A method for preparing a photostable vitamin K1 sustained-release microsphere

Abstract

The application discloses a preparation method of photothermal stable vitamin K1 sustained-release microspheres, which comprises the following steps: A, uniformly mixing vitamin K1 and sustained-release or controlled-release materials in an organic solution to form an oil phase; and preparing an aqueous phase containing a film forming agent; the organic solution is a composite organic solvent formed by two types of organic solvents, one type is an alcohol solvent or a ketone solvent, and the other type is an ester solvent; B, slowly adding the oil phase into the aqueous phase to perform solidification, forming an oil / water stable emulsion; C, performing post-treatment on the oil / water stable emulsion to obtain vitamin K1 sustained-release microspheres. The preparation method can effectively solve the problem of instability, has long-acting sustained-release function, can effectively act on a bleeding site, can maintain a high concentration for a long time, can greatly improve curative effect, can reduce toxic side effects, and has good clinical drug safety.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and particularly relates to a method for preparing vitamin K1 sustained-release microspheres. Background Technology

[0002] Vitamin K1 is a fat-soluble vitamin widely found in green plants, existing in the form of phylloquinone, and can also be synthesized artificially. Vitamin K1 is a vitamin-like drug and is essential for the liver to synthesize clotting factors. The human body cannot synthesize or secrete vitamin K1; the required vitamin K1 mainly comes from food. Vitamin K1 deficiency may cause impaired or abnormal synthesis of these clotting factors, leading to non-clotting blood, clinically manifested as bleeding tendency and prolonged clotting time. Clinically, vitamin K1 can be used for bleeding caused by vitamin K deficiency, such as bleeding caused by obstructive jaundice, bile fistula, and chronic diarrhea; hypoprothrombinemia caused by coumarins, sodium salicylate, etc.; prevention of neonatal hemorrhage; and vitamin K deficiency caused by long-term use of broad-spectrum antibiotics.

[0003] Vitamin K1 is chemically unstable and easily degraded by light, heat, and oxygen. Therefore, improving the stability of vitamin K1 injections has always been a key research focus. Currently, commercially available injectable vitamin K1 formulations include injectable emulsions and lyophilized powders. For example, Chinese patent application CN200710126586.6 discloses injectable lyophilized vitamin K1 powder and its preparation method; Chinese patent CN201610406120.0 discloses a new dosage form of vitamin K1 and its preparation method, which improves drug safety by encapsulating vitamin K1 in mPEG-PE polymer micelles to form a micelle drug delivery system.

[0004] The above patents relate to injectable formulations of vitamin K1, including conventional lyophilized powder injections and injectable emulsions. Both are immediate-release formulations, and their preparation processes are not only complex and costly, but also result in strong drug irritation and short-lived efficacy. Micellar solutions are thermodynamically and kinetically unstable systems, offering no significant advantage in drug stability, posing certain risks with long-term storage, and making it impossible to control the drug release rate and process, thus affecting the therapeutic effect. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing vitamin K1 sustained-release microspheres based on existing technology. The resulting formulation can effectively solve the problem of instability and has a long-lasting sustained-release function. It can target the bleeding site, maintain a high concentration for a longer period of time, greatly improve the efficacy, reduce toxic side effects, and has good clinical drug safety and broad application prospects.

[0006] The objective of this invention can be achieved through the following measures:

[0007] A method for preparing photothermally stable vitamin K1 sustained-release microspheres, comprising the following steps:

[0008] A. Mix vitamin K1 with sustained-release or controlled-release materials in an organic solution to form an oil phase; and prepare an aqueous phase containing a film-forming agent; the organic solution is a composite organic solvent in the form of two types of organic solvents, one of which is an alcohol solvent and the other is an ester solvent;

[0009] B. Slowly add the oil phase to the aqueous phase for curing to form an oil / water stable emulsion;

[0010] C. The oil / water stabilized emulsion was post-processed to obtain vitamin K1 sustained-release microspheres.

[0011] Preferably, in step A, the sustained-release or controlled-release material is selected from at least one of polylactic acid, polyglycolic acid, polylactic-polyglycolic acid, and polycaprolactone. The addition of specific sustained-release or controlled-release materials in this invention not only provides a framework material for vitamin K1 sustained-release microspheres, enabling them to achieve slow drug release characteristics, but also prolongs the drug's efficacy, reduces the number of injections, and greatly improves clinical applicability.

[0012] Preferably, in step A, the mass of the sustained-release or controlled-release material is 15-40% of the mass of the oil phase, more preferably 15-30%, and even more preferably 18-25%.

[0013] Preferably, in step A, the alcohol solvent can be selected from ethanol, methanol, propylene glycol, or benzyl alcohol. Among them, propylene glycol has low allergenicity and low irritation, and good compatibility with raw materials, making it an excellent solvent; the use of benzyl alcohol is more conducive to the stability of vitamin K1 and the release of its effects.

[0014] The ester solvent is selected from polyoxyethylene (35) castor oil, which can promote the dispersion and dissolution rate of vitamin K1 in the alcohol ester solution and improve bioavailability in the sustained-release microspheres. The mass ratio of the ester solvent in the organic solution is 3-13% of the oil phase mass, preferably 5-10%, and more preferably 6-9%.

[0015] Preferably, in step A, the mass content of vitamin K1 in the oil phase is 30-60%, more preferably 45-55%, and even more preferably 48-53%.

[0016] Preferably, in step A, the film-forming agent is selected from at least one of hydroxypropyl cellulose and hydroxypropyl methylcellulose. The use of a film-forming agent in the aqueous phase in this invention increases the adhesion between the components and encapsulates the drug, unexpectedly achieving excellent light-blocking effects and improving product stability. The mass content of the film-forming agent in the aqueous phase is 2-20%, preferably 5-15%, and more preferably 5-10%.

[0017] Preferably, in step A, the aqueous phase further contains glucose, and the mass content of glucose in the aqueous phase is 20-40%, preferably 22-35%, and more preferably 25-30%.

[0018] Preferably, in step B, the oil phase is slowly added to the aqueous phase under the action of a high-shear emulsifier to form an oil / water stable emulsion, with a rotation speed of 5000-7000 RPM and continuous shearing for 1-3 hours.

[0019] Preferably, in step B, the oil phase accounts for 20-40% of the total mass of the oil phase and the water phase, more preferably 25-35%, and even more preferably 25-30%.

[0020] Preferably, in step C, the post-processing is vacuum freeze-drying.

[0021] Preferably, step C further includes collecting the microspheres. The method for collecting the microspheres is to first use a vacuum pump to draw them under negative pressure, and then dry them at 30°C to obtain the finished microspheres.

[0022] Most preferably, the present invention provides a method for preparing vitamin K1 sustained-release microspheres, comprising the following steps:

[0023] (1) Add polylactic acid-polyhydroxyacetic acid to a mixed organic solution of benzyl alcohol and polyoxyethylene (35) castor oil and stir, the weight percentage being 18-25% of the oil phase mass, until dissolved and mixed evenly. Add vitamin K1 and stir evenly to form the oil phase.

[0024] (2) Prepare a glucose aqueous solution with a weight percentage of 25-30% using glucose and deionized water, add hydroxypropyl cellulose, stir to dissolve, mix evenly, and use hydroxypropyl cellulose as the aqueous phase with a weight percentage of 5-10%, preferably 8%.

[0025] (3) The oil phase from step (1) is slowly added to the aqueous phase under the action of a high-shear emulsifier to form a water / oil composite system. The rotation speed is 5000-7000 RPM, and the shearing is continued for 1-3 hours, preferably 1.5-2 hours, to obtain an oil / water stabilized emulsion with uniform emulsion particles.

[0026] (4) The oil / water stabilized emulsion was vacuum freeze-dried to obtain vitamin K1 sustained-release microspheres.

[0027] (5) Collecting microspheres. The method for collecting microspheres is to first use a vacuum pump to draw them under negative pressure, and then dry them at 30°C to obtain the finished microspheres.

[0028] It should be noted that steps (1) and (2) can be performed in any order as described above, that is, the present invention does not restrict the preparation order of the aqueous phase and the oil phase.

[0029] The vitamin K1 sustained-release microspheres prepared by the method of the present invention were tested and found to have a particle size of 180-240 nm and an encapsulation efficiency of 80-90%.

[0030] The beneficial effects of this invention are:

[0031] This invention uses suitable oil phase, aqueous phase, and suitable controlled-release or sustained-release materials, and adopts a new preparation process to effectively overcome the problems of unstable chemical properties and sensitivity to light and heat of vitamin K1, and has a long-lasting controlled-release function, and obtains sustained-release microspheres with relatively stable chemical properties.

[0032] This preparation method significantly improves the stability of vitamin K1, mitigating its photosensitive properties. Furthermore, the resulting dosage form is relatively stable, overcoming the thermal instability of vitamin K1. The method yields high encapsulation efficiency, producing smooth, round, and uniformly shaped sustained-release microspheres that are white, fine, loose, non-collapsed, non-adhesive, and exhibit good redispersibility.

[0033] The vitamin K1 sustained-release microspheres of the present invention have a particle size between 180 and 240 nm; the extremely small particle size range enables the microspheres to achieve a better targeting effect, directly reaching the bleeding point, effectively controlling the amount of bleeding, and resulting in good clinical efficacy.

[0034] This invention extends the release time of the drug, providing a long-lasting sustained-release function and improving drug release efficacy. This dosage form ensures the drug effectively acts on the bleeding site, maintaining a high concentration for a longer period, which can greatly improve efficacy, reduce toxic side effects, and offers more stable quality and good clinical safety.

[0035] The vitamin K1 sustained-release microspheres of the present invention can be used for ischemia and hemorrhage caused by vitamin K deficiency, such as obstructive jaundice, bile fistula, bleeding caused by chronic diarrhea, hypoprothrombinemia caused by coumarins, sodium salicylate, etc., neonatal hemorrhage, and vitamin K deficiency caused by long-term use of broad-spectrum antibiotics. Attached Figure Description

[0036] Figure 1 This is a graph showing the cumulative release rate of vitamin K1 sustained-release microspheres obtained in Examples 1-2 and Comparative Example 1 of the present invention. Detailed Implementation

[0037] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0038] Example 1: Preparation of Vitamin K1 sustained-release microspheres

[0039] (1) Add 8.7534g of polylactic acid-polyhydroxyacetic acid to a mixed organic solution of 7.5167g of benzyl alcohol and 2.5205g of polyoxyethylene (35) castor oil and stir until dissolved and mixed evenly. Add 18.7497g of vitamin K1 and stir evenly to form the oil phase.

[0040] (2) Prepare a 30% glucose aqueous solution by weight using 27.0831g glucose and 63.0492g deionized water, add 7.5024g hydroxypropyl cellulose, stir to dissolve, mix evenly, and use as the aqueous phase.

[0041] (3) Under the action of a high-shear emulsifier, the oil phase is slowly added to the water phase at a speed of 5000 RPM to form an oil / water composite system. The shearing is continued for 1.5 hours.

[0042] (4) The oil / water stabilized emulsion was vacuum freeze-dried to obtain vitamin K1 sustained-release microspheres.

[0043] The prepared vitamin K1 sustained-release microspheres were tested and found to have an average particle size of 205.89 nm and an encapsulation efficiency of 83%.

[0044] Example 2: Preparation of Vitamin K1 sustained-release microspheres

[0045] (1) Add 35.08g of polylactic acid-polyhydroxyacetic acid to a mixed organic solution of 30.05g of benzyl alcohol and 10.07g of polyoxyethylene (35) castor oil and stir until dissolved and mixed evenly. Add 75.03g of vitamin K1 and stir evenly to form the oil phase.

[0046] (2) Prepare a glucose aqueous solution with a weight percentage of 30% using 108.00g glucose and 252.01g deionized water, add 30.05g hydroxypropyl cellulose, stir to dissolve, mix evenly, and use as the aqueous phase.

[0047] (3) Under the action of a high-shear emulsifier, the oil phase is slowly added to the water phase at a speed of 5000 RPM to form an oil / water composite system. The shearing is continued for 2 hours.

[0048] (4) The oil / water stabilized emulsion was vacuum freeze-dried to obtain vitamin K1 sustained-release microspheres.

[0049] Comparative Example 1: Preparation of Vitamin K1 Sustained-Release Microspheres

[0050] (1) Add 10.15g of polylactic acid-polyhydroxyacetic acid to a mixed organic solution of 30.01g of benzyl alcohol and 10.10g of polyoxyethylene (35) castor oil and stir until dissolved and mixed evenly. Add 75.00g of vitamin K1 and stir evenly to form the oil phase.

[0051] (2) Prepare a glucose aqueous solution with a weight percentage of 30% using 107.93g glucose and 252.13g deionized water, add 30.06g hydroxypropyl cellulose, stir to dissolve, mix evenly, and use as the aqueous phase.

[0052] (3) Under the action of a high-shear emulsifier, the oil phase is slowly added to the water phase at a speed of 5000 RPM to form an oil / water composite system, and shearing is continued for 2 hours.

[0053] (4) The oil / water stabilized emulsion was vacuum freeze-dried to obtain vitamin K1 sustained-release microspheres.

[0054] Table 1. Encapsulation efficiency of vitamin K1 sustained-release microspheres (%)

[0055]

[0056]

[0057] Example 3: Preparation of Vitamin K1 sustained-release microspheres

[0058] (1) Add 35.02g of polylactic acid-polyhydroxyacetic acid to a mixed organic solution of 30.22g of benzyl alcohol and 10.15g of polyoxyethylene (35) castor oil and stir until dissolved and mixed evenly. Add 75.01g of vitamin K1 and stir evenly to form the oil phase.

[0059] (2) Prepare a glucose aqueous solution with a weight percentage of 30% using 108.16g glucose and 251.97g deionized water, add 30.09g hydroxypropyl cellulose, stir to dissolve, mix evenly, and use as the aqueous phase.

[0060] (3) Under the action of a high-shear emulsifier, the oil phase is slowly added to the water phase at a speed of 5000 RPM to form an oil / water composite system, and shearing is continued for 4 hours.

[0061] (4) The oil / water stabilized emulsion was vacuum freeze-dried to obtain vitamin K1 sustained-release microspheres.

[0062] Example 4: Preparation of Vitamin K1 sustained-release microspheres

[0063] (1) Add 35.21g of polylactic acid-polyhydroxyacetic acid to a mixed organic solution of 30.03g of benzyl alcohol and 10.09g of polyoxyethylene (35) castor oil and stir until dissolved and mixed evenly. Add 75.00g of vitamin K1 and stir evenly to form the oil phase.

[0064] (2) Prepare a glucose aqueous solution with a weight percentage of 30% using 108.02g glucose and 252.03g deionized water, add 30.01g hydroxypropyl cellulose, stir to dissolve, mix evenly, and use as the aqueous phase.

[0065] (3) Under the action of a high-shear emulsifier, the oil phase is slowly added to the water phase at a speed of 7000 RPM to form an oil / water composite system, and shearing is continued for 2 hours.

[0066] (4) The oil / water stabilized emulsion was vacuum freeze-dried to obtain vitamin K1 sustained-release microspheres.

[0067] Table 2. Detection results of vitamin K1 sustained-release microsphere particle size (nm)

[0068]

[0069] Comparative Example 2: Preparation of Vitamin K1 Sustained-Release Microspheres

[0070] (1) Add 35.07g of polylactic acid-polyhydroxyacetic acid to a mixed organic solution of 30.01g of benzyl alcohol and 10.03g of polyoxyethylene (35) castor oil and stir until dissolved and mixed evenly. Add 75.05g of vitamin K1 and stir evenly to form the oil phase.

[0071] (2) Prepare a glucose aqueous solution with a weight percentage of 30% using 108.06g glucose and 252.08g deionized water, stir to dissolve, mix evenly, and use as the aqueous phase.

[0072] (3) Under the action of a high-shear emulsifier, the oil phase is slowly added to the water phase at a speed of 5000 RPM to form an oil / water composite system. The shearing is continued for 2 hours.

[0073] (4) The oil / water stabilized emulsion was vacuum freeze-dried to obtain vitamin K1 sustained-release microspheres.

[0074] Experimental Example 1: Stability of Vitamin K1 Sustained-Release Microspheres

[0075] The stability of vitamin K1 sustained-release microspheres was investigated under conditions of 40℃ and 5000 lx light irradiation. The results are as follows:

[0076] Table 3. Results of stability study of vitamin K1 sustained-release microspheres

[0077]

[0078] According to the results of the investigation, the formulation of the present invention has good resistance to light and heat; and the addition of the film-forming agent increases the light resistance to a certain extent.

[0079] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing photothermally stable vitamin K1 sustained-release microspheres, characterized in that, Includes the following steps: A. Vitamin K1 is mixed with a sustained-release or controlled-release material in an organic solution to form an oil phase; and an aqueous phase containing a film-forming agent is prepared; the organic solution is a composite organic solvent formed by two types of organic solvents, one of which is an alcohol solvent and the other is polyoxyethylene 35 castor oil, wherein the alcohol solvent is selected from ethanol, methanol, propylene glycol or benzyl alcohol; the film-forming agent is selected from at least one of hydroxypropyl cellulose and hydroxypropyl methylcellulose; the sustained-release or controlled-release material is selected from at least one of polylactic acid, polyglycolic acid, polylactic-polyglycolic acid, and polycaprolactone; the mass of the sustained-release or controlled-release material is 15-30% of the mass of the oil phase. B. The oil phase is slowly added to the aqueous phase for solidification to form an oil / water stable emulsion; C. The oil / water stabilized emulsion is post-processed to obtain vitamin K1 sustained-release microspheres.

2. The method according to claim 1, characterized in that, In step A, the mass of the sustained-release or controlled-release material is 18-25% of the mass of the oil phase.

3. The method according to claim 1, characterized in that, In step A, the mass ratio of polyoxyethylene 35 castor oil in the organic solution is 3-13%.

4. The method according to claim 3, characterized in that, In step A, the mass ratio of polyoxyethylene 35 castor oil in the organic solution is 5-10%.

5. The method according to claim 4, characterized in that, In step A, the mass ratio of polyoxyethylene 35 castor oil in the organic solution is 6-9%.

6. The method according to claim 1, characterized in that, In step A, the mass content of vitamin K1 in the oil phase is 30-60%.

7. The method according to claim 6, characterized in that, In step A, the mass content of vitamin K1 in the oil phase is 45-55%.

8. The method according to claim 7, characterized in that, In step A, the mass content of vitamin K1 in the oil phase is 48-53%.

9. The method according to claim 1, characterized in that, In step A, the mass content of the film-forming agent in the aqueous phase is 2-20%.

10. The method according to claim 9, characterized in that, In step A, the film-forming agent has a mass content of 5-15% in the aqueous phase.

11. The method according to claim 10, characterized in that, In step A, the film-forming agent has a mass content of 5-10% in the aqueous phase.

12. The method according to claim 1, characterized in that, In step A, the aqueous phase also contains glucose, and the glucose content in the aqueous phase is 20-40% by mass.

13. The method according to claim 12, characterized in that, In step A, the aqueous phase also contains glucose, and the glucose content in the aqueous phase is 22-35% by mass.

14. The method according to claim 13, characterized in that, In step A, the aqueous phase also contains glucose, and the glucose content in the aqueous phase is 25-30% by mass.

15. The method according to claim 1, characterized in that, In step B, the oil phase is slowly added to the aqueous phase under the action of a high-shear emulsifier to form an oil / water stable emulsion, with a rotation speed of 5000~7000 RPM and continuous shearing for 1-3 hours.

16. The method according to claim 1, characterized in that, In step B, the oil phase accounts for 20-40% of the total mass of the oil and water phases.

17. The method according to claim 16, characterized in that, In step B, the oil phase accounts for 25-35% of the total mass of the oil and water phases.

18. The method according to claim 17, characterized in that, In step B, the oil phase accounts for 25-30% of the total mass of the oil and water phases.

19. The method according to claim 1, characterized in that, In step C, the post-processing is vacuum freeze drying.

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