WO2018225229A1

WO2018225229A1 - Parenteral aqueous pharmaceutical composition

Info

Publication number: WO2018225229A1
Application number: PCT/JP2017/021392
Authority: WO
Inventors: Chisato IWAKIRI; Mahmoud El-Tamimy; Paul Gavin
Original assignee: Terumo Kabushiki Kaisha; Phosphagenics Limited
Priority date: 2017-06-08
Filing date: 2017-06-08
Publication date: 2018-12-13

Abstract

To provide a parenteral aqueous pharmaceutical composition containing a highly lipid-soluble drug which has suppressed occurrence of white cloudiness or precipitation even after the composition is stored at a room temperature (i.e., 1 to 30 oC). A parenteral aqueous pharmaceutical composition containing propofol, a solubilizing agent, and water in which the solubilizing agent contains polysorbate 80, polysorbate 20, mono(tocopheryl) phosphate, and di(tocopheryl) phosphate, total content of polysorbate 80 and polysorbate 20 is 20 w/v% or less, content mass ratio of polysorbate 80 relative to polysorbate 20 (content mass of polysorbate 80/content mass of polysorbate 20) is 1.80 to 7.0, total content of mono(tocopheryl) phosphate and di(tocopheryl) phosphate is more than 0.20 w/v% but less than 0.74 w/v%, and pH is more than 5.0 but less than 7.0.

Description

PARENTERAL AQUEOUS PHARMACEUTICAL COMPOSITION

The present invention relates to a parenteral aqueous pharmaceutical composition.

Propofol is a general name of 2,6-diisopropylphenol, and, in the field of pharmaceuticals, it is known as a compound that is useful for introducing and maintaining general anesthetics or sedation during mechanical ventilation in intensive treatment. Herein, initiation of anesthesia is mainly regulated by diffusion rate of a drug which passes through a blood-brain barrier. High lipid solubility of propofol also contributes to the blood-brain barrier pass-through and exhibition of rapid anesthetic activity. Meanwhile, although being a compound which is liquid at room temperature, propofol is hardly soluble in water due to its high lipid solubility. For such reasons, propofol is generally administered in the form of an oil-in-water type emulsion containing lipid components such as soy bean oil, medium chain fatty acid triglyceride, or lecithin. However, a preparation containing lipid components has a problem that it is prone to have bacterial proliferation. Furthermore, since a lipid emulsion itself has white cloudiness, contamination by foreign materials or bacteria cannot be determined based on an outer appearance so that a filter for removing them cannot be used. Furthermore, when a large amount of an emulsion containing lipid components is administered parenterally over a long period of time, there is a possibility of having hyperlipidemia.

In this regard, in Patent Literature 1, a parenteral pharmaceutical composition in the form of an aqueous mixture containing propofol and a vehicle (hereinbelow, also simply referred to as a "parenteral aqueous pharmaceutical composition") is disclosed. It is also disclosed that the composition is preferably aseptic and chemically and physically stable over a broad range of environmental conditions. Herein, in addition to benzalkonium chloride, benzethonium chloride, ploxamers, and cremophors, polyoxyethylene sorbitan fatty acid esters (polysorbate 80, polysorbate 20, or the like) are described as a vehicle.

Patent Literature 1: JP 2014-58553 A

Similar to Patent Literature 1, the inventors of the present invention conducted intensive studies under the purpose of obtaining a parenteral aqueous pharmaceutical composition containing propofol. During that process, the inventors attempted to prepare a parenteral aqueous pharmaceutical composition by adopting particular substances as a solubilizing agent. As a result of this attempt, it was found that white cloudiness or precipitation of a solution occurs after the composition is stored at a room temperature. The occurrence of white cloudiness in the parenteral aqueous pharmaceutical composition is not desirable from the viewpoint of not only the quality but also the outer appearance of a pharmaceutical product. As such, the current state is that development of a parenteral aqueous pharmaceutical composition containing propofol, which has suppressed occurrence of white cloudiness or precipitation even after the composition is stored at a room temperature, is needed.

Thus, an object of the present invention is to provide a parenteral aqueous pharmaceutical composition containing propofol which has suppressed occurrence of white cloudiness or precipitation even after the composition is stored at a room temperature.

The inventors of the present invention conducted intensive studies to solve the above problems. As a result, it was surprisingly found that, by using polysorbate 20 in combination with polysorbate 80 as a solubilizing agent, controlling their total content and content mass ratio within a specific range, controlling the total content of TPM in a composition within a specific range, and controlling pH of a composition within a specific range, the above problems can be solved, and the present invention is completed accordingly.

Namely, according to one embodiment of the present invention, a parenteral aqueous pharmaceutical composition containing propofol, a solubilizing agent, and water is provided. In addition, the pharmaceutical composition is characterized in that the solubilizing agent contains polysorbate 80, polysorbate 20, mono(tocopheryl) phosphate, and di(tocopheryl) phosphate, total content of polysorbate 80 and polysorbate 20 is 20 w/v% or less, content mass ratio of polysorbate 80 relative to polysorbate 20 (content mass of polysorbate 80/content mass of polysorbate 20) is 1.80 to 7.0, total content of mono(tocopheryl) phosphate and di(tocopheryl) phosphate is more than 0.20 w/v% but less than 0.74 w/v%, and pH is more than 5.0 but less than 7.0.

According to the present invention, a parenteral aqueous pharmaceutical composition containing propofol which has suppressed occurrence of white cloudiness or precipitation even after the composition is stored at a room temperature can be provided.

Fig. 1 is graphs which illustrate the results of the evaluation of stability of the composition of the present invention after dilution in the Examples.

Hereinbelow, embodiments of the present invention are explained.

<<Parenteral aqueous pharmaceutical composition>>
As described above, one embodiment of the present invention relates to a parenteral aqueous pharmaceutical composition containing propofol, a solubilizing agent, and water, in which the pharmaceutical composition is characterized in that the solubilizing agent contains polysorbate 80, polysorbate 20, mono(tocopheryl) phosphate, and di(tocopheryl) phosphate, total content of polysorbate 80 and polysorbate 20 is 20 w/v% or less, content mass ratio of polysorbate 80 relative to polysorbate 20 (content mass of polysorbate 80/content mass of polysorbate 20) is 1.80 to 7.0, total content of mono(tocopheryl) phosphate and di(tocopheryl) phosphate is more than 0.20 w/v% but less than 0.74 w/v%, and pH is more than 5.0 but less than 7.0. Hereinbelow, this embodiment is explained in greater detail.

<Propofol>
Main drug for forming the parenteral aqueous pharmaceutical composition of this embodiment is propofol, which is a highly lipid-soluble drug.

<Solubilizing agent>
The solubilizing agent is an additive for enhancing the water solubility of propofol as a main drug.

(Polysorbates)
The parenteral aqueous pharmaceutical composition according to this embodiment essentially contains polysorbate 80 and polysorbate 20 as a solublizing agent. Polysorbate 80 and polysorbate 20 are a surfactant which is generally referred to as a polyoxyethylene sorbitan fatty acid ester. In particular, "polysorbate 80" means polyoxyethylene (20) sorbitan oleic acid ester, and it has a structure in which 20 moles of oxyethylene group are ether-bonded per mole of an oleic acid ester of a part of the hydroxyl group of sorbitol anhydride. Meanwhile, "polysorbate 20" means polyoxyethylene (20) sorbitan lauric acid ester, and it has a structure in which 20 moles of oxyethylene group are ether-bonded per mole of a lauric acid ester of a part of the hydroxyl group of sorbitol anhydride (i.e., monolauric acid sorbitan). Herein, the inventors of the present invention used only polysorbate 80 as polyoxyethylene sorbitan fatty acid ester (polysorbates) which is a solubilizing agent, and by using it in combination with TPM, the inventors tried to prepare an aqueous pharmaceutical composition containing propofol. As a result, it was shown that white cloudiness of a solution occurs after the composition is stored at room temperature. On the other hand, it was further found that combined use of polysorbate 20 and suppressing their total content to a value that is within a constant range are effective for suppression of white cloudiness. In the meantime, “room temperature” refers to 1 to 30 ^oC in this specification.

Namely, in the composition according to this embodiment, the total content of polysorbate 80 and polysorbate 20 is essentially 20 w/v% or less. Furthermore, the total content is preferably 15 w/v% or less, and more preferably 10 w/v% or less. Furthermore, the content mass ratio of polysorbate 80 relative to polysorbate 20 (content mass of polysorbate 80/content mass of polysorbate 20) is essentially 1.80 to 7.0. It is preferably 1.83 to 4.70, and more preferably 1.83 to 3.50. As the content of polysorbate 80 and polysorbate 20 satisfies the above condition, an occurrence of white cloudiness or precipitation after storage of the composition is suppressed, and therefore desirable. Furthermore, as the content mass ratio of polysorbate 80 is the same or greater than the lower limit of the above range, the content mass ratio of polysorbate 20, which has a relatively high hemolytic property, is not excessively high, and therefore desirable. Meanwhile, as the content of polysorbate 80 is the same or lower than the upper limit of the above range, the effect of suppressing white cloudiness caused by addition of polysorbate 20 is obtained at high level and heat stability of the composition can be enhanced, and therefore desirable.

(TPM)
Furthermore, the parenteral aqueous pharmaceutical composition according to this embodiment also contains a mixture (i.e., TPM) of mono(tocopheryl) phosphate (also referred to as "TP") and di(tocopheryl) phosphate (also referred to as "T2P") as a solubilizing agent. According to the determination by the inventors of the present invention, controlling the blending amount of TPM is also effective for suppressing the white cloudiness or precipitation after the composition is stored at a room temperature described above.

Namely, in the composition according to this embodiment, the total content of mono(tocopheryl) phosphate and di(tocopheryl) phosphate is essentially more than 0.20 w/v% but less than 0.74 w/v%. Furthermore, the total content is preferably 0.22 to 0.60 w/v%, and more preferably 0.24 to 0.50 w/v%. In the composition according to this embodiment, the content mass ratio of mono(tocopheryl) phosphate relative to di(tocopheryl) phosphate (content mass of mono(tocopheryl) phosphate/content mass of di(tocopheryl) phosphate) is preferably 1.5 to 2.5. It is more preferably 1.6 to 2.4, even more preferably 1.7 to 2.3, and particularly preferably 1.8 to 2.2. Meanwhile, the mixture of mono(tocopheryl) phosphate and di(tocopheryl) phosphate is commercially available as "TPM (registered trademark)" by Phosphagenics Limited.
<Water (and aqueous solvent)>

The composition according to this embodiment essentially contains water as a main component of solvent. The water is preferably purified water, and more preferably water for injection. Within a range in which the working effect of the present invention is not negatively affected, the composition according to this embodiment may contain an aqueous solvent other than water as an additive. Herein, the "aqueous solvent" as an additive indicates a material which is in liquid phase at room temperature (1 to 30 ^oC) and exhibits compatibility with water. Examples thereof include alcohols (ethanol, propylene glycol, glycerin, or the like), ketones (acetone or the like), ethers, polyethylene glycols, and derivatives thereof. In this regard, it is preferable that the main component (50% by volume or more) of a solvent is preferably water. Preferably, 80% by volume or more is water. More preferably, 90% by volume or more is water. Even more preferably, 95% by volume or more is water. Particularly preferably, 98% by volume or more is water. Most preferably, 100% by volume is water.

<pH>
The composition according to this embodiment is also characterized in that pH of the composition is more than 5.0 but less than 7.0. This is based on the determination by the inventors of the present invention that, when pH is 5.0 or less or 7.0 or more, an occurrence of white cloudiness is shown after an accelerated stability test at 40 ± 2 °C and an intermediate stability test at 30 ± 2 °C. Furthermore, pH of the composition according to this embodiment is preferably 5.5 to 6.5.

<Other additives>
The composition according to this embodiment may contain various additives. Examples of the additives which may be included in the composition according to this embodiment include a pH controlling agent, an isotonic agent, a buffering agent, a stabilizing agent, a thickening agent, a preservative, a solubilizing agent other than those described above, and a dissolution aid. Conventionally known knowledge can be suitably referenced with regard to each of those components.

Examples of the pH controlling agent include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, adipic acid, ammonia water, gluconic acid, succinic acid, tartaric acid, lactic acid, and triethanolamine. The pH controlling agent which is preferred in the present invention is hydrochloric acid and sodium hydroxide. Addition amount of the pH controlling agent is not particularly limited, and it is sufficient that an amount enabling control of the pH of the composition which is within the aforementioned range is added.

Examples of the isotonic agent include an ionic isotonic agent and a non-ionic isotonic agent. Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. Examples of the non-ionic isotonic agent include fructose, xylitol, purified white sugar, lactose, glucose, D-sorbitol, concentrated glycerin, propylene glycol, and mannitol. In the present invention, from the viewpoint of suppressing white cloudiness or precipitation of a solution during storage and ensuring the homogeneity of a solution, the isotonic agent is preferably a non-ionic isotonic agent. D-sorbitol or concentrated glycerin is more preferable. Concentrated glycerin is particularly preferable. The addition amount of the isotonic agent is not particularly limited, either. It is sufficient that an amount for obtaining composition osmotic pressure of about 1 is added.

Since effective buffering ability can be shown in a pH range of pKa±1, examples of the buffering agent include citric acid, quinoline, maleic acid, pyridine, p-toluidine, phthalein acid, piperazine, succinic acid, malonic acid, uric acid, tetraethyl ethylenediamine, histidine, 2,4,6-trichlorophenol, 2-morphorinoethan sulfonic acid,cacodylic acid, 3,3-dimethylguluthalic acid, 4-(hydroxymethyl)imidazole, bis(2-hydroxyethyl)aminotris(hydroxymethyl)methane, phosphoric acid, dimethylaminoethylamine, N-(2-acetoamido)iminodiacetic acid, diphosphoric acid, N,N’-bis(3-aminopropyl)ethylenediamine, glycerol-2-phosphoric acid, piperazine-1,4-bis(2-ethanesulfonic acid), 1,3-bis[tris(hydroxymethyl)methylamino]propane, ethylenediamine N-(2-acetoamido)-2-aminoethanesulfonic acid, imidazole, arsenic acid, or salts thereof. In the present invention, citric acid is a preferred buffering agent. Addition amount of the buffering agent can be suitably adjusted in consideration of the main drug (i.e., propofol), other additives, and/or an influence on osmotic pressure ratio. The total amount is preferably 0.01 to 10 w/v%, more preferably 0.05 to 5 w/v%, and even more preferably 0.1 to 2 w/v%.

Examples of the stabilizing agent include edetic acid, sodium edatate, sodium edatate hydrate, sodium citrate, sulfite salt, and a water soluble polymer. Examples of the sulfite salt include sodium sulfite, potassium sulfite, magnesium sulfite, and calcium sulfite. Examples of the water soluble polymer include polyvinyl pyrrolidones, polyvinyl alcohol, carboxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and sodium polyacrylate.

Examples of the preservative include benzalkonium chloride, benzetonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, and chlorobutanol.

Examples of the solubilizing agent other than those described above include ethanol, glycerin, purified soy bean lecithin, soy bean oil, soy bean lecithin, propylene carbonate, medium chain fatty acid triglyceride, concentrated glycerin, propylene glycol, polyoxyl 35 castor oil, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxy hydrogenated castor oil, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polysorbate 60, cetostearyl alcohol-sodium cetostearylsulfonate mixture, Macrogol, acetone, isopropanol, sodium laurylsulfonate, d-a-tocopherol polyethyelen grycol succinate, polyoxyethylene hydroxystearate, polyvinylcaprolactam-polyvinyl acetate-polyehtylene glycol graft copolymer and so on.

<Method for producing parenteral aqueous pharmaceutical composition>
The method for producing a parenteral aqueous pharmaceutical composition according to this embodiment is not particularly limited, but the production can be made according to the following method, for example.
(1) First, the main drug (i.e., propofol), the aforementioned three kinds of essential solubilizing agent, and a dissolution aid are admixed with one another and heated at 60 to 80°C or so under stirring, and dissolution of TPM is confirmed with a naked eye.
(2) Meanwhile, a predetermined amount of an isotonic agent (for example, D-sorbitol) and a buffering agent (for example, citric acid hydrate) as a water soluble component is dissolved in water.
(3) Subsequently, the solution prepared in the above (1) is added to the aqueous solution prepared in the above (2), and by using an aqueous solution of sodium hydroxide, pH of the composition is adjusted to a desired value (for example, 6.0).
(4) Finally, by further adding water, mess-up is carried out to have a pre-determined final concentration. By using a 0.22 mm membrane filter, filter sterilization is carried out, and sealing into a glass ampoule with inert gas like nitrogen gas is carried out.

The parenteral aqueous pharmaceutical composition according to this embodiment is generally used for an injection preparation (namely, the composition according to this embodiment is a composition for injection). The administration form as an injection preparation is not limited, and administration can be made in the administration form including intravenous administration, intraarterial administration, intramuscular administration, and subcutaneous administration. The intravenous administration is a preferred administration form among them.

The parenteral aqueous pharmaceutical composition according to this embodiment can be prepared as a product by filtration and sterilization based on a common method. As for the filtration method, a known method using membrane filter can be applied, for example, and the filter filtration can also play the role of sterilizing operation. As for other methods for sterilization, a known method like high pressure vapor sterilization (for example, 121°C, 20 minutes), hot water immersion sterilization, and shower sterilization can be applied. Meanwhile, mono(tocopheryl) phosphate (TP) as the constitutional component of TPM, which is to be included in the composition according to this embodiment, is easily hydrolyzed by heating (under non-acid conditions, in particular). For such reasons, the composition according to this embodiment is preferably a composition which has been sterilized by filter filtration.

Hereinbelow, the present invention will be described more specifically by using examples. However, technical scope of the present invention is not limited only to the following specific examples.

<Preparation of aqueous pharmaceutical composition (Example 1)>
According to the formulation shown in the following Table 1, the aqueous pharmaceutical composition of this example was prepared.

Specifically, preparation of an aqueous pharmaceutical composition was carried out according to the order shown in the following Table 2.

In the meantime, the “TPM” described in the Table 1 and used in the step 1 in the Table 2 contained TP and T2P at 2 to 1.

Comparative Example 10
White precipitation was observed.

<Evaluation of stability after dilution>
With regard to Diprivan (registered trademark) as an original drug, according to the precautions for use which is described in the package insert, use thereof is allowed under the condition that dilution with another pharmaceutical preparation is only possible with 5% glucose solution for injection and the administration is carried out within 6 hours after dilution. Use thereof is allowed under the condition that 5% Dextrose Injection, Lactated Ringers Injection, Lactated Ringers and 5% Dextrose Injection and 5% Dextrose and 0.45% Sodium Chloride Injection, are administered simultaneously with the preceding intravenous fluids (administered via a three-way cock at neighborhood of the injection site of Diprivan).

Accordingly, determination was also made to see whether or not the preparation of the present invention is acceptable for such use and the preparation can be still used after a long period of time following dilution.

(Summary and purpose of experiment)
In the attached document relating to Diprivan, it is described as a caution for application that "the preparation should not be admixed with other pharmaceutical preparation before administration (except 5% glucose solution for injection). The dilution ratio for diluting the preparation with 5% Dextrose injection (glass container) should not be greater than 5 times (i.e., propofol concentration is 2 mg/mL or higher). The dilution needs to be carried out aseptically right before administration, and use thereof should be made within 6 hours". Furthermore, it is also described that "this preparation may be administered together with 5% Dextrose Injection, USP, Lactated Ringers Injection, USP, Lactated Ringers and 5% Dextrose Injection and 5% Dextrose and 0.45% Sodium Chloride Injection, USP".

Accordingly, determination was made to see whether or not the clear propofol solution of the present invention satisfies the above conditions.

(Method for experiment)
- Preparation
Propofol solution
55 g of polysorbate 80, 30 g of polysorbate 20, 2.5 g of TPM, and 10 g of propofol were stirred at 70°C using a stirrer for dissolution. Accordingly, solution A was obtained. Separately, 30 g of D-sorbitol and 1.7 g of sodium citrate hydrate were dissolved in 500 mL of water for injection. The solution A was added to the resulting solution, and by adding a sodium hydroxide solution, pH was adjusted to 6. Mess-up to 1000 mL was carried out with water for injection and nitrogen replacement was carried out.
- 5% Dextrose and 0.45% Sodium Chloride
Equal volume of 10% Dextrose Injection and 0.9% Sodium Chloride Injection were mixed.
- 5% Dextrose Injection diluted solution (n = 2)
Propofol solution was diluted with 5% Dextrose Injection.
- Lactated Ringers Injection diluted solution (n = 2)
Propofol solution was diluted with Lactated Ringers Injection.
- Lactated Ringers and 5% Dextrose Injection diluted solution (n = 2)
Propofol solution was diluted with Lactated Ringers and 5% Dextrose Injection.
- 5% Dextrose and 0.45% Sodium Chloride Injection diluted solution (n = 2)
Propofol solution was diluted with 5% Dextrose and 0.45% Sodium Chloride Injection.
- Measurement
Items for measurement
Particle size distribution, absorbance at 630 nm, assay and particulate matter (10 mm or larger and 25 mm or larger) were measured immediately after mixing, and 1, 3, 6, 8, or 24 hours after mixing (Particulate matter was tested at 1, 3, 6 and 24 hours. Assay was conducted according to US Pharmacopoeia “Propofol Injectable Emulsion Assay”.

As shown in Fig.1 and Tables 20 to 23, stability was shown for every item without having any change over 24 hours. Thus, it was found that the preparation can be diluted by 5 times with 5% glucose solution for injection, lactic acid Ringers solution, lactic acid Ringers solution added with glucose, and physiological saline added with glucose, and it can be used over 24 hours after dilution.

Claims

A parenteral aqueous pharmaceutical composition comprising propofol, a solubilizing agent, and water
wherein the solubilizing agent contains polysorbate 80, polysorbate 20, mono(tocopheryl) phosphate, and di(tocopheryl) phosphate,
total content of polysorbate 80 and polysorbate 20 is 20 w/v% or less, content mass ratio of polysorbate 80 relative to polysorbate 20 (content mass of polysorbate 80/content mass of polysorbate 20) is 1.80 to 7.0,
total content of mono(tocopheryl) phosphate and di(tocopheryl) phosphate is more than 0.20 w/v% but less than 0.74 w/v%, and
pH is more than 5.0 but less than 7.0.
The parenteral aqueous pharmaceutical composition according to claim 1, wherein the pH is 5.5 to 6.5.
The parenteral aqueous pharmaceutical composition according to claim 1 or 2, wherein the content mass ratio of polysorbate 80 relative to polysorbate 20 (content mass of polysorbate 80/content mass of polysorbate 20) is 1.83 to 4.70.
The parenteral aqueous pharmaceutical composition according to any one of claims 1 to 3, wherein the content mass ratio of mono(tocopheryl) phosphate relative to di(tocopheryl) phosphate (content mass of mono(tocopheryl) phosphate/content mass of di(tocopheryl) phosphate) is 1.5 to 2.5.
The parenteral aqueous pharmaceutical composition according to any one of claims 1 to 4, further comprising one or two or more kinds selected from a group consisting of an isotonic agent, a buffering agent, and a pH controlling agent.
The parenteral aqueous pharmaceutical composition according to claim 5, further comprising D-sorbitol or glycerin as the isotonic agent.
The parenteral aqueous pharmaceutical composition according to any one of claims 1 to 6, wherein the parenteral aqueous pharmaceutical composition is a composition for injection.