CN102058521A - Injection preparation containing Entecavir serving as active ingredient - Google Patents

Abstract

The invention relates to an injection preparation containing Entecavir serving as an active ingredient and a preparation method thereof. The injection preparation is characterized by consisting of Entecavir serving as the active ingredient, a water soluble filler, a pH regulator, a solubilizer, an antioxygen, water for injection and an osmotic pressure regulator, wherein Entecavir serving as the active ingredient accounts for 0.002 to 50 percent of the weight of the injection preparation, and medicinal auxiliary materials and water account for the balance. The invention also discloses preparation methods of freeze-dried preparation, small-needle injection and small infusion solution. The injection preparation containing Entecavir serving as the active ingredient is suitable for treating acute exacerbation of hepatitis.

Description

A kind of preparation that contains active component Entecavir administrated by injection

Technical field

The invention belongs to field of pharmaceutical preparations, more particularly relate to preparation of a kind of administrated by injection that contains the active component Entecavir and preparation method thereof.

Background technology

Hepatitis B virus (HBV) is the single-minded liver of having a liking for Virus, in recent years because Nucleic acidThe progress of molecular hybridization, organ outside liver CellAlso can detect HBV-DNA.The evidence of cellular replication outside liver is provided by the experimental study of Beijing duck hepatitis B hepatovirus.People HBV also may be outside liver time multiplexed cell system, remain further investigation.The HBV infected person anteserum has 3 kinds of virions through electron microscopic examination: 1. Dane granule (HBV granule), and coat protein HBsAg, core contains HBV-DNA and HBVDNAp (DNA-polymerase), HBcAg, HBeAg; 2. pellet shapes granule; 3. tubular granule.The latter two are virus outer (HBsAg) superfluous in the hbv replication process, do not contain nucleic acid.HBV genome (HBV-DNA) is made up of the DNA of the incomplete loop configuration of two strands, contains 3200 nucleotide.Because its host range is less, cell in vitro culture of isolated virus is not success as yet.In recent years the success that is transfection along with the application and the cultured cell in vitro of molecule clone technology has had further understanding to the hbv replication process.HBV-DNA is divided into minus strand (long-chain) and normal chain (short chain) is formed.Its minus strand have 4 open reading frames (Open Reading Frame, ORF): 1. S gene regions, by the S gene, preceding S2 (pre-S2) gene, preceding S1 (pre-S1) genomic constitution.The HBsAg that encodes respectively, pre-S, pre-S1 and polyerized human serum albumin's receptor (PHSA-R); 2. C gene regions is by anterior c gene and C genomic constitution.HBeAg and HBcAg encode respectively; 3. P gene regions, coding HBV-DNAp, and have reverse transcriptase activity; 4. X gene district, coding HBxAg, and have the effect that activates the HBcAg gene.

Entecavir, its chemical name are 2-amino-9-[(1S, 3S, 4S)-and 4-hydroxyl-3-methylol-2-methylene amyl group]-1,9-hydrogen-6-H-purine-6-one-hydrate molecular formula: C12H15N5O3H2O molecular weight: 295.3

Entecavir is inhibited to hepatitis B virus (HBV) polymerase.It can become by phosphorylation and has active triphosphate, and triphosphate is 15 hours in the intracellular half-life.By competing with the natural substrate triphosphoric acid NSC 22837 of HBV polymerase, the Entecavir triphosphate can suppress all three kinds of activity of virus polymerase (reverse transcriptase): the startup of (1) HBV polymerase; (2) formation of pregenomic mRNA reverse transcription minus strand; (3) HBV DNA normal chain is synthetic.The Entecavir triphosphate is 0.0012 μ M to the inhibition constant (Ki) of HBV DNA polymerase.α, the β of Entecavir triphosphate pair cell, δ DNA polymerase and mitochondrion γ DNA polymerase inhibitory action a little less than, the Ki value is 18 as for 160 μ M.The Entecavir sheet is arranged in the market, also have the oral cavity disintegration tablet of the Entecavir of reporting and the patent (200410069355.2 and 02156856.1) of dispersible tablet in the document, do not see the report that entecavir injection is arranged.During the acute hepatitis acute attack, oral administration often onset time slow, can not satisfy clinical requirement.

Summary of the invention

The objective of the invention is overcoming the shortcoming and defect of above-mentioned prior art, provide and be fit to the injectable drug that clinical acute hepatopathy treatment requires, the present invention is active component with the Entecavir, invented preparation of drug administration by injection and preparation method thereof, especially intravenous administration has solved the demand in the treatment.

One, the content of preparation

The ejection preparation of Entecavir, it is characterized in that by active component be Entecavir, adjuvant comprises: water-soluble filler, PH regulator, solubilizing agent, antioxidant, water for injection, osmotic pressure regulator or the like, combined by one or more adjuvants, wherein said preparation comprises freeze-dried powder, small injection and primary infusion.

1. in the described preparation:

A. in the lyophilized preparation, the percentage by weight that active component accounts for total amount is 1-50%, preferred 10-30%.

B. in the small injection, the concentration of active component is 50mg/ml-0.5mg/ml, and preferred 5-30mg/ml comprises 2ml, 4ml, 5ml, 10ml and 20ml specification.

C. the concentration of primary infusion Chinese medicine is 1mg/ml-0.02mg/ml.The specification that comprises 50ml, 100ml, 250ml is with the compound injection of one or more compositions of sodium chloride, glucose or low molecular dextran.

2. water-soluble filler is meant one or more mixture of mannitol, low molecular dextran, sorbitol, Polyethylene Glycol, tween, glucose, lactose, galactose, preferred mannitol, lactose, glucose.

3.PH regulator is: nonvolatile acid such as citric acid, phosphoric acid, malic acids.And potassium hydroxide, sodium hydroxide,, sodium carbonate or potassium or ammonium salt, sodium bicarbonate or potassium or ammonium salt, sodium phosphate or potassium or ammonium salt, disodium-hydrogen or potassium or ammonium salt, sodium dihydrogen phosphate or potassium or acceptable organic or inorganic bronsted lowry acids and bases bronsted lowry of physiology and salt such as ammonium salt, citric acid trisodium salt, sodium acetate or ammonium salt, preferably citric acid, phosphoric acid, potassium hydroxide, sodium hydroxide.

4. solubilizing agent is: polyvinylpyrrolidone, PEG6000, PEG4000, poloxamer, carbomer, polysorbas20-80, sodium lauryl sulphate, Tris etc., preferably polyethylene ketopyrrolidine, PEG6000, PEG4000, poloxamer.

5. antioxidant is: the antioxidant that contains inorganic sulfur or organic sulfur; Inorganic sulfur antioxidant is sulphite, as sodium sulfite, potassium sulfite, sodium pyrosulfite, sodium thiosulfate, sodium sulfite, Potassium acid sulfite; Organic sulfur antioxidant is thioglycerol, thiourea, 2 mercapto ethanol, 2-mercaprol, 1-Thiosorbitol; Antioxidant of the present invention must pharmaceutically allow, and itself is biologically active or pharmacologically active not, preferred especially sulphite is as sodium sulfite, potassium sulfite, sodium pyrosulfite, sodium thiosulfate, sodium sulfite, thioglycerol, thiourea.

6. osmotic pressure regulator is one or both combination of sodium chloride, potassium chloride.

Two, preparation method

The preparation method that contains the preparation of active component Entecavir administrated by injection of the present invention is characterized in that this method comprises the following steps:

I, composition

(2) small injection

(3) primary infusion

The preparation method of II. different administrated by injection preparations comprises the following steps:

(1) lyophilized preparation

Get Entecavir and water-soluble filler, solubilizing agent, antioxidant, osmotic pressure agent etc., it is an amount of to add water for injection, regulates pH value and makes its dissolving to 4-10, adds water to scale, add the 0.1-0.5% active carbon, stirred 10-60 minute down at 20-50 ℃, the filtering with microporous membrane degerming is adopted in decarburization, filtrate is carried out packing, adopt freeze-drying, make the white loose block, seal promptly.

(2) small injection

Get Entecavir and water-soluble filler, solubilizing agent, antioxidant, osmotic pressure agent etc., it is an amount of to add water for injection, regulates pH value and makes its dissolving to 4-10, add water to scale, add the 0.1-0.5% active carbon, stirred 10-60 minute down at 20-50 ℃, decarburization, fine straining, embedding, sterilization.

(3) primary infusion

Get Entecavir and water-soluble filler, solubilizing agent, antioxidant, osmotic pressure agent etc., it is an amount of about 20% to add water for injection, regulates pH value and makes its dissolving to 4-10, add the 0.1-0.5% active carbon, stirred decarburization 10-60 minute down at 20-50 ℃, add water to scale, fine straining, embedding, sterilization.

The specific embodiment

The present invention is described further below in conjunction with embodiment, and embodiment only is indicative explanation, means that never it limits the scope of the invention by any way.

Embodiment 1

Get Entecavir 3g, place container, add solubilizing agent polyvinylpyrrolidone 1g, water for injection 80ml, hydro-oxidation sodium 0.2g stirs and makes dissolving, and the citric acid that adds 1mol/L is regulated PH to 7-9.0, add mannitol 28g, lactose 22g, stir and make dissolving, mend and add water to 100ml.Add the 0.5g activated carbon, stirred 20 minutes down at 30 ℃, the filtering with microporous membrane degerming is adopted in decarburization, and filtrate is carried out packing by every 1ml, after the pre-freeze 2 hours, freezing down drying under reduced pressure 12 hours, to sample temperature after room temperature, dry 5 hours again, make the white loose block, seal and promptly get the Entecavir freeze-dried powder.

Embodiment 2

Get Entecavir 5g, place container, add PEG60002g, water for injection 180ml stirs and makes dissolving, regulates PH to 5.0-9.0 with hydrochloric acid or the sodium hydroxide of 1mol/L, adds mannitol 80g, sorbitol 20g, stirs and makes dissolving, mends and adds water to 200ml.Add the 0.5g activated carbon, stirred 20 minutes down at 30 ℃, the filtering with microporous membrane degerming is adopted in decarburization, and filtrate is carried out packing by every 2ml, after the pre-freeze 2 hours, freezing down drying under reduced pressure 18 hours, to sample temperature after room temperature, dry 5 hours again, make the white loose block, seal and promptly get the Entecavir freeze-dried powder.

Embodiment 3

Get Entecavir 2g, place container, add poloxamer 1g, add injection water 180ml, stirring makes dissolving, hydrochloric acid or sodium hydroxide with 1mol/L are regulated PH to 5.0-9.0, add mannitol 70g, lactose 30g stirs and makes dissolving, benefit adds water to 200ml, add the 0.5g activated carbon, stirred decarburization 40 minutes down at 20 ℃, adopt the filtering with microporous membrane degerming, filtrate is carried out packing by every 2ml, and pre-freeze is after 2 hours, freezing drying under reduced pressure down 15 hours, to sample temperature after room temperature, dry 5 hours again, make the white loose block, seal and promptly get the Entecavir freeze-dried powder.

Embodiment 4

Get Entecavir 10g, join among the water for injection 440ml that dissolves the 5g sodium lauryl sulphate, add 2g sodium thiosulfate stirring and dissolving, adding sodium bicarbonate adjusting PH is 5.5-8.5, adds the 5g active carbon, stirring at room absorption 30 minutes, carbon removal, benefit adds water to 500ml, and fine straining, with every 5ml embedding, sterilization promptly gets the Entecavir injection.

Embodiment 5

Get Entecavir 5g, join among the water for injection 440ml that dissolves the 10g Tris, add the 2gEDTA-2Na stirring and dissolving, adding sodium bicarbonate adjusting PH is 7.5-9.0, mends and adds water to 500ml, add the 5g active carbon, stirring at room absorption 30 minutes, carbon removal, fine straining, with every 2ml embedding, sterilization, promptly get the Entecavir injection.

Embodiment 6

Get Entecavir 1g, add among the water for injection 180ml, add 0.5 gram NaOH stirring and make dissolving, add the 3g sodium pyrosulfite, stirring and dissolving, adjusting PH is 7.0-9.0, add water for injection to 200ml, add the 2g active carbon, stirring and adsorbing 30 minutes, carbon removal, fine straining, with every 2ml embedding, sterilization, promptly get the Entecavir injection.

Embodiment 7

Get sodium entecavir 5g, add 15g sodium hydrogen phosphate and 90g sodium chloride, add injection water 2000ml again, stir and make dissolving, adjusting PH is 7.5-9.0, add the 10g active carbon, stirring and adsorbing 30 minutes, carbon removal, benefit adds water to 10000ml, fine straining, every bottle of 100ml of embedding, sterilization promptly gets the Entecavir sodium chloride injection.

Embodiment 8

Get Entecavir 10g, add 15g sodium hydroxide and 1000g glucose, the 15g sodium pyrosulfite, add injection water 2000ml again, stirring makes dissolving, and adjusting PH is 5.0-8.0, adds the 10g active carbon, stirring and adsorbing 30 minutes, carbon removal is mended and is added water to 10000ml, fine straining, every bottle of 100ml of embedding, sterilization promptly gets the Entecavir glucose injection.

Embodiment 9

Get Entecavir 3.0g, add PEG-400020g, water for injection 2000ml, stirring makes dissolving, adds 15g sodium hydrogen phosphate and 500g low molecular dextran again, 15g EDTA-2Na, stirring makes dissolving, and adjusting PH is 7.0-8.5, adds the 10g active carbon, stirring and adsorbing 30 minutes, carbon removal is mended and is added water to 5000ml, fine straining, every bottle of 50ml of embedding, sterilization promptly gets Entecavir low molecular dextran injection.

Claims (5)

1. a preparation that contains active component Entecavir administrated by injection is characterized in that being made up of active component Entecavir and water-soluble filler, PH regulator, solubilizing agent, antioxidant, water for injection, osmotic pressure regulator.

2. the preparation of administrated by injection as claimed in claim 1 is characterized in that described preparation is meant freeze-dried powder, small injection and the primary infusion that contains Entecavir.

3. the preparation of administrated by injection as claimed in claim 1 is characterized in that described preparation is:

A. the percentage by weight of lyophilized preparation Chinese medicine composition and other pharmaceutic adjuvant is 0.1-50%;

B. the concentration of small injection Chinese medicine is 50mg/ml-0.5mg/ml;

C. the concentration of primary infusion Chinese medicine is 1mg/ml-0.02mg/ml.

4. the preparation of administrated by injection as claimed in claim 3 is characterized in that described primary infusion is meant the compound injection of one or more compositions of active component and sodium chloride, glucose or low molecular dextran.

5. the preparation of administrated by injection according to claim 1 is characterized in that water-soluble filler is mannitol, low molecular dextran, sorbitol, Polyethylene Glycol, tween, glucose, lactose or galactose;

The PH regulator is nonvolatile acid such as citric acid, phosphoric acid, malic acid and potassium hydroxide, sodium hydroxide or potassium or ammonium, sodium carbonate or potassium or ammonium salt, sodium bicarbonate or potassium or ammonium salt, sodium phosphate or potassium or ammonium salt, disodium-hydrogen or potassium or ammonium salt, sodium dihydrogen phosphate or potassium or acceptable organic or inorganic bronsted lowry acids and bases bronsted lowry of physiology and salt such as ammonium salt, citric acid trisodium salt, sodium acetate or ammonium salt;

Solubilizing agent is polyvinylpyrrolidone, PEG6000, PEG4000, poloxamer, carbomer, polysorbas20-80, sodium lauryl sulphate or Tris;

Antioxidant is the antioxidant that contains inorganic or organic sulfur; Inorganic sulfur antioxidant is sodium sulfite, potassium sulfite, sodium pyrosulfite, sodium thiosulfate, sodium sulfite, Potassium acid sulfite; Organic sulfur antioxidant is thioglycerol, thiourea, 2 mercapto ethanol, 2-mercaprol, 1-Thiosorbitol.