CN104473871A - Posaconazole fat emulsion injection and preparation method thereof - Google Patents

Abstract

The invention provides a posaconazole fat emulsion injection and a preparation method thereof. The posaconazole fat emulsion injection is taken as a medicinal active ingredient, and the fat emulsion is prepared from an oily solvent, water, an osmotic pressure regulator, a pH regulator and the like, thus solving the problem of low solubility of posaconazole in water, achieving a high medicine loading capacity and no medicine leakage, and improving the stability of posaconazole in the preparation. The invention further provides a preparation process of the preparation, which is simple, good in reproducibility and capable of realizing industrialized production. The posaconazole fat emulsion injection is prepared and developed into a preparation for intravenous injection, expected to be used for preventing invasive aspergillus infection, and applied to patients with seriously-damaged immune systems.

Description

A kind of posaconazole fat emulsion injection and preparation method thereof

Technical field

The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of posaconazole fat emulsion injection and preparation method thereof.

Background technology

Posaconazole is the derivant of itraconazole, posaconazole (posaconazole, commodity are called Noxafil, CAS registration number 171228-49-2, chemical name: 4-[4-[4-[4-[[(3R, 5R)-5-(2, 4-difluorophenyl)-5-(1, 2, 4-triazol-1-yl methyl) oxa-penta ring-3-base] methoxyl group] phenyl] piperazine-1-base] phenyl]-2-[(2S, 3S)-2-hydroxyl penta-3-base]-1, 2, 4-triazole-3-ketone) be the third generation antifungal agent that Schering-Plough pharmaceutical Co. Ltd researches and develops, in December, 2005 is in German Initial Public Offering, in March, 2006 goes on the market in Britain, on JIUYUE 18th, 2006, obtain FDA to ratify.FDA approved posaconazole injection (18mg/mL) in 2014, this is the novel form of a kind of intravenous injection (IV) of posaconazole, is applicable to 18 years old and above patient.This antifungal drug of Mo Shadong, also with posaconazole (100mg) slow releasing tablet and the list marketing of posaconazole (40mg/mL) oral administration mixed suspension, is applicable to 13 years old and above patient.Be mainly used in prevention aggressive aspergillus fungi to infect, be applicable to the patient because immune system is badly damaged, immune system is badly damaged and comprises graft versus host disease (GVHD) that hematopoietic stem cell transplantation (HSCT) receiver suffers from or patients with malignant hematological diseases causes long-term Neutrophilic granulocytopenia because of chemotherapy.

Posaconazole is the medicine of a kind of alkalescence, poorly water-soluble, in neutrality and alkaline aqueous solution, posaconazole has the dissolubility being less than 1 μ g/ml, listing preparation posaconazole injection adopts modification beta-schardinger dextrin-to be that chelating agen is prepared into venoclysis liquor as solubilizing agent, disodium edetate, achieves the administration to the patient that can not give peroral dosage form (patient as dysphagia or stupor).Posaconazole injection medication is: treatment first day loading dose be 300mg (300mg/ bottle), one day 2 times; From second day for the treatment of, maintenance dose was 300mg (300mg/ bottle), one day 1 time.To use at once after preparation mixing, slowly be instiled about 90 minutes by central vein, otherwise 2 DEG C ~ 8 DEG C stored refrigerated should be placed at.The posaconazole of each bottle of posaconazole injection (16.7ml) containing 300mg and sulfobutyl ether-beta-cyclodextrin 6.68g, disodium edetate 0.003 g, hydrochloric acid and sodium hydroxide regulate pH to 2.6, and water for injection.

Because injection direct injection enters blood circulation, adjuvant is selected improperly may produce safety risks, thus should select inertia, safety preferably, the adjuvant that requires of fulfilling medicinal or injection.But listing preparation posaconazole injection adopts a large amount of modification beta-schardinger dextrin-s (sulfobutyl ether-beta-cyclodextrin) to carry out enclose solubilising to posaconazole, substantially the water solubility problems of posaconazole is solved, but result of study shows, beta-schardinger dextrin-series derivates shows in pharmacological toxicology research has greater risk to human body, and beta-schardinger dextrin-class adjuvant exists nephrotoxicity and haemolysis; Owing to there is above-mentioned shortcoming in such adjuvant, the meeting of European medicine thing, U.S. FDA and Chinese SFDA also require to reappraise the safety of the adjuvant of the type, has a strong impact on the clinical safety application of posaconazole injection.

Summary of the invention

For prior art, the invention provides a kind of not containing the posaconazole fat emulsion injection of beta-schardinger dextrin-series derivates, posaconazole bag is loaded among fat milk breast grain, solve the problem that its dissolubility in water is low, improve its dissolubility in drug delivery system, solve a series of application restrictions such as the serious adverse reaction that in clinical practice, beta-schardinger dextrin-series derivates brings, enhance the compliance of patient.Present invention also offers the preparation method of said preparation, its technique is simple, and repeatability is good, can realize suitability for industrialized production.

The present invention realizes by the following technical solutions:

A kind of posaconazole fat emulsion injection, is characterized in that, each component is by following percentage by weight composition:

Posaconazole 1.6-2.0%

Oil-based solvent 5-15%

Emulsifying agent 1-2%

Osmotic pressure regulator 4.5-5.5%

PH adjusting agent regulates pH to 2 ~ 3

All the other are water for injection.

Preferably, described oil-based solvent comprises one or more in soybean oil, Semen Maydis oil, Oleum sesami, median chain triglyceride oil.

Preferably, described emulsifying agent comprises one or more in lecithin, poloxamer, soybean lecithin, Ovum Gallus domesticus Flavus lecithin.

Preferably, described osmotic pressure regulator is mannitol or glucose, is more preferably mannitol.

Preferably, described pH adjusting agent is one or more in hydrochloric acid, sodium hydroxide, citric acid or acetic acid.

Preferred further, the preparation method of posaconazole fat emulsion injection, is characterized in that comprising the following steps:

(1) mixed homogeneously with emulsifying agent by oil-based solvent under nitrogen protection, be heated to 70-80 DEG C, add principal agent posaconazole while stirring, mixing, obtains oil phase;

(2) in 65-75% water for injection, add osmotic pressure regulator, be uniformly dissolved, be heated to 70-80 DEG C simultaneously, obtain aqueous phase;

(3) under nitrogen protection, dropwise joined in aqueous phase by gained oil phase under high-speed stirred 1800-2500rpm, maintain and stir 5-15min, regulate pH to 2 ~ 3 with pH adjusting agent, benefit adds to the full amount of water for injection, mixing, obtains just emulsion;

(4), under nitrogen protection, under room temperature condition, first for gained emulsion is circulated 4 times with mesohigh under the pressure of 350-1000bar in high pressure homogenizer, obtains Emulsion;

(5) by gained Emulsion, cross 5 μm be after microporous filter membrane, inflated with nitrogen, embedding, 121 DEG C of sterilizing 15min, to obtain final product.

Relative to prior art, the present invention has the following advantages:

1) fat milk of the present invention is O/W type Emulsion, with phospholipid or poloxamer be emulsifying agent, Semen sojae atricolor wet goods for oil-based solvent, be scattered in aqueous phase, posaconazole is fat-soluble medicine, thus can with molecular forms dissolve be dispersed in oil phase, be wrapped among emulsion droplet.Therefore, posaconazole bag is loaded among newborn grain by the present invention, solves the problem that posaconazole dissolubility in water is low; Meanwhile, due to the oral administration biaavailability of posaconazole lower (8-47%), the problem that oral posaconazole preparation bioavailability is low after being therefore prepared into injection, is solved;

2) preparation technology of invention formulation is simple, and repeatability is good, and the loss of preparation process Chinese medicine is less, and improves the stability of posaconazole in preparation, can realize suitability for industrialized production.Through inspection, the envelop rate of said preparation can reach more than 97%, and drug loading is high, and quality appearance is homogeneous, and stability is high; The made sample of the present invention, through to accelerate 6 months and significant change does not occur every quality index of long-term December study on the stability, all meets quality criteria requirements, illustrates that sample prepared by the present invention has good quality stability.

3) this invention also solves a series of application restrictions such as the serious adverse reaction that in the clinical practice of listing posaconazole injection, beta-schardinger dextrin-series derivates brings, and reduce medicine irritation and toxicity, enhance the compliance of patient and the safety of clinical application.Being developed into the preparation of injection for intravenous, to for preventing aggressive aspergillus fungi to infect, being applicable to the patient because immune system is badly damaged.

Accompanying drawing explanation

Below in conjunction with accompanying drawing, the present invention is further illustrated.

Accompanying drawing 1 is the granularity data figure that the fat milk of embodiment 1 preparation detects under particle size analyzer.

Detailed description of the invention

Below in conjunction with drawings and Examples, the present invention is described in detail.Following embodiment is all to one detailed description of the present invention but not is limitation of the present invention.

embodiment 1:1000ml posaconazole fat emulsion injection preparation method

mixed homogeneously with soybean lecithin 10g by soybean oil 100g under nitrogen protection, be heated to 80 DEG C, add principal agent posaconazole 18g while stirring, mixing, obtains oil phase;

in 750ml water for injection, add mannitol 50g, be uniformly dissolved, be heated to 80 DEG C simultaneously, obtain aqueous phase;

under nitrogen protection, by gained oil phase under high velocity agitation (2500rpm) dropwise join among aqueous phase, maintain and stir 5min, regulate pH to 2.0 with pH adjusting agent, benefit adds to the full amount of water for injection, and mixing obtains just emulsion;

under nitrogen protection, under room temperature condition, first for gained emulsion is circulated 4 times (homogenization pressure of setting is 600bar) at high pressure homogenizer mesohigh, obtains Emulsion;

by gained Emulsion, cross 5 μm be after microporous filter membrane, inflated with nitrogen, embedding, sterilizing (121 DEG C, 15min) and get final product.

embodiment 2:1000ml posaconazole fat emulsion injection preparation method

mixed homogeneously with soybean lecithin 20g by soybean oil 100g under nitrogen protection, be heated to 75 DEG C, add principal agent posaconazole 20g while stirring, mixing, obtains oil phase;

in 700ml water for injection, add mannitol 50g, be uniformly dissolved, be heated to 75 DEG C simultaneously, obtain aqueous phase;

under nitrogen protection, by gained oil phase under high velocity agitation (1800rpm) dropwise join among aqueous phase, maintain and stir 5min, regulate pH to 2.6 with pH adjusting agent, benefit adds to the full amount of water for injection, and mixing obtains just emulsion;

under nitrogen protection, under room temperature condition, first for gained emulsion is circulated 4 times (homogenization pressure of setting is 400bar) at high pressure homogenizer mesohigh, obtains Emulsion;

by gained Emulsion, cross 5 μm be after microporous filter membrane, inflated with nitrogen, embedding, sterilizing (121 DEG C, 15min) and get final product.

embodiment 3:1000ml posaconazole fat emulsion injection preparation method

soybean oil 75g, soybean lecithin 5g are mixed homogeneously with poloxamer 5g under nitrogen protection, be heated to 75 DEG C, add principal agent posaconazole 18g while stirring, mixing, obtains oil phase;

in 650ml water for injection, add glucose 55g, be uniformly dissolved, be heated to 75 DEG C simultaneously, obtain aqueous phase;

under nitrogen protection, by gained oil phase under high velocity agitation (2500rpm) dropwise join among aqueous phase, maintain and stir 5min, regulate pH to 3.0 with pH adjusting agent, benefit adds to the full amount of water for injection, and mixing obtains just emulsion;

under nitrogen protection, under room temperature condition, first for gained emulsion is circulated 4 times (homogenization pressure of setting is 500bar) at high pressure homogenizer mesohigh, obtains Emulsion;

by gained Emulsion, cross 5 μm be after microporous filter membrane, inflated with nitrogen, embedding, sterilizing (121 DEG C, 15min) and get final product.

embodiment 4:

In order to investigate some basic physicochemical properties of this preparation, invention has been following experiment:

1) fat milk particle size determination

By the lipomul of embodiment 1 gained, add a certain amount of normal saline dilution suitable multiple, detect granularity under being placed in particle size analyzer, result as shown in Figure 1.As can be seen from Figure, the mean diameter of said preparation is at about 220-300nm.

) envelop rate and drug loading measure

By the fat emulsion formulation of embodiment 1-3 gained, with the content of high phase liquid chromatography for measuring posaconazole, computational envelope rate (EE) and drug loading (DL), specific formula for calculation is as follows, and experimental result sees the following form:

As can be seen from result in table, the envelop rate of medicine is all more than 97%, and the loss of formulation process Chinese medicine is less.

embodiment 5:posaconazole fat emulsion injection stability test is investigated

Acceleration June (25 DEG C) and (2-8 DEG C) stability test investigation in long-term 36 months are carried out, to evaluate the quality of the made sample of the present invention to the posaconazole fat emulsion injection prepared by embodiment 2.Obtain data result as follows:

Result of the test shows that the made sample of the present invention accelerates 6 months and significant change does not occur every quality index of long-term December study on the stability, all meets quality criteria requirements, illustrates that sample prepared by the present invention has good quality stability.

Claims (6)

1. a posaconazole fat emulsion injection, is characterized in that, each component is by following percentage by weight composition:

Posaconazole 1.6-2.0%

Oil-based solvent 5-15%

Emulsifying agent 1-2%

Osmotic pressure regulator 4.5-5.5%

PH adjusting agent regulates pH to 2 ~ 3

All the other are water for injection.

2. a kind of posaconazole fat emulsion injection according to claim 1, is characterized in that: described oil-based solvent comprises one or more in soybean oil, Semen Maydis oil, Oleum sesami, median chain triglyceride oil.

3. a kind of posaconazole fat emulsion injection according to claim 1, is characterized in that: described emulsifying agent comprises one or more in lecithin, poloxamer, soybean lecithin, Ovum Gallus domesticus Flavus lecithin.

4. a kind of posaconazole fat emulsion injection according to claim 1, is characterized in that: described osmotic pressure regulator is mannitol or glucose.

5. a kind of posaconazole fat emulsion injection according to claim 1, is characterized in that: described pH adjusting agent is one or more of hydrochloric acid, sodium hydroxide, citric acid or acetic acid.

6. the preparation method of the arbitrary described posaconazole fat emulsion injection of claim 1-5, is characterized in that comprising the following steps:

(1) mixed homogeneously with emulsifying agent by oil-based solvent under nitrogen protection, be heated to 70-80 DEG C, add principal agent posaconazole while stirring, mixing, obtains oil phase;

(2) in 65-75% water for injection, add osmotic pressure regulator, be uniformly dissolved, be heated to 70-80 DEG C simultaneously, obtain aqueous phase;

(3) under nitrogen protection, dropwise joined in aqueous phase by gained oil phase under high-speed stirred 1800-2500rpm, maintain and stir 5-15min, regulate pH to 2 ~ 3 with pH adjusting agent, benefit adds to the full amount of water for injection, mixing, obtains just emulsion;

(4), under nitrogen protection, under room temperature condition, first for gained emulsion is circulated 4 times with mesohigh under the pressure of 350-1000bar in high pressure homogenizer, obtains Emulsion;

(5) by gained Emulsion, cross 5 μm be after microporous filter membrane, inflated with nitrogen, embedding, 121 DEG C of sterilizing 15min, to obtain final product.