CN100402027C - Abedol slow release tablet and its preparation method - Google Patents

Abstract

The present invention relates to an abedol slow release tablet which is an antivirus medicament. Because abedol hydrochloride hardly dissolves in water, a hydrophilic gel framework slow release tablet and a waxiness framework slow release tablet can be prepared. In the hydrophilic gel framework tablet, hydrophilic gel framework materials account for 10 to 90% of a prescription , preferably hydroxypropyl methyl cellulose; the hydroxypropyl methyl cellulose preferably accounts for 15 to 50% of the prescription, and a common wet granulation technology is adopted. In the waxiness framework slow release tablet, waxiness framework materials account for 5 to 80% of the prescription, preferably glycerol docosanoic acid ester ; the glycerol docosanoic acid ester preferably accounts for 10 to 40% of the prescription, and a direct tablet compressing technology, a wet granulation technology, and a melting or fusing granulation technology are adopted.

Description

Abiduoer slow releasing tablet and preparation method thereof

Technical field

The present invention relates to the slow releasing tablet of antiviral drugs arbidol HCl.

Background technology

Arbidol HCl (Arbidol hydrochloride) is a kind of novel antiviral medicine.It is the most remarkable to the antiviral activity with A, the antigenic influenza virus of Type B, can suppress A, Type B influenza virus duplicating in cell culture medium by selectivity.Abiduoer has immunoregulation effect simultaneously, can induce the generation interferon, and activating macrophage improves the resistance of body to viral infection, is to be used for the treatment of the influenza that A, Type B virus cause and the novel antiviral medicine of acute respiratory viral infection.

Animal pharmacokinetics experiment shows, rat oral gavage gives that Abiduoer (150mg/kg) post-absorption is rapid, and blood plasma tmax is 20min, and t1/2 is 6.7h.Because the Abiduoer half-life is shorter, in order to reach optimum therapeuticing effect, common Abiduoer tablet or capsule need administration 3～4 times every day when clinical application, and each 200mg makes troubles for patient's medication.Therefore, be necessary the slow release method of arbidol HCl is studied.

Summary of the invention

Slow releasing preparation can provide suitable blood drug level to human body on demand in the scheduled period, reduce medicining times and can obtain excellent curative.Its important feature is can make human body keep this kind blood drug level to reach the long period, do not descend faster the ordinary preparation and do not resemble, thereby " peak valley " phenomenon that just can avoid the ordinary preparation frequent drug administration to be occurred increases safety, effectiveness and the adaptability of medicine.

Matrix sustained release tablet is to use one of more oral slow-releasing preparation kind clinically at present, and its preparation technology is easy, and the release stable in properties is suitable for suitability for industrialized production.Matrix sustained release tablet can be divided into insoluble matrix sustained release tablet, hydrogel matrix slow releasing tablet, waxiness matrix sustained release tablet etc. by the framework material difference that it adopted.

For this medicine of arbidol HCl,, therefore can not adopt insoluble framework material, and can only be prepared into hydrogel matrix slow releasing tablet and waxiness matrix sustained release tablet because it is water-soluble hardly.

Abiduoer slow releasing tablet of the present invention is a matrix sustained release tablet, is respectively hydrogel matrix slow releasing tablet, waxiness matrix sustained release tablet.

In Abiduoer hydrogel matrix slow releasing tablet, contain 50～400 milligrams of active ingredient hydrochloric acid Abiduoers.

Hydrophilic gel matrix material shared part by weight in prescription can be 5～90% in hydrogel matrix tablet.

Hydrophilic gel matrix material is a hydrophilic polymer, meet water or Digestive system skeleton and expand, thereby can form firm gel barrier control medicine stripping, and protection label depths is not subjected to the influence of dissolution medium and disintegrate takes place.As time goes on, outer gel layer constantly dissolves, and inside forms gel layer again, dissolves until label to be dissolved in the dissolution medium fully again.

If the active component dissolubility is bigger, its releasing mechanism mainly is the diffusion of active component and the continuous corrosion of gel layer; Belong to indissoluble thing in the water as active component, slow release mechanism mainly shows in the corrosion process of gel layer.

The hydrophilic gel matrix material that is used for the Abiduoer slow releasing tablet comprises: natural gum, cellulose derivative, non-cellulosic polysaccharide, ethene polymers, crylic acid resin.

The hydrophilic gel matrix material natural gum comprises sodium alginate, agar, Calculus Bovis from Northwest of China fin glue etc.

The hydrophilic gel matrix material cellulose derivative comprises methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethylmethyl-cellulose, sodium carboxymethyl cellulose etc.

The hydrophilic gel matrix material non-cellulosic polysaccharide comprises chitin etc.

The hydrophilic gel matrix material ethene polymers comprises polyvinyl alcohol, carbopol etc.

The hydrophilic gel matrix material crylic acid resin comprises Eudragit E, Eudragit RL, Eudragit RS etc.

Above-mentioned hydrophilic gel matrix material is hydroxypropyl emthylcellulose preferably, as the Methocel K series of products of DowChemical.

The preparation of hydrogel matrix tablet can be adopted common wet granulation technology, can add various additive of tablet such as diluent, wetting agent or binding agent, lubricant, fluidizer, stabilizing agent etc. according to different situations.

The character of diluent also can influence the stripping of matrix tablet, and hydrophilic diluents helps medicine to discharge from framework material, and hydrophobic diluents then can delay the release of medicine.Can regulate the rate of release of medicine by adding following different diluent:

Hydrophilic diluents helps the material of moisture penetration in the pharmaceutical preparation as lactose, mannitol, sorbitol, xylitol, starch, microcrystalline Cellulose or other.

Hydrophobic diluents, as glyceryl monostearate, cetylate, hydrogenation or not hydrogenated vegetable oil, wax, single, two one or the tri-substituted glycerol ester, or other can delay the material of moisture penetration in the pharmaceutical preparation.

The optional water of wetting agent or binding agent, ethanol, starch slurry, polyvinylpyrrolidine and various cellulose family.

Lubricant and fluidizer adopt magnesium stearate, stearic acid, Polyethylene Glycol-4000 ,-6000, Talcum, micropowder silica gel etc. usually.

Because Abiduoer is a hydrochlorate, its aqueous solution of 0.07% (g/ml) PH is between 4.85～5.05, and unstable in aqueous solution and under the high temperature, outward appearance is flavescence gradually.And,, can keep the stability of Abiduoer in wet-granulation process as adding acid regulators such as dilute hydrochloric acid, tartaric acid, citric acid, lactic acid in the next stability of improving its aqueous solution of acid condition.

The waxiness matrix sustained release tablet is that framework material is made with materials such as inert fat or wax classes, and along with the corrosion gradually of fat or waxiness, drug slow discharges.

In Abiduoer waxiness matrix sustained release tablet, contain 50～400 milligrams of active ingredient hydrochloric acid Abiduoers.

Waxiness framework material shared weight ratio in prescription is 5～80% in the waxiness matrix tablet.

The waxiness framework material that is used for the Abiduoer slow releasing tablet comprises: hydrogenated vegetable oil, stearic acid, octadecanol, glyceryl stearate, Tridocosanoin etc.

Above-mentioned waxiness framework material is Tridocosanoin preferably, as the COMPRITOL of GATTEFOSSE company ^R888 ATO.

Because the arbidol HCl poorly water-soluble, in its waxiness matrix tablet, need to add hydroaropic substance as pore-forming agent promoting the release of medicine, adoptable porogen has polyvinylpyrrolidone, microcrystalline Cellulose, Polyethylene Glycol-1500,4000,6000 etc.

The preparation of waxiness matrix tablet can be adopted direct compression, wet granulation, fusing or melt granulation technology.

Because COMPRITOL ^R888 ATO have compressibility and cohesive preferably, with mixing such as diluent such as microcrystalline Cellulose, lactose, mannitol, sorbitol, calcium hydrogen phosphate, make direct compression become possibility with directly compressible.

Work as COMPRITOL ^RWhen 888 ATO are used for wet granulation, only need add entry or organic solvent and make wetting agent and get final product.Diluent can adopt the kind that adopts usually in the wet granulation technology.

For wax materials such as hydrogenated vegetable oil, stearic acid, octadecanol, glyceryl stearate, can adopt fusing or melt granulation, waxiness is dissolved in organic solvent or fusion after, add Abiduoer, diluent and porogen, cooling back crushing screening is granulated, and adds the lubricant tabletting.

The specific embodiment

In Abiduoer hydrogel matrix slow releasing tablet, the preferred hydroxypropyl emthylcellulose of hydrophilic gel matrix material, as the Methocel K series of products of Dow Chemical, shared part by weight preferably 15～50% in prescription.

In Abiduoer waxiness matrix sustained release tablet, the waxiness framework material is Tridocosanoin preferably, as the COMPRITOL of GATTEFOSSE company ^R888 ATO, shared part by weight preferably 10～40% in prescription.

With following embodiment the present invention is described.

Embodiment 1: arbidol HCl hydrogel matrix slow releasing tablet

Prescription:

Preparation technology:

Arbidol HCl was pulverized 80 mesh sieves, with behind Methocel K4M and the lactose mix homogeneously with granulating after 10% polyvinylpyrrolidone+2% tartaric acid, 95% alcoholic solution moistening, at 45～50 ℃ of dry back granulate, add magnesium stearate and Pulvis Talci, the mix homogeneously tabletting.

The release test:

For investigating the extracorporeal releasing characteristic of arbidol HCl slow releasing tablet, with the release of 2000 editions two appendix XC first methods of Chinese Pharmacopoeia (basket method) working sample.With water 900ml is solvent, and rotating speed is that per minute 100 changes, and respectively at sampling in 1,2,4,6,8 hour, according to spectrophotography (2000 editions two appendix IVA of Chinese Pharmacopoeia), measures trap, the release of calculation sample at the wavelength place of 257nm.

Result of the test sees Table one.

Time (hour)	Release (%)
		1	12.3
2	21.5
		4	37.4
6	46.7
		8	58.6
10	67.7

12	75.3
		16	86.9
20	94.7
		24	99.5

Active substance can sustained release in about 20 hours.

Embodiment 2: arbidol HCl hydrogel matrix slow releasing tablet

Prescription:

Preparation technology:

Arbidol HCl was pulverized 80 mesh sieves, with behind Methocel K15M and the microcrystalline Cellulose mix homogeneously with granulating after 10% polyvinylpyrrolidone+2% tartaric acid, 95% alcoholic solution moistening, at 45～50 ℃ of dry back granulate, add magnesium stearate and Pulvis Talci, the mix homogeneously tabletting.

Embodiment 3: arbidol HCl hydrogel matrix slow releasing tablet

Preparation technology:

Arbidol HCl was pulverized 80 mesh sieves, with behind sodium alginate and the microcrystalline Cellulose mix homogeneously with granulating after 0.5% hydroxypropyl emthylcellulose+2% tartaric acid, 60% alcoholic solution moistening, granulate after 45～50 dryings adds magnesium stearate and Pulvis Talci, the mix homogeneously tabletting.

Embodiment 4: arbidol HCl waxiness matrix sustained release tablet

Prescription:

Preparation technology:

Arbidol HCl was pulverized 80 mesh sieves, with COMPRITOL ^RBehind 888 ATO and the microcrystalline Cellulose mix homogeneously with granulating after the water-wet, at 40～45 ℃ of dry back granulate, tabletting.

Embodiment 5:

Prescription:

Preparation technology:

Arbidol HCl was pulverized 80 mesh sieves, with glyceryl stearate fusion in 65 water-baths, the mixture that slowly adds arbidol HCl, polyvinylpyrrolidone and microcrystalline Cellulose while stirring, continuing to stir slowly cools off it, solidifying body is crossed 18 mesh sieves granulate, add the magnesium stearate tabletting.

Claims (2)

1. Abiduoer slow releasing tablet, it is characterized in that forming by active ingredient hydrochloric acid arbidol, hydrophilic gel matrix material hydroxypropyl emthylcellulose, lactose, magnesium stearate, Pulvis Talci, wetting agent, sheet weighs 500 milligrams, and wherein 200 milligrams of arbidol hydrochlorides, hydroxypropyl emthylcellulose are that Methcel K4M110 milligram, 130 milligrams of lactose, 5 milligrams of magnesium stearate, 5 milligrams of Pulvis Talci, wetting agent are an amount of 10% polyvinylpyrrolidone and 2% tartaric 95% alcoholic solution.

2. method for preparing the described Abiduoer slow releasing tablet of claim 1, it is characterized by: arbidol hydrochloride was pulverized 80 mesh sieves, with behind Methcel K4M and the lactose mix homogeneously with granulating after 10% polyvinylpyrrolidone and the 2% tartaric 95% alcoholic solution moistening, at 45～50 ℃ of dry back granulate, add magnesium stearate and Pulvis Talci again, the mix homogeneously tabletting.