CN101269069A - Oral preparation containing amoxicillin and clavulanic acid, preparation method and application thereof - Google Patents
Oral preparation containing amoxicillin and clavulanic acid, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a buccal tablet containing amoxicillin and clavulanic acid, the preparation method and the use. The invention aims to provide a buccal tablet with amoxicillin and clavulanic acid adopted as the medicinal ingredients. The buccal tablet can be dissolved among the salvia in the oral cavity and enter the oral cavity, the pharynx and pharyngeal tonsils to play the role of resisting bacteria. The invention adopts amoxicillin, clavulanic acid and salt derivatives as the medicinal ingredients and can be made into various pharmaceutical formulations, such as buccal tablets, candies, dropping pills and so on. The buccal tablet containing amoxicillin and clavulanic acid has the characteristics of fast effect, excellent curative effect and convenient drug delivery, can directly improve the concentration of antibiotic drugs at the pathological part and enhance the antibacterial capacity of the pathological part, and is more suitable for majorities of patients.
Description
Technical field
The present invention relates to a kind of medicine and its production and use, particularly contains buccal lozenge of amoxicillin and clavulanate potassium and its production and use.
Background technology
Pharyngitis is the modal disease of puzzlement modern life, is pharyngeal mucous membrane, submucous tissue and adenoid diffuse inflammation, often is the part of upper respiratory tract infection.Be divided into acute and chronic two kinds clinically.Acute pharyngitis is many in autumn and winter and morbidity at the end of winter and the beginning of spring.Pathological changes ordinary wave and whole pharyngeal cavity also can limit to a place.Can cause by virus, antibacterial and physical chemical factor and high temperature, dust, fumagine, irritative gas etc.Bacterial infection is based on gram-positive coccis such as streptococcus, staphylococcus and Diplococcus pneumoniaes.Wherein serious with A group group B streptococcus causer, antibacterial or toxin enter blood, can cause the purulent lesion of organ at a distance, are called acute septic pharyngitis.Treat with oral or injection antibiotics control infection.
The chronic pharyngitis course of disease is very long, and the symptom stubbornness is often by due to the local infection or general pathological changes secondary, with chronic pathological changes repeatedly acute attack be its characteristics, in many cases, acute attack is to be caused by bacterial infection, therefore, suitable antibacterial therapy helps to control acute symptom.
Acute tonsillitis is a kind of non-specific acute inflammation of very common palatine tonsil, often with to a certain degree pharyngeal mucous membrane and swallow adenoid acute inflammation.Main pathogenic bacterium are streptococcus, staphylococcus, Diplococcus pneumoniae.Adenovirus also can cause primary disease.Antibacterial and virus mixed infection are quite a few to be seen.Antibacterial may be extraneous the intrusion, also may be the antibacterial that is hidden in the tonsillar crypts, when Abwehrkraft des Koepers because of cold, humidity, overworked, have a delicate constitution, tobacco and wine are excessive, when factors such as harmful gas stimulation reduce suddenly, due to bacterial reproduction is strengthened.Acute tonsillitis is acute attack repeatedly on chronic tonsil basis often.Clinical manifestation aversion to cold, hyperpyrexia, pharyngalgia, aggravation etc. when swallowing can the concurrent rheumatic fever relevant with hemolytic streptococcal infection, multiple general diseases such as acute glome-rulonephritis, myocarditis, arthritis.Treatment adopts pain relieving to bring down a fever, oral or injection antibiotics control infection.
The oral cavity infection disease mainly comprises dental disease, periodontal and the disease of cari oris mucosa, as dental caries, pulpitis, periapical periodontitis, periodontitis, recurrent aphtha, oral ulcer, oral leukoplakia, monilial stomatitis, pericoronitis, necrotic stomatitis, thrush, gingivitis, membranous stomatitis, periodontal disease, herpetic stomatitis etc.Antibacterial is the important paathogenic factor that causes the oral cavity infection disease.Intraoral have a large amount of Gram-positives and a gram negative bacteria, and its value volume and range of product all occupies first of the whole body.According to the study, contain antibacterial in every milliliter of saliva and reach 1.5 hundred million.Under certain conditions, incorrect etc. when food debris accumulation, crowded dentition, method for brushing teeth, form dental plaque, tartar, when the kind of antibacterial changes, the amount of pathogenic bacterium increases or passive protective physical fitness descends, cause the generation of oral cavity infection disease.Therefore, oral cavity infection disease is caused by the various bacteria synergism.The patient often has symptoms such as toothache, gingival hemorrhage, redness, odontoseisis displacement, halitosis.Swelling and aching of gum, pyorrhea also can be used as infection focus, cause such as systemic diseases such as arthritis, the heart, cerebrovascular disease.
The amoxicillin is the semi-synthetic penicillium sp rope of a kind of wide spectrum, the stronger bacteria cell wall ability that penetrates is arranged, by suppressing the glycosidase of antibacterial, make the bacteria cell wall biosynthesis block, formation spheroplast breaks and dissolves death rapidly, be the active drug that infects due to a kind of clinical practice wide range of therapeutic gram negative bacteria and the gram positive bacteria, but the independent use in amoxicillin mainly is applicable to the infection due to the sensitive organism that does not produce beta lactamase.Continually develop and be widely used in clinical along with antibiotic, caused drug-resistance of bacteria, antibacterial is day by day increased the drug resistance of common antibiotics.Antibacterial produces drug resistance through number of ways to antibiotic, wherein to produce beta lactamase.Use beta lactamase restrainer can improve the antibiotic antibacterial activity of some beta-lactam class greatly, and enlarge antimicrobial spectrum.The beta lactamase restrainer that is most widely used at present is a clavulanic acid.Clavulanic acid claims clavulanic acid again, is bacteriogenic natural lactamase restrainer, contains the beta-lactam ring in the structure, and antibacterial action is very weak, presses down the enzyme effect but have strong effect wide-spectrum.It with enzyme firm combining takes place makes enzyme deactivation, and the elimination with inhibitor does not bring back to life.The no clinical value of simple use, normal and other beta-lactam class antibiotic share, to strengthen antibacterial action.The beta lactamase that the beta lactamase that clavulanic acid produces staphylococcus aureus, gram negative bacilli produce has obvious inhibitory action.Amoxicillin/clavulanate has been developed into tablet, capsule, injection etc., all adopts whole body administrations such as oral or injection.Be easy to cause the local pain reaction when using inconvenience, administration in view of injection.Oral absorption such as tablet and capsule is slower, and entering behind the blood distributes by whole body dilutes medicine in blood, make medicine lower at the blood drug level of diseased region, and it is also longer to reach time of effective blood drug concentration at diseased region, influences its effective antibacterial efficacy.Therefore, the development buccal lozenge, by the oral cavity buccal, directly act on diseased region with high concentration medicine, be used for pharyngitis, pharyngoamygdalitis and oral cavity infection treatment of diseases, can overcome above-mentioned shortcoming, can kill oral cavity, the various pathogenic microorganism in throat rapidly, for effective treatment of throat oral cavity infection disease provides strong treatment means.
Summary of the invention
The purpose of this invention is to provide a kind of is buccal lozenge of ingredient and its production and use with amoxicillin and clavulanic acid, the medicine through port is contained in the intraoral saliva and dissolves, enter around the oral cavity, pharyngeal and pharyngeal tonsil position, bring into play its antibacterial action, the clinical pharyngitis that is used for the treatment of, pharyngoamygdalitis and oral cavity infection disease, particularly by prolonging preparation in intraoral melting time, it is the disintegration of preparation, prolong the action time of medicine and local lesion, and then improved the treatment pharyngitis, the drug quality of pharyngoamygdalitis and oral cavity infection disease medicament.
For achieving the above object, the present invention has adopted following technical scheme.
The buccal lozenge (amoxicillin and clavulanic acid buccal lozenge) that contains amoxicillin and clavulanic acid of the present invention is made up of ingredient that comprises amoxicillin and clavulanic acid and salt derivative thereof and substrate, wherein the weight ratio of amoxicillin and clavulanate potassium is n: 1, n is the number of 2-14, preferred 2: 1,4: 1,6: 1,7: 1,8: 1,10: 1,12: 1 and 14: 1, medicine: substrate=1: 1-1: 30, through port intracavity buccal administration clinically is characterized in that described amoxicillin and clavulanic acid buccal lozenge are in the treatment pharyngitis, the application of pharyngoamygdalitis and oral cavity infection disease.Select 10-100 minute the disintegration of described amoxicillin and clavulanic acid buccal lozenge, preferred 15-60 minute, more preferably 20-60, preferred 20-40 minute especially, by prolonging preparation in intraoral melting time, and then improve medicine to pharyngitis, pharyngoamygdalitis and oral cavity infection treatment of diseases effect, improve drug quality.
In the comfort level that described drug quality comprises side reaction and other discomfort brought to patient in the comfort level, drug use process of medication effect, drug use, medicine stores and carry, the characteristics such as complexity of drug manufacture one or multinomial.Described raising drug quality comprises the therapeutic effect that strengthens medicine, reduce and causedly in the drug use process do not accommodate misery, conveniently use, be easy to store and carry, improve safety that medicine uses, simplify production technology, reduce in the characteristics such as toxic and side effects of medicine one or multinomial, for example compare with injection, buccal lozenge has that production technology is simple, storage and convenient drug administration, can avoid fully injecting to what patient brought and do not accommodate the unsafe factor that misery and injection bring to patient.
Wherein, selected ingredient is chemical compound and the salt derivative thereof with following feature:
Chinese: amoxicillin
English by name: Amoxicillin
Formal name used at school is: 2S, and 5R, 6R)-3, the 3-dimethyl-6-[(R)-(-)-2-amino-2-(4-hydroxy phenyl) acetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid trihydrate
Molecular formula: C
16H
19N
3O
5S3H
2O
Molecular weight: 419.46
Amoxicillin salt derivative commonly used is the amoxicillin sodium salt
Wherein, selected clavulanic acid is chemical compound and the salt derivative thereof with following feature:
English Clavulanate by name,
Molecular formula: C
8H
8KNO
5,
Molecular weight: 237.25,
Chemical structural formula is:
Clavulanic acid salt derivative commonly used is a clavulanic acid potassium salt.
Wherein said substrate is the preparation adjuvant that is grouped into by one or more one-tenth, comprises diluent (filler), binding agent, disintegrating agent, lubricant, fluidizer, slow releasing agent, coloring agent, correctives, spice etc.
Described preparation type includes but not limited to buccal tablet, drop pill, confection.As a kind of preparation type commonly used, buccal lozenge is meant and is contained in the oral cavity, the drug slow dissolving produces the pharmaceutical preparation of persistent local action, the main local therapeutic effects that rises, detect the whole disintegrates of planted agent in 30 minutes according to version Pharmacopoeia of People's Republic of China in 2005 detection method second disintegration.But the disintegration of present existing buccal lozenge is all below 10 minutes, as GUILIN XIGUA SHUANG buccal tablet, FUFANG CAOSHANHU HANPIAN, ribavirin buccal tablet, gluconic acid calcium tablet, ammonium iodide buccal tablet, JINSANGZIHOUBAO buccal tablet etc.Disintegration, the too fast medicine that then shows was short in partial action time, will obviously influence the topical therapeutic effect of medicine.The inventor is surprised to find by buccal lozenge of the present invention is made in amoxicillin and clavulanic acid by designing different pharmaceutical preparation technologies, remained on more than 10 minutes the disintegration of buccal lozenge, preferred 10-100 minute, the dissolution of ingredient reached more than 80% when making complete disintegrate simultaneously.For the preferred 20-60 minute disintegration of buccal lozenge for the purpose of the taking convenience, significant prolongation the action time of medicine and local lesion, thereby improved the topical therapeutic effect of medicine.
In addition, buccal lozenge is after containing of intraoral disintegration, and ingredient wherein should mainly be present in dissolved state just can bring into play its due therapeutical effect in the saliva.Amoxicillin and clavulanic acid comprise prototype compound and salt derivative two classes; prototype compound slightly soluble in water wherein; do not carry out hydrotropy as preparation process and handle the then medicine purpose that very difficult realization mainly exists with dissolved state in saliva; therefore; the present invention utilizes surfactant polyethylene; polyoxyethylene stearate 40 esters; beta cyclodextrin; poloxamer; carboxymethyl starch sodium; substrate such as stearic acid and medicine material are made solid dispersion or sucrose; maltose; dextrinose; the dextrinose oligosaccharide; panose; cottonseed sugar; stachyose; oligofructose; glucose; fructose; lactose; inulin; protein sugar; stevioside; xylitol; maltose alcohol; sorbitol; gelatinized corn starch; syrup; Icing Sugar such as maltose and medicine material are made solid dispersion; make medicine be molecule; colloid or microcrystalline state are scattered in the substrate; the total surface area of medicine increases; and substrate is hydrophilic; medicine had wetting action; can make medicine molten microgranule or the solution of loosing into rapidly; thereby make the dissolving of medicine and absorb quickening; thereby improved bioavailability, reached the purpose that significantly improves medicine topical therapeutic effect.
The present invention relates to contain the drop pill of following composition:
Described drop pill is made up of ingredient that includes amoxicillin and clavulanic acid and substrate, adopt water-bath, oil bath or other mode of heating, mixed material is heated to fusion, stir, insert on the drop pill machine with suitable speed, splash in 40 →-15 ℃ the condensing agent liquid paraffin, methyl-silicone oil, vegetable oil any one or a few, drying forms, and its mesostroma is by containing Polyethylene Glycol
(2000,4000,6000,8000,10000, 20000), one or more one-tenth in polyoxyethylene stearate 40 esters, beta cyclodextrin, poloxamer, carboxymethyl starch sodium, stearic acid, sodium stearate, glycerin gelatine, glyceryl monostearate, Lac, polyoxyethylene monostearate, polyethers and the medicinal slow release agent are grouped into.
The present invention relates to contain the buccal tablet of following composition:
Described buccal tablet is made up of ingredient that includes amoxicillin and clavulanic acid and substrate, and wherein said substrate contains following material: diluent 1-100%; Binding agent 0-30%; Disintegrating agent 0-10%; Lubricant 0-20%; Fluidizer 0-20%; Slow releasing agent 0-50% and conventional coloring agent, correctives, spice.
The present invention relates to contain the confection of following composition:
Described confection is made up of ingredient that includes amoxicillin and clavulanic acid and substrate, and wherein said substrate contains following material: diluent 1-100%; Binding agent 0-20%; Disintegrating agent 0-10%; Lubricant 0-10%; Fluidizer 0-10%; Slow releasing agent 0-50% and conventional coloring agent, correctives, spice.
Preparation method of the present invention comprises following order and step, but following be not limitation of the invention:
1. the preparation method of buccal tablet: proportionally amoxicillin and clavulanic acid are mixed with substrate; When described substrate was Icing Sugar, substrate contained but is not limited to one or more composition in sucrose, maltose, dextrinose, dextrinose oligosaccharide, panose, cottonseed sugar, stachyose, oligofructose, glucose, fructose, lactose, inulin, protein sugar, stevioside, xylitol, maltose alcohol, sorbitol, gelatinized corn starch, syrup, the maltose etc.; When described substrate was solid dispersion, substrate contained but is not limited to Polyethylene Glycol
(2000, 4000,6000,8000,10000,20000), polyoxyethylene stearate 40 esters, beta cyclodextrin, poloxamer, carboxymethyl starch sodium, stearic acid, sodium stearate, glycerin gelatine, glyceryl monostearate, Lac, polyoxyethylene monostearate, polyethers one or more composition.
(1) takes by weighing an amount of Icing Sugar or other substrate, add water or binding agent, make suitable soft material, add the ingredient that contains amoxicillin and clavulanic acid, stir, cut apart, shaping, drying.
(2) take by weighing an amount of Icing Sugar or other substrate, add the ingredient that contains amoxicillin and clavulanic acid, add water or binding agent, stir, granulate, drying is shaped on tablet machine.
(3) take by weighing an amount of Icing Sugar or other substrate, add the ingredient that contains amoxicillin and clavulanic acid,,, on tablet machine, be shaped then through cooled and solidified through being heated as the miscible or miscible state of semi-molten of fusion.
(4) take by weighing an amount of Icing Sugar or other substrate,, be cooled to 70-100 ℃, add the ingredient that contains amoxicillin and clavulanic acid, stir, on tablet machine, be shaped through being heated as the miscible or miscible state of semi-molten of fusion.
2. the preparation of drop pill: proportionally amoxicillin and clavulanic acid are mixed with substrate; Substrate is by containing Polyethylene Glycol
(2000,4000,6000,8000,10000,20000), one or more one-tenth in polyoxyethylene stearate 40 esters, beta cyclodextrin, poloxamer, carboxymethyl starch sodium, stearic acid, sodium stearate, glycerin gelatine, glyceryl monostearate, Lac, polyoxyethylene monostearate, polyethers are grouped into.Adopt water-bath, oil bath or other mode of heating, mixed material is heated to fusion, stir, insert on the drop pill machine, splash in 40 →-15 ℃ the condensing agent with suitable speed.Condensing agent can be any one or a few in liquid paraffin, methyl-silicone oil, the vegetable oil.
3. the preparation of confection: proportionally amoxicillin and clavulanic acid are mixed with substrate; Matrix filler is to be grouped into by one or more the one-tenth that contains in sucrose, maltose, dextrinose, dextrinose oligosaccharide, panose, cottonseed sugar, stachyose, oligofructose, glucose, fructose, lactose, inulin, protein sugar, stevioside, xylitol, maltose alcohol, sorbitol, gelatinized corn starch, syrup, the maltose etc.
Take by weighing an amount of Icing Sugar or other substrate heat fused, be cooled to uniform temperature then after, add the ingredient contain amoxicillin and clavulanic acid, stir, make into the plasticity magma, cut apart extrusion molding;
Amoxicillin of the present invention is compared with existing general formulation with the clavulanic acid buccal lozenge has following benefit:
1) amoxicillin and the clavulanic acid concentration of raising diseased region improve its antibacterial ability.Medicine dissolves in the saliva in the oral cavity, enters around the oral cavity, pharyngeal and pharyngeal tonsil position.These medicines do not pass through hemodilution, form high local concentrations, strengthen antibacterial ability.Buccal lozenge of the present invention is compared with the dispersible tablet of prior art: aspect treatment pharyngitis and pharyngoamygdalitis, it is 85% that the clinical symptoms of amoxicillin and clavulanic acid buccal tablet group and sign are improved percentage rate, and oral group 50% of amoxicillin and clavulanate potassium dispersible tablets illustrate that the curative effect of buccal tablet is better than oral formulations.Aspect treatment oral cavity infection disease, it is 45% that amoxicillin and clavulanate potassium buccal tablet group clinical symptoms and sign are improved percentage rate, and oral group 25% of amoxicillin and clavulanate potassium dispersible tablets illustrate that the curative effect of buccal tablet is better than oral formulations.
2) rapid-action.Medicine acts on pathological tissues immediately behind dissolved in oral cavity, saved to absorb the time limit that distributes.
3) convenient drug administration.To the injection of need through the parenteral route administration, change into by sucking the messenger drug thing at dissolved in oral cavity, directly act on diseased region then, produce therapeutic effect, avoided the injection drug administration by injection to patient bring painful and inconvenient.
4) production technology is oversimplified.Compare with injection, the production technology of buccal lozenge and the quality of production require all to be lower than injection, can obviously reduce production costs.
5) preparation of buccal lozenge of the present invention and prior art for preparing is relatively: matched group disintegration 14 ± 4 (minute), the dissolution of amoxicillin and clavulanate potassium is 58 ± 6 (%) and 96 ± 8 (%) during disintegrate fully.And be 16 ± 6 the disintegration of buccal lozenge of the present invention (minute), the dissolution of amoxicillin and clavulanate potassium is 95 ± 8 (%) and 97 ± 6 (%) during disintegrate fully.The result shows that buccal lozenge of the present invention has significantly improved the dissolution of amoxicillin.
Specific implementation method
By following concrete embodiment, can further understand the present invention, but following example not a limitation of the invention.
Embodiment 1-amoxicillin confection
Prescription: amoxicillin 71.5g, amoxicillin: clavulanate potassium (2: 1) mixture 42.8g, sucrose 838.2g, citric acid 10g, food pigment-40 0.1g, mannitol 10g, hypromellose 27.5g, 1000 of amount of formulation.
Method: preparation amoxicillin 71.5g, citric acid 10g, food pigment-40 0.1g, mannitol 10g, hypromellose 27.5g mixture grind, and cross 20 purpose sieves.Get sucrose 838.2 grams, be heated to 140 ℃ of fusings, be cooled to 85 ℃, add Amoxicillin Sodium 71.5g, stirring and evenly mixing stirred 10 minutes fast, and room temperature is cooled to solidifies, granulate, cross 20 purpose sieves, add the amoxicillin after sieving: clavulanate potassium (2: 1) mixture 42.8g, stirring and evenly mixing, place extrusion molding on the product shaping machine, every buccal tablet weighs 2 grams.Measure the disintegration of amoxicillin and clavulanate potassium confection in 37 ℃ of 900ml water and the dissolution during complete disintegrate then.
The result: be 17-24 minute disintegration, and fully the dissolution amoxicillin during disintegrate is 91%-95%, and clavulanate potassium is 94%-97%.
Embodiment 2-low sugar amoxicillin and clavulanate potassium confection
Prescription: amoxicillin 71.5g, amoxicillin: clavulanate potassium (2: 1) mixture 42.8g, sucrose 188.2g, oligofructose 300g, xylitol 300g, inulin 50g, citric acid 10g, food pigment-40 0.1g, mannitol 10g, hypromellose 27.5g, 1000 of amount of formulation.
Method: preparation citric acid 10g, food pigment-40 0.1g, mannitol 10g, hypromellose 27.5g mixture grind, and cross 20 purpose sieves.Get sucrose 188.2g, oligofructose 300g, xylitol 300g, inulin 50g, mix, be heated to 140 ℃ of fusings, add the mixture after sieving, stirred fast 10 minutes, be cooled to 85 ℃, add Amoxicillin Sodium 71.5g, stirring and evenly mixing stirred 10 minutes fast, room temperature is cooled to solidifies, and granulates, and crosses 20 purpose sieves, add the amoxicillin after sieving: clavulanate potassium (2: 1) mixture mixture 42.8g, stirring and evenly mixing places extrusion molding on the product shaping machine, and every buccal tablet weighs 2 grams.Measure the disintegration of amoxicillin and clavulanate potassium confection in 37 ℃ of 900ml water and the dissolution during complete disintegrate then.
The result: be 18-25 minute disintegration, and fully the dissolution amoxicillin during disintegrate is 93%-98%, and clavulanate potassium is 96%-100%.
Embodiment 3-amoxicillin and clavulanate potassium buccal tablet
Prescription: amoxicillin 71.5g, amoxicillin: clavulanate potassium (2: 1) mixture 42.8g, hypromellose 128 grams, Polyethylene Glycol
6000756.7 gram, aspartame 1 gram.
Method: preparation hypromellose 128 grams, Polyethylene Glycol
6000756.7 gram, aspartame 1 gram mixed-matrix, heat fused is cooled to 80 ℃, add Amoxicillin Sodium 71.5g, stirring and evenly mixing stirred 10 minutes fast, and room temperature is cooled to solidifies, granulate, cross 20 purpose sieves, add the amoxicillin after sieving: clavulanate potassium (2: 1) mixture 42.8g, stirring and evenly mixing, place extrusion molding on the product shaping machine, every buccal tablet weighs 2 grams.Measure the disintegration of amoxicillin and clavulanate potassium buccal tablet in 37 ℃ of 900ml water and the dissolution during complete disintegrate then.
The result: be 25-32 minute disintegration, and fully the dissolution amoxicillin during disintegrate is 95%-99%, and clavulanate potassium is 92%-96%.
The preparation of embodiment 4-amoxicillin and clavulanate potassium buccal drop pills
Method: taking polyethylene glycol 4,000 8.8 restrains respectively, polyethylene glycol 6000 25 grams, polyoxyethylene stearate 40 esters 1 gram, hypromellose 4 grams, beta cyclodextrin 1 gram, poloxamer 0.5 gram, stearic acid 0.1 gram, sodium stearate 0.1 gram, glycerin gelatine 0.1 gram, glyceryl monostearate 0.1 gram, Lac 0.1 gram, polyoxyethylene monostearate 0.1 gram, polyethers 0.1 gram, mix homogeneously, add the amoxicillin again: clavulanate potassium (2: 1) mixture 30 grams, fully mix, adopt electrically heated mode with the supplementary material mixture heated that makes to molten condition, adopt homemade special drilling pill machine, regulate its water dropper temperature and make it remain on 85 ℃ (error＜2%); With the methyl-silicone oil is condensing agent, the refrigeration control system of regulating the drop pill machine makes the temperature of condensing agent remain on 20 →-5 ℃ (error＜5%), the system of dripping, wait to take out behind the type of being shrunk to, remove the surface condensation agent, drying is made the drop pill that contains amoxicillin and clavulanate potassium 30mg/ grain, carry out then rounding rate (%), dissolve scattered time limit (minute), the mensuration of the ball method of double differences different (%) and hardness.The rounding rate is 81% as a result, and dissolve scattered time limit 11-13 minute, the ball method of double differences was different from 10%, and hardness is qualified, and fully the dissolution amoxicillin during disintegrate is 93%-98%, and clavulanate potassium is 95%-99%.
Embodiment 5-amoxicillin sodium and clavulanate potassium buccal tablet
Prescription: Amoxicillin Sodium 71.5g, amoxicillin: clavulanate potassium (2: 1) mixture 42.8g, gelatin 188.2g, glycerol 40g, water 60g, oligofructose 242.5g, xylitol 192g, inulin 50g, citric acid 10g, food pigment-400.1g, mannitol 10g, magnesium stearate 10g, hypromellose 143 grams, 1000 of amount of formulation.
Method: preparation gelatin 188.2g, glycerol 40g, water 60g mixed-matrix, dry, add Amoxicillin Sodium 71.5g, amoxicillin again: clavulanate potassium (2: 1) mixture 42.8g, oligofructose 242.5g, xylitol 192g, inulin 50g, citric acid 10g, food pigment-400.1g, mannitol 10g, hypromellose 143 gram mixture, grind, cross 20 purpose sieves, granulate with the second alcohol and water, 60 ℃ of dryings, add 10 gram magnesium stearate then, mixing places extrusion molding on the tablet machine, and every buccal tablet weighs 2 grams.Measure the disintegration of amoxicillin sodium and clavulanate potassium buccal tablet in 37 ℃ of 900ml water and the dissolution during complete disintegrate then.
The result: be 41-53 minute disintegration, and fully the dissolution amoxicillin during disintegrate is 64%-69%, and clavulanate potassium is 95%-97%.
Embodiment 6-amoxicillin and clavulanate potassium confection
Prescription: amoxicillin 71.5g, amoxicillin: clavulanate potassium (2: 1) mixture 42.8g, sucrose 145.5g, oligofructose 118.2g, xylitol 300g, inulin 50g, citric acid 10g, food pigment-40 0.1g, mannitol 10g, hypromellose 252 grams, 1000 of amount of formulation.
Method: preparation citric acid 10g, food pigment-40 0.1g, mannitol 10g, hypromellose 252 gram mixture grind, and cross 20 purpose sieves.Get sucrose 145.5g, oligofructose 118.2g, xylitol 300g, inulin 50g, mix, be heated to 140 ℃ of fusings, add the mixture after sieving, stirring and evenly mixing is cooled to 85 ℃ fast, add Amoxicillin Sodium 71.5g, stirring and evenly mixing stirred 10 minutes fast, room temperature is cooled to solidifies, and granulates, and crosses 20 purpose sieves, add the amoxicillin after sieving: clavulanate potassium (2: 1) mixture mixture 42.8g, stirring and evenly mixing places extrusion molding on the product shaping machine, and every buccal tablet weighs 2 grams.Measure the disintegration of amoxicillin and clavulanate potassium confection in 37 ℃ of 900ml water and the dissolution during complete disintegrate then.
The result: be 79-86 minute disintegration, and fully the dissolution amoxicillin during disintegrate is 96%-99%, and clavulanate potassium is 92%-98%.
The tablet of embodiment 7-buccal lozenge of the present invention and prior art is to the contrast test of amoxicillin and the influence of clavulanate potassium dissolution
1. technology one is substrate with the Icing Sugar
Control formulation preparation method: preparation amoxicillin 71.5g, amoxicillin: clavulanate potassium (2: 1) mixture 42.8g, sucrose 865.7 grams, citric acid 10g, food pigment-400.1g, mannitol 10g mixture, grind, cross 20 purpose sieves, place extrusion molding on the product shaping machine, every buccal tablet weighs 2 grams.Measure the disintegration of amoxicillin and clavulanate potassium confection in 37 ℃ of 900ml water and the dissolution during complete disintegrate then.
The preparation method of buccal lozenge of the present invention: preparation citric acid 10g, food pigment-40 0.1g, mannitol 10g mixture grinds, and crosses 20 purpose sieves.Get sucrose 865.7 grams, be heated to 140 ℃ of fusings, add the mixture after sieving, stirring and evenly mixing is cooled to 85 ℃ fast, adds Amoxicillin Sodium 71.5g, stirring and evenly mixing stirred 10 minutes fast, and room temperature is cooled to solidifies, granulate, cross 20 purpose sieves, add the amoxicillin after sieving: clavulanate potassium (2: 1) mixture 42.8g, stirring and evenly mixing, place extrusion molding on the product shaping machine, every buccal tablet weighs 2 grams.Measure the disintegration of amoxicillin and clavulanate potassium confection in 37 ℃ of 900ml water and the dissolution during complete disintegrate then.
The results are shown in Table 1, the present invention is the dissolution that the solid dispersion preparation technology of substrate can significantly improve the amoxicillin with the Icing Sugar.
Table 1, the present invention are the influence of the solid dispersion preparation technology of substrate to drug dissolution with the Icing Sugar
＊p＜0.05
2. technology two is substrate with the surfactant
Control formulation preparation method: preparation amoxicillin 71.5g, amoxicillin: clavulanate potassium (2: 1) mixture 42.8g, hypromellose 100 grams, Polyethylene Glycol
6000785.7 gram, aspartame 0.1 gram mixed-matrix, stirring and evenly mixing is granulated, and places extrusion molding on the tablet machine, and every buccal tablet weighs 2 grams.Measure the disintegration of amoxicillin and clavulanate potassium buccal tablet in 37 ℃ of 900ml water and the dissolution during complete disintegrate then.
The preparation method of buccal lozenge of the present invention: preparation hypromellose 100 grams, Polyethylene Glycol
6000785.7 gram, aspartame 0.1 gram mixed-matrix, heat fused is cooled to 80 ℃, add Amoxicillin Sodium 71.5g, stirring and evenly mixing stirred 10 minutes fast, and room temperature is cooled to solidifies, granulate, cross 20 purpose sieves, add the amoxicillin after sieving: clavulanate potassium (2: 1) mixture 42.8g, stirring and evenly mixing, place extrusion molding on the product shaping machine, every buccal tablet weighs 2 grams.Measure the disintegration of amoxicillin and clavulanate potassium sheet in 37 ℃ of 900ml water and the dissolution during complete disintegrate then.
The results are shown in Table 2, the present invention is the dissolution that the solid dispersion preparation technology of substrate can significantly improve the amoxicillin with the surfactant.
Table 2, the present invention are the influence of the solid dispersion preparation technology of substrate to drug dissolution with the surfactant
＊p＜0.05
The embodiment 8-embodiment of the invention 3 amoxicillin and clavulanate potassium buccal tablets and amoxicillin and clavulanate potassium dispersible tablet of the prior art are in the comparative test to the therapeutical effect effect of acute pharyngitis and acute pharyngoamygdalitis
Medicine: trial target: the embodiment of the invention 3 amoxicillin and clavulanate potassium buccal tablet 0.1143g/ sheets, reference substance: the clavulanate potassium amoxicillin dispersible tablet 0.2285g/ sheet that Lunan Pharmacy Co. Ltd produces
Method: choose acute pharyngitis and acute pharyngoamygdalitis case, be divided into oral group of clavulanate potassium amoxicillin dispersible tablet, the amoxicillin and clavulanate potassium buccal tablet is sucked group.Each group awards 8/day of 16 slices/day of embodiment 3 amoxicillin and clavulanate potassium buccal tablets or clavulanate potassium amoxicillin dispersible tablets respectively.Oral group with per 6 hours once, each 2, through water delivery service.Suck group with per 6 hours once, 4 of each buccal continuously, every tablet of medicine time of oral cavity including reservation greater than 20 minutes.Each is organized case and all observed 48 hours, improves situation respectively at observation in 4,8,16,24,48 hours and record clinical symptoms and sign after the administration.By writing down the case load that each time point clinical symptoms and sign are improved, analyze the therapeutic effect of buccal lozenge to acute pharyngitis and acute pharyngoamygdalitis.Clinical symptoms and sign be improved as that heating is disappeared, pharyngalgia disappears, pharyngeal or tonsil is congested alleviates three indexs and occurs one at least.
Result: as seen by table 3, by laboratory observation to 40 routine cases, it is amoxicillin and clavulanate potassium buccal tablet group 85% that 48 hours clinical symptoms of taking medicine and sign are improved percentage rate, and oral group 50% of clavulanate potassium amoxicillin dispersible tablet illustrates that the curative effect of buccal tablet is better than oral formulations.
The efficacy test result of study of table 3, buccal lozenge of the present invention
＊p＜0.05
The embodiment 9-embodiment of the invention 3 amoxicillin and clavulanate potassium buccal tablets and amoxicillin and clavulanate potassium dispersible tablet of the prior art are in the comparative test to the therapeutical effect effect of oral cavity infectious disease
Medicine: trial target: the embodiment of the invention 3 amoxicillin and clavulanate potassium buccal tablet 0.1143g/ sheets, reference substance: the clavulanate potassium amoxicillin dispersible tablet 0.2285g/ sheet that Lunan Pharmacy Co. Ltd produces
Method: choose bacterial infection periodontitis case, be divided into oral group of amoxicillin and clavulanate potassium dispersible tablet, the amoxicillin and clavulanate potassium buccal tablet is sucked group.Each group awards 8/day of 16 slices/day of embodiment 3 amoxicillin and clavulanate potassium buccal tablets or amoxicillin and clavulanate potassium dispersible tablets respectively.Oral group with per 6 hours once, each 2, through water delivery service.Suck group with per 6 hours once, 4 of each buccal continuously, every tablet of medicine time of oral cavity including reservation greater than 20 minutes.Each is organized case and all observed 7 days, improves situation respectively at observation in 1,3,7 day and record clinical symptoms and sign after the administration.By writing down the case load that each time point clinical symptoms and sign are improved, analyze the therapeutic effect of buccal lozenge to the bacterial infection periodontitis.Clinical symptoms and sign are improved as that gingival hemorrhage alleviates, gingiva hyperemia alleviates two indexs and occurs one at least.
Result: as seen by table 4, by laboratory observation to 40 routine cases, it is amoxicillin and clavulanate potassium buccal tablet group 45% that 7 days clinical symptoms of taking medicine and sign are improved percentage rate, and oral group 25% of amoxicillin and clavulanate potassium dispersible tablet illustrates that the curative effect of buccal tablet is better than oral formulations.
The efficacy test result of study of table 4, buccal lozenge of the present invention
＊p＜0.05
Claims (10)
- One kind improve the treatment pharyngitis, pharyngoamygdalitis and oral cavity infection disease drug quality be the buccal lozenge of main ingredient with amoxicillin and clavulanic acid, it is characterized in that described buccal lozenge is made up of ingredient that includes amoxicillin and clavulanic acid and salt derivative thereof and substrate, wherein the weight ratio of amoxicillin and clavulanic acid is n: 1, and n is the number of 2-14.
- 2. buccal lozenge according to claim 1, be 10-100 minute the disintegration of described amoxicillin and clavulanic acid buccal lozenge.
- 3. buccal lozenge according to claim 2, be 20-60 minute the disintegration of described amoxicillin and clavulanic acid buccal lozenge.
- 4. the buccal lozenge of amoxicillin according to claim 1 and clavulanic acid is characterized in that: described buccal lozenge type comprises buccal tablet, drop pill, confection.
- 5. the preparation method of the buccal tablet in the described buccal lozenge that contains amoxicillin and clavulanic acid of claim 4, it is characterized in that: described buccal tablet is through being heated as the miscible or miscible state of semi-molten of fusion by the ingredient that contains amoxicillin and clavulanic acid and substrate, then through cooled and solidified, and then make described buccal tablet.
- 6. the preparation method of the drop pill in the described buccal lozenge that contains amoxicillin and clavulanic acid of claim 4, it is characterized in that: proportionally amoxicillin and clavulanic acid are mixed with substrate, adopt water-bath, oil bath or other mode of heating, mixed material is heated to fusion, stir, insert on the drop pill machine with suitable speed, splash in 40 →-15 ℃ the condensing agent and be shaped.
- 7. the preparation method of the confection in the described buccal lozenge that contains amoxicillin and clavulanic acid of claim 4, it is characterized in that: described confection be earlier with substrate through being heated as the miscible state of fusion, then through being cooled to semi-solid, add the ingredient that contains amoxicillin and clavulanic acid then, stirring and evenly mixing, make into the plasticity magma, cut apart, extrusion molding.
- 8. claim 5 or 6 or 7 preparation method, wherein said substrate is one or more compositions that comprise in Polyethylene Glycol, polyoxyethylene stearate 40 esters, beta cyclodextrin, poloxamer, carboxymethyl starch sodium, stearic acid, glycerin gelatine, glyceryl monostearate, Lac, polyoxyethylene monostearate, polyethers, the Icing Sugar.
- 9. according to claim 5,6,7 described preparation methoies, it is characterized in that: described substrate comprises one or more medicinal slow releasing agent and coloring agent, correctives, spice and other pharmaceutic adjuvant.
- 10. the application of the buccal lozenge of claim 1 in preparing the medicine that can improve treatment pharyngitis, pharyngoamygdalitis and oral cavity infection disease drug quality.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100871407A CN101269069A (en) | 2007-03-22 | 2007-03-22 | Oral preparation containing amoxicillin and clavulanic acid, preparation method and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2007100871407A CN101269069A (en) | 2007-03-22 | 2007-03-22 | Oral preparation containing amoxicillin and clavulanic acid, preparation method and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110051637A (en) * | 2019-05-21 | 2019-07-26 | 葵花药业集团北京药物研究院有限公司 | Amoxicillin and clavulanate potassium preparation and preparation method thereof |
| CN117379378A (en) * | 2023-12-07 | 2024-01-12 | 山东金瑞生物科技有限公司 | Compound amoxicillin soluble powder for livestock and preparation process thereof |
-
2007
- 2007-03-22 CN CNA2007100871407A patent/CN101269069A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110051637A (en) * | 2019-05-21 | 2019-07-26 | 葵花药业集团北京药物研究院有限公司 | Amoxicillin and clavulanate potassium preparation and preparation method thereof |
| CN117379378A (en) * | 2023-12-07 | 2024-01-12 | 山东金瑞生物科技有限公司 | Compound amoxicillin soluble powder for livestock and preparation process thereof |
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