CN102512358B - Rifaximin vaginal suppository for livestock and preparation method for same - Google Patents

Abstract

Translated fromChinese

本发明属于兽药领域，涉及家畜用利福昔明阴道栓剂及其制备方法。该栓剂包含如下组分：利福昔明固体分散体8.5-25.5重量份、基质30-88重量份、水：6.0-12.5重量份、表面活性剂：0.01-1.0重量份；增效剂：0.01-10.0重量份、防腐剂：0.01-5.0重量份，其中所述的利福昔明固体分散体是将固体分散体载体7.3-21.9重量份于70℃-80℃水浴熔融后，加入已用2-16重量份无水乙醇溶解1.2-3.6重量份利福昔明得到的利福昔明溶液，搅匀，70℃-80℃水浴蒸去无水乙醇后，迅速降温冷却固化，即得。本发明栓剂既能确保确保主药均匀分散；又克服甘油明胶基质耐热性低融变时限长之虑。The invention belongs to the field of veterinary medicine, and relates to a rifaximin vaginal suppository for livestock and a preparation method thereof. The suppository comprises the following components: 8.5-25.5 parts by weight of rifaximin solid dispersion, 30-88 parts by weight of matrix, 6.0-12.5 parts by weight of water, 0.01-1.0 parts by weight of surfactant, and 0.01 parts by weight of synergist -10.0 parts by weight, preservative: 0.01-5.0 parts by weight, wherein the rifaximin solid dispersion is obtained by melting 7.3-21.9 parts by weight of the solid dispersion carrier in a water bath at 70°C-80°C, and then adding the used 2 The rifaximin solution obtained by dissolving 1.2-3.6 parts by weight of rifaximin in 16 parts by weight of absolute ethanol is stirred evenly, evaporated in a water bath at 70° C. to 80° C. to remove the absolute ethanol, and the temperature is rapidly lowered to cool and solidify. The suppository of the invention can not only ensure the uniform dispersion of the main ingredient, but also overcome the problem of low heat resistance of the glycerin gelatin matrix and long time limit for melting.

Description

Domestic animal rifaximin vaginal suppository and preparation method thereof

Technical field

The invention belongs to field of veterinary, relate to domestic animal rifaximin vaginal suppository and preparation method thereof.

Background technology

Rifaximin (Rifaximin) is the semi-synthetic derivant of Rifamycin Sodium, is intestinal or the topical antibiotics of wide spectrum, efficient, low toxicity.This medicine is developed by Italian Alpha Co., Ltd, at first went on the market in Italy as anti-infection property diarrhoea medicine in 1987, be widely used in Europe, the U.S. etc. afterwards, used at China's clinical medicine through SFDA approval in 2004, and be mainly used in preventing and treating the caused acute and chronic intestinal infection of sensitive organism etc.Report that the listing dosage form has dry suspension, oral capsule, tablet, granule etc.

The rifaximin has a broad antifungal spectrum, antibacterial activity is strong.To the golden Portugal bacterium in the gram positive aerobic bacteria, staphylococcus epidermidis, enterococcus, clostridium difficile etc., to Gram negative escherichia coli, Salmonella, shigella, yersinia and Grain-positive anaerobe all have the height antibacterial activity, the activity of its anti-gram positive bacteria is better than gram-negative bacteria.

Rifaximin is the same with other rifamycinoid antibiotics, and bactericidal action mechanism also is the synthetic of the anti-bacteria RNA by irreversibly being combined with the B-subunit of DNA of bacteria-dependenc RNA polymerase, and finally anti-bacteria protein is synthetic.Since with the combination of enzyme be irreversible, so rifaximin is bactericidal activity to sensitive organism, bring into play rapidly antibacterial action in the part by killing intestinal or local pathogen.

Rifaximin is oral, substantially without absorbing, only has the rifaximin of less than 0.025% to discharge from urine with original shape, so orally be fit to very much prevent and treat enterobacterial infection.Behind the rat single oral rifaximin 100mg/kg, only there is a small amount of medicine (0.2 μ g/ml, 9.6 μ g/ml) in serum and the liver,, reach higher concentration at gastrointestinal mucosa, it is few to distribute at liver, kidney, lung, and most of medicine passes through defecate.Rat single oral rifaximin 25mg/kg 72 hours, the response rate in the feces is 53.4%, the response rate in the urine only is 0.29%.People healthy volunteer fasting is after 9 hours, and oral rifaximin 400mg does not detect this medicine in the plasma sample; In the administration 48 hours, the original shape medicine of visible minute quantity in the urine (be lower than dosage 0.01%).Lactation period or the dry milk phase milch cow, each nipple injects 100mg rifaximin, does not detect rifaximin in the blood plasma.

Compare with traditional rifamycin analog derivative such as rifampicin, rifaximin has strengthened anti-gram negative bacteria effect, does not absorb, and without systemic side effects, does not especially propagate Mycobacterium tuberculosis drug-resistant, it is used at veterinary clinic obtain possibility.Compare with aminoglycoside antibiotics, the rifaximin antimicrobial spectrum is wider, and activity is stronger, and without systemic side effects (do not damage auditory function, can not cause renal insufficiency), intestinal does not need intestinal spasmolytic and intestinal adsorbent drug yet when using.Compare with third generation Development of Fluoroquinolone Antibacterials, rifaximin has increased the effect to positive bacterias such as streptococcus, and safety is larger.

The rifaximin better tolerance, untoward reaction is slight, and toxicity is little.Oral LD50＞the 5g/kg of mice.The SD rat gavages rifaximin 25,50 and 100mg/kg every day, continuous 180d, and except the female rats serum total cholesterol occurs dosage correlation increases, other hematologys, serum biochemistry and histopathologic examination are showed no abnormal change.Rat and rabbit experiment are not all observed fetal toxicity and the teratogenesis toxic action of rifaximin.

At present, rifaximin is mainly used in preventing and treating responsive microbial acute and chronic intestinal infection, diarrhoea syndrome, summer diarrhea, traveler's diarrhea, enterocolitis and the prophylactic of average of operation periods intestinal etc. on the clinical medicine.Related experiment shows that its curative effect is better than the medicines such as ciprofloxacin, neomycin, sulfamethoxazole/Sulfamonomethoxine.With research deeply, its indication expands skin and mucosa local application to, is used for the sensitive organisms such as control periodontal, skin and vagina and infects.

The rifaximin effect is strong, and toxicity is low.European Union, the U.S. have allowed rifaximin to be applied to veterinary clinic, and control is by the microbial part of sensitivity and skin infection.Be mainly used in clinically breast perfusion control mammitis of cow, intrauterine drug administration preventing and controlling cow endometritis, the local infection of external control many animals such as cattle, sheep, goat, horse, rabbit, house pet etc. etc.On China's veterinary clinic, there is not yet its application report.

Suppository is the common formulations of control endometritis, has reported in the dosage form at rifaximin, there is not yet suppository formulation.In the suppository preparation, need to consider the problem of dissolving of insoluble drug.Rifaximin is insoluble in water, and when conventional method prepared suppository, disintegration and stripping were often overtime, affected its antibacterial action.The present invention has announced a kind of ingenious solid dispersions technique that utilizes and has prepared the method that domestic animal is used the rifaximin vaginal suppository, namely adopt solid dispersions technique, rifaximin can be existed with molecularity in solid carrier, and this carrier can be used as again the suppository base material simultaneously, increases suppository hardness.In actual the enforcement, at first with carrier material rifaximin is prepared into solid dispersion, again with the suppository base mix homogeneously, bolt processed can solve preferably the principal agent distribution uniformity and melt the change horizon problem, is conducive to suppository and better plays a role.

Borneolum Syntheticum, thymol, Folium eucalypti globueli (Eucalyptus globulus Labill.) wet goods have certain antibiotic, antiinflammatory action, are commonly used for the ancillary drug of endometritis suppository, and the antibacterial and anti-inflammation functions that increases principal agent is worked in coordination with in performance, are conducive to the comprehensive therapeutic effect of preparation.

Summary of the invention

The objective of the invention is the above-mentioned deficiency for prior art, a kind of domestic animal rifaximin vaginal suppository is provided.

Another object of the present invention provides the preparation method of this suppository.

Purpose of the present invention can be achieved through the following technical solutions:

Domestic animal rifaximin vaginal suppository comprises following component: rifaximin solid dispersion 8.5-25.5 weight portion, substrate 30-88 weight portion, water: 6.0-12.5 weight portion, surfactant: 0.01-1.0 weight portion; Synergist: 0.01-10.0 weight portion, antiseptic: 0.01-5.0 weight portion, wherein said rifaximin solid dispersion be with solid dispersion carrier 7.3-21.9 weight portion after 70 ℃ of-80 ℃ of water-bath meltings, add the rifaximin solution that has obtained with 2-16 weight portion anhydrous alcohol solution 1.2-3.6 weight portion rifaximin, stir evenly, after 70 ℃ of-80 ℃ of water-baths boil off dehydrated alcohol, cooling down is solidified rapidly, and get final product; Described domestic animal with the preparation method of rifaximin vaginal suppository is: at first take hot fusion method to prepare the rifaximin solid dispersion, rifaximin solid dispersion and substrate and surfactant, synergist, the antiseptic of preparation prepared rifaximin suppository by hot fusion method.

Described rifaximin solid dispersion carrier be selected from PEG300, PEG400, PEG600, PEG1000, PEG4000, PEG6000, PEG10000, PVP40000, poloxamer series, Myrij class, brejs, citric acid, succinic acid, carbamide, malic acid, polyvidone, sucrose, stearic acid, glucosan, ethanol, dimethyl formamide, dimethyl acetylamide, propylene glycol, the alpha-pyrrolidone any one or multiple.Preferred rifaximin solid dispersion principal agent and carrier are: contain rifaximin: 1.8-3.6 weight portion, cetomacrogol 1000: 4.0-9.5 weight portion, and Macrogol 4000: 4.5-12.4 weight portion.Dehydrated alcohol: 4.0-16.0 weight portion.

Described suppository base be selected from glycerol, gelatin, PEG300, PEG400, PEG600, PEG1000, PEG4000, PEG6000, PEG10000,, in the poloxamer series, semi-synthetic fatty acid glyceride, cocoa butter, oleum sapii any one or multiple; Preferably glycerine: 55-75 weight portion, gelatin: 10-25 weight portion, cetomacrogol 1000: 4.0-11.5 weight portion and Macrogol 4000: 4.5-14.0 weight portion.

Described surfactant be selected from poloxamer class, sodium lauryl sulphate, tween 80, Tween-60, Tween-40, tween 20, stearyl alcohol sodium sulfonate, polyoxyethylene high fatty alcohol, sucrose ester, sorbitol fatty ester or the soybean phospholipid any one or multiple.

Described synergist be selected from eucalyptus oil, thymol, Borneolum Syntheticum, PEG400, disodium edetate, trisodium citrate, boric acid, sodium bicarbonate or dimethyl sulfoxine any one or multiple.

Described antiseptic be selected from ethylparaben, butyl p-hydroxybenzoate, phenol, domiphen bromide, boric acid, phenylmercuric nitrate, eucalyptus oil, thymol, potassium sorbate, sodium benzoate, thimerosal any one or multiple.

The described domestic animal preparation method of rifaximin vaginal suppository, comprise following steps: 1. with after solid dispersion carrier and 70 ℃ of-80 ℃ of water-bath meltings, add the rifaximin ethanol solution, stir evenly, after 70 ℃ of-80 ℃ of water-baths boiled off dehydrated alcohol, cooling down was solidified to get the rifaximin solid dispersion rapidly; 2. take by weighing substrate by formulation content, add entry, heating in water bath, stirring and evenly mixing; 3. the rifaximin solid dispersion is joined in the matrix solution 2., and add synergist, surfactant and antiseptic, behind the stirring and evenly mixing, impouring scribbles in the bolt mould of lubricant to slightly overflowing die orifice; 4. 4 ℃ of-0 ℃ of cold putting a few hours are pruned after solidifying fully and are overflowed part, and die sinking is taken out, and get final product.

Beneficial effect:

The rifaximin antibacterial action is strong, has a broad antifungal spectrum, and multiple Grain-positive, gram negative aerobic bacteria and anaerobe are all had the height antibacterial activity.Rifaximin is oral not to be absorbed, and untoward reaction is slight, and so far there are no, and serious adverse reaction is reported.The antibacterial action characteristics of rifaximin are suitable for preventing and treating the animal endometritis such as domestic animal such as milch cow, cattle, pig, sample, dog very much.

Suppository is the dosage form that more often adopt with medicine in the uterus.Glycerol gelatin matrix is as vaginal suppository substrate, and toughness is stronger, and goods are flexible, frangibility not, but its thermostability (softening temperature) is low, and the substrate thickness is made trouble in addition; On the other hand, because rifaximin is insoluble in water, conventional hot melt prepares rifaximin glycerin gelatine bolt, and medicine is outstanding to be mixed in the substrate, affects its release, even affect its clinical efficacy.

The present invention at first adopts solid dispersions technique, prepares rifaximin solid dispersion solution with appropriate carrier, guarantees the principal agent Uniform Dispersion; And selected carrier possesses and the glycerol gelatin matrix characteristic that mixes, and becomes the part of suppository base, and can overcome the low worry of melting limit for length when becoming of glycerol gelatin matrix thermostability.Optimize suppository base by orthogonal experiment, reach optimal thermal resistance and become the time limit with melting, good looking appearance, thermostability is higher, is difficult for softening.

Specific embodiment:

Embodiment 1:

The preparation of rifaximin solid dispersion

Prescription:

Take by weighing PEG1000, PEG4000 by prescription content, after 70 ℃ of-80 ℃ of water-bath meltings, add the rifaximin solution of having used the 8.0g anhydrous alcohol solution, stir evenly, after 70 ℃ of-80 ℃ of water-baths boiled off ethanol, cooling down was solidified rapidly, namely gets the rifaximin solid dispersion.

Embodiment 2

The preparation of rifaximin solid dispersion

Prescription:

Take by weighing PEG1000, poloxamer F68 by prescription content, after 70 ℃ of-80 ℃ of water-bath meltings, add the rifaximin solution of having used the 8.0g anhydrous alcohol solution, stir evenly, after 70 ℃ of-80 ℃ of water-baths boiled off ethanol, cooling down was solidified rapidly, namely gets the rifaximin solid dispersion.

Embodiment 3

The preparation of rifaximin solid dispersion

Prescription:

Take by weighing PEG4000, poloxamer F68 by prescription content, after 70 ℃ of-80 ℃ of water-bath meltings, add the rifaximin solution of having used the 8.0g anhydrous alcohol solution, stir evenly, after 70 ℃ of-80 ℃ of water-baths boiled off ethanol, cooling down was solidified rapidly, namely gets the rifaximin solid dispersion.

Embodiment 4

Conventional method prepares rifaximin suppository

Prescription:

Method for making: take by weighing gelatin by formulation content, add distilled water dipping 1h, after 40 ℃ of water-bath dissolvings, add glycerol, 65 ℃ of stirred in water bath mixings; Rifaximin is joined in the above-mentioned substrate, and the limit edged stirs, and behind the mixing, impouring scribbles in the bolt mould of lubricant to slightly overflowing die orifice; 4. in 4 ℃ of-0 ℃ of cold putting a few hours, prune after solidifying fully and overflow part, die sinking is taken out, and get final product.

Above-mentioned prescription is the used theory prescription consumption of 50 pieces of suppositorys of preparation.Every piece of heavily about 2 grams of rifaximin vaginal suppository contain principal agent 50mg.44 pieces of actual preparations.

3 test sample thermostabilitys of casual inspection (softening temperature) all are lower than≤and 33.5 ℃.Melt and become the time limit experiment: select 3 of self-control suppositorys, melt according to " Chinese veterinary pharmacopoeia " (2010) and become the inspection of overtime check method.Be limited to when 3 test samples melt just as a result: 70.2min, 78.6min, 81.1min all above 60 minutes, do not meet the pharmacopeia regulation.

Embodiment 5

Substrate influence factor's screening of rifaximin glycerol gelatin matrix vaginal suppository

On embodiment 4 bases, single factors content prepares rifaximin suppository in change glycerol, gelatin, the water-based, finds: when being increased to 30 gram with the components of gelatin consumption by 20 grams, the suppository softening temperature changes little, to become the time limit longer but melt, and the substrate viscosity is too high, also is unfavorable for preparing suppository.The glycerin component consumption reduces, and the suppository softening temperature increases, and to become the time limit longer but melt.

Embodiment 6

The substrate optimization of rifaximin glycerol gelatin matrix vaginal suppository

Select glycerol, solid dispersion carrier material such as cetomacrogol 1000 and Macrogol 4000 three factors, each factor is divided three levels, prepares suppository with hot melt.Be limited to the investigation standard with thermostability with melting when becoming, the substrate ratio that screening is best sees Table 1.

Table 1

As can be known from the above table, melting just in the time limit scope of regulation, qualified prescription number only has 3,5,7 three groups, finally selects the highest substrate prescription of thermostability (softening temperature) to be A₁B₃C₃Its optimum substrate ratio is per 50 pieces of suppositorys (every piece 2 grams), and matrix group becomes: water, 6g; Gelatin, 12g; Glycerol, 60g; PEG1000,5g; PEG4000,5g.

The optimum substrate suppository preparation of embodiment 7 rifaximin vaginal suppositories

Above-mentioned prescription is the used theory prescription consumption of 50 pieces of suppositorys of preparation.Every piece of heavily about 2 grams of rifaximin vaginal suppository contain principal agent 50mg.45 pieces of actual preparations.

Method for making: take by weighing gelatin by formulation content, add distilled water dipping 1h, after 40 ℃ of water-bath dissolvings, add glycerol, 65 ℃ of stirred in water bath mixings; The rifaximin solid dispersion is added wherein, and the limit edged stirs, evenly after, add the stirring and evenly mixings such as Borneolum Syntheticum, sodium lauryl sulphate, 5% ethylparaben alcoholic solution, impouring scribbles in the bolt mould of lubricant to slightly overflowing die orifice; In 4 ℃ of-0 ℃ of cold putting a few hours, to prune after solidifying fully and overflow part, die sinking is taken out, and get final product.

3 test samples of casual inspection melt and become the time limit, and method is respectively with embodiment 4: 54min, 55min, 53min, all dissolvings in 60 minutes meet the pharmacopeia regulation.Softening temperature is: 36.1 ℃, 36.2 ℃, 36.1 ℃

Embodiment 8

Above-mentioned prescription is the used theory prescription consumption of 50 pieces of suppositorys of preparation.Every piece of heavily about 2 grams of rifaximin vaginal suppository contain principal agent 50mg.44 pieces of actual preparations.

Preparation method: with embodiment 7.3 test samples of casual inspection melt and become time limit and softening temperature, and method is respectively with embodiment 4: 59min, 58.5min, 59.3min, all dissolvings in 60 minutes meet the pharmacopeia regulation.Softening temperature is divided into: 36.8 ℃, 36.9 ℃, 36.2 ℃

Embodiment 9

Above-mentioned prescription is the used theory prescription consumption of 50 pieces of suppositorys of preparation.Every piece of heavily about 2 grams of rifaximin vaginal suppository contain principal agent 50mg.45 pieces of actual preparations.

Preparation method: with embodiment 7.3 test samples of casual inspection melt and become time limit and softening temperature, and method is with embodiment 4.Be limited to when 3 test samples melt just as a result: 59.5min, 57.5min, 58.3min, all dissolvings in 60 minutes meet the pharmacopeia regulation.Softening temperature is divided into: 36.0 ℃, 36.1 ℃, 36.2 ℃

Claims (5)

1. utilize the domestic animal rifaximin vaginal suppository of solid dispersions technique preparation, it is characterized in that comprising following component: rifaximin solid dispersion 8.5-25.5 weight portion, substrate 30-88 weight portion, water: 6.0-12.5 weight portions, surfactant: 0.01-1.0 weight portion; Synergist: 0.01-10.0 weight portion, antiseptic: 0.01-5.0 weight portion, wherein said rifaximin solid dispersion be with solid dispersion carrier 7.3-21.9 weight portion after 70 ℃ of-80 ℃ of water-bath meltings, add the rifaximin solution that has obtained with 2-16 weight portion anhydrous alcohol solution 1.2-3.6 weight portion rifaximin, stir evenly, after 70 ℃ of-80 ℃ of water-baths boil off dehydrated alcohol, cooling down is solidified rapidly, and get final product; Described domestic animal with the preparation method of rifaximin vaginal suppository is: at first take hot fusion method to prepare the rifaximin solid dispersion, rifaximin solid dispersion and substrate and surfactant, synergist, the antiseptic of preparation prepared rifaximin suppository by hot fusion method; Described solid dispersion carrier is selected from multiple arbitrarily in any one or PEG300, PEG400 in PEG4000, PEG6000, PEG10000, the poloxamer series, PEG600, PEG1000, PEG4000, PEG6000, PEG10000, the poloxamer series, and described substrate is selected from glycerin gelatine.

2. the domestic animal rifaximin vaginal suppository that utilizes solid dispersions technique preparation according to claim 1, it is characterized in that described surfactant be selected from poloxamer class, sodium lauryl sulphate, tween 80, Tween-60, Tween-40, tween 20, stearyl alcohol sodium sulfonate, polyoxyethylene high fatty alcohol, sucrose ester, sorbitol fatty ester or the soybean phospholipid any one or multiple.

3. the domestic animal rifaximin vaginal suppository that utilizes solid dispersions technique preparation according to claim 1, it is characterized in that described synergist be selected from eucalyptus oil, thymol, Borneolum Syntheticum any one or multiple.

4. the domestic animal rifaximin vaginal suppository that utilizes solid dispersions technique preparation according to claim 1, it is characterized in that described antiseptic be selected from butyl p-hydroxybenzoate, phenol, domiphen bromide, boric acid, phenylmercuric nitrate, eucalyptus oil, thymol, potassium sorbate, sodium benzoate, thimerosal, ethylparaben any one or multiple.

5. domestic animal claimed in claim 1 is characterized in that comprising following steps with the preparation method of rifaximin vaginal suppository:

The solid dispersion carrier after 70 ℃ of-80 ℃ of water-bath meltings, is added the rifaximin ethanol solution, stir evenly, after 70 ℃ of-80 ℃ of water-baths boiled off dehydrated alcohol, cooling down was solidified to get the rifaximin solid dispersion rapidly;

Take by weighing substrate by formulation content, add entry, heating in water bath, stirring and evenly mixing;

The rifaximin solid dispersion is joined

In the solution, and add synergist, surfactant and antiseptic, behind the stirring and evenly mixing, impouring scribbles in the bolt mould of lubricant to slightly overflowing die orifice;

4 ℃ of-0 ℃ of cold putting a few hours are pruned after solidifying fully and are overflowed part, and die sinking is taken out, and get final product.