Pharmaceutical composition comprising high concentration of apivanserin

Abstract

The invention discloses a pharmaceutical composition containing apivanserin at a high concentration. More specifically, disclosed is a pharmaceutical composition comprising apivanserin, or a pharmaceutically acceptable salt thereof; a carrier selected from the group consisting of sodium benzoate, trisodium citrate, sodium salicylate, and mixtures thereof; and a solvent for injection.

Description

Technical Field

[0001] Disclosed is a pharmaceutical composition containing a high concentration of opiranserin. More specifically, disclosed is a pharmaceutical composition containing opiranserin or a pharmaceutically acceptable salt thereof; a carrier selected from sodium benzoate, trisodium citrate, sodium salicylate, and mixtures thereof; and a solvent for injection. Background Art

[0002] Many drugs currently used as medicaments have poor solubility and show low bioavailability due to low solubility when administered to a subject. Various formulation methods are being studied to dissolve poorly soluble drugs. However, due to the insignificant or limited effects of formulation and application, there are few practical application cases in drug development.

[0003] Formulation techniques for improving drug solubility are mainly divided into physical modification and chemical modification. Examples of physical modification include methods of reducing the particle size of a drug, methods of modifying polymorphic crystallization, methods of dispersing a drug into a carrier such as a eutectic mixture or a solid dispersant, methods of complexing by using a complexing agent, and solubilization methods using surfactants of microemulsions and self - microemulsifying drug delivery systems (SMEDDS). Examples of chemical modification include methods of improving drug solubility by adjusting pH or using salts.

[0004] [Patent Literature]

[0005] U.S. Patent No. 9,359,346

[0006] International Publication No. WO 2020 / 256456 Summary of the Invention

[0007] Technical Problem

[0008] An object of the present invention is to provide a pharmaceutical composition containing a high concentration of opiranserin.

[0009] Another object of the present invention is to provide a method for rapidly and safely preparing a bolus intravenous infusion composition by using the pharmaceutical composition.

[0010] Solution to the Problem

[0011] To solve the above - mentioned technical problems, there is provided a pharmaceutical composition containing opiranserin or a pharmaceutically acceptable salt thereof; a carrier selected from sodium benzoate, trisodium citrate, sodium salicylate, and mixtures thereof; and a solvent for injection.

[0012] In addition, there is provided a pre - filled syringe containing the pharmaceutical composition.

[0013] Furthermore, provided is a method for preparing a bolus intravenous infusion composition, comprising: preparing an intravenous administration container (IV container) containing a saline solution; and injecting the pharmaceutical composition into the intravenous administration container (IV container) in one go.

[0014] Advantages of the Invention

[0015] According to the present invention, a pharmaceutical composition containing a high concentration of opiranserin can be prepared. The pharmaceutical composition containing a high concentration of opiranserin according to the present invention can be stored and delivered in a small volume, and can be used to rapidly and safely prepare a bolus intravenous infusion composition, thereby providing convenience for medical staff and patients. Description of the Drawings

[0016] Figure 1 It is a graph showing the analysis results of the plasma concentration measured in Experimental Example 6. Detailed Description of the Invention

[0017] The present invention will be described in detail below.

[0018] 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 injection solvent.

[0019] Opiranserin used herein is 4-butoxy-N-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-3,5-dimethoxybenzamide of Formula 1 below:

[0020] [Formula 1]

[0021]

[0022] Opiranserin is also known as VVZ-149. The synthesis method of opiranserin, its use for treating postoperative pain, and reducing the analgesic requirement for treating postoperative pain are disclosed in U.S. Patent No. 9,359,346 and International Publication No. WO 2020 / 256456, and the content thereof is incorporated herein by reference.

[0023] In one embodiment according to the present invention, the pharmaceutically acceptable salt of opiranserin may be hydrochloride, phosphate, or sulfate. In another embodiment according to the present invention, the pharmaceutically acceptable salt of opiranserin may be hydrochloride. Opiranserin hydrochloride has a solubility of 25 mg / mL and can be regarded as "slightly soluble". Currently, opiranserin hydrochloride is clinically used as an injection at a concentration of 10 mg / mL. A 100 mL injection of opiranserin at a concentration of 10 mg / mL is diluted with physiological saline and injected into adult patients (about 60 kg) in the form of an infusion.

[0024] In another embodiment according to the present invention, based on the total volume of the composition, the content of opiran serin or its pharmaceutically acceptable salt may be from 0.1 mol / L to 0.7 mol / L. In another embodiment according to the present invention, based on the total volume of the composition, the content of opiran serin or its pharmaceutically acceptable salt may be from 0.2 mol / L to 0.7 mol / L.

[0025] In the pharmaceutical composition according to the present invention, in order to prepare a composition containing a high concentration of poorly soluble opiran serin, a carrier selected from sodium benzoate, trisodium citrate, sodium salicylate, and mixtures thereof is used. In another embodiment according to the present invention, the carrier may be a hydrotropic agent. A hydrotropic agent is an amphiphilic low molecular weight compound that is readily soluble in an aqueous solution. It has been proposed that some hydrotropic agents improve the solubility of drugs by non-covalent self-aggregation in non-polar microdomains above the minimum hydrotropic agent concentration (MHC). Similar to surfactants, hydrotropic agents consist of a lipophilic part and a hydrophilic part, but the lipophilic part of a hydrotropic agent is relatively shorter and has a cyclic or branched shape compared to the lipophilic part of a surfactant. In addition, hydrotropic agents do not form micelles, so they are not classified as surfactants. Commercially, hydrotropic agents are mainly used in functional cosmetics and vehicle cleaners. Examples of hydrotropic agents include nicotinamide, N,N-diethylnicotinamide, sodium benzoate, benzyl benzoate, sodium 4-aminobenzoate, sodium salicylate, resorcinol, piperazine, sodium 2-butoxyethylsulfonate, lysine, urea, sodium citrate, trisodium citrate, etc.

[0026] In the pharmaceutical composition according to the present invention, the amount of the carrier (hydrotropic agent) can be adjusted depending on the hydrotropic agent component used, the allowable amount of the hydrotropic agent administered to the subject, and the content of opiran serin.

[0027] In another embodiment according to the present invention, based on the total volume of the composition, the content of sodium benzoate may be from 0.2 mol / L to 2.0 mol / L, and more specifically from 0.26 mol / L to 0.90 mol / L. In another embodiment according to the present invention, based on the total volume of the preparation composition to be prepared, the content of the added sodium benzoate may be from 30 mg / mL to 300 mg / mL, and more specifically from 37 mg / mL to 130 mg / mL.

[0028] In another embodiment according to the present invention, based on the total volume of the composition, the content of trisodium citrate may be from 0.08 mol / L to 0.35 mol / L. Trisodium citrate may be added in the form of, for example, the dihydrate, and based on the total volume of the composition to be prepared, the content of the added trisodium citrate dihydrate may be from 25.0 mg / mL to 100 mg / mL.

[0029] In another embodiment according to the present invention, based on the total volume of the composition, the content of sodium salicylate can be from 0.015 mol / L to 0.10 mol / L. In another embodiment according to the present invention, based on the total volume of the composition to be prepared, the content of added sodium salicylate can be from 2.5 mg / mL to 16 mg / mL.

[0030] In another embodiment according to the present invention, the content of the carrier (water-soluble adjuvant) can be determined according to its molar ratio with opiranoline or its pharmaceutically acceptable salt. In another embodiment according to the present invention, the molar ratio of opiranoline or its pharmaceutically acceptable salt to sodium benzoate can be from 1:0.5 to 3.0, specifically from 1:1.0 to 2.4, more specifically from 1:1.2 to 1.6, and even more specifically from 1:1.3 to 1.5. In another embodiment according to the present invention, the molar ratio of opiranoline or its pharmaceutically acceptable salt to sodium benzoate can be from 1:1.4 to 1.6, and specifically from 1:1.48 to 1.49.

[0031] By using a carrier (water-soluble adjuvant) selected from sodium benzoate, trisodium citrate, sodium salicylate and their mixtures, the content of opiranoline or its pharmaceutically acceptable salt in the pharmaceutical composition according to the present invention can be ensured to be above 0.1 mol / L, specifically above 0.2 mol / L, more specifically above 0.4 mol / L, and even more specifically above 0.7 mol / L based on the total volume of the composition. In another embodiment according to the present invention, opiranoline hydrochloride can be dissolved in the pharmaceutical composition in an amount of above 50 mg / mL, above 100 mg / mL, above 200 mg / mL, or up to 300 mg / mL, and stability can be ensured when stored at room temperature and / or refrigerated conditions.

[0032] In another embodiment according to the present invention, the injection solvent can be water for injection.

[0033] In another embodiment according to the present invention, the pharmaceutical composition can further comprise one or more pharmaceutically acceptable excipients. Examples of excipients include but are not limited to surfactants, antioxidants, pH regulators, penetrants, acidifiers, alkalizers, preservatives, buffers, chelating agents, stabilizers, emulsifiers and / or solubilizers.

[0034] Each of the excipients described above 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 may further comprise a surfactant to enhance cold storage stability. Specific examples of surfactants include, but are not limited to, polysorbate 20, polysorbate 80, polyoxyethylene 35 castor oil, polyoxyethylene 15 hydroxystearate, or mixtures thereof. In another embodiment according to the present invention, based on the total volume of the composition, the content of the surfactant may be from 1 mg / mL to 50 mg / mL.

[0035] In another embodiment of the present invention, the pharmaceutical composition can be prepared by the following steps: a) dissolving a carrier (aqueous solubility aid) selected from sodium benzoate, trisodium citrate, sodium salicylate, and mixtures thereof in water for injection to obtain a solvent system; b) preparing a solution by adding opiranoline or a pharmaceutically acceptable salt thereof to the solvent system; and c) performing aseptic filtration.

[0036] According to another aspect of the present invention, there is provided a pharmaceutical composition as an analgesic injection, which, based on the total volume of the injection, comprises 0.1 mol / L to 0.7 mol / L of opiranoline or a pharmaceutically acceptable salt thereof.

[0037] According to another aspect of the present invention, there is provided a prefilled syringe containing the pharmaceutical composition according to the present invention. In another embodiment according to the present invention, the pharmaceutical composition can be used as an analgesic injection and can be used in the form of a prefilled syringe, wherein a single dose is prefilled into the syringe.

[0038] According to another aspect of the present invention, there is provided a method for preparing a bolus intravenous infusion composition, which includes: preparing an intravenous administration container (IV container) containing a salt solution; and injecting the pharmaceutical composition according to the present invention into the intravenous administration container (IV container) in one go.

[0039] According to another aspect of the present invention, there is provided a method for preparing a bolus intravenous infusion composition, which includes: preparing an intravenous administration container (IV container) containing a salt solution; and injecting the pharmaceutical composition filled in a prefilled syringe into the intravenous administration container (IV container) in one go.

[0040] Example

[0041] Hereinafter, the present invention will be explained in more detail with the following examples. However, it must be understood that the scope of protection of the present invention is not limited to the examples.

[0042] Experimental Example 1: Measurement of the solubility of opiranserin hydrochloride according to the solvent

[0043] An excessive amount of opiran serin hydrochloride was added to the solvents shown in Table 1, stirred under the following conditions, centrifuged and filtered, and the filtrate was diluted. The solubility of the drug was measured using high performance liquid chromatography (HPLC).

[0044] [Table 1]

[0045]

[0046] Experimental Example 2: Room temperature stability of dissolved opiranserin hydrochloride

[0047] Among the solvents showing high solubility in Experimental Example 1, as shown in Table 2, solvents that are non-irritating or can minimize irritation during the preparation of the drug were selected. Then, the solubility of opiran serin hydrochloride and its short-term room temperature stability were estimated based on the concentration content. By adjusting the solvent according to the concentration, an excessive amount of opiran serin hydrochloride was added and stirred at 40 °C for 3 hours to prepare each preparation. The preparation was centrifuged, the supernatant was transferred to a vial, and stored at room temperature to observe the properties and analyze the content. The content of opiran serin hydrochloride was analyzed using liquid chromatography (HPLC), and samples were taken after the completion of the preparation and after storing at room temperature for 65 hours.

[0048] [Table 2]

[0049]

[0050]

[0051] In Experimental Example 1, the opiran serin hydrochloride preparation dissolved in a 6 w / v% triacetin solvent (Solvent 20) was dissolved to approximately 86 mg / mL. However, during the short-term room temperature stability test, recrystallization with a needle-like structure occurred, thereby confirming that the solubility of opiran serin hydrochloride in the preparation decreased to 38.1 mg / mL.

[0052] From the above results, it can be seen that it is difficult to prepare a high-concentration opiran serin hydrochloride solution using only conventional surfactants or excipients that contribute to solubilization, and it is also difficult to maintain the stability at the required level.

[0053] Experimental Example 3: Screening of water-soluble aids for improving the solubility of opiranserin hydrochloride

[0054] Using a water-soluble auxiliary agent that can be used for pharmaceuticals, the screening as shown in Table 3 below was carried out. After adding 50 mL of water for injection to a 200 mL beaker, add the weight of the water-soluble auxiliary agent corresponding to the target content thereto, and stir at room temperature until completely dissolved. Then, add the weight of opiranserin hydrochloride corresponding to the target concentration, and stir at room temperature until completely dissolved. If it does not completely dissolve in some solvents, raise the temperature to 40 °C and perform additional stirring. When the added materials are completely dissolved, add water for injection to the beaker until it reaches the 100 mL mark, and further stir to ensure complete mixing of the composition. Filter the prepared composition using a 0.2 μm syringe filter and then dispense it into vials for injection.

[0055] [Table 3]

[0056]

[0057]

[0058] As can be seen from Table 3, when using sodium benzoate as the water-soluble auxiliary agent, up to 300 mg / mL of opiranserin hydrochloride can be dissolved. When using trisodium citrate dihydrate as the water-soluble auxiliary agent, opiranserin hydrochloride can be stably dissolved to 100 mg / mL. When using sodium salicylate as the water-soluble auxiliary agent, opiranserin hydrochloride can be stably dissolved to 100 mg / mL.

[0059] Experimental Example 4: Dissolution stability according to the molar ratio of opiranserin hydrochloride and sodium benzoate

[0060] To evaluate the dissolution stability of opiranserin hydrochloride according to the content of sodium benzoate, compositions with the concentrations shown in Table 4 were prepared. The concentration of opiranserin hydrochloride was selected considering the packaging unit of the finished product and the convenience of preparing intravenous infusion diluents to be administered to patients. To prepare each composition, add 50 mL of water for injection to a 200 mL beaker, add the corresponding amount of sodium benzoate thereto, and stir at room temperature until completely dissolved. Then, add the corresponding amount of opiranserin hydrochloride, stir at 40 °C for 1 hour until completely dissolved, and then adjust the volume to 100 mL using water for injection. Filter the prepared composition using a 0.2 μm syringe filter and dispense it into vials for injection.

[0061] [Table 4]

[0062]

[0063] The compositions filled in the vials for injection in Table 4 were stored at room temperature and under refrigeration conditions respectively, and the dissolution stability of opiranserin hydrochloride at each storage temperature was evaluated in each composition. The results are shown in Table 5.

[0064] [Table 5]

[0065]

[0066]

[0067] ○: Clear and transparent liquid, X: Formation of recrystallization

[0068] Experimental Example 5: Preparation of intravenous infusion (IV infusion) diluent

[0069] Comparative Example

[0070] Currently, the clinically used opiranoline product is a concentrated composition. Among them, considering the basic solubility of opiranoline hydrochloride and ensuring the stability during the product sales period, the concentration of opiranoline hydrochloride in conventional injection water is 10 mg / mL, and it is filled in vials in units of 100 mL. In clinical practice, opiranoline is administered to patients with postoperative pain in the form of intravenous infusion. Before administration, the infusion diluent needs to be prepared according to the following steps.

[0071] First, use a sterilized syringe to take out 100 mL of saline solution from a commercially available 500 mL saline solution bag. Use a new syringe to take out the concentrated composition from the vial filled with opiranoline and add it to the saline solution bag, with a total of 100 mL. Mix the contents well, and the resulting solution is used as the infusion diluent. In the addition step, if a conventional syringe with a capacity less than 100 mL is used, the concentrated composition must be aspirated with the syringe several times. In this case, close attention should be paid to accurately and quickly add the required amount while maintaining sterility.

[0072] Examples 1 and 2

[0073] In Examples 1 and 2, concentrated compositions prepared at high concentrations of 102 mg / mL and 202 mg / mL were used respectively. Since it is manufactured at a high concentration, the final volume of the product can be reduced to 10 mL to 5 mL, so it can be used by filling vials or sterilized prefilled syringes.

[0074] For the products of Examples 1 and 2, during the process of preparing the intravenous infusion diluent for administration to patients, there is no need to remove part of the saline solution from the saline solution bag, and the intravenous infusion diluent can be prepared by injecting only once with a conventional syringe. Therefore, it can be manufactured quickly and accurately, and the sterilization conditions can be ensured during the manufacturing process.

[0075] [Table 6] Preparation of finished products

[0076]

[0077] [Table 7] Preparation of infusion diluent

[0078]

[0079] Experimental Example 6: Measurement of plasma concentration of high-concentration opiranserin hydrochloride injection

[0080] To confirm the equivalence of the comparative example with the infusion diluents of Examples 1 and 2, male Sprague-Dawley rats were used to analyze plasma concentration. The infusion diluent prepared in Experimental Example 5 was administered to male Sprague-Dawley rats at a flow rate of 1 mL / hour for 4 hours, and blood was collected at 1, 2, 4, 5, 6, 8, and 28 hours after the start of administration. Subsequently, the plasma concentration was analyzed using a QTRAP 4500 tandem mass spectrometer (LC-MS / MS) (ABSciex Pte. Ltd.), and the results are as Figure 1 shown. When blood was collected 1 hour after the infusion administration, the plasma concentration was 1,500 to 3,000 ng / mL, and when blood was collected 4 hours after the administration, the plasma concentration was less than 5,500 ng / mL. Both Example 1 and Example 2 showed the same plasma concentration as the comparative example. Thus, it was confirmed that the high-concentration injection prepared according to the present invention showed the same efficacy as the current clinical product.

[0081] Experimental Example 7: Surfactant

[0082] When manufacturing a high-concentration opiranoline hydrochloride injection using a water-soluble adjuvant technique, the feasibility and stability of the preparation of the surfactant used as a solubilizer in the injection were confirmed.

[0083] Each preparation was prepared using the method of Experimental Example 4. After preparation by adding a solubilizer commonly used for injections, the stability was evaluated. The results are shown in Table 9.

[0084] [Table 8] Preparation of the final composition containing a solubilizer

[0085]

[0086] [Table 9] Property stability of the final composition containing a solubilizer (stored at room temperature / refrigerated conditions)

[0087]

[0088] ○: Clear and transparent liquid, X: Recrystallization formed

[0089] As a result of adding polysorbate 80, a representative surfactant, as a solubilizer to the high-concentration opiranoline injection, the property stability was maintained for a long time within a wide molar ratio range.

Claims

1. 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 a solvent for injection.

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

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

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

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

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

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

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

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

10. 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 to 3.

0.

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 to 2.

4.

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 to 1.

6.

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 to 1.

49.

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

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

16. A prefilled syringe containing the pharmaceutical composition as defined in any one of claims 1 to 14.

17. A method for preparing a bolus intravenous infusion composition, comprising: preparing an intravenous administration container (IV container) containing a salt solution; and injecting the pharmaceutical composition as defined in any one of claims 1 to 14 into the intravenous administration container (IV container) in one go.

18. A method for preparing a bolus intravenous infusion composition, comprising: preparing an intravenous administration container (IV container) containing a salt solution; and injecting the pharmaceutical composition filled in the prefilled syringe as defined in claim 16 into the intravenous administration container (IV container) in one go.

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