CN1679606A - Soft capsules of azithromycin and preparation thereof - Google Patents

Abstract

A softgel of azimycin is prepared from azimycin, diluent, antioxidizing agent, solubilizer and cosolvent through dissolving gelatin in water, adding glycerine, vacuum degassing, laying aside, sequentially mixing solubilizer, diluent, azimycin and antioxidizing agent, stirring, pilling, drying and polishing.

Description

Azithromycin soft capsule and preparation method thereof

Technical field:

The futuramic Azithromycin dosage forms soft capsule of the present invention belongs to medical technical field.

Background technology:

(erythromycin is Ery) as most widely used macrolide antibiotics, in clinical practice many decades for erythromycin.But unstable to acid because of it, blood concentration is low, dosage is big, to characteristics such as liver are toxic, so relevant scientist by its chemical constitution of transformation, develops a series of new derivative of macrolides.(azithromycin is the nitrogenous Macrolide new drug of first 15 ring Azi) to azithromycin, is at first formulated the exploitation listing of U.S. Pfizer drugmaker by Yugoslavia Pliva drugmaker.In recent years, reported and estimated its antibacterial action abroad, a piece of writing surplus the article of pharmacokinetics and clinical practice has 20, widely world's pharmacy and medical expert are certainly.Azi and Ery have common point on the chemical constitution He on the mechanism of action, but their biological characteristics is completely different.Azi not only has stable, the partly sad phase of acid long, and infection site tissue and IC height, evident in efficacy, advantages such as safety and better tolerance, and application clinically has good prospect, and domestic many pieces of articles are introduced Zitromax.

Azi reaches antibacterial action by suppressing ribosome 50s protein subunit matter surface.It has antibacterial activity to multiple aerobic and anaerobism gram positive bacteria, can suppress many important aerobic and anaerobic gram negative bacterias.To the isolating common pathogen of genitourinary system, as the urea bacteria of chlamydia trachomatis and dissolved urea, azithromycin all has activity, and atypia respiratory tract pathogenic bacterium, Chlamydia pneumoniae, mycoplasma pneumoniae are also had bacteriostatic activity.Clinical isolating campylobacter jejuni is higher than erythromycin, Clarithromycin to the sensitivity of Azi.Clinical isolating helicobacter pylori is to ten fens sensitivities of Azi.For some bacterial strains that produce beta-lactamase, as producing enzyme staphylococcus aureus, hemophilus influenza, haemophilus parainfluenzae, Moraxella catarrhalis etc., Azi all can be suppressed effectively.

Because the Azi interior concentration of histiocyte in vivo can reach more than the 3mg/kg, considerably beyond many former minimum inhibitory concentrations that cause a disease, thereby has bactericidal action.Azi is bactericidal action to chlamydia trachomatis of hemophilus influenza, legionella pneumophilia, Chlamydia pneumoniae, streptococcus pneumoniae etc.

The bioavailability of oral azithromycin 500mg is 37% on an empty stomach.It is 0.4-0.45mg/L that the single agent of 500mg reached the peak blood concentration in oral back 2.5 hours, and peak blood drug level slightly rises behind the multiple dosing.Area under curve in 0-72 hour (AUC) is 3.39mg/ (L.h).The plasma protein binding rate of azithromycin is low, is 50% during blood drug level 0.2mg/L, is 12% during 0.5mg/L.

The tissue permeability of azithromycin is good, tissue concentration be the same period blood drug level 10-100 doubly.Oral back 12 hours to 3 days of single agent 500mg, the concentration in tonsil, lung, prostate, the female reproductive system tissue reaches 1-9mg/L, surpasses the minimum inhibitory concentration of respiratory tract, urogenital tract encountered pathogenic bacteria.Medicine is held time in tissue for a long time, at prostate, tonsil Chinese medicine t _1/2Reach 2.3 days to 3.2 days.

Convenient because of azithromycin oral, be suitable for child's administration, foreign study Azithromycin for Suspension, Chinese Pharmacopoeia version in 2000 has also been recorded Azithromycin for Suspension.Because the azithromycin flavor is extremely bitter, domestic commercially available Azithromycin for Suspension taste is also bitter, and the child is difficult for accepting, and develops a kind of new dosage form that is applicable to child's oral administration and necessitates.

Azithromycin soft capsules of the present invention has following advantage:

Soft capsule improves bitterness---pharmaceutical pack is rolled in the capsule, cover the bitterness of medicine, be suitable for the child and use.

The soft capsule volume that makes things convenient for medication 10mg-250mg specification is 0.1-0.2ml only, is suitable for the child and uses.

Improve stability-pharmaceutical pack is rolled in the capsule, avoided the influence of moisture, air, light; Adopt non-aqueous solvent systems simultaneously, avoid the hydrolysis and the oxidation of medicine, protection reaches stablizes medicine.

Medicine is rapid-action in vivo--and-medicine dissolution discharges with breaking of capsule shells at gastrointestinal tract in The suitable solvent, and the medicine in the solution disperses rapidly and absorbs, and is rapid-action.

Therefore developing this product has great social significance and good market prospect.

Azithromycin is the 1st the 15 membered ring lactone class antibiotic of being developed by Puli watt (Pliva) drugmaker abroad.Its oral raw material and preparation are produced by families such as China Qilu Pharmaceutical Factory, Shijiazhuang first pharmaceutical factory, Beijing Tai Yang Pharma Inc.s.Pfizer Inc. is production Azithromycin for Suspension now, and specification is the 100mg/ bag.At present domestic still do not have Azithromycin soft capsules to go on the market.

Summary of the invention:

The novel form that the purpose of this invention is to provide a kind of azithromycin, its objective is and make azithromycin can be prepared into soft capsule, can improve its disease at the treatment viral infection, application in the acute respiratory syndrome that causes as hepatitis, viral influenza, viral infection etc., and be suitable for the child especially and use.

Medicinal soft capsule of the present invention is characterized in that: azithromycin is scattered in the The suitable solvent makes.Wherein solvent can be Macrogol 200-1000, propylene glycol, glycerol, soybean oil, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Oleum Sesami, Semen Maydis oil, Fructus Canarii albi wet goods; Also can add solubilizing agent or cosolvent and antioxidant etc.

Soft capsule of the present invention also can be selected following adjuvant for use: diluent is as Macrogol 200-1000, propylene glycol, glycerol, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Oleum Sesami, Semen Maydis oil, Fructus Canarii albi wet goods; Solubilizing agent is as Tweens, pluronic F-68, polyoxyethylene ether Oleum Ricini, polyvidone, sodium cholate, sodium lauryl sulphate etc.; Antioxidant is as propyl gallate, di-tert-butyl hydroxy-methylbenzene (BHT), butylated hydroxyarisol (BHA), vitamin E, ascorbyl palmitate, sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, glycine, methionine, lysine, valine, arginine, leucine, isoleucine, tryptophan, glutathion etc.Cosolvent is as sodium sulfite, sodium carbonate, sodium bicarbonate, potassium dihydrogen phosphate, Ammonium biphosphate etc.; Amides compound such as carbamide, acetamide, nicotiamide, thiourea, Benzoylamide etc., amino acids such as arginine, aspartic acid, serine, glycine, methionine, histidine, glutamic acid, isoleucine, threonine, cysteine, cystine, tryptophan, phenylalanine, lysine, the chemical compound of hydroxyl or carboxyl such as sucrose, glucose, fructose, xylose, mannose, citric acid and sodium salt thereof, lactic acid, sodium salicylate etc.

The ratio of gelatin, glycerol and water can suitably be regulated in the glue shell, is advisable 1: 0.3～0.4: 0.7～1.4 as gelatin/glycerin/water three's ratio, also can add other compositions in the glue shell, as antiseptic: P-hydroxybenzoic acid first, second, third, butyl ester etc.; Plasticizer such as sorbitol etc.; Stabilizing agent such as arabic gum etc.; Opacifier is as titanium dioxide, barium sulfate, precipitated calcium carbonate etc.; Antioxidant such as amino acids; Pigment such as sunset yellow, lemon yellow, light blue, carmine etc.

Soft consumption with each composition of wafer is among the present invention: diluent such as Polyethylene Glycol (200-1000) 0.1-0.5ml, and suitable consumption is 0.1-0.4ml; The consumption of solubilizing agent such as Tween 80 is 0.0%-30.0%, and suitable consumption is 1.0%-20.0%; The consumption of cosolvent such as polyvidone is 1.0%-100.0%, and suitable consumption is 10.0%-50.0%; The consumption of antioxidant is 0.001%-0.5%, and suitable consumption is 0.01%-0.1%.

The amount of application of Chinese medicine of the present invention can be according to variations such as the type of patient age, body weight, body surface area, the disease of being treated and the orders of severity, and its daily dose can be 10-500mg.Can use by one or many.

The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.

Embodiment 1

Azithromycin soft capsules

Prescription: every of content contains the glue shell

Azithromycin 50mg gelatin 46.00%

PEG400 0.2ml glycerol 17.82%

Water 36.18%

Get azithromycin and be dissolved among the PEG400, this solution is made soft capsule.Every contains azithromycin 50mg.

Embodiment 2

Azithromycin soft capsules

Prescription: every of content contains the glue shell

Azithromycin 50mg gelatin 46.00%

PEG400 0.1ml glycerol 17.82%

Tween 80 0.02ml water 36.18%

Get azithromycin and be dissolved in PEG400 and the Tween 80, this solution is made soft capsule.Every contains azithromycin 50mg.

Embodiment 3

Azithromycin soft capsules

Prescription: every of content contains the glue shell

Azithromycin 50mg gelatin 46.00%

PEG400 0.1ml glycerol 17.82%

Tween 80 0.02ml water 36.18%

30 POVIDONE K 30 BP/USP 30 30mg

Polyvidone is dissolved in PEG400 and the Tween 80, adds azithromycin and make its dissolving, this solution is made soft capsule.Every contains azithromycin 50mg.

Embodiment 4

Azithromycin soft capsules

Prescription: every of content contains the glue shell

Azithromycin 50mg gelatin 46.00%

PEG400 0.1ml glycerol 17.82%

Tween 80 0.02ml water 36.18%

30 POVIDONE K 30 BP/USP 30 30mg

Butylated hydroxyarisol (BHA) 0.01mg

Get polyvidone and be dissolved in PEG400 and the Tween 80, azithromycin and BHA are dissolved in wherein,

This solution is made soft capsule.Every contains azithromycin 50mg.

Embodiment 5

Azithromycin soft capsules

Prescription: every of content contains the glue shell

Azithromycin 125mg gelatin 46.00%

PEG400 0.1ml glycerol 17.82%

Tween 80 0.02ml water 36.18%

Get azithromycin and be dissolved in PEG400 and the Tween 80, this solution is made soft capsule.Every contains azithromycin 125mg.

Embodiment 6

Azithromycin soft capsules

Prescription: every of content contains the glue shell

Azithromycin 250mg gelatin 46.00%

PEG400 0.2ml glycerol 17.82%

Tween 80 0.04ml water 36.18%

Get azithromycin and be dissolved in PEG400 and the Tween 80, this solution is made soft capsule.Every contains azithromycin 250mg.

Claims (7)

1, Azithromycin soft capsules is characterized in that, medicinal liquid contains the azithromycin and the pharmaceutic adjuvant of effective dosage, and pharmaceutic adjuvant comprises diluent, antioxidant, solubilizing agent, cosolvent etc.By the normal capsules grain, contain azithromycin 0.01～0.25 gram in every medicinal liquid.

2, Azithromycin soft capsules as claimed in claim 1 is characterized in that, described diluent is one or more in vegetable oil, glycerol, propylene glycol, Polyethylene Glycol (molecular weight 200-1000), the mineral oil.

3, Azithromycin soft capsules as claimed in claim 1, it is characterized in that described antioxidant is one or more in propyl gallate, di-tert-butyl hydroxy-methylbenzene (BHT), butylated hydroxyarisol (BHA), vitamin E, ascorbyl palmitate, sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, glycine, methionine, lysine, valine, arginine, leucine, isoleucine, tryptophan, the glutathion.

4, Azithromycin soft capsules as claimed in claim 1 is characterized in that, described solubilizing agent is Tween 80, pluronic F-68, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, polyvidone, sodium cholate, sodium lauryl sulphate etc.;

5, Azithromycin soft capsules as claimed in claim 1 is characterized in that, and is described that cosolvent is sodium sulfite, sodium carbonate, sodium bicarbonate, potassium dihydrogen phosphate, Ammonium biphosphate etc.; Amides compound such as carbamide, acetamide, nicotiamide, thiourea, Benzoylamide etc., amino acids such as arginine, aspartic acid, serine, glycine, methionine, histidine, glutamic acid, isoleucine, threonine, cysteine, cystine, tryptophan, phenylalanine, lysine, one or more in the chemical compound of hydroxyl or carboxyl such as sucrose, glucose, fructose, xylose, mannose, citric acid and sodium salt thereof, lactic acid, the sodium salicylate.

6, Azithromycin soft capsules as claimed in claim 1 is characterized in that, the content of each component in the described medicinal liquid:

Every of component

Azithromycin 0.01-0.25g

Diluent 0.1-0.5ml

Antioxidant 0.001%-0.5%

Solubilizing agent 0.0%-30.0%

Cosolvent 1.0%-100.0%

7, the preparation method of the described Azithromycin soft capsules of claim 1 may further comprise the steps:

(1) gelatin places the glue jar, adds the purified water of solubilized gelatin amount, 70～80 ℃ of glue jar temperature, and the in-depth back adds glycerol, antiseptic, with the cologne earth toning, stirs, and is incubated set aside for use after the vacuumize degassing;

(2) solubilizing agent and (or cosolvent) are added in the diluent, add azithromycin, treat to add antioxidant again behind the complete mixing, stir, room temperature leaves standstill;

(3) medicinal liquid for preparing poured in the pellet processing machine, finalized the design, put drying, scrape promptly.