CN1742728A - Baloxin capsule and preparing method - Google Patents
Baloxin capsule and preparing method Download PDFInfo
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- CN1742728A CN1742728A CN 200510105798 CN200510105798A CN1742728A CN 1742728 A CN1742728 A CN 1742728A CN 200510105798 CN200510105798 CN 200510105798 CN 200510105798 A CN200510105798 A CN 200510105798A CN 1742728 A CN1742728 A CN 1742728A
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Abstract
The present invention provides a baloxacin capsule and its preparation method. Every 1000 baloxacin capsules contain 90-110g of baloxacin, 35-50g of hydroxypropyl methyl cellulose, 8-10g of microcrystalline cellulose and 1g of magnesium stearate. Said invention also provides the concrete steps of its preparation method.
Description
Technical field
The present invention relates to a kind of balofloxacin capsule and its preparation method, belong to field of pharmaceutical preparations.
Background technology
Q-35 (balofloxacin) is a fluoroquinolone antibacterial agent of new generation, is developed by Japanese Chugai Seiyaku company.
Science of culture title wherein: 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxyl group-7-3-methylamino-piperidino)-and 4-oxo-3-quinoline carbonyl acid dihydrate, molecular formula is C
20H
24FN
3O
42H
2O, molecular weight are 425.46, and molecular structural formula is:
Q-35 is different with cephalo-type and Penicillin antibiotics, the antibacterial activity of Q-35 is not subjected to antibacterial whether to produce the influence of beta-lactamase, it is that DNA with antibacterial is the effect target, play a role and make DNA of bacteria can't form superhelix by hindering DNA topology isomerase II and IV, further cause chromosomal irreversible lesion, cause the antibacterial can't division growth.
The Q-35 has a broad antifungal spectrum has very high activity to gram positive bacteria and anaerobe.Its inhibition is strong 4 times than ofloxacin and ciprofloxacin to the staphylococcic activity of fluoroquinolone medicaments insensitive, and is strong 2 times than ofloxacin and ciprofloxacin to streptococcus and enterococcal bactericidal activity.Q-35 a little less than tosufloxacin and Sparfloxacin, but is the strongest in above-mentioned each fluoroquinolones to the activity of Resistant strain to the activity of the staphylococcus aureus of fluoroquinolones sensitivity and epidermis Portugal coccus.
In the test, Q-35 is better than ofloxacin, ciprofloxacin and erythromycin etc. to the bactericidal activity of mycoplasma pneumoniae, has only this product effective to the variant of anti-erythromycin in being subjected to the reagent thing in vitro and in vivo.In the hamster model of pulmonary infection mycoplasma, infect in back 24 hours per os and gave this product 200mg/Kg/ days, successive administration 5 days, Q-35 and ofloxacin therapeutic equivalence, ciprofloxacin is then invalid.Use this product mid-term in infection, also can produce curative effect preferably, be better than ofloxacin and ciprofloxacin.
After Q-35 enters in the body with oral way, absorb rapidly fully bioavailability 82%, protein binding rate 15%.The Q-35 pharmacokinetics is similar to ofloxacin, linear pharmacokinetics in vivo distributes, half-life in the blood plasma reaches 8 hours, the concentration that can be distributed widely in each tissue is close to or higher than the same time blood concentration, enter the ratio height in the cerebrospinal fluid, mainly by draining in the urine, small part is through bile excretion, and all the other are discharged through feces.
In general, Q-35 has characteristics such as has a broad antifungal spectrum, toxicity be low, especially the drug resistance strain of anti-fluoroquinolones is had antibacterial action, and its oral absorption is complete rapidly.
The capsule conduct is oral administration route simply and easily, is first-selected peroral dosage form.The drug bioavailability height of capsule need not resemble plus-pressure the tablet, thus in gastrointestinal tract, disperse fast, good absorbing; And capsule can be covered the bitterness and the abnormal flavour of medicine, can improve stability of drug.In the lighttight capsule shells of packing into, can keep medicine not to be subjected to the influence of oxygen in light, dampness and the air.
Thereby, be necessary to develop the Baloxin capsule preparation.
Summary of the invention
The object of the present invention is to provide a kind of Baloxin capsule.
Another object of the present invention is to provide a kind of preparation method of Baloxin capsule.
Per 1000 of Baloxin capsule of the present invention comprises following component:
Q-35 90-110g
Hydroxypropyl methylcellulose 35-50g
Microcrystalline Cellulose 8-10g
Magnesium stearate 1g.
Preferred per 1000 of Baloxin capsule comprises following component:
Q-35 100g
Hydroxypropyl methylcellulose 38g
Microcrystalline Cellulose 8g
Magnesium stearate 1g.
Hydroxypropyl methylcellulose can be hydroxypropyl methylcellulose E
5, hydroxypropyl methylcellulose E
3Or hydroxypropyl methylcellulose 60RT15; Preferred hydroxypropyl methylcellulose 60RT15.
Microcrystalline Cellulose preferably uses microcrystalline Cellulose MCC
112
Simultaneously, in preparation process, be aided with an amount of 8% 30 POVIDONE K 30 BP/USP
30Alcoholic solution.
Preparation method of the present invention: each crude drug is crossed 100 mesh sieves respectively, get recipe quantity Q-35, hydroxypropyl methylcellulose and microcrystalline Cellulose, increase progressively the principle mix homogeneously, add an amount of 8% 30 POVIDONE K 30 BP/USP by equivalent
30Alcoholic solution system soft material is crossed 20 mesh sieves, and the system wet granular 55-65 ℃ of C drying 4～5 hours, makes pellet moisture reduce to 5-10%, crosses 20 mesh sieve granulate, adds the recipe quantity magnesium stearate then, mix homogeneously, No. 2 capsule shells of fill, capsule finished product.
Product of the present invention is a hard capsule, and content is faint yellow granule, and every capsule contains the 100mg. Q-35, be applicable to streptococcus, enterococcus, Morganella, Colibacter, Providence Pseudomonas, citric acid bacterium genus, Klebsiella, Enterobacter, Serratia, Bacillus proteus, Rhodopseudomonas, the simple property urinary tract infection that Peptostreptococcus causes, each 100mg that is grown up, twice of every day.According to patient age, the degree of being in a bad way can be adjusted dosage as one sees fit.
Because 7 at the Q-35 parent nucleus have 3-methylamino piperidine ring, not only enlarged antimicrobial spectrum, strengthened antibacterial activity, especially gram positive bacteria comprised that MRSA, streptococcus pneumoniae and mycoplasma pneumoniae comprise that bacterial strain, chlamydia trachomatis and the Linterrogans etc. of anti-erythromycin all have strong activity, and reduced zooblast inhibition of proliferation activity.
The noticeable characteristics of another of Q-35 are owing to introduce methoxyl group at 8, therefore can avoid or reduce photosensitivity and phototoxicity.
In addition, because this product is low to the rate of dividing a word with a hyphen at the end of a line of cerebrospinal fluid, therefore a little less than the effect to the central nervous system.
Because Q-35 existing all has clear improvement as, photosensitivity low to gram-positive bacteria activity or phototoxicity and central nervous system's toxicity and cytotoxicity aspect aspect the major defect of veriety overcoming, and therefore is the important new varieties of a significant.
Description of drawings
Fig. 1 is the inventive method flow chart
The specific embodiment
Embodiment 1
With Q-35, hydroxypropyl methylcellulose (Ruitai Cellulose Co Ltd, Tai'an; Quality standard meets 2000 editions 775 pages of standards of Chinese Pharmacopoeia), (the auspicious Mel father and son company of stepping on of Germany makes: general reaching (China) company sells microcrystalline Cellulose; Quality standard meets Chinese Pharmacopoeia (PRCP) and American Pharmacopeia (USP), dispensatory of the United States of America (NF), the prescription of European Pharmacopoeia and Japanese Pharmacopoeia) and magnesium stearate (Yangzhou pharmaceutical factory provides; Quality standard meets 2000 editions two ones 833 of Chinese Pharmacopoeias and standard) each crude drug crosses 100 mesh sieves respectively, gets Q-35 100g, hydroxypropyl methylcellulose E
535g, microcrystalline Cellulose MCC
11210g increases progressively the principle mix homogeneously by equivalent, adds an amount of 8% 30 POVIDONE K 30 BP/USP
30(Beijing east ring amalgamation factory) alcoholic solution system soft material is crossed 20 mesh sieves, and the system wet granular 55 ℃ of dryings 4 hours, makes pellet moisture reduce to 8%, crosses 20 mesh sieve granulate, adds the 1g magnesium stearate then, mix homogeneously, and No. 2 capsule shells of fill get capsule finished product.
Embodiment 2
Each crude drug of Q-35, hydroxypropyl methylcellulose, microcrystalline Cellulose and magnesium stearate is crossed 100 mesh sieves respectively, get Q-35 110g, hydroxypropyl methylcellulose E
538g, microcrystalline Cellulose MCC
1128g increases progressively the principle mix homogeneously by equivalent, adds an amount of 8% 30 POVIDONE K 30 BP/USP
30Alcoholic solution system soft material is crossed 20 mesh sieves, and the system wet granular 60 ℃ of dryings 5 hours, makes pellet moisture reduce to 5%, crosses 20 mesh sieve granulate, adds the 1g magnesium stearate then, mix homogeneously, No. 2 capsule shells of fill, capsule finished product.
Embodiment 3
Each crude drug of Q-35, hydroxypropyl methylcellulose, microcrystalline Cellulose and magnesium stearate is crossed 100 mesh sieves respectively, get Q-35 90g, hydroxypropyl methylcellulose E
350g, microcrystalline Cellulose MCC
11210g increases progressively the principle mix homogeneously by equivalent, adds an amount of 8% 30 POVIDONE K 30 BP/USP
30Alcoholic solution system soft material is crossed 20 mesh sieves, and the system wet granular 57 ℃ of dryings 5 hours, makes pellet moisture reduce to 10%, crosses 20 mesh sieve granulate, adds the 1g magnesium stearate then, mix homogeneously, No. 2 capsule shells of fill, capsule finished product.
Embodiment 4
Each crude drug of Q-35, hydroxypropyl methylcellulose, microcrystalline Cellulose and magnesium stearate is crossed 100 mesh sieves respectively, get Q-35 100g, 41g hydroxypropyl methylcellulose 60RT15,8g microcrystalline Cellulose MCC
112, increase progressively the principle mix homogeneously by equivalent, add an amount of 8% 30 POVIDONE K 30 BP/USP
30Alcoholic solution system soft material is crossed 20 mesh sieves, and the system wet granular 65 ℃ of dryings 4 hours, makes pellet moisture reduce to 8%, crosses 20 mesh sieve granulate, adds the 1g magnesium stearate then, mix homogeneously, No. 2 capsule shells of fill, capsule finished product.
Embodiment 5
Each crude drug of Q-35, hydroxypropyl methylcellulose, microcrystalline Cellulose and magnesium stearate is crossed 100 mesh sieves respectively, get Q-35 100g, 38g hydroxypropyl methylcellulose 60RT15,8g microcrystalline Cellulose MCC
112, increase progressively the principle mix homogeneously by equivalent, add an amount of 8% 30 POVIDONE K 30 BP/USP
30Alcoholic solution system soft material is crossed 20 mesh sieves, and the system wet granular 63 ℃ of dryings 5 hours, makes pellet moisture reduce to 8%, crosses 20 mesh sieve granulate, adds the 1g magnesium stearate then, mix homogeneously, No. 2 capsule shells of fill, capsule finished product.
Experimental example 1
This experimental example is the dissolution test of embodiment 1-5 product.
Dissolving-out method: change the basket method
Solvent: 0.1mol/L hydrochloric acid 900ml
Rotating speed: 100 rev/mins
Temperature: 37 ℃ ± 0.5 ℃
Detection method: ultraviolet spectrophotometry
Detect wavelength: 294nm
Dissolution determination the results are shown in Table 1.
Table 1: a dissolution determination result writes out a prescription
| Embodiment 1 | Time (branch) | 5 | 15 | 30 | 45 | 60 |
| Stripping quantity (%) | 44.16 | 82.35 | 86.11 | 86.87 | 87.44 | |
| Embodiment 2 | Time (branch) | 5 | 15 | 30 | 45 | 60 |
| Stripping quantity (%) | 73.43 | 91.64 | 95.24 | 97.72 | 94.26 | |
| Embodiment 3 | Time (branch) | 5 | 15 | 30 | 45 | 60 |
| Stripping quantity (%) | 22.02 | 52.34 | 78.02 | 90.27 | 94.84 | |
| Embodiment 4 | Time (branch) | 5 | 15 | 30 | 45 | 60 |
| Stripping quantity (%) | 33.21 | 56.42 | 91.92 | 95.97 | 99.26 | |
| Embodiment 5 | Time (branch) | 5 | 15 | 30 | 45 | 60 |
| Stripping quantity (%) | 33.36 | 74.24 | 94.85 | 99.20 | 98.33 |
Experimental example 2
This experimental example is the stability experiment parameter of product of the present invention.
Abide by new drug evaluation relevant requirements, and with reference to by in " chemical drugs and treatment are studied guideline with biological product " (trying) book of Zheng's oats cornel chief editor about the chemical preparation estimation of stability, carry out the preparation factors influencing, the main variation of investigating related substance, content, outward appearance and dissolution, with the capsule of embodiment 5 respectively at high light (4500LX ± 500LX) placed 10 days under high temperature (60 ℃) high humidity (RH90 ± 5%) condition.
Place the variation of front and back related substance with HPLC method (normalization method) inspection.
Check the variation of content before and after placing with ultraviolet method (zero day to be 100% to compare), the capsule after placing is carried out dissolution determination.Observe the variation of medicine character such as capsule appearance luster simultaneously.
Experimental result sees Table 2-5.
1, placing the front and back related substance changes
Table 2 is placed related substance situation of change after 10 days
2, place the variation of front and back content
Table 3 is placed changes of contents situation after 10 days
3, place the front and back cosmetic variation
Table 4 is placed cosmetic variation situation after 10 days
| Zero day | The content off-white color |
| High temperature (with 0 day ratio) | Capsule shells is crisp firmly, the content off-white color |
| High humidity (with 0 day ratio) | Capsule shells is soft, the content off-white color |
| Illumination (with 0 day ratio) | The content off-white color is slightly deepened |
4, dissolution test situation
Table 5 is placed dissolution test situation (n=6) after 10 days
Brief summary: influence factor's result of the test shows two groups of prescriptions under these conditions, dissolution and content with relatively had no significant change in 0 day, under three kinds of influence factor's conditions, related substance is above 1% after 10 days.
Experimental example 3
This experimental example is a Baloxin capsule acute toxicity test data of the present invention.
Material and method
1. be subjected to reagent thing: embodiment 5 products, oral.
2. animal subject and raising condition
2.1. mice
Slc-ddy is the SPF mice, and the male and female dual-purpose was 6 ages in week when administration begins.The male weight range 28.2～33.8g of oral administration, female 22.3～28.8g.Testing every treated animal male and female is 6.
2.2. rat
Slc-SD is the SPF rat, and the male and female dual-purpose was 6 ages in week when administration begins.The male weight range 148.0～169.1g of oral administration, female 110.5～133.5g.Testing every treated animal male and female is 6.
5 of every cage number of animals, same sex.23 ± 2 ℃ of temperature, relative humidity 55 ± 10%.Rate of ventilation 14-16/ hour.Artificial circadian rhythm, 5:00 to 19:00 fluorescent lamp lighting.Preceding 5 days to administration animal instructionization phase is by body weight error random packet.Solid foodstuff is raised.Tap water is put into water bottle and is uninterruptedly supplied water.Animal carries out individual identification with ear tag method numbering.
2.3.Beagle dog
The Beagle dog, the male and female dual-purpose was 7 monthly ages when administration begins, male weight range 9.8～10.6kg, female 9.0～9.7kg.Testing every treated animal male and female is 1.
1 of animal places metal cage.23 ± 5 ℃ of temperature, relative humidity 60 ± 20%.Rate of ventilation 14-16/ hour.Artificial circadian rhythm, 6:00 to 18:00 fluorescent lamp lighting.Preceding 5 days to administration animal instructionization phase is by body weight error random packet.Solid foodstuff is raised.Tap water is put into water bottle and is uninterruptedly supplied water.Animal carries out individual identification with ear tag method numbering.
3. test method
3.1. mice and rat
Mice and rat oral administration, fasting 19h before the administration establishes 5000,3571,2551 and 1822mg/kg dosage group, is 25% (w/v) concentration with the dissolved in distilled water dilution, and the administration capacity is respectively 20.0,14.3,10.2 and 7.3ml/kg.Matched group gives distilled water solution.Dosage is calculated based on the body weight on the animals administer same day.
3.2.Beagle dog
Fasting is 20 hours before the administration, and dosage is respectively 400,100 and three of 50mg/kg, and Q-35 is placed oral administration in the capsule.
4. observation item
4.1. mice and rat
4.1.1. general situation
Observe continuously in 30 minutes after the administration, observed in 1,3 and 5 hour after the administration, and between week next day to 2, observe morning every day 1 time, confirm that in the afternoon animal has or not death.
4.1.2. body weight
Mice and rat were measured after the administration before administration on the 1st, 2,4,7,10 and 14.
4.1.3. cut open inspection and histopathologic examination
Find in the test that dead animal cuts open inspection rapidly, the existence animal is cutd open inspection after finishing in 2 observation periods in week, and perusal has or not internal organs unusual.
4.2.Beagle dog
4.2.1. general situation
Observe continuously in 6 hours after the administration, between week next day to 2, observe morning every day 1 time, confirm that in the afternoon animal has or not death.
4.2.2. body weight
With mice and rat
4.2.3. food ration and water uptake
Viewing duration is measured every day.
4.2.4. hematology and blood biochemical analysis
Respectively at checking before the administration and after the observation period end.Check that index comprises routine blood test, red blood cell count(RBC), hemoglobin, platelet count, packed cell volume, numeration of leukocyte etc.; Blood biochemistry index comprises: GOT, GPT, AL-P, LDH, ChE, GTP, Glu, Tcho, BUN etc.Detection method is based on autoanalyzer method.
The result:
1. the acute toxicity of Q-35 its mouse oral administration: minimum lethal dose: Q-35 oral administration dosage is respectively 5000,3571,2551 and during 1822mg/kg, and the minimal lethal dose of male and female mice is greater than 5000mg/kg.Referring to table 1, table 2.General situation: each dosage group male and female mice no abnormality seen changes.Body weight: each dosage group male and female mice no abnormality seen changes.Cut open inspection: each dosage group male and female mice no abnormality seen changes.
2. the acute toxicity of Q-35 rat oral administration: minimum lethal dose: rat oral is respectively 5000,3571,2551 and 1822mg/kg for Q-35 dosage, and the minimal lethal dose of male and female rat is greater than 5000mg/kg.General situation: spontaneous activity in 5 hours is low after the 1 routine administration of 5000mg/kg dosage group male rat.After the administration 1 day, each dosage group male and female rat no abnormality seen changes.Body weight: compare with matched group, 2551,3571 and the administration of 5000mg/kg dosage group after 1 to 2 daily weight amplification descend.Cuing open each dosage group male and female rat no abnormality seen of inspection changes.
3. the peroral administration acute toxicity of Q-35 Beagle dog: each dosage group is not seen animal dead.General situation: after the male administration of 50mg/kg dosage group about 40 minutes, visible vomiting for several times after 1.5 hours after the female administration, 2.5 hours visible sialorrheas after this dosage treated animal administration.As seen vomitted and the symptom of scratching where it itches in about 50 minutes after the male administration of 100mg/kg dosage group, visible successional vomiting about 1 hour after the female administration, sialorrhea and spontaneous activity reduce, and as seen tremble in 4 hours after the administration.After the male administration of 400mg/kg dosage group about 40 minutes, visible vomiting in 1.5 hours after the female administration, vomitus is for being subjected to the reagent thing, and facial edema and the comparatively intensive symptom of scratching where it itches, and as seen trembles in 4 hours after the female administration.Above-mentioned symptom recovers in 6 hours after administration, and administration is the no abnormality seen discovery after 1 day.Body weight: 400mg/kg dosage group oral administration the 2nd day, weight loss one property crossed decline.Food ration: 100mg/kg dosage group oral administration the 1st to 6 day, food ration descends.Water uptake: each dosage group male and female Beagle dog no abnormality seen changes.Hematology and blood biochemical analysis show that each dosage group male and female Beagle dog no abnormality seen changes.
Experimental example 4
This experimental example repeats the oral administration toxicity test June for embodiment 5 product rats.
Materials and methods
1, reagent thing: embodiment 5 capsule products
2, animal subject and raising condition: (Slc:SD) be the SPF rat, the male and female dual-purpose, animal subject was 6 ages in week when administration began, buck weight range 167.5-186.4g, female weight range 135.5-156.2g.5 of every cage number of animals, same sex.23 ± 2 ℃ of temperature, relative humidity 55 ± 10%.Rate of ventilation 14-16/ hour.Artificial circadian rhythm, 5:00 to 19:00 fluorescent lamp lighting.Preceding 5 days to administration animal instructionization phase is by body weight error random packet.Solid foodstuff is raised.Tap water is put into water bottle and is uninterruptedly supplied water.Animal carries out individual identification with ear tag method numbering.
3, dosage and group: the dosage group is provided with and repeats the oral administration toxicity test January, the dosage group is respectively 30,100,300 and 1000mg/kg, the visible loose stool of 100mg/kg dosage group wherein, water uptake increases, electrolyte excretion reduces in the urine, 300mg/kg or the visible sialorrhea of above dosage and liver weight reduce, and the visible body weight amplification of 1000mg/kg dosage group is slight to descend and the food ration minimizing, and hepatocyte and the formation of renal cells cavity.Setting high dose group according to above result of the test is 300mg/kg, and next coming in order are 100,30 and 10mg/kg dosage group and distilled water matched group.Test divides a matched group, and 300,100,30 and 10mg/kg dosage group.Each 10 of every group of male and female, every group wherein each 10 of male and female when administration administration in the June phase finishes, put to death, each 10 of residue male and female finish the back execution in the off-drug period.
4, administration phase, route of administration and method: be subjected to reagent liquid to give the rat oral gavage administration 1 time/day, administration volume 5ml/kg.Successive administration between 26 weeks.Control animals gives isopyknic distilled water solution.
5, observation index and method:
1) general state: during the administration, administration preceding observation animal general state and Excreta have no abnormal, observe the animal general state after the administration in the 1h and behind the 3h.
2) body weight: administration begins day mensuration, and administration is 4 weeks just, measure weekly 2 times, afterwards, measure weekly 1 time.
3) food ration: administration begins preceding mensuration, and the same body weight of minute is calculated according to the give appetite and the residue appetite on the same day afterwards.
4) water uptake: after administration begins, according to body weight determination the day before yesterday confluent and the surplus water on body weight determination same day calculate.
5) urine examination: respectively at administration the 12nd week with respectively organize each 5 example collection urine detection of male and female the 25th week.Test item: pH, albumen, glucose in urine, ketoboidies, urobilinogen, bilirubin, occult blood, proportion, and survey 24h urine amount, Na, K
+And Cl
-
6) ophthalmology checks: respectively at the 12nd week of administration with respectively organize each 4-5 example of male and female the 25th week and detect optical fundus and eye outward appearance, and carry out the optical fundus and make a video recording.
7) hematological examination:, adopt sufficient vein to get the capable hematological examination of blood respectively at the 12nd week of administration and the 25th all each treated animals.Test item: RBC number, hemoglobin, hemoglobin concentration, platelet count, leukocyte count, leukocyte percentage rate, mean corpuscular volume, mean corpuscular hematochrome amount, mean corpuscular hemochrome concentration and reticulocyte ratio.When cuing open inspection, each organizes each 5 routine animal of male and female, the blood sampling of anesthesia arteria abdominalis inferior, and centrifugalize goes out blood plasma, and the promoting the circulation of blood of going forward side by side slurry haemoglutinin time and part activate the thrombokinase timing.
8) detection of blood parameters: when cuing open inspection, all animals is in the blood sampling of anesthesia arteria abdominalis inferior, and after room temperature was placed 30min, centrifugalize went out serum and detects.Test item: GOT, GPT, ALP, ChE, γ-GPT, blood urea nitrogen, uric acid amount, creatinine, glucose, T-CHOL, Phos, Ca
2, total protein, albumin, total bilirubin, bilirubin direct, free cholesterol, CPK, Fe, LAP, LDH, free fatty, phospholipid, triglyceride Na
+, K
+, Cl
-, the separating of A/G, unconjugated bilirubin, ALb and globulin.
9) cut open inspection and organ weights: dead routine animal is cutd open inspection immediately, lives in depositing animal and finish next day under etherization in administration, and the blood-letting of enlarged abdomen arteriovenous causes death, and inner each internal organs of perusal have no abnormal.Take by weighing the weight of following organ: brain (brain, cerebellum and brain stem), pendant, salivary gland (submaxillary gland and sublingual gland), thymus, heart, lungs, liver, kidney, adrenal gland, spleen, caecum, testis, epididymis, prostate uterus, pendant and ovary, and calculate organ coefficient.
10) pathological examination: remove the extraorgan of above-mentioned weight check, also comprise eyeball, gland of Harder (accessory lacrimal glands), outer lachrymal gland, tongue, trachea, bronchus, thyroid, epithelium corpusculum, esophagus, stomach, duodenum, jejunum, ileum, colon, rectum, mesenteric lymph node, pancreas, spinal cord, skeletal muscle, breastbone, femur, go up carpal bone, bone marrow, submandibular lymph nodes, skin, mammary gland, large artery trunks, bladder, epididymis and vagina.
11) statistical disposition: after body weight, food ration, water uptake, uroscopy, hematological examination, blood biochemical analysis and organ weights are calculated meansigma methods and standard deviation with each group male and female rat, after being subjected to the difference employing isodispersity calibrating (F calibrating) of examination group and matched group, Deng adopting Student t check under the dispersion condition, do not wait employing Aspin-Welch t check under the dispersion condition.
The result:
1. general situation: 100mg/kg or the administration of above dosage group are dispersed in visible loose stool when finishing after 6 days.After 300mg/kg dosage group male rat the 5th week of administration, the property sialorrhea is crossed in female rats administration the 15th all backs visible on the same group.Female 1 routine the 24th week of administration of 10mg/kg dosage group is dead, and dead preceding visible hematuria and autonomic movement are low.Cut open the visible calculus of urethra of inspection, the mucous membrane of urethra kermesinus, the wall of urinary bladder plumpness, kidney and heart are white in color.Histopathologic examination, the companion is hemorrhage for the mucous membrane of urethra epithelial proliferation, kidney pars papillaris and myocardium lime precipitation, matter inflammatory cell infiltration and pyelitis.Be thought of as accidental death.
2. body weight: the 12nd week of 300mg/kg dosage group male rat administration back body weight amplification slightly descend, female rats slightly descends in the 18th week of administration back amplification when administration finishes on the same group.
3. food ration: do not see and tried the thing ANOMALOUS VARIATIONS that is associated.
4. water uptake: 100mg/kg or the administration of above dosage group male rat the 3rd day be to the 5th week, and 300mg/kg dosage group female rats administration the 3rd day to the 2nd all water uptakes increase.
5. as seen the 12nd week urinated Na after uroscopy: 100mg/kg or the administration of above dosage group female rats
+, Cl
-And K
+Excretion reduces; The 25th week visible urine Na after the administration of 300mg/kg dosage group male rat
+Excretion reduces.
6. ophthalmologic examination: do not see and tried the ANOMALOUS VARIATIONS that thing is associated.
7. hematological examination: the 12nd week and 25 weekly checks after the rat administration, compare with matched group, 10,30 and 100mg/kg dosage group male rat RBC number, hemoglobin, hemoglobin concentration low, 10mg/kg dosage group male rat mean corpuscular volume, mean corpuscular hematochrome amount and mean corpuscular hemochrome concentration are low, and as seen other variation is dispersed in.Above-mentioned variation is thought of as in the physiology mobility scale with to be tried thing unconnected.
8. blood biochemical analysis: 100mg/kg or above dosage male rat total protein reduce, and the albumins/globulins ratio increases, and alkaline phosphatase activities increases; The female male rat content of inorganic phosphorus of 300mg/kg dosage group increases, and the male rat triglyceride reduces on the same group, and female rats ferrum and potassium increase on the same group.
9. pathological examination:
1) cut open inspection: 10mg/kg or above dosage group, visible caecum are slightly expanded to moderate.
2) organ weights: 10mg/kg or above dosage group, caecum weight (wet weight and relative weight) increases; 300mg/kg dosage group male rat liver (wet weight and relative weight) weight reduces.Other are not seen and are tried the ANOMALOUS VARIATIONS that thing is associated.
3) histopathologic examination: male 4 examples of 300mg/kg dosage group and the visible cecum mucosa epithelial cell mild swelling of female 2 examples.Other, the heart tissue sphaerocyst gathers, the convoluted tubule of testis atrophy, be thought of as accidental due to.
In sum, rat to repeat the non-toxic of oral administration June be 30mg/kg/ day.
Claims (9)
1, a kind of Baloxin capsule is characterized in that, per 1000 of described Baloxin capsule comprises following component:
Q-35 90-110g
Hydroxypropyl methylcellulose 35-50g
Microcrystalline Cellulose 8-10g
Magnesium stearate 1g.
2, Baloxin capsule according to claim 1 is characterized in that, per 1000 of described Baloxin capsule comprises following component:
Q-35 100g
Hydroxypropyl methylcellulose 38g
Microcrystalline Cellulose 8g
Magnesium stearate 1g.
3, Baloxin capsule according to claim 1 and 2 is characterized in that, described hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E
5, hydroxypropyl methylcellulose E
3Or hydroxypropyl methylcellulose 60RT15.
4, Baloxin capsule according to claim 3 is characterized in that, described hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 60RT15.
5, Baloxin capsule according to claim 3 is characterized in that, described microcrystalline Cellulose is microcrystalline Cellulose MCC
112
6, the preparation method of the described arbitrary Baloxin capsule of claim 1-5, it is characterized in that, described method is: each crude drug is crossed 100 mesh sieves respectively, get recipe quantity Q-35, hydroxypropyl methylcellulose and microcrystalline Cellulose, increase progressively the principle mix homogeneously by equivalent, add an amount of 8% 30 POVIDONE K 30 BP/USP
30Alcoholic solution system soft material is crossed 20 mesh sieves, and the system wet granular 55-65 ℃ of drying 4～5 hours, makes pellet moisture reduce to 5-10%, crosses 20 mesh sieve granulate, adds the recipe quantity magnesium stearate then, mix homogeneously, No. 2 capsule shells of fill, capsule finished product.
7, preparation method according to claim 6 is characterized in that, described hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E
5, hydroxypropyl methylcellulose E
3Or hydroxypropyl methylcellulose 60RT15.
8, preparation method according to claim 7 is characterized in that, described hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 60RT15.
9, preparation method according to claim 6 is characterized in that, described microcrystalline Cellulose is microcrystalline Cellulose MCC
112
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101057987A CN1332670C (en) | 2005-09-29 | 2005-09-29 | Baloxin capsule and preparing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNB2005101057987A CN1332670C (en) | 2005-09-29 | 2005-09-29 | Baloxin capsule and preparing method |
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| CN1742728A true CN1742728A (en) | 2006-03-08 |
| CN1332670C CN1332670C (en) | 2007-08-22 |
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| CNB2005101057987A Expired - Fee Related CN1332670C (en) | 2005-09-29 | 2005-09-29 | Baloxin capsule and preparing method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101627999B (en) * | 2009-08-20 | 2011-05-04 | 山东罗欣药业股份有限公司 | Balofloxacin composition, preparation method thereof and synthesis method of material medicament |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH07184583A (en) * | 1993-12-28 | 1995-07-25 | Kumamoto Pref Gov | Production of miso |
| CN1190439C (en) * | 2000-03-24 | 2005-02-23 | 中国药科大学 | Tetracyclic fluoroquinolone carboxylic acid, its preparin method and medicinal composition with it as active component |
| CN1116300C (en) * | 2000-03-24 | 2003-07-30 | 中国药科大学 | Tetracyclic fluoquinolone carboxylic acid, its preparing process and medicinal composition containing it as active component |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101627999B (en) * | 2009-08-20 | 2011-05-04 | 山东罗欣药业股份有限公司 | Balofloxacin composition, preparation method thereof and synthesis method of material medicament |
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| CN1332670C (en) | 2007-08-22 |
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