WO2004014341A1

WO2004014341A1 - Oral injectable pharmaceutical composition comprising florfenicol as an active ingredient

Info

Publication number: WO2004014341A1
Application number: PCT/KR2003/001266
Authority: WO
Inventors: Si-Young Chang; Jae-Seung Choi; Sung-Bae Park; Jong-Myung Park; Byeung-Gie Kim; Ji-Hoon Park
Original assignee: Dae Han New Pharm Co., Ltd.
Priority date: 2002-08-13
Filing date: 2003-06-27
Publication date: 2004-02-19
Also published as: AU2003244259A1; KR20040015624A

Abstract

Disclosed herein is a pharmaceutical composition for oral administration comprising a florfenicol-containing microemulsion as an effective ingredient wherein the microemulsion is obtained by adding an oil and a surfactant to a solution of florfenicol in a hydrophilic or amphiphilic dispersion medium. The pharmaceutical composition for oral administration comprises a high concentration active ingredient with excellent bioavailability in which the concentration of the active ingredient can be easily controlled by drinking water upon oral administration.

Description

Oral Injectable Pharmaceutical Composition Comprising Florfenicol as An Active Ingredient

Technical Field

The present invention relates to a pharmaceutical composition comprising florfenicol as an active ingredient, and more particularly to a pharmaceutical composition for oral administration comprising a florfenicol-containing microemulsion as an effective ingredient which is obtained by adding an oil and a surfactant to a solution of florfenicol in a hydrophilic or amphiphilic dispersion medium.

Background Art

Florfenicol [D-(threo)- 1 -p-methylsulfonylphenyl-2-dichloroacetoamido-3 - fluoro-1-propanol] is a derivative wherein the hydroxyl group at C-3 position of thiamphenicol [D-d-threo-2-dichloroacetoamido- 1 -(4-methylsulfonyl)phenyl- 1,3- propandiol] is substituted with a fluorine atom. Florfenicol exhibits a broad antibacterial activity against pathogenic bacterial strains including enteric bacteria such as Enterobacter, Shigella, Salmonella and E. coli. These enteric bacteria exhibit a resistance to chloramphenicol and thiamphenicol due to enzymatic inactivation by chloramphenicol transacetylase. Florfenicol is widely used for veterinary purposes (Atep, M., Disposition Kinetics of Florfenicol in Goats by Using Two Analytical Methods. J. Vet. Med. A 48, 129-146, 2001; Varma, K., Pharmacokinetics of Florfenicol in veal calves. J. Vet. Pharmacol. Therap. 9, 412- 425, 1986).

Although florfenicol has an antibacterial mechanism similar to chloramphenicol, it exhibits excellent antibacterial effects compared to chloramphenicol. In addition, florfenicol has an advantage of not causing irreversible aplastic anemia (AA). Since florfenicol, however, has a low water- solubility (about 1.3 mg/ml), it is difficult to formulate a concentrated aqueous solution of florfenicol in organic solvents such as 1,2-propandiol, glycerin, polyethylene glycol, propylene glycol and benzyl alcohol, which is required for oral therapeutic dosing. PCT publication WO 92/04016 and U. S. Pat. No. 5,082,863 disclose a method for solubilizing water-insoluble florfenicol in aprotic polar solvents, e.g., N-methyl-2-pyrrolidone or 2-pyrrolidone. However, this method is limited to injectable preparations, and the solvents were proven to cause irritation at injected sites and tissue damage when administered intramuscularly.

Disclosure ofthe Invention

Therefore, the present invention has been made in view of the above problems, and it is an object of the present invention to provide a pharmaceutical composition comprising a high concentration active ingredient with excellent bioavailability in which the concentration of the active ingredient can be easily controlled by drinking water upon oral administration.

In accordance with the present invention, there is provided a pharmaceutical composition for oral administration comprising a florfenicol- containing microemulsion as an effective ingredient wherein the microemulsion is obtained by adding an oil and a surfactant to a solution of florfenicol in a hydrophilic or amphiphilic dispersion medium.

The microemulsion containing florfenicol as an active ingredient enables the provision of the pharmaceutical composition comprising the active ingredient in the high concentration with excellent bioavailability in which the concentration of the active ingredient can be easily controlled by drinking water upon oral administration.

The hydrophilic or amphiphilic solvent as a dispersion medium is at least one solvent selected from the group consisting of diethyleneglycol monoethylether,

1,2-propyleneglycol, polyethyleneglycol, tetrahydrofurfuryl alcohol, polyethyleneglycolether and mixtures thereof, but is not particularly limited to these solvents.

The weight ratio of the florfenicol to the hydrophilic or amphiphilic solvent is preferably within the range of 1: 0.5~5, and more preferably 1: 1~3.

When the ratio is less than 1: 0.5, florfenicol is likely to be precipitated during prolonged storage. When the ratio exceeds 1: 5, there is a risk of phase separation. However, although florfenicol is dissolved in the solvent out of this range, it will be appreciated that the present invention can be sufficiently realized.

Accordingly, this range is given only for the purpose of illustration, and is not to be construed as limiting the scope ofthe invention. So long as the surfactant can easily form an emulsion when the surfactant is mixed with an oil and a dispersion medium and the mixture is diluted in water, it is not particularly limited. The surfactant preferably has a hydrophilic lipophlic balance (HLB) of 1~20.

The surfactant usable in the present invention is at least one compound selected from the group consisting of reaction products between vegetable hardened oils and ethylene glycol (e.g., Cremophor RH40, Cremophor RH60); polyethylene sorbitan fatty acid esters (e.g., Tween 20, Tween 40); polyoxyethylene fatty acid esters; polyoxyethylene-polyoxypropylene copolymers; and ester group transfer reaction products between vegetable oil triglycerides and polyalkylenepolyols (e.g., Labrafil, Labrasol). Preferably, the surfactant includes polyethyleneglycol 40 castor hardened oil and polyethyleneglycol 35 castor hardened oil.

The weight ratio of the florfenicol to the surfactant is preferably within the range of 1 : 0.1~10, and more preferably 1 : 0.5~5. When the ratio is less than 1: 0.1, addition effect of the surfactant is none or little. When the ratio exceeds 1: 10, there is a risk of phase separation. However, although the florfenicol and the surfactant are out of this range, it will be appreciated that the present invention can be sufficiently realized. Accordingly, this range is given only for the purpose of illustration, and is not to be construed as limiting the scope ofthe invention.

The oil used in the present invention is at least one compound selected from the group consisting of vegetable oils, esterification products of vegetable oils and highly unsaturated fatty acids. The weight ratio of the florfenicol to the oil is preferably within the range of 1: 0.1~10, and more preferably 1: 0.5~3. When the ratio is less than 1: 0.1, addition effect of the oil is none or little. When the ratio exceeds 1 : 10, there is a risk of phase separation. However, this range is given only for the purpose of illustration, and is not to be construed as limiting the scope ofthe invention.

If necessary, the pharmaceutical composition for oral administration of the present invention comprising the florfenicol-containing microemulsion may further comprise various medically acceptable additives. Examples of these additives include antioxidants (butylparahydroxy benzoic acid, butylhydroquinone, tocopherol, etc.), viscosity enhancing agents (sodium alginate, carboxymethylcellulose, methylcellulose, tragacanth, agar, polyvinylpyrrolidone, etc.), aromatics (orange oil, peppermint, vanilla, cocoa, etc.), preservative agents (methyl paraoxybenzoate, propyl paraoxybenzoate, sodium benzoylbenzoate, benzalkonium chloride, etc), colorants (Red #40, Yellow #4, Green #3, Blue #1), and the like. BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawing, in which:

Fig. 1 is a graph showing the concentration of an active ingredient in blood, measured at predetermined time intervals after a pharmaceutical composition of the present invention is orally administered into male rats.

Best Mode for Carrying Out the Invention

Hereinafter, the present invention will be described in more detail with reference to the following Examples. However, these Examples are given for the purpose of illustration and are not to be construed as limiting the scope of the invention.

<Examples 1~5> Preparation of pharmaceutical preparations for oral administration lOg of florfenicol was added to 40ml of Transcutol P, in accordance with the compositions shown in Table 1 below. The resulting mixture was heated to 80°C to completely dissolve the florfenicol, and then cooled to room temperature. Miglyol 812 as an oil and Cremophor RH40 as a surfactant were added thereto, and stirred until a transparent solution was obtained. The solution was cooled to room temperature. Transcutol P was added until the total volume reached 100ml to prepare a pharmaceutical preparation for oral administration.

<Table 1> Compositions of injectable solutions

<Test Example> Measurement of pharmacological effects

The pharmaceutical preparation prepared (florfenicol lOOmg/kg) in Example 1 was orally administered for an adsorption experiment. As experimental animals, Sprague-Dawley rats (male, body weight 300±20g) were used. The three rats were divided into one group, respectively, and starved before the experiment. Relative bioavailability was measured on the experimental animal groups. Blank blood samples were obtained prior to the administration. Blood samples (0.2ml) were obtained from the jugular veins at predetermined time intervals after administration for analysis of florfenicol in blood. High performance liquid chromatography (HPLC) was used to analyze the concentrations of florfenicol in the blood samples.

The concentrations of florfenicol in the blood samples are shown in Fig. 1. The bioavailability of florfenicol in the experimental animal groups was identified to be excellent.

Industrial Applicability

As apparent from the above description, the pharmaceutical composition for oral administration according to the present invention comprises a high concentration active ingredient with excellent bioavailability in which the concentration of the active ingredient can be easily controlled by drinking water upon oral administration.

Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit ofthe invention as disclosed in the accompanying claims.

Claims

Claims:

1. A pharmaceutical composition for oral administration comprising a florfenicol-containing microemulsion as an effective ingredient, wherein the microemulsion is obtained by adding an oil and a surfactant to a solution of florfenicol in a hydrophilic or amphiphilic dispersion medium.

2. The pharmaceutical composition for oral administration according to claim 1, wherein the dispersion medium is at least one solvent selected from the group consisting of diethyleneglycol monoethylether, 1,2-propyleneglycol, polyethyleneglycol, tetrahydrofurfuryl alcohol and polyethyleneglycolether.

3. The pharmaceutical composition for oral administration according to claim 1, wherein the weight ratio of the florfenicol to the dispersion medium is 1: 0.5-5.

4. The pharmaceutical composition for oral administration according to claim 1, wherein the surfactant has a hydrophilic lipophlic balance (HLB) of 1-20.

5. The pharmaceutical composition for oral administration according to claim 1 or 2, wherein the surfactant is at least one compound selected from the group consisting of reaction products between vegetable hardened oils and ethylene glycol; polyethylene sorbitan fatty acid esters; polyoxyethylene fatty acid esters; polyoxyethylene-polyoxypropylene copolymers; and ester group transfer reaction products between vegetable oil triglycerides and polyalkylenepolyols.

6. The pharmaceutical composition for oral administration according to claim 1, wherein the weight ratio of the florfenicol to the surfactant is within the range of 1: 0.1-10.

7. The pharmaceutical composition for oral administration according to claim 1, wherein the oil is an esterifϊcation product of a vegetable oil and glycerin.

8. The pharmaceutical composition for oral administration according to claim 1, wherein the weight ratio ofthe florfenicol to the oil is within the range of 1: 0.1-10.