Injectable pharmaceutical composition containing tilebalosin tartrate and method for producing the same

Abstract

The present invention relates to pharmaceutical formulations or compositions comprising tilebalosin tartrate, as well as methods for manufacturing or producing the same for injectable applications and veterinary use, wherein the formulation or pharmaceutical composition is non-aqueous and contains an adjuvant to stabilize macrolide antibiotics such as tilebalosin, which are administered parenterally.

Description

Technical Field

[0001] The present invention belongs to the technical field of the pharmaceutical industry, mainly the veterinary pharmaceutical industry.

Background Art

[0002] The development of pharmaceutical compositions or formulations mainly for parenteral administration, containing tilvalosin with its active ingredient stabilized, meets the current needs for the treatment and prevention of respiratory and intestinal diseases caused by Mycoplasma-sensitive microorganisms such as chronic respiratory diseases due to mycoplasmosis, necrotizing enteritis, bacterial enteritis, and infections caused by Ornithobacterium rhinotracheale, Mycoplasma pneumonia, ileitis, dysentery, and porcine colitis.

[0003] In the field of patents, the pamphlet of International Publication No. WO 2020 / 049570 is known. This mentions the stability of sustained-release formulations and the influence of said stability on the release profile of the active agent. When using a combination of a poloxamer, an organic solvent, and optionally a cellulose derivative in a sustained-release formulation of an antibacterial agent, a stable injectable dispersion formulation with a consistent and reproducible release profile results. Thus, a composition is provided that includes a poorly soluble antibacterial agent, at least one poloxamer, an organic solvent, a cellulose derivative that is at least partially soluble in the organic solvent, and an aqueous medium. The composition is for injection, the active ingredient exceeds 35% or 40% by weight, and the active ingredient may be selected from florfenicol, lincomycin, tylosin, metronidazole, tilmicosin, spiramycin, erythromycin, tulathromycin, tiamulin, ampicillin, amoxicillin, clavulanate, penicillin, streptomycin, trimethoprim, sulfonamide, sulfamethoxazole, pleuromutilin, avilosin, tilvalosin, doxycycline, and oxytetracycline in organic solvents such as dimethyl sulfoxide (DMSO) and propylene glycol.

[0004] This is also known from International Publication No. 2021 / 183762, which teaches immunomodulatory compounds of formula (I) and their stereoisomers and pharmaceutically acceptable salts (wherein R0, R1, R2, R10, W, ring C and n are as defined in the specification), these stereoisomers and their pharmaceutically acceptable salts; and compositions comprising the said compounds. The invention also includes the administration of additional agents such as macrolide ionophores (e.g., erythromycin, gamithromycin, tildipyrosine, tilmicosine, tulathromycin, M9 metabolite of tulathromycin, tylosine, tilebalosine, etc.) in a solvent such as benzyl alcohol and an antioxidant such as butylhydroxyanisole.

[0005] On the other hand, the patent document, International Publication No. 2016 / 112317, teaches a method for treating diseases caused by filariasis using macrolide antibiotics, the method comprising the step of administering a therapeutically effective amount of macrolide antibiotic to a subject suffering from a disease caused by filariasis. The macrolide antibiotic is tylosin A, tylosin A analogues, tylosin A derivatives, or salts thereof. The macrolide antibiotic is tylosin tartrate (marketed as Tylan®), and in certain embodiments, the macrolide antibiotic is tilebalosin tartrate (marketed as Ibrosin®) or tilmycosine phosphate (marketed as Mycotyl®). The composition may contain glycols such as propylene glycol for injectable formulations, and the active ingredient may be present in a proportion of 50-90% by weight in the liquid formulation.

[0006] Patent CN107485604 relates to an improved soluble powder of tilebalosine tartrate, comprising 5 to 25 parts by mass of tilebalosine tartrate, 5 to 40 parts by mass of cyclodextrin, 45 to 85 parts of a water-soluble carrier, 0.1 to 1 part of an acidic additive, 0.1 to 1 part of a neutralizing agent, and 0.05 to 0.5 parts of an attractant. The soluble powder is prepared by sieving the components and mixing the components. The solubility of the soluble powder (calculated based on the active ingredient, tilebalosine tartrate) can be 20,000 ppm or higher at room temperature, whereas the solubility of a typical soluble powder of tilebalosine tartrate is 10,000 ppm. The solubility of tilebalosine tartrate is clearly increased, and the improved soluble powder of tilebalosine tartrate has good stability, good palatability, and high bioavailability of the drug.

[0007] Patent document CN107308119 teaches highly water-soluble tilebalosine tartrate particles and a method for preparing them. The highly water-soluble tilebalosine tartrate particles contain 5-30% tilebalosine tartrate, 15-20% water-soluble starch, 43-76.5% anhydrous glucose powder, 1-2% dimethyl sulfoxide, 0.5-1% hydroxypropyl methylcellulose, and 2-4% L-tartaric acid. The preparation method comprises: Step 1, which includes performing heat fusion with dimethyl sulfoxide in a 40°C water bath; sieving tilebalosine tartrate, water-soluble starch, anhydrous glucose powder, dimethyl sulfoxide, hydroxypropyl methylcellulose, and L-tartaric acid through an 80-mesh sieve; and weighing according to the formulation for further use; Step 2, which includes sequentially adding the dimethyl sulfoxide, hydroxypropyl methylcellulose, water-soluble starch, and L-tartaric acid from Step 1 to 60°C warm water and stirring to obtain a mixture; Step 3, which includes mixing the tilebalosine tartrate from Step 1 with anhydrous glucose powder to obtain a mixture; and Step 4, which includes taking the mixture from Step 2 as an adhesive and performing granulation using a vertical fluidized bed.

[0008] In this regard, reference CN107213470 refers to a soluble powder of tilebalosine tartrate and a method for preparing it. This method includes the steps of: mixing hydroxypropyl-beta-cyclodextrin and water and stirring until dissolved to obtain a first liquid; mixing the first liquid, crude tilebalosine tartrate and a pH adjuster in a cold water bath and stirring until a clarified liquid is obtained; and spray-drying the obtained clarified liquid through a spray-drying column to obtain a powder. The prepared soluble powder of tilebalosine tartrate can mask the odor of the drug, is highly soluble, and is stable.

[0009] In this sense, there remains a need to provide stable pharmaceutical compositions or formulations of parenterally administered antibiotic macrolides, primarily tilebalosin tartrate, which would enable the assurance of dosage, treatment, and prevention of respiratory and intestinal diseases caused by tilebalosin-sensitive microorganisms in infected animals. [Overview of the project]

[0010] The present invention relates to pharmaceutical formulations or pharmaceutical compositions containing a veterinary injectable antibiotic comprising tilebalosin tartrate, and methods for manufacturing or producing the same, wherein the formulation or pharmaceutical composition is non-aqueous and contains an adjuvant to stabilize a macrolide antibiotic such as tilebalosin that is administered parenterally.

[0011] Macrolide antimicrobial agents are primarily active against Gram-positive bacteria and Mycoplasma, exhibiting limited activity against many Gram-negative bacteria. A key chemical characteristic common to all macrolides is the presence of a macrocyclic lactone ring. Macrolide antimicrobial agents used in veterinary medicine include tylosin, tilmicosin, and tilebalosin. These two are semi-synthetic derivatives of tylosin.

[0012] [ka] Tylosin

[0013] [ka] Chilmycosine 4A-O-De(2,6-dideoxy-3-C-methyl-al-ribo-hexopyranosyl)-20-deoxo-20-(3,5-dimethyl-1-piperidinyl)tylosine

[0014] [ka] Tile Baroque 3-Acetyl-4"-Isovaleryltyrosine Tartrate [Modes for carrying out the invention]

[0015] In a first embodiment, the present invention refers to a pharmaceutical composition or formulation for parenteral administration that stabilizes an active ingredient, in particular tilebalosin, in particular tilebalosin tartrate, which is a macrolide antibiotic, comprising the active ingredient and a pharmaceutically acceptable excipient in an amount of 5% to 20% by weight, preferably 10% to 15% by weight, and more preferably 10% by weight of the whole composition.

[0016] Pharmaceutically acceptable excipients or components that may be present in a pharmaceutical composition or formulation include organic solvents, preservatives, antioxidants, and co-solvents or diluents.

[0017] The solvent may be an organic solvent such as dimethyl sulfoxide (DMSO) and may be present in the final pharmaceutical formulation at a concentration of 10% to 60% by weight, more preferably 40% by weight.

[0018] The preservative may be an aromatic alcohol such as benzyl alcohol (C6H5CH2OH) and may be present in the pharmaceutical composition or formulation in an amount of 1% to 10% by weight, more preferably 5% by weight, of the final formulation.

[0019] The antioxidant may be one or more synthetically produced antioxidants such as butylated hydroxyanisole (BHA) (C 11 H 16 O2) and butylated hydroxytoluene (BHT) (C 15 H 24 O), and may be present in the pharmaceutical composition or formulation at a ratio of 0.0002 to 0.03% by weight, more preferably 0.01% of the final formulation.

[0020] The co-solvent or diluent may be a diol such as propylene glycol (C3H8O2), and may be present in the pharmaceutical composition or formulation at a ratio of 10% to 60% by weight of the final formulation, more preferably in an amount sufficient to adjust the volume.

[0021] In a second aspect, the present invention relates to a method for producing an injectable pharmaceutical composition comprising tilebarosin tartrate, the method comprising: a) dissolving an antioxidant in a preservative; b) dispersing an active ingredient in a co-solvent or diluent; c) adding the product obtained in step b) to the product obtained in step a) and mixing until completely dissolved; and d) making it 100% with a diluent including.

[0022] In step a), the dissolution of the antioxidant is carried out using mechanical stirring in a container of sufficient volume until complete dissolution, and the stirring is carried out for 5 to 20 minutes, preferably 10 minutes.

[0023] In step b), the dispersion of the active ingredient in the co-solvent or diluent is carried out in another container using mechanical stirring for 15 to 60 minutes, preferably 30 to 45 minutes, even more preferably 45 minutes.

[0024] In step c), the mixing is carried out by stirring for 10 to 40 minutes, preferably 15 to 30 minutes, preferably 20 minutes.

[0025] In step d), each fraction is filled to volume with the co-solvent while stirring for 5 to 20 minutes, preferably 10 to 15 minutes, until it is completely homogenized.

[0026] Table 1 shows some of the formulations evaluated in this study, which were prepared according to the same guidelines: a) the step of dissolving the antioxidant, b) the step of dissolving the macrolide active ingredient, in this case tilebalosine tartrate, c) the step of equalizing the volume, and d) the step of adjusting the pH to the specified range, in this case 6.0 to 7.0.

[0027] [Table 1]

[0028] Various formulations were stored at 30°C and 40°C to determine their stability under these conditions. In this study, samples were analyzed using high-performance liquid chromatography (HCM) technology at baseline, 7 days, and 6 months. The results are shown in Table 2.

[0029] [Table 2]

[0030] As can be seen, formulations A, B, C, and D showed degradation of more than 10% relative to their initial tilebalosine tartrate content. Therefore, samples were re-analyzed 7 days after storage at 30°C and 40°C to examine the degradation trend and whether temperature is a significant factor. No significant correlation was found for formulations A and B; however, the effect of temperature on the formulation was observed in formulation D, while formulation C was shown to be the most unstable formulation with degradation of more than 60% from the start, and the percentage of tilebalosine was 4% and 0% when stored at 30°C and 40°C, respectively. Formulation E was the most stable from the initial analysis, indicating no degradation of the active ingredient during the manufacturing process. Six months after storage of samples at 30°C and 40°C, degradation of the active ingredient was minimal, and the obtained variability is considered to be within the range of a 2% standard deviation expected in the analytical method.

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