EA036750B1 - Freeze dried parenteral composition of tigecycline and process for preparation thereof - Google Patents

Abstract

A stable, freeze dried pharmaceutical composition comprising tigecycline along with sulfobutyl ether betacyclodextrin sodium as stabilizing agent for parenteral administration. The pharmaceutical composition provides stabilization of tigecycline thereby improving the shelf life during storage. The invention further discloses a process of preparation of said composition.

Description

The technical field to which the invention relates

The present invention relates to a stable lyophilized pharmaceutical composition of tigecycline in combination with a suitable stabilizing agent and acidulant for parenteral administration. The pharmaceutical composition stabilizes the tigecycline, thereby increasing shelf life during the storage period. The invention further relates to a method for preparing this composition.

State of the art

Tigecycline, a minocycline derivative that has been modified to overcome tetracycline resistance, is the first antibiotic in a new class of glycylcycline and has a broad spectrum of action. It is active in vitro against a wide range of gram-positive and gram-negative bacteria, anaerobes, atypical bacteria, as well as against many types of drug-resistant strains [e.g. vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus (MRSillin), penicillin -resistant Streptococcus pneumoniae and multidrug-resistant (MDR) Acinetobacter baumannii]. Similarly to tetracyclines, tigecycline inhibits protein translation by reversibly binding to the 30S subunit of the bacterial ribosome, which interferes with the synthesis of amino acids. Despite the fact that the ribosomal binding sites of tigecycline are similar to those for tetracycline, tigecycline binds five times more efficiently than tetracyclines. This allows tigecycline to overcome the common ribosomal defense mechanisms associated with tetracyclines resistance. Due to its long side chain, which blocks binding to most efflux proteins and transporters, tigecycline also overcomes the efflux mechanism of tetracyclines resistance. In particular, since the discovery of New Delhi-1 metallo-β-lactamase (NDM-1) in gram-negative bacteria, which had high resistance to all antibiotics except tigecycline and colistin, tigecycline has received great attention, and it was also considered as the last hope for antibiotic-resistant bacteria (International Journal of Antimicrobial Agents 41 (2013) 110-116).

The first tetracycline antibiotics were discovered more than 50 years ago and offered significant benefits for the treatment of many infections caused by gram-positive and gram-negative bacteria. However, after their widespread use in the beginning, the high incidence of tetracyclines resistance in many bacteria has led to tetracyclines being classified as second- or third-line therapy.

In an attempt to restore the potential of tetracyclines as broad-spectrum antibiotics in the early 1990s. a systematic search was carried out for tetracycline analogues that would have activity against both tetracycline-sensitive and tetracycline-resistant microorganisms. These attempts have led to the discovery of glycylcycline including tigecycline (Nature Reviews Drug Discovery 4, 809-810 (October 2005).

Tigecycline is a tetracycline derivative (glycylcycline) for intravenous infusion. The chemical name of tigecycline is (4S, 4aS, 5aR, 12aS) -9- [2- (tertbutylamino) acetamido] -4,7-bis (dimethylamino) -1,4,4а, 5,5а, 6,11,12а -octahydro-3,10,12,12а-tetrahydroxy-1,11-dioxo-2-naphthacene carboxamide. The empirical formula is C ₂₉ H ₃₉ N ₅ O ₈ and the molecular weight is 585.65 g / mol. Tigecycline is an orange, light-sensitive, hygroscopic powder that dissolves easily in water and isotonic sodium chloride solution (Daily Med). The structural chemical formula of tigecycline is demonstrated further

Tigecycline is available as a lyophilized intravenous infusion formulation by Wyeth Pharmaceuticals Inc. of Pfizer Inc. under the tradename Tigacil® (Tygacil®). The use of tigecycline is indicated for the treatment of patients aged 18 years and older who have: complicated infections of the skin and soft tissues, complicated intra-abdominal infections and community-acquired bacterial pneumonia.

Currently available tigecycline formulations are in lyophilized form in a vial containing lactose monohydrate as a stabilizing agent, which does not provide the desired stability due to the sensitivity of tigecycline to environmental factors.

In addition, tigecycline is unstable to light, heat, humidity, acids, etc. in general and forms a degradation product of the tigecycline epimer, therefore, there is a need to develop a pharmaceutical composition that stabilizes the active compound and its salt, for parenteral administration.

In view of the unstable nature of tigecycline and the resulting problems in the preparation of a lyophilized preparation for parenteral administration, as previously indicated, the present inventors felt the need to develop a stable tigecycline composition for injection with a suitable stabilizing agent that will reduce degradation of the active ingredient and increase the shelf life of the composition.

Indian Patent No. 268331 discloses a stable pharmaceutical composition of tigecycline in lyophilized form comprising lactose as a stabilizing agent. IN '331 further discloses that suitable carbohydrates stabilize tigecycline against epimer formation at acidic pH. Examples of suitable carbohydrates include anhydrous, hydrated and solvated forms of mono- and disaccharides selected from aldose monosaccharide or disaccharide such as lactose, mannose, sucrose and glucose; preferably such as lactose and sucrose. Lactose is most preferred.

Commercially available Tigecycline formulations and compositions known in the art contain a higher percentage of impurities in the form of degradation products, which include an impurity of the tigecycline epimer.

To overcome the previously mentioned problem, there is a need in the art to provide an improved / stable lyophilized tigecycline composition that can reduce the formation of tigecycline epimers and other oxidative degradation impurities, providing drug stability over extended shelf life.

The above object is achieved by the present invention by providing a stable lyophilized pharmaceutical composition comprising tigecycline and a suitable stabilizing agent that reduces the formation of tigecycline epimer and other degradation products while increasing the shelf life of the composition.

The essence of the invention

According to the above, the present invention provides a stable lyophilized pharmaceutical composition for parenteral administration, comprising: a) tigecycline or pharmaceutically acceptable salts thereof in an amount of 50 to 200 mg; b) sodium β-cyclodextrin sulfobutyl ester as a stabilizing agent in an amount of 1000 to 4000 mg; and c) hydrochloric acid for adjusting the pH in the range from 4.5 to 7.0.

In the present invention, the stabilization of tigecycline is achieved by the addition of stabilizing agents selected from cyclodextrin derivatives, in particular sodium β-cyclodextrin sulfobutyl ester.

In this aspect, a pharmaceutical composition of tigecycline and a stabilizing agent is lyophilized and provided as a drug concentrate.

In another aspect, the present invention provides a method for preparing a stable lyophilized pharmaceutical composition of tigecycline, comprising combining an aqueous solution of tigecycline or its pharmaceutically acceptable salts with sodium β-cyclodextrin sulfobutyl ester, adjusting the pH in the range from 4.5 to 7.0 with an HCl solution, and lyophilizing to obtaining a lyophilized tigecycline composition.

Detailed description of the invention

Hereinafter, the present invention will be described in detail in connection with some preferred and optional embodiments, so that their various aspects may be fully understood and obvious.

The present invention discloses a stable, lyophilized pharmaceutical composition for parenteral administration comprising tigecycline or a pharmaceutically acceptable salt thereof as an active ingredient in combination with a stabilizing agent and an acidulant. The composition provides stabilization of tigecycline with low degradation of the active ingredient, thus increasing the shelf life of the composition during the storage period and equally reducing the formation of tigecycline epimers.

Accordingly, in a preferred embodiment, the present invention provides a stable, lyophilized pharmaceutical composition for parenteral administration, comprising:

i) tigecycline or a pharmaceutically acceptable salt thereof; and ii) a stabilizing agent selected from cyclodextrin derivatives, wherein the pH of the composition is maintained in the range from 4.5 to 7.0 using an acidulant.

Tigecycline or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 1 to 200 mg per vial; more preferably 50 mg per vial and 150 mg per vial.

Stabilization of tigecycline is ensured by the use of a suitable stabilizing agent,

- 2 036750 where tigecycline can be kept dissolved in aqueous solution, thus preventing crystallization or slowing the rate of crystallization of tigecycline. The stabilizing agent is selected from cyclodextrin derivatives, preferably sodium β-cyclodextrin sulfobutyl ester.

The composition of the present invention includes sodium β-cyclodextrin sulfobutyl ester as a stabilizing agent in an amount of 100 to 4000 mg, preferably 100 to 2000 mg, more preferably 100 to 1500 mg.

The pH of the composition is maintained within the range of 4.5 to 7 using an acidulant such as dilute hydrochloric acid solution.

In an embodiment, the present invention discloses a stable, lyophilized pharmaceutical composition for parenteral administration, comprising:

a) tigecycline or its pharmaceutically acceptable salts in an amount of 1 to 200 mg per vial;

b) a stabilizing agent such as sodium β-cyclodextrin sulfobutyl ester in an amount of 100 to 4000 mg, and

c) an acidifying agent such as dilute hydrochloric acid solution to adjust the pH in the range from 4.5 to 7.0.

In another embodiment, the present invention provides a stable, lyophilized pharmaceutical composition comprising:

a) tigecycline or its pharmaceutically acceptable salts in an amount of 50 mg per vial;

b) sulfobutyl ester β-cyclodextrin sodium in an amount of 1000 mg and

c) a solution of dilute hydrochloric acid for adjusting the pH in the range from 4.5 to 7.0.

In another embodiment, the present invention provides a stable, lyophilized pharmaceutical composition comprising:

a) tigecycline or its pharmaceutically acceptable salts in an amount of 150 mg per vial;

b) sodium sulfobutyl ester β-cyclodextrin in an amount of 3000 mg, and

c) a solution of dilute hydrochloric acid for adjusting the pH in the range from 4.5 to 7.0.

The composition of the present invention, after lyophilization, is chemically and physically stable over a long period of time and is suitable for its intended pharmaceutical use after reconstitution with sodium chloride injection or 5% dextrose injection. The lyophilization process includes cooling the desired composition at a suitable temperature of at least -45 ° C, increasing the temperature to 0 ° C at a suitable pressure from 150 to 100 m Torr in 35 hours, then at 50 mTorr, then increasing the temperature to + 35 ° C in 15 h.

Lyophilized tigecycline, when diluted with 5 ml of a suitable diluent, contains the final drug concentrate at 10 mg / ml.

In another embodiment, the pharmaceutical composition of the invention described herein is a lyophilized composition that can also be prepared by dissolving tigecycline first in an aqueous solvent containing a stabilizing agent, then filtering the solution and filling it into a 10 ml glass vial.

With the development of the lyophilization process for this composition, the lyophilized drug can be reconstituted with suitable diluents prior to administration as an intravenous injection. The final concentration of the solution can be reduced further to the desired level prior to administration to the patient using a 5% dextrose solution for infusion.

The pharmaceutical composition of the present invention is useful for the treatment of various infections caused by gram-positive and gram-negative bacteria, such as complicated skin and soft tissue infections, complicated intra-abdominal infections, and community-acquired bacterial pneumonia.

The pharmaceutical compositions of the present invention are administered to a patient according to a regimen. It should be understood that the particular dosage regimen for any particular patient will depend on many factors, including age, weight, general health, gender, diet, time of administration, the particular disease being treated, and the severity of the condition, among other factors, and from the decision of the attending physician.

Industrial advantages

1. A pharmaceutical composition containing tigecycline as an active substance and sodium β-cyclodextrin sulfobutyl ester, without compromising the stability of the drug or its solution, before lyophilization has a pH between 4.5 and 7.0.

2. The composition is stable during the entire shelf life.

Other properties and embodiments of the invention will become apparent from the following examples, which are given to illustrate the invention rather than limit its intended scope. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art.

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Example 1.

P / p No. Ingredient Function number one . Tigecycline or its pharmaceutically acceptable salts Active ingredient 1 mg to 200 mg 2. Sulfobutyl ether beta cyclodextrin sodium Stabilizing means 100 mg to 4000 mg 3. Diluted solution PH regulator how many required (for

of hydrochloric acid pH correction between 4.5 and 7.0) 4 . Water for injection Solvent how many required

Example 2.

P / p No. Ingredient Function number one . Tigecycline or its pharmaceutically acceptable salts Active ingredient 50 mg 2. Sulfobutyl ether beta cyclodextrin sodium Stabilizing means 1000 mg 3. Diluted hydrochloric acid solution PH regulator How much is required (for pH correction between 4.5 and 7.0) 4 . Water for injection Solvent how many required

Example 3.

P / p No. Ingredient Function number one . Tigecycline or its pharmaceutically acceptable salts Active ingredient 150 mg 2. Sulfobutyl ether beta cyclodextrin sodium Stabilizing means 3000 mg 3. Diluted solution PH regulator how many required

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of hydrochloric acid (for pH correction between 4.5 and 7.0) 4 . Water for injection Solvent how many required

A method of preparing the compositions of examples 1-3.

a) Dissolving tigecycline or its pharmaceutically acceptable salts in an aqueous solvent containing sodium β-cyclodextrin sulfobutyl ester, and

b) adjusting the pH of the composition with a dilute hydrochloric acid solution in the range of 4.5 to 7.0, followed by lyophilization.

Experimental part.

Various studies were conducted and analyzed prior to narrowing to the present composition. These studies are briefly discussed below to emphasize the inventiveness of the present invention, and the analysis was performed as for the United States Pharmacopoeia (USP) 38.

Example 4.

1.0 g of tigecycline (active substance) or a pharmaceutically acceptable salt thereof is added to an aqueous solution containing 2.0 g of sodium β-cyclodextrin sulfobutyl ester and stirred for a while. The pH is adjusted to approximately 5.45 with 1.0 N HCl solution (pH range 4.5 to 7.0). The solution is filtered and the resulting solution is distributed into 20 vials (10 ml), each of which contains 2.5 ml of solution. The solution in each vial is lyophilized using a lyophilizer according to a standard method, thus obtaining lyophilized compositions, each containing 50 mg of tigecycline. The resulting lyophilized composition is stored at different storage temperatures for different periods of time, the contents of the tigecycline are examined. The result is presented in table. 1 further.

Table 1

Period Analysis (%) ph Epimer tigecycline line (%) Straightforward to her (%) Temper atura is stored in the Colour Original Non-dispensed nth solution 99.07 5.45 0.61 0.79 2-8 ° C Transparent orange solution Oven lyophilizer 99.01 * 5.36 0.62 0.88 25 ° C Lyofiliziro bathroom tablet orange colors After 24 hours 98.65 - 0.92 1.23 70 ° C Lyofiliziro bathroom tablet orange colors

* Dilution of 5 ml of 0.9% sodium chloride solution.

Example 5.

1.0 g of tigecycline (active substance) or a pharmaceutically acceptable salt thereof is added to an aqueous solution containing 5.0 g of sodium β-cyclodextrin sulfobutyl ester and stirred for a while. The pH is adjusted to approximately 5.4 5 with 1.0 N HCl solution (pH range 4.5 to 7.0). The solution is filtered and the resulting solution is distributed into 20 vials (10 ml), each of which contains 2.5 ml of solution. The solution in each vial is lyophilized using a lyophilizer according to a standard method, thus obtaining lyophilized compositions, each containing 50 mg of tigecycline. The resulting lyophilized composition is stored at different storage temperatures for different periods of time, the contents of the tigecycline are examined. The result is presented in table. 2 further.

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table 2

Period Analysis (%) pH Epimer tigetsi wedge Take this all Tempe rathur a Colour

(%) (%) storage

(%) (%) keep NIJ Original Bulk solution 99.17 5.45 0.61 0.89 2-8 ° C Transparent orange solution Lyophilized 99.08 * 5.36 0.60 0.92 25 ° C Lyophilized orange tablet After 24 hours 98.85 - 0.77 1.09 7 0 ° C Lyophilized orange tablet

* Dilution of 5 ml of 0.9% sodium chloride solution.

Example 6.

1.0 g of tigecycline (active substance) or a pharmaceutically acceptable salt thereof is added to an aqueous solution containing 10.0 g of sodium β-cyclodextrin sulfobutyl ester and stirred for a while. The pH is adjusted to approximately 5.45 with 1.0 N HCl solution (pH range 4.5 to 7.0). The solution is filtered and the resulting solution is distributed into 20 vials (10 ml), each of which contains 5.0 ml of solution. The solution in each vial is lyophilized using a lyophilizer according to a standard method, thus obtaining lyophilized compositions, each containing 50 mg of tigecycline. The resulting lyophilized composition is stored at different storage temperatures for different periods of time, the contents of the tigecycline are examined. The result is presented in table. 3 further.

Table 3

Period Analysis (%) pH Epimer tigecycline (%) Admixture to her total (%) Storage temperature Colour

Outgoing Bulk solution 99.31 5.45 0.53 0.65 2-8 ° C Transparent orange solution Freeze-dried 99.23 * 5.35 0.53 0.69 25 ° C Lyophilized orange tablet After 24 hours 99.14 - 0.60 0.80 70 ° C Lyophilized orange tablet

* Dilution of 5 ml of 0.9% sodium chloride solution.

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Example 7.

1.0 g of tigecycline (active substance) or a pharmaceutically acceptable salt thereof is added to an aqueous solution containing 15.0 g of sodium β-cyclodextrin sulfobutyl ester and stirred for a while. The pH is adjusted to approximately 5.45 with 1.0 N HCl solution (pH range 4.5 to 7.0). The solution is filtered and the resulting solution is distributed into 20 vials (10 ml), each of which contains 5.0 ml of solution. The solution in each vial is lyophilized using a lyophilizer according to a standard method, thus obtaining lyophilized compositions, each containing 50 mg of tigecycline. The resulting lyophilized composition is stored at different storage temperatures for different periods of time, the contents of the tigecycline are examined. The result is presented in table. 4 further.

Table 4

Period An al i z (%) pH Epimer tigeci wedge (%) Take this all (%) Tempe rathur a keep NIJ Colour Original Bulk 99.34 5.45 0.54 0.72 2-8 ° C Clear solution

solution orange colors Lyophilized 99.21 * 5.34 0.57 0.75 25 ° C Lyophilized orange tablet After 24 hours 99.16 - 0.62 0.79 70 ° C Lyophilized orange tablet

* Dilution of 5 ml of 0.9% sodium chloride solution.

Example 8.

1.0 g of tigecycline (active substance) or a pharmaceutically acceptable salt thereof is added to an aqueous solution containing 20.0 g of sodium β-cyclodextrin sulfobutyl ester and stirred for a while. The pH is adjusted to approximately 5.4 5 with 1.0 N HCl solution (pH range 4.5 to 7.0). The solution is filtered and the resulting solution is distributed into 20 vials (10 ml), each of which contains 5.0 ml of solution. The solution in each vial is lyophilized using a lyophilizer according to a standard method, thus obtaining lyophilized compositions, each containing 50 mg of tigecycline. The resulting lyophilized composition is stored at different storage temperatures for different periods of time, the contents of the tigecycline are examined. The result is presented in table. 5 further.

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Table 5

Analyzes Initially After 24 After 15 Across Nerasfasov Lyophilizer hours days 40 anny oval (storage (storage days solution (storage at 7 0 ° C) at (store (storage at 25 ° C) 40 ° C / 70% nie at 2-8 ° C) relative at new 40 ° C / 70 humidity % RH)

(OV)) Colour Transparent orange solution Lyophilized orange tablet Lyophilized orange tablet Freeze-dried orange tablet Lyophilic isirovna orange tablet pH (limitation: 4.5 to 5.5) 5.45 * 5.26 % Analysis (limit: 96.0 to 116.0%) 99, 53 99, 48 99.42 99, 31 98.87 Impurities Open ring tigecycline (limit: no more than 0.15%) 12-oxo-I- hydroxy- tigecycline (limitation: no more than 0.5%) 0.02 0.04 Concomitant impurity B tigecycline (limitation: no more than 0.7%) 0.02 0.05 Epimer of tigecycline 0, 48 0.49 0.51 0.55 0.79

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(limitation: no more than 2.0%) Quinone analogue of tigecycline (limitation: no more than 0.3%) Minocycline - - - 0, 06 0.09 Tricyclic analogue of tigecycline (limit: no more than 0.5%) Any single unidentified degradation product (limitation: no more than 0.2%) - 0.02 0.02 0.03 0.04 Degradation products in total (limitation: no more than 6.0%) 0, 48 0.51 0.53 0, 69 1.01

* Dilution of 5 ml of 0.9% sodium chloride solution.

In the previous examples, it can be observed that a composition comprising tigecycline and sodium β-cyclodextrin sulfobutyl ester exhibits good stability with less impurities after 40 days (Example 8).

Example 9.

3.0 g of tigecycline (active substance) or a pharmaceutically acceptable salt thereof is added to an aqueous solution containing 60.0 g of sodium β-cyclodextrin sulfobutyl ester and stirred for a while. The pH is adjusted to approximately 5.45 with 1.0 N HCl solution (pH range 4.5 to 7.0). The solution is filtered and the resulting solution is distributed into 20 vials (30 ml), each of which contains 15.0 ml of solution. The solution in each vial is lyophilized using a lyophilizer according to a standard method, thus obtaining lyophilized compositions, each containing 150 mg of tigecycline. The resulting lyophilized composition is stored at different storage temperatures for different periods of time, the contents of the tigecycline are examined.

Claims (4)

CLAIM 1. Stable lyophilized pharmaceutical composition for parenteral administration, including: a) tigecycline or its pharmaceutically acceptable salts in an amount of from 50 to 200 mg; - 9 036750 b) sodium β-cyclodextrin sulfobutyl ester as a stabilizing agent in an amount of 1000 to 4000 mg, and c) hydrochloric acid to adjust the pH in the range from 4.5 to 7.0. 2. A stable, lyophilized pharmaceutical composition according to claim 1, wherein the composition comprises: a) tigecycline or its pharmaceutically acceptable salts in an amount of 50 mg; b) sulfobutyl ester β-cyclodextrin sodium in an amount of 1000 mg and c) hydrochloric acid to adjust the pH in the range from 4.5 to 7.0. 3. A stable, lyophilized pharmaceutical composition according to claim 1, wherein the composition comprises: a) tigecycline or its pharmaceutically acceptable salts in an amount of 150 mg; b) sodium sulfobutyl ester β-cyclodextrin in an amount of 3000 mg, and c) hydrochloric acid to adjust the pH in the range from 4.5 to 7.0. 4. A method of obtaining a stable lyophilized pharmaceutical composition of tigecycline according to claim 1, comprising combining an aqueous solution of tigecycline or its pharmaceutically acceptable salts with sodium β-cyclodextrin sulfobutyl ether, adjusting the pH in the range from 4.5 to 7.0 using an HCl solution and lyophilizing to obtain a lyophilized tigecycline composition.