mesh sieves.
The Macrogol 4000 of recipe quantity and PEG400 are heated in water-bath and dissolves, then recipe quantity mesalazine and N-acetylcystein to be added in the substrate of dissolving and to mix, medicaments uniformity is made to be dispersed in substrate, then impouring while hot cools and scribbles in the bolt mould of polyoxyethylene (hydrogenation) Oleum Ricini, linoleic acid, fatty glyceride and vegetable oil to slightly overflowing die orifice for degree, to be cooled solidify after, to prune spilling part with cutter, release suppository, dry, obtain water solublity medicated bougie.
Embodiment 4: four (recipe quantities: 1000) of compound suppository of mesalazine and N-acetylcystein and preparation method thereof
Mei Lasha piperazine 800g
N-acetylcystein 400g
Poloxamer 400g
Glycerol 400g
Sucrose ester 140g
Beta-schardinger dextrin-10g
Polysorbate85 20g
Ethanol 30g
Preparation method: mesalazine being carried out micronization, to cross 300 mesh sieves for subsequent use.All the other solid-state adjuvants all cross 80 mesh sieves.
The poloxamer of recipe quantity and glycerol are heated in water-bath and dissolves, then recipe quantity mesalazine and N-acetylcystein to be added in the substrate of dissolving and to mix, medicaments uniformity is made to be dispersed in substrate, then impouring while hot cools and scribbles in the bolt mould of sucrose ester, beta-schardinger dextrin-, polysorbate85 and ethanol to slightly overflowing die orifice for degree, to be cooled solidify after, to prune spilling part with cutter, release suppository, dry, obtain water solublity medicated bougie.
Embodiment 5: five (recipe quantities: 1000) of compound suppository of mesalazine and N-acetylcystein and preparation method thereof
Mei Lasha piperazine 1000g
N-acetylcystein 200g
Poloxamer 900g
Sodium lauryl sulphate 100g
Beta-schardinger dextrin-10g
Polysorbate85 20g
Liquid paraffin 20g
Preparation method: mesalazine being carried out micronization, to cross 300 mesh sieves for subsequent use.All the other solid-state adjuvants all cross 80 mesh sieves.
The poloxamer of recipe quantity is heated in water-bath and dissolves, then recipe quantity mesalazine and N-acetylcystein to be added in the substrate of dissolving and to mix, medicaments uniformity is made to be dispersed in substrate, then impouring while hot cools and scribbles in the bolt mould of sodium lauryl sulphate, beta-schardinger dextrin-, polysorbate85 and liquid paraffin to slightly overflowing die orifice for degree, to be cooled solidify after, to prune spilling part with cutter, release suppository, dry, obtain water solublity medicated bougie.
Embodiment 6: carried out by medicated bougie obtained in embodiment 2-6 melting the detection becoming time limit, dissolution, content, the assay method of dissolution is shown in the method in embodiment 1, and final sampling measures at 60min.Content detection is with reference to USP.The results are shown in following table:
Met the requirements by the change time limit of melting of table this stype visible, and dissolution rate is also very fast.
Embodiment 7: animal effect experiment
Mesalazine-NAC the sample prepared according to embodiment is improved composite algorithm with employing and is made Rat with Ulcerative Colitis (acetic acid+high fat diet).Modeling method: by rat High-fat diet, after the depilation of nape portion, every day is with 20gL
-12,4 dinitrochlorobenzene (DNCB) acetone drops carry on the back 1 time, each 0.3mL, continuous l4 days.Within l5 days, the nylon conduit per anum with diameter 3mm inserts colon 8cm place, injects 0.1%DNCB ethanol 0.25mL, within the 16th day, injects 8% acetic acid solution 2mL with position, use 5mL normal saline flushing after accurate timing 15s.
Animal is divided into 5 groups immediately: blank group (30): with normal saline enema after routine feeding 16d, 10mL (kgd)
-1, every day 1 time; Model group (30): after modeling, every day gives normal saline enema, l0mL (kgd)
-1, every day 1 time; Only add mesalazine according to embodiment 2 and do not contain the stype group (30) become prepared by N-acetylcystein: every day gives mesalazine, 10mL (kgd)
-1, every day 1 time; Mesalazine-N-acetylcystein stype group (30) according to prepared by embodiment 2: giving concentration every day is lgmL
1mesalazine-NAC coloclysis, 10mL (kgd)
-1, every day 1 time.Rat divides cage to feed, room temperature about 23 DEG C, keeps normal humidity, gives high lipid food and normal water, altogether drug treatment 4 weeks.
Course inflammatory activity index (DAI) scoring is carried out in administration after 4 weeks, the detection euzymelinked immunosorbent assay (ELISA) of DAI=(weight loss mark+stool mark+mark of having blood in stool)/3, TNF-alpha expressions.DAI scoring and TNF-alpha expression see the following form.
| DAI marks | TNF-α | |
| Blank group | 0.8±0.64 | 59.2±1.80 |
| Model group | 12.3±0.85 | 385.5±5.77 |
| Mesalazine group | 5.6±0.95 | 193.8±3.73 |
| Mesalazine-NAC group | 3.9±0.76 | 159.1±7.81 |
DAI scoring shows that mesalazine group, mesalazine-NAC group to compare with model group and has significant difference (P<0.01), and both explanations all effectively can treat colitis.Tissue injury's situation and the TNF-alpha expression of mesalazine-NAC group rat are all less than mesalazine group, illustrate that mesalazine obviously can reduce rat colon tissue damaged situation compared with alone with mesalazine with N-acetylcystein coupling.
Claims (5)
1., containing a compound suppository for mesalazine and N-acetylcystein, include the micronized mesalazine of effective amount and N-acetylcystein and pharmaceutically acceptable carrier; The drug regimen of unit dose comprises micronized mesalazine 200mg ~ 1000mg, N-acetylcystein 50mg ~ 250mg; Pharmaceutically acceptable vehicle group becomes substrate, solubilizing agent, absorption enhancer, plasticizer, lubricant; The substrate of suppository is selected from PEG400, Macrogol 4000, glycerol, gelatin, polyoxyethylene 40, one or more of poloxamer;
Described solubilizing agent be selected from polyglycerol monooleate, HS15, polyoxyethylene hydrogenated Oleum Ricini condensation substance, sucrose ester, sodium lauryl sulphate, tween one or more;
Described absorption enhancer be selected from polyethyleneglycol glyceride, EDTA and salt thereof, citric acid and salt, cholic acid and salt thereof, linoleic acid and salt thereof, Mentholum, beta-schardinger dextrin-one or more;
Described plasticizer be selected from tween 85, fatty glyceride, Oleum Ricini, glycerol or propylene glycol one or more;
Described lubricant is selected from the lubricant that the green soap of greasing base, glycerol and ethanol are made, and for the liquid Paraffin of hydrophilic matrix, vegetable oil one or more; The weight ratio of carrier composition shared by mesostroma is: 50-90; Weight ratio shared by solubilizing agent is: 2-15; Weight ratio shared by absorption enhancer is: 0.5-3; Plasticizer weight ratio is: 1-3; Lubricant: 0.5-3.
2. the compound suppository containing mesalazine and N-acetylcystein according to claim 1, is characterized in that: the substrate of described suppository is the combination of PEG400 and poloxamer.
3. the preparation method of the compound suppository of micronized mesalazine and N-acetylcystein described in claim 1 or 2, comprises following operation:
1. calculate the amount of required principal agent and substrate by the gauge of bolt mould used, the substrate of recipe quantity is heated in water-bath and dissolves;
2. mesalazine carries out micronization, crosses 300 mesh sieves for subsequent use; All the other solid-state adjuvants all cross 80 mesh sieves;
3. the mesalazine of recipe quantity and N-acetylcystein to be added in the substrate of dissolving and to mix, making medicaments uniformity be dispersed in substrate;
4. impouring while hot cools and scribbles to slightly overflowing die orifice for degree in the bolt mould of solubilizing agent, absorption enhancer, plasticizer and lubricant, to be cooled solidify after, to prune spilling part with cutter, release suppository, dry, to obtain final product.
4. according to the preparation method described in claim 3: it is characterized in that: the micronized method of mesalazine is the one in mechanical lapping, supercritical fluid micronization technology of preparing, Cryogenic spray technology and aqueous solution evaporate deposition technique.
5. according to the preparation method described in claim 4: it is characterized in that: the micronized method of mesalazine is supercritical fluid micronization technology of preparing.
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| CN108553410A (en) * | 2018-06-11 | 2018-09-21 | 成都医学院 | A kind of mesalazine rectum original position thermo-sensitive gel and its preparation method and application |
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| CN102970971A (en) * | 2009-12-16 | 2013-03-13 | 加拿大阿普塔利斯制药公司 | Mesalamine suppository |
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Effective date of registration: 20170814 Address after: 430000 Wuhan East Lake new technology development zone of Hubei province Kuanshan two road a international business center 3 Building 6 layer 1 Patentee after: Wuhan Grand Hoyo Co., Ltd. Address before: 430074 Hubei Development Zone, East Lake, Optics Valley Venture Street, building 6, building 2, building Patentee before: Wuhan Wuyao Technology Co., Ltd. |