CN101028274A - Ursodeoxycholic acid preparation in treatment of hepatobiliary diseases and its making method - Google Patents
Ursodeoxycholic acid preparation in treatment of hepatobiliary diseases and its making method Download PDFInfo
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Abstract
A low-release or release-controlled ursodeoxycholic acid in the form of injection, capsule, or dripping pill for treating hepatobiliary disease and its preparing process are disclosed.
Description
Technical field
The present invention relates to Ursodeoxycholic acid preparation for the treatment of liver and gall diseases and preparation method thereof, belong to technical field of medicaments.
Technical background
Ursodesoxycholic acid (UDCA) is a hydrophilic chenodiol (chemical constitution: 3a, a 7b-dihydroxy-5b cholanic acid), is to separate from Chinese black bear bile the earliest.Behind the oral unconjugated UDCA, 30%～60% dosage carries out effective liver picked-up (institute's absorbtivity of＞60%) in small intestinal and the passive absorption of large intestine.Bonded UDCA is secreted in bile duct branch and the small intestinal then, and carries out the liver sausage circulation, and ileum is heavily absorbed in a large number endways.(every day 10～15mg/kg), it can become in the liver and the interior main cholic acid of body circulation the ring UDCA of continuous oral pharmacology dosage, accounts for 40%～60% of circulation cholate.Pharmacodynamic experiment proof UDCA has following effect:
(1) cytoprotection: can protect the inductive hepatocyte injury because of TCDCA with the bonded UDCA of taurine, stop the release of hepatocyte enzyme, other cytoprotection also comprises influences cell membrane and DNA mitochondrial DNA.
(2) stimulate bile secretion: UDCA can increase bile flow, may be because with mobilized intracellular calcium ion after taurine combines, cause cell endoplasm-cell membrane transporter to increase, stimulated vesicle transportation and biliary effluxing.
(3) immunoregulation effect: UDCA can suppress the hepatocellular I class of patients with primary biliary cirrhosis HLA to express, and reduction serum IgM, also can suppress the hypertrophy of peripheral mononuclear cells and the generation of immunoglobulin simultaneously, these all point out UDCA that immunoregulation effect is arranged.
(4) antioxidation: the hydrophobicity bile salt can activate the Kuffer Schwann Cells, causes its secretion activity oxygen (ROS).ROS can cause the liver plasma membrane infringement by lipid peroxidation; the Kuffer Schwann Cells that UDCA can suppress to be caused by the hydrophobicity bile acid is activated; in addition; UDCA can increase hepatocyte glutathion inside and sulfydryl protein level; and the protection hepatocyte avoids the damage of oxidant; therefore, UDCA can be used as an antioxidant.
(5) anti-apoptotic effect: hepatocellular apoptosis is one of principal character of cholestasis hepatopathy widely.UDCA not only can suppress the inductive hepatocellular apoptosis of DCA, also can suppress by inductive apoptosis such as ethanol, FASL and TGF-β.Prompting UDCA has the anti-apoptosis effect of broad-spectrum, and the formation of keeping the stable of mitochondrial membrane and inhibition mitochondrial membrane permeability passage is the main mechanism of its anti-apoptosis.
The preparation of ursodesoxycholic acid has tablet clinically at present, is mainly used in the treatment of liver and gall diseases.But ursodesoxycholic acid bitter in the mouth, tablet itself has child and coma patient to be difficult for swallowing, add adjuvant during with tabletting and can influence the stripping of medicine and the shortcoming of bioavailability, can not satisfy the present situation of clinical application at the ursodesoxycholic acid sheet, the present invention has developed the injectable powder of the ursodesoxycholic acid of injectable or the transfusion use of dissolving back, taking convenience, the ursodesoxycholic acid capsule that bioavailability is high, drop pill and can reduce administration number of times, reduce drug toxicity, reduce the ursodesoxycholic acid slow release or the controlled release preparation of GI irritation, perfect dosage form, and can satisfy the different demands of clinical application.
Summary of the invention: it is rapid that injectable powder has drug effect, reliable effect, and all be injected directly in tissue, blood vessel or the organ of human body with liquid condition during to clinical practice.So absorb soon, effect rapidly.Particularly intravenous injection, medicinal liquid can directly enter blood circulation, is more suitable for rescuing the usefulness of critical illness.And because of injection without gastrointestinal tract, so be not subjected to the influence of digestive system and food.Therefore dosage is accurate, reliable effect.Be applicable to should not oral administration the patient: often run into coma, tic, the convulsion patient of state such as faint clinically, or the patient who suffers from the digestive system obstacle all can not oral administration, adopting injection then is the advantage of effective route of administration; Capsule has bitterness, the raising medicine stability that can cover ursodesoxycholic acid, and makes medicine play the fast advantage of medicine in vivo; The adjusting of the advantage of drop pill by drop pill substrate can make the effect of medicine or long-acting slow-release quick-acting according to the needs performance of pain therapy, and medicine stability increases, and can replace enteric coating, suppository.The drop pill that particularly uses enteric substrate to make makes medicine not disintegrate under one's belt, just disintegrate in the intestinal, and can remove enteric coated operating procedure from.Drop pill is the same with water solublity suppository, and water soluble adjuvants such as available Polyethylene Glycol are made substrate, compares with suppository, have medicine biological expenditure height, effect is fast, convenient for production, cost is low advantage.Compare with regular dosage form, the major advantage of slow release, controlled release preparation is to reduce administration number of times, improves patient's compliance; Reduce the peak valley phenomenon of blood drug level, reduce toxic and side effects, improve curative effect; Increase the stability of Drug therapy.Sustained-release preparation can also avoid medicine to the gastrointestinal zest in addition, avoids the administration at night.The inventor makes injectable powder, drop pill, capsule, slow releasing tablet and controlled release tablet with ursodesoxycholic acid, and the perfect dosage form of Ursodeoxycholic acid preparation adapts to the multiformity of clinical application more.
The present invention constitutes like this: described preparation is injection and the oral formulations that ursodesoxycholic acid and suitable adjuvant are made, and wherein ejection preparation comprises: be directly used in the injection with small volume of drug administration by injection, directly for the venous transfusion of intravenous drip, need to be used for after the dilution concentrated solution for injection and the injectable sterile powder of intravenous drip; Oral formulations comprises: all acceptable dosage forms on the pharmaceuticss such as tablet, dispersible tablet, oral cavity disintegration tablet, capsule, soft capsule, granule, drop pill, oral liquid, slow releasing preparation, controlled release preparation.Say accurately: described preparation be ursodesoxycholic acid and suitable adjuvant make the injection with small volume that is directly used in drug administration by injection, directly for the venous transfusion of intravenous drip, need to be used for after the dilution concentrated solution for injection of intravenous drip and injectable sterile powder, capsule, drop pill, slow releasing preparation, controlled release preparation.Described ursodesoxycholic acid injectable sterile powder is a kind of the making of adopting in solvent crystallization, spray drying method, the freeze-drying.
Slow or the controlled release preparation of described ursodesoxycholic acid is matrix tablet, hydrophilic gel matrix tablet, erodible matrix, insoluble matrix tablet, slow release or controlled release granule or microcapsule compressed tablet, slow release or controlled release capsule, osmotic pump controlled release tablet.Described ursodesoxycholic acid sterilized powder is preparation like this: get ursodesoxycholic acid, be incorporated as the water for injection of full dose 60%, be stirred to dissolving fully; Add mannitol, stir and make dissolving, add water to full dose, regulate pH to 4.5～5.0 with the sodium hydroxide solution of 1.0mol/L; Other adds the active carbon of full dose 0.03% through 115-120 ℃ of activation 2 hours, places rustless steel container, and 80 ℃ of insulated and stirred absorption 30 minutes, coarse filtration was taken off charcoal; The compound membrane filtration of forming with 0.45 μ m and 0.22 μ m is to clear and bright, aseptic subpackaged, and per hour heat up after 4 hours 3 ℃ of dryings 20 hours of-40 ℃ of pre-freezes to 30 ℃ of freeze-day with constant temperature 6 hours, that is, promptly get injectable sterile powder.Described ursodesoxycholic acid capsule is preparation like this: get ursodesoxycholic acid, add the dextrin of equivalent, mix homogeneously is granulated, and is encapsulated, promptly gets capsule.Described Ursodeoxycholic acid pills is preparation like this: get ursodesoxycholic acid, in adjuvant: the ratio of medicine is 1.5: 1-1: 3 polyethylene glycol 6000 is put in the rustless steel container, mix homogeneously, be heated to 80-85 ℃, after treating whole fusions, 70-75 ℃ of insulation, mechanical high-speed are stirred 15min to evenly, are transferred in the reservoir, 70～75 ℃ of insulations, regulate the dropping liquid valve, splash in 30～35 ℃ the kerosene, drip apart from 5～6cm, drip 40～45 droplets/minute of speed, kerosene is use up and wiped to the drop pill drop that forms, and packing promptly gets drop pill.Described ursodesoxycholic acid slow release or controlled release preparation are preparations like this:
(1) hydrophilic gel matrix tablet: ursodesoxycholic acid is crossed 120 mesh sieves, in medicine: the ratio of adjuvant is 1: 2 acrylic resin, in medicine: 1: 1 HPMC of the ratio of adjuvant, in medicine: 1: 0.8 microcrystalline Cellulose mix homogeneously of the ratio of adjuvant, with with principal agent be that the 2%PVP and an amount of ethanol of 1: 1 ratio is made soft material, granulate with 18 eye mesh screens, 50～80 ℃ of oven dry, 18 eye mesh screen granulate are with an amount of stearate acid magnesium mixing, tabletting; With with the principal agent ratio be 20: 1 ratio get HPMC, with principal agent be that 1: 4 ratio taking polyethylene glycol, an amount of distilled water, an amount of 80% ethanol are made coating solution, the sheet that preceding makes is carried out coating, promptly get slow releasing tablet;
(2) osmotic pump controlled release tablet: get ursodesoxycholic acid, in with principal agent be that 1: 1 ratio is got mannitol, in with principal agent be that 40: 1 ratio is got oxirane, cross mix homogeneously behind 40 mesh sieves respectively, PVP is dissolved in the ethanol slowly adds in the above-mentioned blending ingredients, stir, crossing 10 mesh sieves granulates, 30～80 ℃ of dryings, behind 10 mesh sieve granulate, add the stearic acid mixing, tabletting, the label of making placed in the coating pan rotate, the blowing hot-air preheating sparges the cellulose acetate solution of debita spissitudo on the label of rolling, treat unilateral moistening slightly, be that cold wind dries up, hot air drying, so repeatable operation is closed requirement until the coating thickness; Adopt the tablet laser drilling machine, bore the suitable hole of a diameter, promptly get controlled release tablet in coated tablet central authorities.
Adjuvant in described slow release or the controlled-release pharmaceutical formulation can be a Carnauba wax, castor oil hydrogenated, castor wax, hydrogenated soya phosphatide, spermaceti, Lac, gelatin, sodium alginate, sodium alginate, Sodium Alginate, sodium alginate, matrium alginicum, chitosan, fibrin and Fibrinogen, amylopectin, agar, carrageenin, guar gum, methylcellulose, ethyl cellulose, Aquacoat, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, cellulose acetate, the phthalic acid hydroxypropyl methylcellulose, cellulose acetate-phthalate, crylic acid resin, carbopol, polyvinyl alcohol, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, crospolyvinylpyrrolidone, silicone rubber, among the pluronic F127 one or more.
Described pharmaceutical preparation is used to prepare the medicine of diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, alcoholic liver disease, non-alcoholic stellato-hepatitis.
Compared with prior art, child and coma patient that the present invention has overcome tablet are difficult for swallowing, add adjuvant during with tabletting and can influence the stripping of medicine and the shortcoming of bioavailability, can not satisfy the present situation of clinical application with the ursodesoxycholic acid sheet, ursodesoxycholic acid is prepared into the injectable powder of the ursodesoxycholic acid of injectable or the transfusion use of dissolving back, taking convenience, the ursodesoxycholic acid capsule that bioavailability is high, drop pill and can reduce administration number of times, reduce drug toxicity, reduce the ursodesoxycholic acid slow release or the controlled release preparation of GI irritation, perfect dosage form, and can satisfy the different demands of clinical application.
For proving that medicine provided by the invention has effective effect, the applicant has carried out a series of experiments:
Experimental example 1, preparation experiment:
1.1 injectable sterile powder:
1.1.1 the screening of excipient and amount of excipient thereof:
Table 1 injectable sterile powder excipient and amount of excipient thereof
| Sample number into spectrum | The excipient type | Amount of excipient % | Outward appearance | The dissolving situation |
| 1 | Off-white color, solid | Jolting 5min dissolves, has small amount of fines | ||
| 2 | Glycine | 0.2 | Off-white color, not full | Jolting 5min dissolving |
| 3 | Glycine | 5 | Off-white color, loose | The jolting dissolving |
| 4 | Glycine | 10 | Off-white color, loose | Jolting 5min dissolving |
| 5 | Mannitol | 0.2 | Off-white color, loose | The jolting dissolving |
| 6 | Mannitol | 5 | Off-white color, loose | Dissolving rapidly |
| 7 | Mannitol | 10 | Off-white color, loose | Dissolving rapidly |
For selecting for use mannitol to do excipient, be that the applicant is selected after carrying out a series of experiments, definite among the present invention; Conventional excipient has sodium chloride, sodium hydrogen phosphate, mannitol, glycine etc., find when selecting: the dissolution velocity of manufactured goods differs bigger, in actual applications, the fast product of dissolution velocity has reasonable result of use and clinical value; So we have selected the excipient of the fastest mannitol of dissolution velocity as this product.
1.1.2 the selection of freeze-dry process:
Freezing dry process comprises pre-freeze, distillation and dry again three phases.The freeze-dry process that adopts has designed three kinds of lyophilisation conditions altogether and has tested when screening with reference to excipient, and relatively every index of dried frozen aquatic products under three kinds of lyophilisation conditions is selected best freeze-dry process.
The selection of table 2 freeze-dry process (40mg/20mg)
| Technology one | -20 ℃ of pre-freezes 2 hours ,-40 ℃ freezing 3 hours ,-35 ℃ of vacuum dehydrating at lower temperature 15 hours ,-2 ℃ of vacuum dryings 5 hours, 30 ℃ of normal temperature drying 2 hours |
| Technology two | -40 ℃ of pre-freezes 4 hours ,-20 ℃ of vacuum dehydrating at lower temperature 15 hours ,-2 ℃ of vacuum dryings 4 hours, 35 ℃ of normal temperature drying 4 hours |
| Technology three | Per hour heat up after 4 hours 3 ℃ of dryings 20 hours of-40 ℃ of pre-freezes were to 30 ℃ of freeze-day with constant temperature 6 hours |
Table 3 freeze-dry process evaluation of result (40mg/20mg)
| Technology one | It is poor slightly to freeze type, and a little sample surfaces has the crack, and the phenomenon of caving in is arranged, the water content height |
| Technology two | It is poor slightly to freeze type, and some sample surfaces has bubbling, and water content is higher |
| Technology three | It is better to freeze type, and water content is low |
As seen from the experiment: the pre-freeze time is short, the easy crack of sample surfaces; Cooling time is too short, easily causes sample freezing not exclusively, and occurs bubbling when causing vacuum drying.Technology one and technology two heat up all very fast, be not easy to remove most of water of crystallization, thereby water content are higher.Technology three is that avoiding distils suddenly causes the sample surfaces bubbling, has improved preferably and has frozen type with at the uniform velocity slow temperature-raising method.Therefore determine that technology three is as the freeze dried process conditions of this product.
1.3 drop pill:
The adjuvant screening of table 4 drop pill
| The prescription number | 1 | 2 | 3 | 4 | 5 | 6 |
| Medicine (g) | 10 | 10 | 10 | 10 | 10 | 10 |
| Polyethylene glycol 6000 (g) | 5 | 10- | 15- | 20 | 30 | 35 |
| The drop pill outward appearance | ----------- | Roundness is poor, hangover | Smooth, roundness is good | Smooth, roundness is good | Smooth, roundness is good | Smooth, roundness is good |
| Drop pill hardness | ----------- | Hardness is little | Hardness is better | Hardness is better | Hardness is better | Hardness is better |
| The ball method of double differences is different | ----------- | 20％ | 8.0％ | 8.5％ | 8.8％ | 15.5％ |
| Dissolve scattered time limit (min) | ----------- | 7～8 | 4～5 | 4～5 | 4～5 | 9～10 |
The result shows that the optimum amount of substrate polyethylene glycol 6000 is 1.5-3 a times of medicine.
1.4 slow releasing tablet:
The selection of table 5 sustained-release matrix material
| Supplementary material (mg) | Scheme 1 | Scheme 2 | Scheme 3 | Scheme 4 | Scheme 5 | Scheme 6 |
| UDCA | 500 | 500 | 500 | 500 | 500 | 500 |
| HPMCK4M | 400 | - | - | 500 | - | - |
| HPMCK15M | - | 400 | - | - | 500 | - |
| HPMCK100 M | - | - | 400 | - | - | 500 |
The different sustained-release matrix materials of table 6 are to the influence of cumulative release degree
| Time (h) | Scheme 1 | Scheme 2 | Scheme 3 | Scheme 4 | Scheme 5 | Scheme 6 |
| 1 | 28.71±12.31 | 46.13±5.42 | 32.16±10.11 | 18.15±2.07 | 20.18±11.18 | 38.98±14.25 |
| 3 | 80.63±10.62 | 89.46±4.33 | 77.85±12.41 | 42.61±1.35 | 67.64±3.64 | 74.66±10.76 |
| 5 | 85.18±9.21 | 95.12±6.72 | 83.36±9.83 | 70.43±1.80 | 86.12±10.62 | 81.31±8.64 |
| 8 | 88.79±11.63 | 97.25±3.67 | 91.47±5.06 | 83.64±1.06 | 90.75±4.51 | 95.42±7.52 |
| 12 | 89.98±12.40 | 98.57±5.41 | 95.66±8.14 | 96.45±1.34 | 94.18±9.82 | 97.22±1.49 |
The result shows that the viscosity of HPMC to the release influence obviously should select HPMC (K4M) as main framework material.
The selection of table 7 filler
| Supplementary material (mg) | Scheme 1 | Scheme 2 | Scheme 3 |
| UDCA | 500 | 500 | 500 |
| HPMCK4M | 300 | 500 | 700 |
| Acrylic resin III number | 700 | 1000 | 1200 |
| 2％PVP(ml) | 300 | 500 | 700 |
| Microcrystalline Cellulose | 200 | 400 | 600 |
| Magnesium stearate | In right amount | In right amount | In right amount |
The different filleies of table 8 to the influence of release (x ± s, %)
| Time (h) | Scheme 1 | Scheme 2 | Scheme 3 |
| 1 | 26.58±15.33 | 18.55±10.03 | 30.61±10.55 |
| 3 | 55.32±12.26 | 41.16±9.35 | 56.82±13.33 |
| 5 | 72.52±13.64 | 55.72±12.34 | 68.42±13.53 |
| 8 | 85.44±13.32 | 82.65±7.34 | 83.14±15.06 |
| 12 | 94.42±10.65 | 95.11±12.23 | 97.44±11.53 |
By the table in the result as can be known, up to specification with the drug release rate that scheme 2 filleies make, answer selection scheme 2 as filler.
Experimental example 2 pharmacodynamic experiments:
2.1 influence to normal rat bile:
Get healthy male rat, random packet, i.e. normal group, matched group, UDCA tablet group, UDCA injectable powder group, UDCA Capsules group, UDCA drop pill group, UDCA controlled release tablet group.Fasting 8～12h (can't help water) before the experiment, press 4.5mg/kg amount anesthetized rat with pentobarbital sodium during experiment, open the abdominal cavity, make the common bile duct intubate with polyethylene tube, bile drainage, treat the preceding 30min bile of stable back collection administration, respectively organize rat then and give medicine by duodenum respectively that blank group then gives the N.S of same volume.After the administration, collect bile 1 time, totally 3 times, measure bile component every 30min.Total bilirubin in the preparation group rat bile of the present invention as a result, bilirubin direct content increases.The results are shown in Table 9.
2.2 influence to APIT hepatic injury rat bile
Get the male and healthy rat, be divided into blank group, APIT model group, UDCA tablet group, UDCA injectable powder group, UDCA Capsules group, UDCA drop pill group, UDCA slow releasing tablet group at random.Test the 1st the sky, afternoon except that blank group, all the other each groups of APIT group to thing 1 time, administration 1 time again in the 2nd day morning, all the other each groups all give APIT113mg/kg the olive oil except that the blank group gives behind the 1h then, fasting 12h (can't help water) before the experiment, capable again bile drainage is collected bile 1 time every 1h, continuous 4 times behind the 24h, give 5% glucose saline 5ml/kg1 time every the 1h duodenum, measure bile component.Total bilirubin in the bile of preparation group rat of the present invention as a result, bilirubin direct content increases.The results are shown in Table 10.
Table 9 UDCA is to the influence of rat bile composition
| Group | Dosage (mg/kg) | Number of animals | Cholesterol (u mol/L) | Bile acid (m mol/L) | The content of bilirubin total bilirubin | (umol/L) bilirubin direct |
| The normal saline group | - | 8 | ＜1 | 1358.6±20.65 | 85.25±22.91 | 86.26±35.96 |
| Ursodesoxycholic acid sheet group | 100 | 8 | ＜1 | 1372.6±15.49 | 127.46±51.09 | 105.42±35.72 |
| UDCA injectable powder group | 150 | 8 | ＜1 | 1369.4±20.70 | 134.49±31.25 | 110.31±30.67 |
| The UDCA Capsules group | 150 | 8 | ＜1 | 1362.7±17.44 | 128.68±25.36 | 106.45±12.31 |
| UDCA drop pill group | 150 | 8 | ＜1 | 1363.29±20.63 | 130.61±20.20 | 107.09±38.47 |
| UDCA controlled release agent group | 150 | 8 | ＜1 | 1365.7±19.62 | 149.62±42.55 | 118.46±28.19 |
Table 10 UDCA to the oral APIT of rat after the influence of bile component
| Group | Dosage (mg/kg) | Number of animals | Cholesterol (u mol/L) | Bile acid (m mol/L) | The content of bilirubin total bilirubin | (umol/L) bilirubin direct |
| The normal saline group | - | 8 | ＜1 | 1389.7±52.31 | 40.16±21.18 | 35.79±13.40 |
| The APIT model group | 100 | 8 | ＜1 | 1294.5±64.02 | 28.62±10.41 | 20.57±12.58 |
| Ursodesoxycholic acid sheet group | 100 | 8 | ＜1 | 1375.6±15.49 | 81.46±26.09 | 66.42±32.07 |
| UDCA injectable powder group | 150 | 8 | ＜1 | 1373.4±12.56 | 88.54±18.77 | 70.67±22.19 |
| The UDCA Capsules group | 150 | 8 | ＜1 | 1362.1±25.14 | 83.25±30.69 | 67.02±42.65 |
| UDCA drop pill group | 150 | 8 | ＜1 | 1368.5±34.71 | 84.06±29.51 | 68.62±18.94 |
| UDCA slow releasing agent group | 150 | 8 | ＜1 | 1371.3±25.35 | 93.50±18.43 | 78.17±23.15 |
Concrete embodiment:
Embodiment 1: ursodesoxycholic acid 500g is crossed 120 mesh sieves, will with principal agent be 1: 2 ratio get acrylic resin III number, with principal agent be 1: 1 ratio get HPMC, with principal agent be that 1: 0.8 ratio is got the microcrystalline Cellulose mix homogeneously, with with principal agent be that 1: 1 ratio is got 2%PVP and an amount of ethanol is made soft material, granulate with 18 eye mesh screens, 50～80 ℃ of oven dry, 18 eye mesh screen granulate are with an amount of stearate acid magnesium mixing, tabletting; With with the principal agent ratio be 20: 1 ratio get HPMC, with principal agent be that 1: 4 ratio taking polyethylene glycol, an amount of distilled water, an amount of 80% ethanol are made coating solution, the sheet that preceding makes is carried out coating, promptly get slow releasing tablet.Instructions of taking: oral, an a slice, once-a-day.
Embodiment 2: get ursodesoxycholic acid 500g, with principal agent be that 1: 1 ratio is got mannitol, with principal agent be that 40: 1 ratio is got oxirane, cross mix homogeneously behind 40 mesh sieves respectively, PVP is dissolved in the ethanol slowly adds in the above-mentioned blending ingredients, stir, crossing 10 mesh sieves granulates, 30～80 ℃ of dryings, behind 10 mesh sieve granulate, add the stearic acid mixing, tabletting, the label of making placed in the coating pan rotate, the blowing hot-air preheating sparges the cellulose acetate solution of debita spissitudo on the label of rolling, treat unilateral moistening slightly, be that cold wind dries up, hot air drying, so repeatable operation is closed requirement until the coating thickness; Adopt the tablet laser drilling machine, bore the suitable hole of a diameter, promptly get controlled release tablet in coated tablet central authorities.
The cumulative release rate of UDCA ordinary tablet and controlled release tablet relatively
| Cumulative release rate (%) | 120min | 180min | 240min | 300min |
| The UDCA sheet | 99.1 | 99.4 | 99.9 | 100.5 |
| The UDCA controlled release tablet | 17.9 | 26.3 | 35.2 | 46.8 |
Embodiment 3: get ursodesoxycholic acid 500g, be incorporated as the water for injection of full dose 60%, be stirred to dissolving fully; Add mannitol, stir and make dissolving, add water to full dose, regulate pH to 4.5～5.0 with the sodium hydroxide solution of 1.0mol/L; Other adds the active carbon of full dose 0.03% through 115-120 ℃ of activation 2 hours, places rustless steel container, and 80 ℃ of insulated and stirred absorption 30 minutes, coarse filtration was taken off charcoal; The compound membrane filtration of forming with 0.45 μ m and 0.22 μ m is to clear and bright, aseptic subpackaged, and per hour heat up after 4 hours 3 ℃ of dryings 23 hours of-40 ℃ of pre-freezes to 30 ℃ of freeze-day with constant temperature 6 hours, that is, promptly get injectable sterile powder.
Embodiment 4: get ursodesoxycholic acid 500g, add the dextrin of equivalent, mix homogeneously is granulated, and is encapsulated, promptly gets capsule.
Embodiment 5: get ursodesoxycholic acid 500g, in adjuvant: the ratio of medicine is that 2: 1 polyethylene glycol 6000 is put in the rustless steel container mix homogeneously, be heated to 80-85 ℃, treat whole fusions after, 70-75 ℃ of insulation, mechanical high-speed stirs 15min to evenly, is transferred in the reservoir 70～75 ℃ of insulations, regulate the dropping liquid valve, splash in 30～35 ℃ the kerosene, drip apart from 5～6cm, drip 40～45 droplets/minute of speed, kerosene is use up and wiped to the drop pill drop that forms, and packing promptly gets drop pill.
Embodiment 6: get ursodesoxycholic acid 500g, be incorporated as the water for injection of full dose 60%, be stirred to dissolving fully; Add mannitol, stir and make dissolving, add the water full dose, regulate pH to 4.5～5.0 with the sodium hydroxide solution of 1.0mol/L; Other adds the active carbon of full dose 0.03% through 115-120 ℃ of activation 2h, places rustless steel container, and 80 ℃ of insulated and stirred absorption 30 minutes, coarse filtration was taken off charcoal; The compound membrane filtration of forming with 0.45 μ m and 0.22 μ m is to clear and bright, to go into the tower pathogenic wind-warm: 140 ℃, charging rate: 15ml/min, go into tower blast :-1650Pa, carry out spray drying, packing promptly gets injectable powder.
Embodiment 7: get ursodesoxycholic acid 500g, be incorporated as the water for injection of full dose 60%, be stirred to dissolving fully; Add mannitol, stir and make dissolving, add water to full dose, regulate pH to 4.5～5.0 with the sodium hydroxide solution of 1.0mol/L; Other adds the active carbon of full dose 0.03% through 115-120 ℃ of activation 2 hours, places rustless steel container, and 80 ℃ of insulated and stirred absorption 30 minutes, coarse filtration was taken off charcoal; Extremely clear and bright with the compound membrane filtration that 0.45 μ m and 0.22 μ m form, use the organic solvent recrystallization, promptly get injectable powder.
Embodiment 8: get ursodesoxycholic acid 1g, in principal agent: the ratio of adjuvant=1: 1 adds microcrystalline Cellulose, and presses principal agent: the crospolyvinylpyrrolidone of adjuvant=1: 0.8, evenly mixed, make soft material in right amount with 75% ethanol, cross 20 mesh sieve system granules, 55 ℃ of dryings, take out, cross 30 mesh sieve granulate, add an amount of Pulvis Talci, micropowder silica gel, evenly mixed, tabletting promptly gets dispersible tablet.
Embodiment 9: gets ursodesoxycholic acid 1000g, adds appropriate amount of starch, and evenly mixed, make soft material in right amount with 75% ethanol, the system granule, drying, granulate adds an amount of Pulvis Talci, micropowder silica gel, and evenly mixed, tabletting promptly gets tablet.
Claims (10)
1, the Ursodeoxycholic acid preparation of treatment liver and gall diseases, it is characterized in that: described preparation is injection and the oral formulations that ursodesoxycholic acid and suitable adjuvant are made, and wherein ejection preparation comprises: be directly used in the injection with small volume of drug administration by injection, directly for the venous transfusion of intravenous drip, need to be used for after the dilution concentrated solution for injection and the injectable sterile powder of intravenous drip; Oral formulations comprises: all acceptable dosage forms on the pharmaceuticss such as tablet, dispersible tablet, oral cavity disintegration tablet, capsule, soft capsule, granule, drop pill, oral liquid, slow releasing preparation, controlled release preparation.
2, the Ursodeoxycholic acid preparation of treatment liver and gall diseases as claimed in claim 1 is characterized in that: described preparation be ursodesoxycholic acid and suitable adjuvant make the injection with small volume that is directly used in drug administration by injection, directly for the venous transfusion of intravenous drip, need to be used for after the dilution concentrated solution for injection of intravenous drip and injectable sterile powder, capsule, drop pill, slow releasing preparation, controlled release preparation.
3, the Ursodeoxycholic acid preparation of treatment liver and gall diseases as claimed in claim 1 or 2 is characterized in that: described ursodesoxycholic acid injectable sterile powder is a kind of the making of adopting in solvent crystallization, spray drying method, the freeze-drying.
4, the Ursodeoxycholic acid preparation of treatment liver and gall diseases as claimed in claim 1 or 2 is characterized in that: the slow or controlled release preparation of described ursodesoxycholic acid is matrix tablet, hydrophilic gel matrix tablet, erodible matrix, insoluble matrix tablet, slow release or controlled release granule or microcapsule compressed tablet, slow release or controlled release capsule, osmotic pump controlled release tablet.
5, the Ursodeoxycholic acid preparation of treatment liver and gall diseases as claimed in claim 1 or 2 is characterized in that: described ursodesoxycholic acid sterilized powder is preparation like this: get ursodesoxycholic acid, be incorporated as the water for injection of full dose 60%, be stirred to dissolving fully; Add mannitol, stir and make dissolving, add water to full dose, regulate pH to 4.5～5.0 with the sodium hydroxide solution of 1.0mol/L; Other adds the active carbon of full dose 0.03% through 115-120 ℃ of activation 2 hours, places rustless steel container, and 80 ℃ of insulated and stirred absorption 30 minutes, coarse filtration was taken off charcoal; The compound membrane filtration of forming with 0.45 μ m and 0.22 μ m is to clear and bright, aseptic subpackaged, and per hour heat up after 4 hours 3 ℃ of dryings 20 hours of-40 ℃ of pre-freezes to 30 ℃ of freeze-day with constant temperature 6 hours, that is, promptly get injectable sterile powder.
6, the Ursodeoxycholic acid preparation of treatment liver and gall diseases as claimed in claim 1 or 2 is characterized in that: described ursodesoxycholic acid capsule is preparation like this: get ursodesoxycholic acid, add the dextrin of equivalent, mix homogeneously is granulated, and is encapsulated, promptly gets capsule.
7, the Ursodeoxycholic acid preparation of treatment liver and gall diseases as claimed in claim 1 or 2, it is characterized in that: described Ursodeoxycholic acid pills is preparation like this: get ursodesoxycholic acid, in adjuvant: the ratio of medicine is 1.5: 1-1: 3 polyethylene glycol 6000 is put in the rustless steel container, mix homogeneously, be heated to 80-85 ℃, treat whole fusions after, 70-75 ℃ of insulation, mechanical high-speed stirs 15min to even, be transferred in the reservoir, the dropping liquid valve is regulated in 70～75 ℃ of insulations, splash in 30～35 ℃ the kerosene, drip apart from 5～6cm, drip 40～45 droplets/minute of speed, to the greatest extent and wipe kerosene the drop pill drop that forms, packing promptly gets drop pill.
8, the Ursodeoxycholic acid preparation of treatment liver and gall diseases as claimed in claim 1 or 2 is characterized in that: described ursodesoxycholic acid slow release or controlled release preparation are preparations like this:
(1) hydrophilic gel matrix tablet: ursodesoxycholic acid is crossed 120 mesh sieves, in medicine: the ratio of adjuvant is 1: 2 acrylic resin, in medicine: 1: 1 HPMC of the ratio of adjuvant, in medicine: 1: 0.8 microcrystalline Cellulose mix homogeneously of the ratio of adjuvant, with with principal agent be that the 2%PVP and an amount of ethanol of 1: 1 ratio is made soft material, granulate with 18 eye mesh screens, 50～80 ℃ of oven dry, 18 eye mesh screen granulate are with an amount of stearate acid magnesium mixing, tabletting; With with the principal agent ratio be 20: 1 ratio get HPMC, with principal agent be that 1: 4 ratio taking polyethylene glycol, an amount of distilled water, an amount of 80% ethanol are made coating solution, the sheet that preceding makes is carried out coating, promptly get slow releasing tablet;
(2) osmotic pump controlled release tablet: get ursodesoxycholic acid, in with principal agent be that 1: 1 ratio is got mannitol, in with principal agent be that 40: 1 ratio is got oxirane, cross mix homogeneously behind 40 mesh sieves respectively, PVP is dissolved in the ethanol slowly adds in the above-mentioned blending ingredients, stir, crossing 10 mesh sieves granulates, 30～80 ℃ of dryings, behind 10 mesh sieve granulate, add the stearic acid mixing, tabletting, the label of making placed in the coating pan rotate, the blowing hot-air preheating sparges the cellulose acetate solution of debita spissitudo on the label of rolling, treat unilateral moistening slightly, be that cold wind dries up, hot air drying, so repeatable operation is closed requirement until the coating thickness; Adopt the tablet laser drilling machine, bore the suitable hole of a diameter, promptly get controlled release tablet in coated tablet central authorities.
9, the Ursodeoxycholic acid preparation of treatment liver and gall diseases as claimed in claim 8 is characterized in that: the adjuvant in described slow release or the controlled-release pharmaceutical formulation can be a Carnauba wax, castor oil hydrogenated, castor wax, hydrogenated soya phosphatide, spermaceti, Lac, gelatin, sodium alginate, sodium alginate, Sodium Alginate, sodium alginate, matrium alginicum, chitosan, fibrin and Fibrinogen, amylopectin, agar, carrageenin, guar gum, methylcellulose, ethyl cellulose, Aquacoat, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, cellulose acetate, the phthalic acid hydroxypropyl methylcellulose, cellulose acetate-phthalate, crylic acid resin, carbopol, polyvinyl alcohol, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, crospolyvinylpyrrolidone, silicone rubber, among the pluronic F127 one or more.
10, as the Ursodeoxycholic acid preparation of any described treatment liver and gall diseases of claim 1～8, it is characterized in that: described pharmaceutical preparation is used to prepare the medicine of diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, alcoholic liver disease, non-alcoholic stellato-hepatitis.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100587266A CN101028274A (en) | 2006-03-03 | 2006-03-03 | Ursodeoxycholic acid preparation in treatment of hepatobiliary diseases and its making method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100587266A CN101028274A (en) | 2006-03-03 | 2006-03-03 | Ursodeoxycholic acid preparation in treatment of hepatobiliary diseases and its making method |
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| CN101028274A true CN101028274A (en) | 2007-09-05 |
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| CNA2006100587266A Pending CN101028274A (en) | 2006-03-03 | 2006-03-03 | Ursodeoxycholic acid preparation in treatment of hepatobiliary diseases and its making method |
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| CN101606906B (en) * | 2009-07-23 | 2012-05-30 | 中国人民解放军第三○二医院 | Ursodeoxycholic acid nano suspension and preparation method thereof |
| WO2013057741A2 (en) * | 2011-10-21 | 2013-04-25 | Genovo Development Services Limited | Pharmaceutical compositions of ursodeoxycholic acid |
| CN103385880A (en) * | 2013-07-09 | 2013-11-13 | 荣港生技医药科技（北京）有限公司 | Ursodeoxycholic acid vitamin composition, preparation method and applications thereof |
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| CN110898036A (en) * | 2019-12-18 | 2020-03-24 | 乐普制药科技有限公司 | Ursodeoxycholic acid sustained-release enteric-coated capsule and preparation method thereof |
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| CN101606906B (en) * | 2009-07-23 | 2012-05-30 | 中国人民解放军第三○二医院 | Ursodeoxycholic acid nano suspension and preparation method thereof |
| WO2013057741A2 (en) * | 2011-10-21 | 2013-04-25 | Genovo Development Services Limited | Pharmaceutical compositions of ursodeoxycholic acid |
| WO2013057741A3 (en) * | 2011-10-21 | 2013-06-20 | Genovo Development Services Limited | Pharmaceutical compositions of ursodeoxycholic acid |
| CN103385880A (en) * | 2013-07-09 | 2013-11-13 | 荣港生技医药科技（北京）有限公司 | Ursodeoxycholic acid vitamin composition, preparation method and applications thereof |
| CN103385880B (en) * | 2013-07-09 | 2015-11-25 | 上海颐程医药科技有限公司 | A kind of ursodesoxycholic acid vitamin combination, Preparation Method And The Use |
| CN105326808B (en) * | 2013-12-02 | 2018-05-15 | 北京三泉医药技术有限公司 | Capsule for clearing heat and eliminating phlegm removing toxic substances |
| CN105326808A (en) * | 2013-12-02 | 2016-02-17 | 李兴惠 | Capsules for heat and phlegm clearing and detoxification |
| WO2015198258A1 (en) * | 2014-06-28 | 2015-12-30 | Shilpa Medicare Limited | Dispersible tablet comprising ursodeoxycholic acid or its salts |
| CN105732517A (en) * | 2016-02-01 | 2016-07-06 | 哈尔滨医科大学 | Medicine preparation containing 5-fluorouracil drug eutectic with nicotinamide as precursor and preparation method of medicine preparation |
| CN108383175A (en) * | 2018-02-07 | 2018-08-10 | 优德太湖水务（苏州）有限公司 | Slow release tablet and preparation method thereof for decentralized type sewage advanced treating |
| CN109248152A (en) * | 2018-11-02 | 2019-01-22 | 河北医科大学第二医院 | A kind of pharmaceutical preparation and preparation method thereof for treating disease in the liver and gallbladder |
| CN109248152B (en) * | 2018-11-02 | 2021-01-12 | 河北医科大学第二医院 | A pharmaceutical preparation for treating liver and gallbladder diseases, and its preparation method |
| CN109568288A (en) * | 2019-01-28 | 2019-04-05 | 四川迪菲特药业有限公司 | A kind of ursodesoxycholic acid capsule and preparation method thereof |
| CN109908088A (en) * | 2019-04-08 | 2019-06-21 | 合肥医工医药股份有限公司 | A kind of Ursodeoxycholic acid preparation for covering bitter taste using the netted inclusion technique of lipid |
| CN110898036A (en) * | 2019-12-18 | 2020-03-24 | 乐普制药科技有限公司 | Ursodeoxycholic acid sustained-release enteric-coated capsule and preparation method thereof |
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