Pharmaceutical compositions containing high concentrations of opiranserin

Abstract

A pharmaceutical composition containing high concentrations of opiranserin is disclosed. More specifically, the pharmaceutical composition contains opiranserin or a pharmaceutically acceptable salt thereof, a carrier selected from sodium benzoate, trisodium citrate, sodium salicylate, and mixtures thereof, and an injectable solvent.

Description

[Technical Field]

[0001] The present invention discloses a pharmaceutical composition containing high concentrations of opiranserin. More specifically, the pharmaceutical composition comprises opiranserin or a pharmaceutically acceptable salt thereof, a carrier selected from sodium benzoate, trisodium citrate, sodium salicylate, and mixtures thereof, and an injectable solvent. [Background technology]

[0002] Many drugs currently used as pharmaceuticals are poorly soluble, meaning that they exhibit low bioavailability when administered to subjects. Various formulation methods have been studied to solubilize poorly soluble drugs, but their effectiveness is limited or there are limitations on formulation and dosage, so their actual application in pharmaceutical development is rare.

[0003] Formulation techniques for improving drug solubility can be divided into two main categories: physical modifications and chemical modifications. Examples of physical modifications include reducing the size of drug particles, modifying the crystallization of polymorphs, dispersing drugs in carriers such as eutectic mixtures or solid dispersions, complexation using complexing agents, and surfactant solubilization using microemulsions or self-microemulsifying drug delivery systems (SMEDDS). Examples of chemical modifications include adjusting pH or using salts to improve drug solubility. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 9,359,346 [Patent Document 2] WO2020 / 256456 Summary of the Invention [Problem to be solved by the invention]

[0005] One object of the present invention is to provide a pharmaceutical composition containing high concentrations of opiranserin.

[0006] Another object of the present invention is to provide a method for rapidly and safely preparing a bolus intravenous infusion composition using said pharmaceutical composition. [Means for solving the problem]

[0007] To solve the above technical problems, a pharmaceutical composition is provided, comprising: opiranserin or a pharmaceutically acceptable salt thereof; a carrier selected from sodium benzoate, trisodium citrate, sodium salicylate, and mixtures thereof; and an injectable solvent.

[0008] Also provided is a pre-filled syringe containing the pharmaceutical composition.

[0009] Further provided is a method for preparing a bolus intravenous infusion composition, comprising the steps of: providing an intravenous administration container (IV container) containing saline; and injecting the pharmaceutical composition into the intravenous administration container (IV container) once. [Effects of the Invention]

[0010] According to the present invention, a pharmaceutical composition containing high concentrations of opiranserin can be prepared. The pharmaceutical composition containing high concentrations of opiranserin according to the present invention can be stored and transported in a small volume, and a bolus intravenous infusion composition can be prepared quickly and safely, thereby providing convenience to medical professionals and patients. [Brief explanation of the drawings]

[0011] [Figure 1] 1 is a graph showing the results of analyzing the plasma concentrations measured in Experimental Example 6.

[0012] (Best Mode for Carrying Out the Invention) The present invention will now be described in further detail.

[0013] According to one aspect of the present invention, there is provided a pharmaceutical composition comprising: opiranserin or a pharmaceutically acceptable salt thereof; a carrier selected from sodium benzoate, trisodium citrate, sodium salicylate, and mixtures thereof; and an injectable solvent.

[0014] Opiranserin used in the present application is a compound represented by the following formula (1): [ka] The compound is 4-butoxy-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-3,5-dimethoxybenzamide, represented by the formula:

[0015] Opiranserin is also known as VVZ-149. Methods for synthesizing opiranserin, its use in treating postoperative pain, and reducing the need for analgesics in treating postoperative pain are disclosed in U.S. Patent Nos. 5,627,999 and 5,727,999, the contents of which are incorporated herein by reference.

[0016] In one embodiment of the present invention, the pharmaceutically acceptable salt of opiranserin may be a hydrochloride, phosphate, or sulfate. In another embodiment of the present invention, the pharmaceutically acceptable salt of opiranserin may be a hydrochloride. The solubility of opiranserin hydrochloride is 25 mg / mL, which can be considered "slightly soluble." Opiranserin hydrochloride is currently used clinically as an injection at a concentration of 10 mg / mL. For an adult patient (approximately 60 kg), 100 mL of an injection having a concentration of 10 mg / mL of opiranserin is diluted with saline and injected in the form of an infusion.

[0017] In another embodiment of the present invention, the content of opiranserin or a pharmaceutically acceptable salt thereof may be 0.1 mol / L to 0.7 mol / L based on the total volume of the composition. In another embodiment of the present invention, the content of opiranserin or a pharmaceutically acceptable salt thereof may be 0.2 mol / L to 0.7 mol / L based on the total volume of the composition.

[0018] In the pharmaceutical composition according to the present invention, a carrier selected from sodium benzoate, trisodium citrate, sodium salicylate, and mixtures thereof is used to prepare a composition containing poorly soluble opiranserin at a high concentration. In another embodiment according to the present invention, the carrier may be a hydrotrope. A hydrotrope is an amphiphilic low-molecular-weight compound that is readily soluble in aqueous solution. It has been suggested that some hydrotropes improve drug solubility through non-covalent self-aggregation in non-polar microdomains above the minimum hydrotrope concentration (MHC). Similar to surfactants, hydrotropes are composed of lipophilic and hydrophilic moieties, but the lipophilic moiety is relatively short and cyclic or branched compared to surfactants. Furthermore, hydrotropes do not form micelles and are therefore not classified as surfactants. Hydrotropes are primarily used in commercial applications such as functional cosmetics and car detergents. Examples of hydrotropes include nicotinamide, N-N-diethylnicotinamide, sodium benzoate, benzyl benzoate, sodium 4-aminobenzoate, sodium salicylate, resorcinol, piperazine, 2-butoxyethylsulfonic acid sodium salt, lysine, urea, sodium citrate, trisodium citrate, and the like.

[0019] In the pharmaceutical composition according to the present invention, the amount of carrier (hydrotrope) can be adjusted depending on the components of the hydrotrope used, the tolerable amount of the hydrotrope administered to an individual, and the content of opiranserin.

[0020] In another embodiment of the present invention, the content of sodium benzoate may be 0.2 mol / L to 2.0 mol / L, more specifically 0.26 mol / L to 0.90 mol / L, based on the total volume of the composition. In another embodiment of the present invention, the content of sodium benzoate added may be 30 mg / mL to 300 mg / mL, more specifically 37 mg / mL to 130 mg / mL, based on the total volume of the composition to be produced.

[0021] In another embodiment of the present invention, the content of the trisodium citrate may be 0.08 mol / L to 0.35 mol / L based on the total volume of the composition. The trisodium citrate may be added, for example, in the form of a dihydrate, and the content of the added trisodium citrate dihydrate may be 25.0 mg / mL to 100 mg / mL based on the total volume of the composition to be produced.

[0022] In another embodiment of the present invention, the content of sodium salicylate may be 0.015 mol / L to 0.10 mol / L based on the total volume of the composition. In another embodiment of the present invention, the content of sodium salicylate added may be 2.5 mg / mL to 16 mg / mL based on the total volume of the composition produced.

[0023] In another embodiment of the present invention, the content of the carrier (hydrotrope) is determined as the molar ratio to opiranserin or a pharmaceutically acceptable salt thereof. In another embodiment of the present invention, the molar ratio of opiranserin or a pharmaceutically acceptable salt thereof to sodium benzoate may be 1:0.5-3.0, specifically 1:1.0-2.4, more specifically 1:1.2-1.6, and even more specifically 1:1.3-1.5. In another embodiment of the present invention, the molar ratio of opiranserin or a pharmaceutically acceptable salt thereof to sodium benzoate may be 1:1.4-1.6, specifically 1:1.48-1.49.

[0024] The pharmaceutical composition according to the present invention can ensure a content of opiranserin or a pharmaceutically acceptable salt thereof of 0.1 mol / L or more, specifically 0.2 mol / L or more, more specifically 0.4 mol / L or more, and even more specifically up to 0.7 mol / L, based on the total volume of the composition, by using a carrier (hydrotrope) selected from sodium benzoate, trisodium citrate, sodium salicylate, and a mixture thereof. In another embodiment according to the present invention, opiranserin hydrochloride can be dissolved in an amount of 50 mg / mL or more, 100 mg / mL or more, 200 mg / mL or more, or up to 300 mg / mL, based on the total volume of the composition, and stability is ensured when stored at room temperature and / or under refrigerated conditions.

[0025] In another embodiment according to the present invention, the solvent for injection may be water for injection.

[0026] In another embodiment according to the invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, examples of which include, but are not limited to, surfactants, antioxidants, pH adjusting agents, osmotic bases, acidifying agents, alkalizing agents, preservatives, buffering agents, chelating agents, stabilizers, emulsifiers and / or solubilizing agents.

[0027] Each of the excipients constitutes a separate embodiment and can be added to any claim in any suitable combination. For example, in another embodiment according to the present invention, the pharmaceutical composition can further comprise a surfactant to enhance refrigeration stability. Specific examples of surfactants include, but are not limited to, polysorbate 20, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 15 hydroxystearate, or mixtures thereof. In another embodiment according to the present invention, the content of the surfactant can be 1 mg / mL to 50 mg / mL based on the total volume of the composition.

[0028] In another embodiment according to the present invention, the pharmaceutical composition can be prepared by the steps of: a) dissolving a carrier (hydrotrope) selected from sodium benzoate, trisodium citrate, sodium salicylate, and mixtures thereof in water for injection; b) adding opiranserin or a pharmaceutically acceptable salt thereof to the solvent to prepare a solution; and c) performing sterile filtration.

[0029] Another aspect of the present invention provides a pharmaceutical composition as an analgesic injection, which contains 0.1 mol / L to 0.7 mol / L of opiranserin or a pharmaceutically acceptable salt thereof based on the total amount of the injection.

[0030] According to another aspect of the present invention, there is provided a pre-filled syringe containing the pharmaceutical composition according to the present invention. In another embodiment of the present invention, the pharmaceutical composition is used as an analgesic injection and can be used in a pre-filled form in which a single dose is pre-filled in a syringe.

[0031] According to another aspect of the present invention, there is provided a method for producing a bolus intravenous infusion composition, comprising the steps of: preparing an intravenous administration container (IV container) containing physiological saline; and injecting the pharmaceutical composition according to the present invention into the intravenous administration container (IV container) once.

[0032] According to another aspect of the present invention, there is provided a method for producing a bolus intravenous infusion composition, comprising the steps of: preparing an intravenous administration container (IV container) containing physiological saline; and injecting the pharmaceutical composition loaded in the prefilled syringe into the intravenous administration container (IV container) once. [Example]

[0033] The present invention will be described in more detail below with reference to examples, but it should be understood that the scope of protection of the present invention is not limited to these examples.

[0034] Experimental Example 1: Solubility measurement of Opiranserin hydrochloride in solvents An excess amount of opiranserin hydrochloride was added to the solvent shown in Table 1 below, stirred under the following conditions, centrifuged, filtered, and the filtrate was diluted. The solubility of the drug was measured using high-performance liquid chromatography (HPLC).

[0035] [Table 1]

[0036] Experimental Example 2: Room temperature stability of dissolved opiranserin hydrochloride Among the solvents that demonstrated high solubility in Experimental Example 1, solvents that could cause no or minimal irritation during pharmaceutical preparation were selected, as shown in Table 2. Next, the solubility and short-term room temperature stability of opiranserin hydrochloride at various concentrations were evaluated. Each preparation was adjusted according to the solvent concentration, and an excess amount of opiranserin hydrochloride was added and stirred at 40°C for 3 hours. The preparations were centrifuged, and the supernatant was transferred to a glass vial and stored at room temperature for observation and analysis of the content. Liquid chromatography (HPLC) was used to analyze the content of opiranserin hydrochloride. Samples were taken upon completion of preparation and after 65 hours of storage at room temperature.

[0037] [Table 2]

[0038] In Experimental Example 1, the opiranserin hydrochloride preparation dissolved in 6 w / v% triacetin solvent (solvent 20) was dissolved to approximately 86 mg / mL. However, during a short-term room temperature stability test, recrystallization of needle-like structures occurred, and it was confirmed that the solubility of opiranserin hydrochloride in the preparation was reduced to 38.1 mg / mL.

[0039] The above results confirmed that it is difficult to prepare a highly concentrated opiranserin hydrochloride solution and maintain the desired level of stability when using only conventional surfactants or excipients that aid dissolution.

[0040] Experimental Example 3: Screening of hydrotropes to improve the solubility of opiranserin hydrochloride Screening for hydrotropes suitable for pharmaceutical use was performed as shown in Table 3 below. 50 mL of water for injection was added to a 200 mL beaker, and then a weight of hydrotrope corresponding to the target content was added and stirred at room temperature until completely dissolved. Next, a weight of opilanserin hydrochloride corresponding to the target concentration was added and stirred at room temperature until completely dissolved. If complete dissolution was not achieved in some solvents, the temperature was raised to 40°C and further stirring was performed. After the added substance was completely dissolved, water for injection was added to the beaker to bring it up to the 100 mL mark, and further stirring was performed to ensure complete miscibility of the composition. The prepared composition was filtered through a 0.2 μm syringe filter and dispensed into injection vials.

[0041] [Table 3]

[0042] As can be seen from Table 3, when sodium benzoate was used as the hydrotrope, opiranserin hydrochloride could be dissolved up to a maximum of 300 mg / mL. When trisodium citrate dihydrate was used as the hydrotrope, opiranserin hydrochloride could be stably dissolved up to 100 mg / mL. When sodium salicylate was used as the hydrotrope, opiranserin hydrochloride could be stably dissolved up to 100 mg / mL.

[0043] Experimental Example 4: Dissolution stability depending on the molar ratio of opiranserin hydrochloride and sodium benzoate To evaluate the dissolution stability of opiranserin hydrochloride depending on the sodium benzoate content, compositions with the concentrations shown in Table 4 were prepared. The opiranserin hydrochloride concentration was selected based on the packaging unit of the finished product and the convenience of preparing the IV infusion diluent for administration to patients. To prepare each composition, 50 mL of water for injection was added to a 200 mL beaker, and the corresponding amount of sodium benzoate was added and dissolved completely by stirring at room temperature. Next, the corresponding amount of opiranserin hydrochloride was added and stirred at 40°C for 1 hour until completely dissolved, after which the volume was adjusted to 100 mL with water for injection. The prepared compositions were filtered through a 0.2 μm syringe filter and dispensed into injection vials.

[0044] [Table 4]

[0045] The compositions in Table 4 were filled into injection vials and stored at room temperature and in a refrigerator, respectively. The dissolution stability of opiranserin hydrochloride in each composition was evaluated at each storage temperature. The results are shown in Table 5.

[0046] [Table 5]

[0047] Experimental Example 5: Preparation of intravenous infusion (IV infusion) diluent Comparative Example The opiranserin formulation currently in clinical use is a concentrated formulation prepared in 100mL vials using ordinary water for injection to a concentration of 10mg / mL, taking into account the solubility of opiranserin hydrochloride in base and ensuring stability throughout the product's distribution period. In clinical practice, opiranserin is administered intravenously to patients with postoperative pain, but prior to administration, the infusion diluent must be prepared using the following procedure.

[0048] First, 100 mL of saline solution is removed from a commercially available 500 mL saline bag using a sterilized syringe. Using a new syringe, concentrate is drawn from the vial containing opilanserin and added to the saline bag to make a total of 100 mL. The contents are thoroughly mixed, and the resulting solution is used as the infusion diluent. If a conventional syringe with a capacity of less than 100 mL is used during the addition process, the concentrate must be drawn into the syringe in several portions. In this case, careful attention must be paid to maintaining sterility and adding the concentrate accurately and quickly.

[0049] Examples 1 and 2 Concentrated compositions prepared to high concentrations of 102 mg / mL and 202 mg / mL, respectively, were used in Examples 1 and 2. Because they were manufactured at high concentrations, the final volume of the product could be reduced to 10 mL to 5 mL, and it could be filled into vials or sterilized prefilled syringes for use.

[0050] The products of Examples 1 and 2 do not require the step of removing a portion of the saline solution from the saline bag during the process of preparing the diluent for intravenous infusion for patients, and can be prepared by simply injecting the solution once with a regular syringe. This allows for rapid and accurate production, and sterility during the manufacturing process can be guaranteed.

[0051] [Table 6]

[0052] [Table 7]

[0053] Experimental Example 6: Measurement of plasma concentration of high-concentration opilanserin hydrochloride injection To confirm the equivalence of the infusion dilutions of Comparative Example, Examples 1, and 2, plasma concentrations were analyzed using male SD rats. The infusion dilution prepared in Experimental Example 5 was administered to male SD rats at a flow rate of 1 mL / hr for 4 hours, and blood samples were collected 1, 2, 4, 5, 6, 8, and 28 hours after the start of administration. Plasma concentrations were then analyzed using a QTRAP 4500 tandem mass spectrometer (LC-MS / MS) (AB Sciex Pte.), and the results are shown in Figure 1. When blood was collected 1 hour after administration of the infusion, the plasma concentration was 1,500 to 3,000 ng / mL, and when blood was collected 4 hours after administration, the plasma concentration was 5,500 ng / mL or less. Examples 1 and 2 both showed plasma concentrations similar to those of the Comparative Example. Thus, it was confirmed that the high-concentration injectable preparations according to the present invention exhibit efficacy equivalent to that of current clinical pharmaceuticals.

[0054] Experimental Example 7: Surfactants When preparing a high-concentration opiranserin hydrochloride injection using hydrotrope technology, the preparation feasibility and stability of the injection with surfactants used as solubilizers were confirmed.

[0055] Each preparation was prepared according to the method of Experimental Example 4. After preparation with the addition of a solubilizing agent commonly used in injections, the stability was confirmed, and the results are shown in Table 9.

[0056] [Table 8]

[0057] [Table 9]

[0058] When polysorbate 80, a typical surfactant, was added as a solubilizing agent to a high-concentration opiranserin injection, the stability of the properties was maintained for a long period of time over a wider range of molar ratios.

Claims

1. Opiranserin or a pharmaceutically acceptable salt thereof; a carrier selected from sodium benzoate, trisodium citrate, sodium salicylate, and mixtures thereof; and Injection solvent; 10. A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition according to claim 1, wherein the content of the opiranserin or a pharmaceutically acceptable salt thereof is 0.1 mol / L to 0.7 mol / L based on the total volume of the composition.

3. 3. The pharmaceutical composition according to claim 2, wherein the content of the opiranserin or a pharmaceutically acceptable salt thereof is 0.2 mol / L to 0.7 mol / L based on the total volume of the composition.

4. 2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of opiranserin is a hydrochloride, a phosphate, or a sulfate.

5. 5. The pharmaceutical composition according to claim 4, wherein the pharmaceutically acceptable salt of opiranserin is the hydrochloride salt.

6. 2. The pharmaceutical composition according to claim 1, wherein the content of sodium benzoate is 0.2 mol / L to 2.0 mol / L based on the total volume of the composition.

7. 7. The pharmaceutical composition according to claim 6, wherein the content of sodium benzoate is 0.26 mol / L to 0.90 mol / L based on the total volume of the composition.

8. 2. The pharmaceutical composition according to claim 1, wherein the content of trisodium citrate is 0.08 mol / L to 0.35 mol / L based on the total volume of the composition.

9. 2. The pharmaceutical composition according to claim 1, wherein the content of sodium salicylate is 0.015 mol / L to 0.10 mol / L based on the total volume of the composition.

10. 2. The pharmaceutical composition according to claim 1, wherein the molar ratio of opiranserin or a pharmaceutically acceptable salt thereof to sodium benzoate is 1:0.5-3.

0.

11. 11. The pharmaceutical composition according to claim 10, wherein the molar ratio of opiranserin or a pharmaceutically acceptable salt thereof to sodium benzoate is 1:1.0-2.

4.

12. 12. The pharmaceutical composition according to claim 11, wherein the molar ratio of opiranserin or a pharmaceutically acceptable salt thereof to sodium benzoate is 1:1.4-1.

6.

13. 13. The pharmaceutical composition according to claim 12, wherein the molar ratio of opiranserin or a pharmaceutically acceptable salt thereof to sodium benzoate is 1:1.48-1.

49.

14. 2. The pharmaceutical composition according to claim 1, wherein the solvent for injection is water for injection.

15. A pharmaceutical composition for use as an analgesic injection, comprising 0.1 mol / L to 0.7 mol / L of opiranserin or a pharmaceutically acceptable salt thereof based on the total amount of the injection.

16. A pre-filled syringe containing the pharmaceutical composition according to any one of claims 1 to 14.

17. providing an intravenous container (IV container) containing saline; and A step of injecting the pharmaceutical composition according to any one of claims 1 to 14 into the intravenous administration container (IV container) once; 1. A method for preparing a bolus intravenous infusion composition comprising:

18. providing an intravenous container (IV container) containing saline; and A step of injecting the pharmaceutical composition contained in the prefilled syringe of claim 16 into the intravenous administration container (IV container) once; 1. A method for preparing a bolus intravenous infusion composition comprising:

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