CN111840511A

CN111840511A - Composition of daptomycin or salt thereof containing arginine

Info

Publication number: CN111840511A
Application number: CN202010354655.4A
Authority: CN
Inventors: 鞠明珠; 韩江彬; 王捷
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd
Priority date: 2019-04-30
Filing date: 2020-04-29
Publication date: 2020-10-30

Abstract

The present disclosure provides a composition of daptomycin or a salt thereof that contains arginine. In particular, the mass ratio of daptomycin or salt thereof to arginine in the composition is 5:1 to 1:5, so that the composition has better stability and can improve the antibacterial curative effect.

Description

Composition of daptomycin or salt thereof containing arginine

Technical Field

The disclosure relates to the field of medicines, and provides a composition of daptomycin or salt thereof containing arginine and a preparation method thereof.

Background

Daptomycin is a cyclic lipopeptide antibiotic and has the following structure:

daptomycin is a cyclic lipopeptide antibiotic used in the treatment of infections of complex skin and skin structures and bacteremia. Daptomycin for injection can be administered intravenously, and the lyophilized powder needs to be reconstituted or reconstituted before use.

Daptomycin lyophilized powder for injection shows premature degradation during reconstitution, and the reconstituted daptomycin solution also shows degradation during short-term storage, so daptomycin is not suitable for long-term storage in a liquid form. The major degradants of daptomycin are daptomycin hydrolysates, the beta-isomer of daptomycin, and anhydro-daptomycin. The hydrolysis product (ring-opened compound) has a Relative Retention Time (RRT) of about 0.66, the beta-isomer of daptomycin at RRT of about 0.97, and anhydro daptomycin at RRT of about 1.1. Therefore, there is a need to develop more stable daptomycin compositions (formulations).

In order to improve the stability of daptomycin compositions, the prior art often adds at least one stabilizer, and the commonly used stabilizers include sugar stabilizers (lyoprotectants) such as lactose and sucrose, and buffering agents (such as citric acid-sodium citrate). Alternatively, the stability of daptomycin compositions is addressed by optimizing the formulation process.

WO2011063419 reports a solid daptomycin formulation containing glycine and a non-reducing sugar (e.g., sucrose, trehalose, or mannitol) as lyophilization protecting groups, which has certain stability and good reconstitution rate.

CN1616083A reports a lyophilized preparation of daptomycin containing pH adjusting agent (such as hydrochloric acid, sulfuric acid, acetic acid, lactic acid, methanesulfonic acid, phosphoric acid, citric acid or amino acid, etc.).

WO2013103801 reports the preparation of lyophilized formulations containing daptomycin and polyethylene glycol using a spray drying process.

CN104511011A reports a sterile powder containing daptomycin and a pH regulator, wherein the particle size of the daptomycin is 50-150 mu m. CN106943587 reports a freeze-dried powder injection containing daptomycin, a stabilizer and a buffer salt, wherein the stabilizer comprises glutathione or arginine. In the method, the daptomycin degradation pathway is mainly hydrolysis and oxidation, and therefore the method is solved from two aspects, namely, screening glutathione or arginine as a stabilizer, simultaneously carrying out deoxidation operation (such as nitrogen filling) on a liquid medicine, and considering that pH fluctuation is a factor causing product degradation, and controlling the pH of the solution by using citric acid-sodium citrate to further prevent the product degradation.

WO2011062676 reports a daptomycin composition containing a calcium source (e.g., calcium chloride and calcium lactate) wherein the daptomycin concentration is less than or equal to 25mg/ml, the pH is 6-7, and the total impurity growth is less than 10% after storage for at least 18 months at 5-25 ℃. The composition can be stored for a long period of time. It is believed that calcium ions bind to amino groups in daptomycin structures to stabilize daptomycin, and that a daptomycin composition containing calcium ions has superior stability compared to arginine, which has a weak stabilizing effect on daptomycin and is insufficient to obtain a stable formulation.

Disclosure of Invention

The disclosure provides a daptomycin composition containing arginine. Theoretically, the existence of arginine plays a role in stabilizing daptomycin, and can effectively inhibit daptomycin impurity A, impurity 1, dehydration impurity and beta isomer. The daptomycin composition exhibits excellent stability in a stability test, such as, for example, 2-8 ℃ for at least 3 months, at least 6 months, at least 12 months, at least 18 months, or at least 24 months.

Further, the mass ratio of daptomycin or salt thereof to arginine in the compositions described in this disclosure is 5:1 to 1: 5. In alternative embodiments, the mass ratio of daptomycin or salt thereof to arginine is any value in the range of 5:1 to 1:5, including but not limited to 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, and 1:5, preferably 5:4 to 4: 5.

Further, the pH of the composition also affects the stability of the composition, particularly at a pH of 4.0 to 6.0, the composition exhibits excellent stability, and affects the appearance and reconstitution time of the composition after conversion to a solid composition. In non-limiting embodiments, the PH can be 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, or any value in between, preferably 4.5 to 5.5.

In an alternative embodiment, the pH of the daptomycin or salt and arginine mixture may be adjusted using a pH adjusting agent. Agents used to adjust the pH include, but are not limited to, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, and the like.

"buffering agent" refers to a buffer that is resistant to pH changes through the action of its acid-base conjugate components, thereby providing a stable pH environment for the pharmaceutical composition, stabilizing the active. Examples of buffers to control the pH in the appropriate range include succinate, gluconate, histidine, oxalate, lactate, phosphate, citrate, tartrate, fumarate, glycylglycine and other organic acid buffers. Arginine in the compositions of the present disclosure will in some sense pair with a pH adjusting agent to stabilize the pH in the composition, but no additional buffering agent is included in the pharmaceutical compositions of the present disclosure. Avoiding the use of additional buffers (or buffers) presents advantages in terms of quality control of the composition, reduction of production costs and operability of the production process.

Further, provided in embodiments of the present disclosure is a composition of daptomycin or a salt thereof and arginine that does not contain citrate buffer.

Further, provided in embodiments of the present disclosure is a composition of daptomycin or salt thereof and arginine that does not contain a succinate buffer.

Further, provided in embodiments of the present disclosure is a composition of daptomycin or a salt thereof and arginine that does not contain a histidine buffer.

On the other hand, WO2011062676 reports that calcium ions can be combined with amino groups in daptomycin structures to stabilize daptomycin, compared with arginine, the daptomycin composition containing calcium ions has more excellent stability, and arginine has weak effect on daptomycin stabilization, so that a stable preparation cannot be obtained. In fact, the compositions of the present disclosure without calcium ions can still have excellent stability. Agents that provide calcium ions include, but are not limited to, gadolinium lactate, calcium carbonate, calcium hydroxide, and calcium chloride.

In alternative embodiments, the arginine-containing, calcium ion-free daptomycin composition is stable at 2-8 ℃ for at least 3 months, at least 6 months, at least 12 months, at least 18 months, or at least 24 months.

Still further, the compositions of the present disclosure do not contain sugar stabilizers, including but not limited to lactose or sucrose, among others.

Further, the compositions of the present disclosure do not contain non-reducing sugars, including but not limited to mannitol, glutathione, and the like.

In a preferred embodiment, the concentration of daptomycin or salt thereof in the compositions of the present disclosure is selected from the group consisting of 20-200 mg/ml, and in non-limiting examples may be 20mg/ml, 22mg/ml, 24mg/ml, 26mg/ml, 28mg/ml, 30mg/ml, 32mg/ml, 34mg/ml, 36mg/ml, 38mg/ml, 40mg/ml, 42mg/ml, 44mg/ml, 46mg/ml, 48mg/ml, 50mg/ml, 52mg/ml, 54mg/ml, 56mg/ml, 58mg/ml, 60mg/ml, 62mg/ml, 64mg/ml, 66mg/ml, 68mg/ml, 70mg/ml, 72mg/ml, 74mg/ml, 76mg/ml, 78mg/ml, 80mg/ml, 82mg/ml, 84mg/ml, 86mg/ml, 88mg/ml, 90mg/ml, 92mg/ml, 94mg/ml, 96mg/ml, 98mg/ml, 100mg/ml, 102mg/ml, 104mg/ml, 106mg/ml, 108mg/ml, 110mg/ml, 112mg/ml, 114mg/ml, 116mg/ml, 118mg/ml, 120mg/ml, 122mg/ml, 124mg/ml, 126mg/ml, 128mg/ml, 130mg/ml, 132mg/ml, 134mg/ml, 136mg/ml, 138mg/ml, 140mg/ml, 142mg/ml, 144mg/ml, 146mg/ml, 148mg/ml, 150mg/ml, 152mg/ml, B, 154mg/ml, 156mg/ml, 158mg/ml, 160mg/ml, 162mg/ml, 164mg/ml, 166mg/ml, 168mg/ml, 170mg/ml, 172mg/ml, 174mg/ml, 176mg/ml, 178mg/ml, 180mg/ml, 182mg/ml, 184mg/ml, 186mg/ml, 188mg/ml, 190mg/ml, 192mg/ml, 194mg/ml, 196mg/ml, 198mg/ml, 200mg/ml or any value therebetween.

In another aspect, in some embodiments, the pharmaceutical composition consists essentially of daptomycin or salt thereof and arginine, and further wherein the pharmaceutical composition or the composition, after reconstitution, has a pH of 4.0 to 6.0, e.g., 4.7. In some embodiments, no or substantially no other buffering agent is present in the pharmaceutical composition. In other embodiments, the pharmaceutical composition is free or substantially free of citrate buffer.

The present disclosure also provides a composition of daptomycin or salt thereof containing arginine that does not contain citrate buffer.

In alternative embodiments, the mass ratio of daptomycin or salt thereof to arginine is any value in the range of 5:1 to 1:5, including 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, and 1:5, preferably 5:4 to 4: 5.

Further, in alternative embodiments, the pH of the composition is any value within the range of 4.0 to 6.0, and may be 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, preferably 4.5 to 5.5.

Still further, in alternative embodiments, the composition may contain daptomycin or a salt thereof in an amount selected from the group consisting of 20 to 200mg/ml, and in non-limiting examples 20mg/ml, 22mg/ml, 24mg/ml, 26mg/ml, 28mg/ml, 30mg/ml, 32mg/ml, 34mg/ml, 36mg/ml, 38mg/ml, 40mg/ml, 42mg/ml, 44mg/ml, 46mg/ml, 48mg/ml, 50mg/ml, 52mg/ml, 54mg/ml, 56mg/ml, 58mg/ml, 60mg/ml, 62mg/ml, 64mg/ml, 66mg/ml, 68mg/ml, 70mg/ml, 72mg/ml, 74mg/ml, 76mg/ml, 78mg/ml, or a salt thereof, 80mg/ml, 82mg/ml, 84mg/ml, 86mg/ml, 88mg/ml, 90mg/ml, 92mg/ml, 94mg/ml, 96mg/ml, 98mg/ml, 100mg/ml, 102mg/ml, 104mg/ml, 106mg/ml, 108mg/ml, 110mg/ml, 112mg/ml, 114mg/ml, 116mg/ml, 118mg/ml, 120mg/ml, 122mg/ml, 124mg/ml, 126mg/ml, 128mg/ml, 130mg/ml, 132mg/ml, 134mg/ml, 136mg/ml, 138mg/ml, 140mg/ml, 142mg/ml, 144mg/ml, 146mg/ml, 148mg/ml, 150mg/ml, 152mg/ml, B, 154mg/ml, 156mg/ml, 158mg/ml, 160mg/ml, 162mg/ml, 164mg/ml, 166mg/ml, 168mg/ml, 170mg/ml, 172mg/ml, 174mg/ml, 176mg/ml, 178mg/ml, 180mg/ml, 182mg/ml, 184mg/ml, 186mg/ml, 188mg/ml, 190mg/ml, 192mg/ml, 194mg/ml, 196mg/ml, 198mg/ml, 200mg/ml or any value therebetween.

The present disclosure also provides a composition of daptomycin or salt thereof that contains arginine, which does not contain calcium ions.

The present disclosure also provides a composition of daptomycin or salt thereof that contains arginine, which does not contain a carbohydrate stabilizer.

The present disclosure also provides a composition of daptomycin or salt thereof containing arginine that does not contain non-reducing sugars, including but not limited to mannitol, glutathione, and the like.

Still further, in an alternative embodiment, the content of daptomycin or salt thereof in the composition is selected from the group consisting of 20 to 200 mg/ml. May be, in non-limiting examples, 20mg/ml, 22mg/ml, 24mg/ml, 26mg/ml, 28mg/ml, 30mg/ml, 32mg/ml, 34mg/ml, 36mg/ml, 38mg/ml, 40mg/ml, 42mg/ml, 44mg/ml, 46mg/ml, 48mg/ml, 50mg/ml, 52mg/ml, 54mg/ml, 56mg/ml, 58mg/ml, 60mg/ml, 62mg/ml, 64mg/ml, 66mg/ml, 68mg/ml, 70mg/ml, 72mg/ml, 74mg/ml, 76mg/ml, 78mg/ml, 80mg/ml, 82mg/ml, 84mg/ml, 86mg/ml, 88mg/ml, 90mg/ml, 92mg/ml, 94mg/ml, 96mg/ml, 98mg/ml, 100mg/ml, 102mg/ml, 104mg/ml, 106mg/ml, 108mg/ml, 110mg/ml, 112mg/ml, 114mg/ml, 116mg/ml, 118mg/ml, 120mg/ml, 122mg/ml, 124mg/ml, 126mg/ml, 128mg/ml, 130mg/ml, 132mg/ml, 134mg/ml, 136mg/ml, 138mg/ml, 140mg/ml, 142mg/ml, 144mg/ml, 146mg/ml, 148mg/ml, 150mg/ml, 152mg/ml, 154mg/ml, 156mg/ml, 158mg/ml, 160mg/ml, 162mg/ml, 164mg/ml, 166mg/ml, 168mg/ml, 170mg/ml, 172mg/ml, 174mg/ml, 176mg/ml, 178mg/ml, 180mg/ml, 182mg/ml, 184mg/ml, 186mg/ml, 188mg/ml, 190mg/ml, 192mg/ml, 194mg/ml, 196mg/ml, 198mg/ml, 200mg/ml or any value therebetween.

In another aspect, the present disclosure also provides a method of preparing the aforementioned composition, comprising the step of mixing daptomycin or a salt thereof with arginine.

Further, the method also comprises the step of adjusting the pH value, wherein the pH value is 4.0-6.0, and preferably 4.5-5.6.

In some embodiments, the compositions of the present disclosure are stable at 2-8 ℃ for at least 3 months, at least 6 months, at least 12 months, at least 18 months, or at least 24 months.

In some embodiments, the compositions of the present disclosure are stable at 40 ℃/75% RH for at least 7 days, at least 14 days, or at least 28 days.

In another aspect, the present disclosure also provides a solid composition obtained by transforming the aforementioned composition, or the aforementioned composition can be obtained by re-dissolving the solid composition in a liquid medium, wherein the liquid medium used for re-dissolving is preferably water.

In some embodiments, the transformation mode is selected from, but not limited to, freeze drying, vacuum drying, or spray drying.

The present disclosure also provides a liquid formulation obtained by reconstituting or reconstituting the aforementioned solid composition.

The present disclosure also provides a method of preparing the aforementioned liquid formulation, comprising the step of reconstituting or reconstituting the aforementioned pharmaceutical composition.

The liquid medium used for reconstitution or reconstitution in the present disclosure is selected from, but not limited to, water for injection and physiological saline.

The present invention further provides an article comprising a composition comprising any of the stabilized compositions described herein and a solvent for reconstitution or reconstitution of the composition.

Term(s) for

By "composition" is meant a composition containing one or more daptomycin or salt thereof as described herein in admixture with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity. As used herein, a "composition" and a "formulation" are not mutually exclusive. A "histidine buffer" is a buffer comprising histidine ions. Examples of histidine buffers include histidine-hydrochloride, histidine-acetate, histidine-phosphate, histidine-sulfate and like buffers, preferably histidine-hydrochloride buffer. The histidine-hydrochloride buffer solution is prepared by histidine and hydrochloric acid or histidine and histidine hydrochloride.

A "citrate buffer" is a buffer that includes citrate ions. Examples of citrate buffers include citric acid-sodium citrate, citric acid-potassium citrate, citric acid-calcium citrate, citric acid-magnesium citrate, and the like. The preferred citrate buffer is a citric acid-sodium citrate buffer.

A "succinate buffer" is a buffer comprising succinate ions. Examples of succinate buffers include succinic acid-sodium succinate, succinic acid-potassium succinate, succinic acid-calcium succinate, and the like. The preferred succinate buffer is a succinic acid-sodium succinate buffer.

A "phosphate buffer" is a buffer comprising phosphate ions. Examples of the phosphate buffer include disodium hydrogenphosphate-sodium dihydrogenphosphate, disodium hydrogenphosphate-potassium dihydrogenphosphate, and the like. The preferred phosphate buffer is disodium hydrogen phosphate-sodium dihydrogen phosphate buffer.

A "citrate buffer" is a buffer comprising citrate ions. Examples of citrate buffers include citric acid-sodium citrate, citric acid-potassium citrate, and the like. The preferred citrate buffer is citric acid-sodium citrate.

"about" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. In the context of a particular assay, result, or embodiment, "about" means within one standard deviation, or a range of up to 5%, according to common practice in the art, unless explicitly stated otherwise in the examples or elsewhere in the specification. In addition, the numerical values in the disclosure are measured values of instruments, and have a certain degree of error, and generally, plus or minus 10% of the numerical values belong to a reasonable error range. It will of course be appreciated that the context in which the value is used, for example the pH of the composition, is such that the error does not vary by more than plus or minus 10%, and may be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.

The present disclosure "free" means substantially free, i.e., substantially free or free of an amount of an adjuvant such as calcium ions, sufficient to provide improved stability or improved reconstitution time or improved appearance, morphology, etc. of the composition. The stabilized composition was such that no significant change was observed under the following conditions: stored at refrigeration temperatures (2-8 ℃) for at least 3 months, preferably 6 months, more preferably 1 year, and even more preferably up to 2 years. In addition, stable liquid formulations include liquid formulations that: which exhibits a desired profile after a period of time including storage at 25 ℃ for 1 month, 3 months, 6 months, or storage at 40 ℃ for 1 month. Typical acceptable criteria for stability are as follows: typically no more than about 10%, preferably no more than about 5%, of daptomycin is degraded as measured by HPLC. The composition was colorless by visual analysis. The concentration, pH of the composition or liquid formulation has no more than ± 10% variation.

Detailed Description

The present disclosure is further illustrated in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure. Experimental procedures, where specific conditions are not noted in the examples of the disclosure, are generally in accordance with conventional conditions favorable to production or in accordance with conditions recommended by the manufacturer of the raw materials or goods. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.

Example 1

Daptomycin (DPT) was dissolved in water to obtain a 150mg/mL solution, different types of stabilizers were added according to the prescription in Table 1 to dissolve, and then the volume was determined to obtain 100mg/mL daptomycin solutions, during which the pH was adjusted with 1N sodium hydroxide solution or acetic acid to obtain the pH shown in Table 1 below. Freeze drying (5.0-50 deg.c, pre-freeze drying for 12 hr, drying at-25-40.0 deg.c and 12.0Pa for 24 hr) to obtain freeze dried daptomycin powder for injection. The samples were stored under the conditions shown in Table 1 below

The aforementioned samples were tested by HPLC at a wavelength of 223nm for sample related substances after initial preparation, and for the times shown in table 1 below. Specific data are shown in Table 1

TABLE 1

Note: a daptomycin solution; b test results of samples left at 40 ℃ for 30 days; c acceleration conditions were 40 ℃/75% RH.

And (4) conclusion: compared with other auxiliary materials, the composition containing arginine has shorter redissolution time, and the freeze-dried substance has loose appearance and does not cake when observed by naked eyes. On the other hand, the composition containing calcium ions has a longer reconstitution time, and bubbles in the bottom powder may be released and attached to the powder surface, so that the powder cannot be moistened, and a large insoluble powder lump may be formed locally.

Example 2

1. 200mg of glutathione is weighed and dissolved, 21.875mg of citric acid and 22.79mg of trisodium citrate are dissolved in 12mL of water, 2.1g of daptomycin is added, the volume is adjusted to 20mL, and the solution of daptomycin with the pH value of 3.97 is obtained.

2. 100mg of arginine, 8.75mg of citric acid and 13.67mg of trisodium citrate are weighed and dissolved in 12mL of water, 2.1g of daptomycin is added, and the volume is adjusted to 20mL, so that a daptomycin solution with the pH value of 4.61 is obtained.

3. 80mg of glutathione is weighed and dissolved, 17.5mg of citric acid and 13.67mg of trisodium citrate are dissolved in 16mL of water, 2.1g of daptomycin is added, and the volume is fixed to 20mL, so that a daptomycin solution with the pH value of 4.02 is obtained.

The aforementioned samples were tested by HPLC at a wavelength of 223nm for sample related substances after initial preparation, and for the times shown in table 2 below. Specific data are shown in Table 2

TABLE 2

Note: 10% of daptomycin, and if the auxiliary material is 1%, the ratio of the daptomycin to the auxiliary material in the composition is 10: 1.

Example 3

Weighing 10g of Daptomycin (DPT), respectively adding an L-arginine solution (preparing a solution according to the amount of the auxiliary materials in the table 3), stirring for dissolving, adjusting the pH, and freeze-drying (5.0-50 ℃, pre-freeze-drying for 12 h; 25-40.0 ℃, 12.0Pa, drying for 24h) to obtain the daptomycin freeze-dried powder injection.

And (3) placing the sample under the condition of 40 ℃/75% RH, detecting related substance data, and inspecting the stability condition of the sample:

TABLE 3

Note: 10% of daptomycin, if 3% of auxiliary material, the ratio of the two in the composition is 10: 3.

Example 4:

4.34g Daptomycin (DPT) was dissolved in 23mL of water, and then an L-arginine solution (prepared according to the prescription in Table 4) was added, and 2N acetic acid was used to adjust the pH of the solution to 4.7 and the volume to 20mL for use.

And (3) carrying out spray drying (spray drying parameters: inlet/outlet air temperature is 120-.

The aforementioned samples were tested by HPLC at a wavelength of 223nm for sample related substances after initial preparation, and for the times shown in table 4 below. The specific data are shown in Table 4

TABLE 4

Note: 10% of daptomycin, and if the auxiliary material is 8%, the ratio of the daptomycin to the auxiliary material in the composition is 5: 4.

Example 5

12g of Daptomycin (DPT) was dissolved in water, arginine solution (arginine or sucrose solutions of different concentrations were prepared according to the prescription in Table 4) was added, and respective volumes were determined to obtain daptomycin solutions, during which the pH was adjusted with acetic acid to obtain the pH shown in Table 5 below. Freeze drying (5.0-50 deg.c, pre-freeze drying for 12 hr, drying at-25-40.0 deg.c and 12.0Pa for 24 hr) to obtain freeze dried daptomycin powder for injection. The samples were stored under the conditions shown in Table 4 below

The aforementioned samples were tested by HPLC at a wavelength of 223nm for sample related substances after initial preparation, and for the times shown in table 4 below. The specific data are shown in Table 5

TABLE 5

Example 6

Weighing 10g of Daptomycin (DPT), respectively adding an L-arginine solution, a histidine solution and a proline solution (preparing solutions according to the amount of the auxiliary materials in the table 6), stirring for dissolving, adjusting the pH value to obtain compositions with different pH values, and freeze-drying (5.0-50 ℃, pre-freeze-drying for 12 hours; 25-40.0 ℃, 12.0Pa, drying for 24 hours) to obtain the daptomycin freeze-dried powder injection.

TABLE 6

Note: and (3) acceleration conditions: 40 ℃/75% RH, 10% daptomycin, if the auxiliary material is 8%, the ratio of the two in the composition is 5: 4.

And (4) conclusion: compared with histidine and proline, the pharmaceutical composition containing arginine has more excellent stability, the growth of related substances is within a controllable range, particularly the pH is lower than 5.5, after the pharmaceutical composition containing 8% of arginine is placed for 1 month in an accelerated way, the related substances are lower than 0.5%, and the pharmaceutical composition meets the Chinese medicine quality standard.

Example 7

Weighing 10g of Daptomycin (DPT), respectively adding an L-arginine solution and a sucrose solution (preparing the solutions according to the amount of the auxiliary materials in the table 7), stirring for dissolving, adjusting the pH, and freeze-drying (5.0-50 ℃, pre-freeze-drying for 12h, drying for 24h, at-25-40.0 ℃ and 12.0 Pa) to obtain the daptomycin freeze-dried powder injection.

Placing the sample under the condition of 25 ℃/60% RH, detecting related substance data, and inspecting the stability condition of the sample:

TABLE 7

Note: the dehydration impurities are not detected, the daptomycin accounts for 10 percent, if the auxiliary material accounts for 8 percent, the ratio of the daptomycin to the auxiliary material in the composition is 5: 4.

And (4) conclusion: the arginine-containing composition has substantially equivalent long-term stability to the sucrose-containing composition without substantial difference, but the production of major daptomycin impurities (such as impurity A, impurity 1 and beta-isomer) in the arginine-containing composition is obviously inhibited, so that the quality-controlled pharmaceutical composition is obtained, and the storage condition of the composition is milder.

Claims

1. A composition comprising daptomycin or a salt thereof and arginine, wherein the mass ratio of daptomycin or salt thereof to arginine is 5:1 to 1:5, preferably 5:4 to 4:5, such as 5:3, 5:4 or 1: 1.

2. A composition according to claim 1, wherein the pH is 4.0-6.0, preferably 4.5-5.5, such as 4.7.

3. A composition according to claim 1 or 2, wherein no citrate buffer is present.

4. A composition as claimed in any one of claims 1 to 3, which is free of calcium ions.

5. The composition of any one of claims 1-4, wherein no saccharide stabilizer is present.

6. The composition according to any one of claims 1-5, wherein the concentration of daptomycin or salt thereof is selected from the group consisting of 20-200 mg/ml.

7. A pharmaceutical composition consisting essentially of daptomycin or salt thereof and arginine, further wherein the pharmaceutical composition or the composition after reconstitution has a pH of 4.0 to 6.0, preferably 4.5 to 5.5, e.g., 4.7.

8. The composition of any one of claims 1-7, which is in liquid form.

9. A method of making the composition of any one of claims 1-8, comprising the step of mixing daptomycin or salt thereof with arginine.

10. The method of claim 9, further comprising the step of adjusting the pH to a value of 4.0-6.0, preferably 4.5-5.5, such as 4.7.

11. A solid composition obtained by conversion of a composition according to any one of claims 1 to 10, preferably by means of a conversion selected from freeze drying, vacuum drying or spray drying; or the solid composition is reconstituted in a liquid medium, preferably water, to obtain a composition according to any one of claims 1 to 10.

12. A liquid formulation obtained by reconstitution or reconstitution of the solid composition of claim 11.

13. A process for preparing a liquid formulation according to claim 12, comprising the step of reconstituting or reconstituting a solid composition according to claim 11.