CN102232929A - Voriconazole dried suspension and preparation method thereof - Google Patents

Abstract

The invention relates to a Voriconazole dried suspension, comprising 5-15wt% of Voriconazole, 3-20wt% of suspending agent, 30-60wt% of filling agent, 20-50wt% of sweetening agent, 0.1-10wt% of PH regulator, 0.2-2wt% of lubricant, 0.1-2wt% of flavoring agent and 1-5wt% of opacifier. The Voriconazole dried suspension is a fine particle dosage form with more advantages than tablet and other solid dosage forms, has the advantages of large distribution area in gastrointestinal tract, fast absorption and high bioavailability, and can avoid the disadvantage of difficult swallowing of the tablet. Dried suspension is stored as solid, and is given through the mouth in suspension state, so as to be suitable for drugs with low water stability, and for children, the old and the patients who has difficult in swallowing.

Description

Voriconazole dry suspension and preparation method thereof

Technical field

The present invention relates to treat the pharmaceutical preparation of fungus, relate in particular to a kind of voriconazole dry suspension and preparation method thereof.

Background technology

Voriconazole is disclosed in European patent EP 0440372, and can effectively treat fungal infection.

Voriconazole (Voriconazole) is a kind of new synthetic triazole type medicine, is the synthetic fluconazol derivant of the second filial generation.As a kind of novel antifungal agent, have has a broad antifungal spectrum, characteristics that antibacterial efficacy is strong.According to " foreign medical science ", this medicine has been applied to clinically abroad morely at present, and has obtained satisfied curative effect.

A large amount of experimentation and in vitro testses show that voriconazole has wider antimicrobial spectrum and stronger effect as a kind of new synthetic chemical compound compared with present antifungal agent.When being used for Candida, no matter be to the fluconazol sensitivity or to the drug-fast bacterial strain of fluconazol, voriconazole all has the antibacterial activity that is better than other antifungal, only not obvious to minority bacterial strain effects such as Candida krusei.Its anti-neogenesis cryptococcus ability and specific activity fluconazol are high 16 times, and be similar in appearance to ketoconazole, higher 2 times than itraconazole.Voriconazole and fluconazol, itraconazole, amphotericin B show the in vitro study of 19 fungus strain effects, itraconazole has certain antibiotic advantage to aspergillosis, most of filamentous bacteria and yeast bacteria, particularly the drug-fast native mycete of amphotericin B is had no drug resistance, have potential clinical value.But it is not good enough to part Rhodothece glutinis, eggplant disease fusarium, Sporothrix schenckii and paecilomyces varioti effect.To the drug sensitive test results suggest of 19 kinds of different dermatophytosises, voriconazole is than ketoconazole, fluconazol sensitivity height, but more lower slightly than itraconazole and terbinafine.

At present, clinically mainly suppress and kill Cryptococcus, aspergillus and Candida with voriconazole, in particular for to fluconazol invalid read coccus infect, to the invalid aspergillin infection of itraconazole and amphotericin B with to the drug-fast native fungal infection of amphotericin B etc., for the clinical treatment mycosis provides a kind of new active drug.

The mechanism of action of voriconazole is the 14 α-sterol demethylation that is mediated by Cytochrome P450 in the inhibition fungus, thereby suppresses the biosynthesis of ergosterol.In vitro tests shows that voriconazole has the broad-spectrum antifungal effect.This product has antibacterial action to Candida (Candida krusei that comprises anti-fluconazol, Candida glabrata and Candida albicans persister), and the aspergillus fungus of all detections is had bactericidal action.In addition, voriconazole also has bactericidal action external to other pathogenic funguses, comprises the existing lower Pseudomonas of antifungal agent sensitivity, for example Scedosporium and Fusarium.Zoopery finds that the minimum inhibitory concentration value of voriconazole is relevant with its curative effect.But in clinical research, there is no dependency between minimum inhibitory concentration and the clinical efficacy, and as if also do not have dependency between the blood concentration of medicine and the clinical efficacy.This is the characteristics of pyroles antifungal agent.

Voriconazole listing dosage form has: freeze-dried powder, tablet, and can oral and intravenously administrable.Because the dissolubility of voriconazole in water lower (almost insoluble during pH=7, dissolubility 0.2mg/ml during pH=3), and unstable (being reassembled as a kind of inactive enantiomer) by the contrary aldol product of hydrolysis.Freeze-dried powder has solved the water solublity problem, but it uses inconvenience, and patient compliance is poor; And tablet, because the voriconazole poorly water-soluble, its dissolution is lower, and differences between batches are bigger, therapeutic response is not good enough.

Summary of the invention

It is low to the objective of the invention is to solve existing peroral dosage form medicine stripping, and the problem that bioavailability is low provides a kind of itraconazole dry suspension fast, that bioavailability is high and suitable child old man takes that absorbs.

The present invention is to provide the voriconazole dry suspension, dry suspension is a kind ofly to have more the fine particles dosage form of advantage than solid dosage formss such as tablets, and it is big at the gastrointestinal distribution area, absorb fast, bioavailability height, the shortcoming that can avoid the tablet difficulty to swallow simultaneously.It is slow that it has not only changed the conventional tablet oral absorption, is unfavorable for the shortcoming that old man, child and dysphagia person take, and easily obey quick-dissolving characteristics by medicine, and making it in vivo can faster better performance curative effect of medication.Dry suspension stores with solid form, and oral with the confession of suspension form, therefore is particularly suitable for hydrolabil medicine; Dry suspension has the patient of dysphagia applicable to child, old man and part.

In order to realize the foregoing invention purpose, the present invention adopts following technical scheme:

The voriconazole dry suspension comprises voriconazole 5%～15%, suspending agent 3%～20%, filler 30%～60%, sweeting agent 20%～50%, pH regulator agent 0.1%～10%, lubricant 0.2%～2%, correctives 0.1%～2% and opacifier 1%～5%.

Voriconazole dry suspension of the present invention can also comprise 5～20% flocculating agent, 0.05～0.5% antiseptic.

Described suspending agent is one or more mixing in xanthan gum, sodium carboxymethyl cellulose, arabic gum, sodium alginate, guar gum, hydroxypropyl cellulose, hypromellose, the polyvinylpyrrolidone.

Described filler is one or more mixing in lactose, sucrose, pregelatinized Starch, microcrystalline Cellulose, the mannitol.

Described PH regulator is one or more mixing in citric acid, tartaric acid, the malic acid acetic acid.

Described flocculating agent is citric acid sodium or Soluble tartar..

Described opacifier is a titanium dioxide.

The invention also discloses the preparation method of voriconazole dry suspension, comprise the steps:

(1), behind the dry mixing of the voriconazole of having pulverized with described proportioning, suspending agent, filler, flocculating agent, sweeting agent, pH regulator agent, crosses 80～200 mesh sieves;

(2), the mixed material of step (1) is added the binding agent of described proportioning, the system soft material is granulated with 18～30 mesh sieves then, and drying becomes dried particles;

(3), behind the dried particles and opacifier, lubricant, correctives and antiseptic mixing that step (2) is obtained, packing gets final product.

Voriconazole dry suspension of the present invention has more the fine particles dosage form of advantage than solid dosage formss such as tablets, and it is big at the gastrointestinal distribution area, absorb fast, bioavailability height, the shortcoming that can avoid the tablet difficulty to swallow simultaneously.Dry suspension stores with solid form, and oral with the confession of suspension form, therefore is particularly suitable for hydrolabil medicine; Dry suspension has the patient of dysphagia applicable to child, old man and part.

The specific embodiment

The present invention is described further below by specific embodiment.

Embodiment 1

Prescription

Composition weight (g) ratio (%)

Voriconazole 200 6

Xanthan gum 216.7 6.5

Sucrose 2516.7 75.5

Citric acid 33.3 1

Sodium citrate 253.3 7.6

Sodium benzoate 3.3 0.1

Micropowder silica gel 33.3 1

Orange flavor essence 10 0.3

Titanium dioxide 66.7 2

Make 1000 bags.

Preparation method:

(1), behind the dry mixing of the voriconazole of having pulverized with recipe quantity, xanthan gum, sucrose, sodium citrate, citric acid, crosses 100 mesh sieves.

(2), the mixed material of step (1) is added suitable quantity of water, the system soft material is granulated with 30 mesh sieves then, and drying becomes dried particles.

(3), with the dried particles of step (2) again with titanium dioxide, micropowder silica gel, orange flavor essence and the sodium benzoate mixing of recipe quantity after, packing gets final product.

Embodiment 2:

Prescription

Composition weight (g) ratio (%)

Voriconazole 200 10

Carboxymethyl cellulose 300 15

Sucrose 1,250 62.5

Citric acid 42 2.1

Sodium citrate 160 8

Sodium benzoate 2 0.1

Micropowder silica gel 20 1

Cream flavour 6 0.3

Titanium dioxide 40 2

Make 1000 bags.

Preparation method:

(1), behind the dry mixing of the voriconazole of having pulverized with recipe quantity, carboxymethyl cellulose, sucrose, sodium citrate, citric acid, crosses 100 mesh sieves.

(2), the mixed material of step (1) is added suitable quantity of water, the system soft material is granulated with 18 mesh sieves then, and drying becomes dried particles.

(3), with the dried particles of step (2) again with titanium dioxide, micropowder silica gel, cream flavour and the sodium benzoate mixing of recipe quantity after, packing gets final product.

Embodiment 3:

Prescription

Composition weight (g) ratio (%)

Voriconazole 200 8

Xanthan gum 250 10

Microcrystalline Cellulose 870 34.8

Sucrose 1,100 44

Tartaric acid 25 1

Soluble tartar. 245 9.8

Sodium benzoate 2.5 0.1

Micropowder silica gel 25 1

Apple essence 7.5 0.3

Titanium dioxide 52

Make 1000 bags.

Preparation method:

(1), behind the voriconazole of having pulverized with recipe quantity, xanthan gum, microcrystalline Cellulose, sucrose, Soluble tartar., the dry mixing of tartaric acid acid, crosses 100 mesh sieves.

(2), the mixed material of step (1) is added suitable quantity of water, the system soft material is granulated with 30 mesh sieves then, and drying becomes dried particles.

(3), with the dried particles of step (2) again with titanium dioxide, micropowder silica gel, apple essence and the sodium benzoate mixing of recipe quantity after, packing gets final product.

Claims (7)

1. the voriconazole dry suspension is characterized in that comprising voriconazole 5%～15%, suspending agent 3%～20%, filler 30%～60%, sweeting agent 20%～50%, pH regulator agent 0.1%～10%, lubricant 0.2%～2%, correctives 0.1%～2% and opacifier 1%～5%.

2. voriconazole dry suspension according to claim 1 is characterized in that comprising 5～20% flocculating agent, 0.05～0.5% antiseptic.

3. voriconazole dry suspension according to claim 1 is characterized in that described suspending agent is one or more mixing in xanthan gum, sodium carboxymethyl cellulose, arabic gum, sodium alginate, guar gum, hydroxypropyl cellulose, hypromellose, the polyvinylpyrrolidone.

4. voriconazole dry suspension according to claim 1 is characterized in that described filler is one or more mixing in lactose, sucrose, pregelatinized Starch, microcrystalline Cellulose, the mannitol.

5. the dried suspendible of voriconazole according to claim 1 is characterized in that described PH regulator is one or more mixing in citric acid, tartaric acid, the malic acid acetic acid.

6. voriconazole dry suspension according to claim 2 is characterized in that described flocculating agent is citric acid sodium or Soluble tartar..

7. voriconazole dry suspension according to claim 1 is characterized in that described opacifier is a titanium dioxide.

8,, it is characterized in that comprising the steps: according to the preparation method of the described voriconazole dry suspension of claim 1～7

(1), behind the dry mixing of the voriconazole of having pulverized with described proportioning, suspending agent, filler, flocculating agent, sweeting agent, pH regulator agent, crosses 80～200 mesh sieves;

(2), the mixed material of step (1) is added the binding agent of described proportioning, the system soft material is granulated with 18～30 mesh sieves then, and drying becomes dried particles;

(3), behind the dried particles and opacifier, lubricant, correctives and antiseptic mixing that step (2) is obtained, packing gets final product.