Emulsion containing drug poorly soluble in water and oil and method for producing same

Abstract

The present invention addresses the problem of providing: an emulsion containing a drug poorly soluble in water and oil; and a method for producing same. As a means for solving said problem, this emulsion is constituted from at least (1) a drug poorly soluble in water and oil, (2) at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol, (3) an emulsifier (excluding the use of lecithin alone), and (4) an aqueous medium.

Description

Emulsion containing poorly water- and oil-soluble drugs and method for producing same

[0001] The present invention relates to an emulsion containing a poorly water- and oil-soluble drug and a method for producing the same.

[0002]

[0003] Today, various drugs have been found as active ingredients in pharmaceuticals and are being put to practical use. However, in order to fully exert the effects of the drugs, it is of course important how to formulate the drugs. Among these, liquid formulations are highly valuable because they can be used in various dosage forms, including injections. However, poorly water- and oil-soluble drugs are difficult to formulate into liquid formulations because they are poorly soluble in both water and oil (oils and fats). For example, even with the drug-containing lipid emulsion technology proposed by the present inventor in Patent Document 1, it is sometimes difficult to formulate them into liquid formulations.

[0003] Patent No. 5340954

[0004] Therefore, an object of the present invention is to provide an emulsion containing a poorly water- and oil-soluble drug and a method for producing the same.

[0005] The present inventors have conducted extensive research in light of the above points and have found that an emulsion containing a poorly water- and oil-soluble drug can be produced by dissolving the poorly water- and oil-soluble drug using benzyl alcohol, phenoxyethanol, or phenethyl alcohol and emulsifying the resulting solution using an emulsifier.

[0006] Based on the above findings, the water- and oil-soluble drug-containing emulsion of the present invention, as set forth in claim 1, comprises at least the following components: (1) a water- and oil-soluble drug; (2) at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol; (3) an emulsifier (excluding lecithin alone); and (4) an aqueous medium. The water- and oil-soluble drug-containing emulsion of claim 2 comprises the water- and oil-soluble drug-containing emulsion of claim 1, further comprising: (5) a pharmaceutically acceptable salt of an aromatic carboxylic acid and / or polyethylene glycol. The water- and oil-soluble drug-containing emulsion of claim 3 comprises the water- and oil-soluble drug-containing emulsion of claim 1, further comprising: (6) an oil or fat. The water- and oil-soluble drug-containing emulsion of claim 4 comprises the water- and oil-soluble drug-containing emulsion of claim 1, further comprising: (7) an aromatic carboxylic acid. The method for producing an emulsion containing a poorly water- and oil-soluble drug of the present invention comprises emulsifying components including at least: (1) a poorly water- and oil-soluble drug; (2) at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol; (3) an emulsifier (excluding the use of lecithin alone); and (4) an aqueous medium, as described in claim 5.

[0007] According to the present invention, an emulsion containing a poorly water- and oil-soluble drug and a method for producing the same can be provided.

[0008] The emulsion containing a poorly water- and oil-soluble drug of the present invention comprises at least the following components: (1) a poorly water- and oil-soluble drug; (2) at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol; (3) an emulsifier (excluding the use of lecithin alone); and (4) an aqueous medium.

[0009] In the present invention, a poorly water- and oil-soluble drug refers to a drug that is poorly soluble in both water and oil. Poorly water-soluble refers to, for example, a solubility in water that meets the criteria specified in the Japanese Pharmacopoeia General Rules as being "slightly soluble" (the amount of solvent required to dissolve 1 g or 1 mL of solute is 30 mL or more but less than 100 mL; the solute corresponds to the drug and the solvent corresponds to water), preferably "slightly soluble" (same, solvent amount is 100 mL or more but less than 1000 mL), more preferably "extremely soluble" (same, solvent amount is 1000 mL or more but less than 10,000 mL), and even more preferably "practically insoluble" (same, solvent amount is 10,000 mL or more). Poorly oil-soluble refers to a solubility in fats and oils, such as soybean oil or medium-chain triglycerides, at 25°C of less than 25 mg / mL, preferably less than 15 mg / mL, and more preferably less than 5 mg / mL.The types of drugs are not particularly limited, and include antibiotics such as clarithromycin, azithromycin, cefdinir, erythromycin, etc.; antibacterial drugs such as norfloxacin, levofloxacin, tosufloxacin, etc.; antifungal drugs such as itraconazole, ketoconazole, luliconazole, etc.; antiviral drugs such as vidarabine, acyclovir, ivermectin, etc.; hypnotics and sedatives such as triazolam, quazepam, nitrazepam, etc.; antiepileptic drugs such as carbamazepine, clonazepam, zonisamide, etc.; drugs for schizophrenia such as zotepine, pimozide, olanzapine, risperidone, etc.; tranquilizers such as oxazolam, diazepam, ethyl loflazepate, alprazolam, etc.; neuroprotective drugs such as edaravone, etc.; indomethacin, ketoprofen, piroxicam, ampirox, etc. Examples of the anti-inflammatory analgesic include cicam, meloxicam, celecoxib, acetaminophen, and other anti-inflammatory drugs; methylprednisolone, prednisolone, fluorometholone, betamethasone, beclomethasone propionate, dexamethasone, and other synthetic corticosteroids; argatroban, cilostazol, and other anti-cancer drugs; irinotecan, etoposide, docetaxel, cabazitaxel, sirolimus, letrozole, exemestane, flutamide, paclitaxel, and other anti-cancer drugs; tacrolimus, and other immunosuppressants; noscapine, and other antitussives; bosentan, and other cardiovascular drugs; and domperidone, and other anti-emetic drugs.

[0010] In the present invention, at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol is used because these are liquids that are poorly soluble in aqueous media and can dissolve poorly water- and oil-soluble drugs (for example, they have a dissolving power at 25°C that is 10 times or more that of fats and oils), and therefore these alcohols, in which poorly water- and oil-soluble drugs are dissolved, are present in the emulsion as droplets in which the poorly water- and oil-soluble drugs are dissolved (corresponding to fat particles in which the drug is dissolved in a drug-containing fat emulsion). These alcohols may be used alone or in combination of two or more.

[0011] In the present invention, the emulsifier used to disperse droplets of at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol, in which a poorly water- and oil-soluble drug is dissolved, in an emulsion may be any of known emulsifiers, such as lecithin (egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, etc.), sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters (polysorbates 20, 40, 60, 65, 80, etc.), polyoxyethylene fatty acid esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyoxyl stearate, which may be used alone or in combination of two or more. Among these, lecithin, which is highly safe, is preferably used, but lecithin is not used alone. Since lecithin does not have a strong emulsifying power, its use alone requires an increased amount, which increases the viscosity and makes emulsification difficult. This makes it difficult to produce an emulsion in which droplets with a uniform particle size distribution are dispersed, which may lead to instability of the emulsion. Therefore, it is important to use lecithin in combination with other emulsifiers.

[0012] In the present invention, specific examples of aqueous media include water (pure water, purified water, water for injection, etc.), as well as acetic acid-sodium acetate, boric acid-sodium carbonate, boric acid-sodium tetraborate, hydrochloric acid-sodium tetraborate, phosphoric acid-sodium phosphate, sodium dihydrogen phosphate-disodium hydrogen phosphate, citric acid-sodium hydroxide, hydrochloric acid-potassium hydrogen phthalate, sodium hydroxide-potassium hydrogen phthalate, citric acid-disodium hydrogen phosphate, succinic acid-sodium tetraborate, ammonia-ammonium chloride, potassium dihydrogen phosphate-disodium hydrogen phosphate-phosphoric acid, and potassium dihydrogen phosphate-phosphoric acid water. Examples of such buffer solutions include those prepared by adding trisodium citrate-sodium hydroxide, potassium dihydrogen phosphate-disodium hydrogen phosphate, potassium dihydrogen phosphate-sodium hydroxide, disodium hydrogen phosphate-sodium hydroxide, Tris (abbreviation for trishydroxymethylaminomethane, the same applies hereinafter)-hydrochloric acid, Tris-EDTA, Tris-acetate-EDTA, trisodium citrate-sodium hydroxide-sodium chloride, sodium dihydrogen phosphate-EDTA-sodium chloride, or the like to water, to adjust the pH to a predetermined range, for example, 3.5 to 9.0, preferably 5.0 to 8.5, and more preferably 6.5 to 8.0.

[0013] The emulsion containing a poorly water- and oil-soluble drug of the present invention may further contain a pharmaceutically acceptable salt of an aromatic carboxylic acid and / or polyethylene glycol. The inclusion of these compounds reduces the particle size of droplets containing the poorly water- and oil-soluble drug dissolved therein, and the droplets are composed of at least one alcohol selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol. Specific examples of pharmaceutically acceptable salts of aromatic carboxylic acids include pharmaceutically acceptable salts of benzoic acid, salicylic acid, phthalic acid, isophthalic acid, and terephthalic acid, such as alkali metal salts (e.g., sodium salts and potassium salts) and alkaline earth metal salts (e.g., magnesium salts and calcium salts). Specific examples of polyethylene glycol include macrogol 200, 300, 600, 1000, and 1540. These may be used alone or in combination.

[0014] The emulsion containing a poorly water- and oil-soluble drug of the present invention may further contain an oil or fat. The inclusion of an oil or fat is particularly effective when lecithin is used as an emulsifier in combination with other emulsifiers, and can reduce the particle size of droplets containing the poorly water- and oil-soluble drug dissolved in at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol. This also contributes to the stabilization of the emulsion by homogenizing the particle size distribution of the droplets. Specific examples of oils or fats include vegetable oils such as soybean oil, corn oil, palm oil, safflower oil, perilla oil, olive oil, castor oil, and cottonseed oil, as well as animal oils such as lanolin, egg yolk oil, fish oil, mineral oils such as liquid paraffin, medium-chain fatty acid triglycerides, chemically synthesized triglycerides, and gelled hydrocarbons. These oils or fats may be used alone or in combination of two or more.

[0015] The emulsion containing poorly water- and oil-soluble drugs of the present invention may further contain an aromatic carboxylic acid. By further containing an aromatic carboxylic acid, the dissolving power of poorly water- and oil-soluble drugs in at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol can be enhanced. Specific examples of aromatic carboxylic acids include benzoic acid, salicylic acid, phthalic acid, isophthalic acid, and terephthalic acid. These may be used alone or in combination of two or more.

[0016] The content of the poorly water- and oil-soluble drug in the poorly water- and oil-soluble drug-containing emulsion of the present invention may be, for example, 0.001 to 30 mg / g (the upper limit is preferably 20 mg / g, more preferably 10 mg / g). The content of at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol is preferably at least twice the content of the poorly water- and oil-soluble drug, more preferably at least 5 times, and even more preferably at least 10 times. If the content is less than twice the content of the poorly water- and oil-soluble drug, even if an aromatic carboxylic acid is further added to increase the dissolving power of the poorly water- and oil-soluble drug in the emulsion, it may not be possible to dissolve the entire amount of the poorly water- and oil-soluble drug. However, the upper limit is preferably 250 mg / g, more preferably 150 mg / g, and even more preferably 100 mg / g. The content of the emulsifier is preferably 0.5 to 5 times the content of at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol. If the content is less than 0.5 times the content of the poorly water- and oil-soluble drug, emulsification may be difficult. However, the upper limit is preferably 200 mg / g, more preferably 150 mg / g, and even more preferably 100 mg / g. When lecithin is used as an emulsifier in combination with other emulsifiers, the upper limit of the lecithin content in the emulsifier content (total content of lecithin and other emulsifiers) is preferably 95%, more preferably 85%. If the lecithin content in the emulsifier content exceeds 95%, it becomes difficult to produce an emulsion in which droplets with a uniform particle size distribution are dispersed, which may lead to instability of the emulsion. When a pharmaceutically acceptable salt of an aromatic carboxylic acid and / or polyethylene glycol is further contained, the content thereof is, for example, 0.5 to 6 times the content of at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol. However, the upper limit is preferably 200 mg / g, more preferably 150 mg / g, and even more preferably 100 mg / g. When fats and oils are further contained, the content thereof is, for example, 0.01 to 0.5 times the content of at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol.Since the oil and fat are mixed with at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol, a high content of oil and fat may hinder the dissolution of poorly water- and oil-soluble drugs by at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol.When an aromatic carboxylic acid is further contained, the upper limit of its content is preferably 0.5 times the content of at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol.

[0017] The method for producing the emulsion containing a poorly water- and oil-soluble drug of the present invention is not particularly limited, and examples thereof include a method in which the contents of the poorly water- and oil-soluble drug, at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol, emulsifier, pharmaceutically acceptable salt of aromatic carboxylic acid and / or polyethylene glycol (if further included), oil (if further included), and aromatic carboxylic acid (if further included) are set within the above-mentioned numerical ranges, and the oil phase component is prepared by dissolving the poorly water- and oil-soluble drug, oil (if further included), and aromatic carboxylic acid (if further included) in at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol, and the aqueous phase component is prepared by dissolving the emulsifier and the pharmaceutically acceptable salt of aromatic carboxylic acid and / or polyethylene glycol (if further included) in an aqueous medium, and then the components are mixed and emulsified. The mixed liquid of the oil phase component and the aqueous phase component may be emulsified by manual shaking or using a device such as a stirrer (mixer), ultrasonic emulsifier, or ultrasonic cleaner. The emulsification time may be, for example, 1 to 30 minutes. The droplets of at least one alcohol selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol in which a poorly water- and oil-soluble drug is dissolved (when an aromatic carboxylic acid is further contained, the aromatic carboxylic acid is also contained in these droplets) preferably have an average particle size of 500 nm or less, more preferably 400 nm or less, even more preferably 300 nm or less, even more preferably 200 nm or less, and most preferably 100 nm or less. The lower limit is, for example, 1 nm (this can be adjusted, for example, by adjusting the emulsification conditions).

[0018] The emulsion containing a poorly water- and oil-soluble drug of the present invention can be easily sterilized by filtration by reducing the mean droplet size of the droplets to, for example, 200 nm or less, and can also be subjected to autoclaving. Autoclaving can be carried out by filling the emulsion containing a poorly water- and oil-soluble drug of the present invention into a glass ampoule or a synthetic resin container, and then performing the autoclaving under general conditions (e.g., 120-122°C x 10-15 minutes).

[0019] The poorly water- and oil-soluble drug-containing emulsion of the present invention may have its pH adjusted (e.g., 3.5 to 9.0) or its osmotic pressure adjusted by adding a known pH adjuster or osmotic pressure adjuster. Furthermore, the poorly water- and oil-soluble drug-containing emulsion of the present invention may also contain known preservatives, antioxidants, stabilizers, etc., as needed.

[0020] The poorly water- and oil-soluble drug-containing emulsions of the present invention have excellent stability and can be stored at room temperature (e.g., 5 to 30°C). Furthermore, the transparency of the poorly water- and oil-soluble drug-containing emulsions of the present invention, with a turbidity of 0.5 or less, facilitates visual inspection of the presence or absence of deterioration, foreign matter contamination, and formulation changes, and also provides a sense of security to patients receiving the emulsions. These effects are particularly effective when the poorly water- and oil-soluble drug-containing emulsions of the present invention are used as liquid preparations such as injections, oral preparations, lotions, eye drops, nasal drops, ear drops, and inhalants (which may be diluted with an aqueous medium as necessary). However, the use of the poorly water- and oil-soluble drug-containing emulsions of the present invention is not limited to liquid preparations and may also include topical preparations such as creams, ointments, and patches.

[0021] The present invention will be described in detail below with reference to examples, but the present invention should not be construed as being limited to the following description.

[0022] Examples and Comparative Examples: The contents of test tubes containing predetermined amounts of four components, (1) a poorly water- and oil-soluble drug, (2) either benzyl alcohol, phenoxyethanol, or phenethyl alcohol, (6) an oil or fat, and (7) an aromatic carboxylic acid, were dissolved until homogeneous using an ultrasonic cleaner (ASU-30, hereinafter the same) filled with water at 50°C (operating time: 15 minutes) manufactured by AS ONE Corporation (oil phase component). The contents of test tubes containing predetermined amounts of three components, (3) an emulsifier, (5) a pharmaceutically acceptable salt of an aromatic carboxylic acid or polyethylene glycol, and (4) an aqueous medium, were dissolved until homogeneous using either an ultrasonic cleaner filled with water at 50°C (operating time: 15 minutes when lecithin was not used as an emulsifier) ​​or an ultrasonic emulsifier (UH-50) manufactured by SMT Corporation (operating time: 5 minutes when lecithin was used as an emulsifier) ​​(aqueous phase component). The aqueous phase components were added to the test tube containing the oil phase components, mixed, and emulsified for 5 minutes using an AS ONE test tube mixer (HM-10) to produce an emulsion containing a poorly water- and oil-soluble drug. The types and amounts of the seven components used are shown in Tables 1 and 2. In Table 2, (3) Polysorbate 20 and 80 from NOF Corporation were used. Egg yolk lecithin was PL-100M from Kewpie Corporation. POE castor oil (polyoxyethylene castor oil) was Uniox C-35 from NOF Corporation. POE (60) hydrogenated castor oil (polyoxyethylene (60) hydrogenated castor oil) and POE (40) hydrogenated castor oil (polyoxyethylene (40) hydrogenated castor oil) were NIKKOL HCO-60 (for pharmaceutical use) and NIKKOL HCO-40 (for pharmaceutical use), respectively, from Nikko Chemicals. For POE / POP glycol (polyoxyethylene polyoxypropylene glycol), Pronon #188P from NOF Corporation was used. (4) The aqueous medium was purified water (1 mL = 1000 mg). (5) For polyethylene glycol, Pharmaceutical Additive Macrogol 300 from NOF Corporation was used. (6) For MCT (medium-chain fatty acid triglyceride), MCT oil from Nisshin Oillio Group was used. For castor oil, Croda Oil was used. "None" means that it was not used as a constituent component.

[0023]

[0024]

[0025] The average particle size of droplets contained in the poorly water- and oil-soluble drug-containing emulsions immediately after production was measured using a Malvern particle size analyzer (Zetasizer Nano ZS) using photon correlation spectroscopy. The test tubes containing the poorly water- and oil-soluble drug-containing emulsions were capped and left in a room for 12 hours, after which the emulsions were visually evaluated for their properties. The results are shown in Table 3. As is clear from Table 3, the poorly water- and oil-soluble drug-containing emulsions produced in all Examples were stable, with no phase separation or precipitates or sediments occurring, even after 12 hours of production. There was no visible change in their properties even after continued storage in a room for more than one month. The turbidity of the emulsions containing poorly water- and oil-soluble drugs immediately after production was measured at a wavelength λ of 620 nm using an ultraviolet spectrophotometer (UV1800) manufactured by Shimadzu Corporation, with the samples placed in a measuring cell with a cell width of 1 cm (pure water used as the blank).The majority of the emulsions, except for those containing poorly water- and oil-soluble drugs produced in Examples 31 and 32, were 0.1 or less, and even if they exceeded 0.1, they were 0.3 or less.The turbidity of the emulsions containing poorly water- and oil-soluble drugs produced in Examples 31 and 32 was 1 or more.

[0026] It was also found that the average particle size of droplets contained in the emulsion could be reduced by further including a pharmaceutically acceptable salt of an aromatic carboxylic acid, such as sodium salicylate or sodium benzoate, or polyethylene glycol as a constituent of the emulsion (comparison of Example 10 and Example 24).

[0027] Furthermore, when lecithin is used as an emulsifier in combination with other emulsifiers, it was found that the average particle size of the droplets contained in the emulsion can be reduced by further including fats and oils such as MCT and castor oil as components of the emulsion (comparison of Example 2 and Example 33).

[0028] Furthermore, it was found that by further including aromatic carboxylic acids such as benzoic acid and salicylic acid as constituents of the emulsion, the dissolving power of poorly water- and oil-soluble drugs in benzyl alcohol and the like is increased, making it possible to dissolve the same amount of poorly water- and oil-soluble drugs in a smaller amount of benzyl alcohol and the like (comparison between Example 3 and Example 23, comparison between Example 26 and Example 28), or to dissolve a larger amount of poorly water- and oil-soluble drugs in the same amount of benzyl alcohol and the like (comparison between Example 3 and Example 22, comparison between Example 26 and Example 27).

[0029] The average particle size of the droplets contained in the emulsion was not measured because precipitates appeared immediately after production of the emulsion containing poorly water- and oil-soluble drugs produced in Comparative Example 1. The poor stability of the emulsion containing poorly water- and oil-soluble drugs produced in Comparative Example 1 was thought to be due to the use of lecithin alone as an emulsifier (compared to Example 3; although the MCT content was different, the results were the same when compared with the same MCT content).

[0030]

[0031] Furthermore, emulsions containing poorly water- and oil-soluble drugs of the present invention were prepared using the types and amounts of components shown in Tables 4 and 5, and their stability and transparency were confirmed. The results are shown in Table 6.

[0032]

[0033]

[0034]

[0035] INDUSTRIAL APPLICABILITY The present invention has industrial applicability in that it can provide an emulsion containing a poorly water- and oil-soluble drug and a method for producing the same.

Claims

1. An emulsion containing a poorly water- and oil-soluble drug, comprising as at least the following components: (1) a poorly water- and oil-soluble drug; (2) at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol; (3) an emulsifier (excluding the use of lecithin alone); and (4) an aqueous medium.

2. (5) An emulsion containing a poorly water- and oil-soluble drug according to claim 1, further comprising a pharmaceutically acceptable salt of an aromatic carboxylic acid and / or polyethylene glycol as a constituent.

3. An emulsion containing a poorly water- and oil-soluble drug according to claim 1, further comprising (6) oils and fats as constituent components.

4. The emulsion containing a poorly water- and oil-soluble drug according to claim 1, further comprising (7) an aromatic carboxylic acid as a constituent.

5. A method for producing an emulsion containing a poorly water- and oil-soluble drug by emulsifying components including at least: (1) a poorly water- and oil-soluble drug; (2) at least one selected from the group consisting of benzyl alcohol, phenoxyethanol, and phenethyl alcohol; (3) an emulsifier (excluding the use of lecithin alone); and (4) an aqueous medium.

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