Vitamin K1 pharmaceutical composition, preparation prepared from composition as well as preparation method and application of vitamin K1 pharmaceutical composition

Abstract

The invention relates to a vitamin K1 composition, a vitamin K1 preparation prepared from the composition as well as a preparation method and application of the vitamin K1 preparation. Compared with the prior art, the vitamin K1 preparation disclosed by the invention not only has excellent dissolution property and pharmacokinetic characteristics, but also can remarkably inhibit the generation of impurities in the production and transportation processes, and shows higher stability, so that the safety of the medicine is effectively improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to vitamin K1 pharmaceutical compositions, formulations prepared from the compositions, their preparation methods, and their uses. Background Technology

[0002] Vitamin K1 (Phylloquinone, Phytonadione, Phytomenadione), also known as phylloquinone or plant-derived menadione, is a clear, yellow to amber-colored viscous liquid. It is insoluble in water, soluble in chloroform, and slightly soluble in ethanol. It is used to treat various coagulation disorders caused by vitamin K deficiency or impaired vitamin K activity.

[0003] Because vitamin K1 is a water-insoluble viscous liquid, preparing vitamin K1 oral solid dosage forms is more difficult than conventional oral solid dosage forms. For example, it is difficult to obtain a free-flowing powder when mixing the liquid active ingredient with solid pharmaceutical excipients. In addition, directly mixing vitamin K1 with solid pharmaceutical excipients can lead to localized aggregation of vitamin K1 in the formulation, causing problems with content uniformity.

[0004] Furthermore, tableting liquid vitamin K1 with suitable excipients presents significant technical challenges because viscous liquids tend to migrate to the formulation surface under pressure. However, increasing pressure to improve tablet strength may adversely affect key properties such as disintegration time and dissolution profile. More importantly, vitamin K1 exhibits extremely low solubility in aqueous media in the gastrointestinal tract, a characteristic that directly leads to a significant reduction in its bioavailability.

[0005] US2018 / 0177735A1 discloses a vitamin K1 formulation and its preparation method. The method involves dispersing vitamin K1 in an aqueous binder solution or organic solution to form a dispersion, using the dispersion to granulate inner particulate materials (such as diluents or disintegrants), drying, sieving, mixing with outer particulate materials, lubricating, and then compressing into tablets. Summary of the Invention

[0006] The purpose of this invention is to provide a novel vitamin K1 pharmaceutical composition, a vitamin K1 formulation prepared from the composition, a method for preparing the formulation, and its uses. Compared with the prior art, the vitamin K1 formulation of this invention has lower impurity levels and exhibits excellent dissolution properties and bioavailability.

[0007] In a first aspect, the present invention provides a vitamin K1 pharmaceutical composition comprising an internal additive and an external additive; wherein the internal additive comprises, based on the total weight of the vitamin K1 composition: 3.0%-4.0% of the active ingredient vitamin K1; 15.0%-25.0% of a first filler lactose; 15.0%-25.0% of a second filler microcrystalline cellulose; 4.0%-6.0% of a disintegrant croscarmellose sodium; and 1.5%-3.5% of a binder hydroxypropyl cellulose; the external additive comprises, based on the total weight of the vitamin K1 composition: 15.0%-25.0% of the first filler lactose; 15.0%-25.0% of the second filler microcrystalline cellulose; 0.5%-1.5% of a flow aid gel silica; and 0.5%-1.5% of a lubricant magnesium stearate.

[0008] In a second aspect, the present invention also provides a method for preparing a vitamin K1 formulation, comprising: a. providing a vitamin K1 composition as described in the first aspect; b. sieving the lactose and croscarmellose sodium in the added material separately, and mixing them with the microcrystalline cellulose in the added material as a base material; c. preparing the hydroxypropyl cellulose in the added material into a solution, and dispersing the vitamin K1 therein to obtain an active ingredient solution; d. granulating the base material using the active ingredient solution, drying it, and then performing a dry granulation process to obtain dry granules; e. sieving the lactose and gelled silica in the added material separately, mixing them with the dry granules from step d and the microcrystalline cellulose in the added material, and then adding the sieved magnesium stearate for lubrication to obtain a total mixture; f. compressing the total mixture into tablets to obtain vitamin K1 tablets; and g. optionally, packaging the vitamin K1 tablets.

[0009] Thirdly, the present invention also provides a vitamin K1 preparation, which is prepared from the vitamin K1 composition of the first aspect of the present invention or by the preparation method of the second aspect of the present invention.

[0010] Fourthly, the present invention also relates to the use of the vitamin K1 composition of the first aspect or the vitamin K1 preparation of the third aspect in the preparation of a medicament for treating coagulation disorders related to vitamin K deficiency or interference with its activity. Detailed Implementation

[0011] The present invention will now be described in further detail. This description is for illustrative purposes only and is not intended to limit the invention. Those skilled in the art will readily understand other advantages and effects of the invention from the disclosure herein. The invention can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and changes without departing from the spirit of the invention.

[0012] General definitions and terms

[0013] Unless otherwise stated, all publications, patent applications, patents and other references mentioned herein are incorporated herein in their entirety by way of citation.

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions provided herein shall prevail.

[0015] When a quantity, concentration, or other value or parameter is expressed as a range, preferred range, or preferred upper and lower limits, it should be understood that this is equivalent to specifically disclosing any range by combining any pair of upper or preferred values ​​with any lower or preferred values, regardless of whether the range is specifically disclosed. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions within that range. For example, "15.0%-25.0%" encompasses 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 21.9%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, 25.0%, etc., as well as any subrange consisting of any two of these values, such as 16.0%-24.0%, 18.0%-23.0%, 21.5%-22.5%, etc.

[0016] When used with a numerical variable, the terms “about” or “approximately” usually mean that the value of the variable and all values ​​of the variable are within the experimental error (e.g., within a 95% confidence interval for the mean) or within ±10% of the specified value, or a wider range (e.g., within ±15%).

[0017] Furthermore, if the number of components or parts of the present invention is not previously specified, it indicates that there is no limitation on the number of times a component or part may appear (or be present). Therefore, it should be interpreted as including one or at least one, and the singular form of a component or part also includes the plural, unless the value explicitly indicates a singular number. When methods, components, or steps are described, the use of letters or numbers for identification purposes is for distinguishing purposes only and does not imply that these methods, components, or steps must be performed in the indicated order or sequence. Those skilled in the art can make reasonable adjustments. For example, "first filler" and "second filler" are used for distinguishing purposes only and do not indicate an order or sequence relationship between them; the objects referred to by different identifiers may be the same or different.

[0018] The term “optional” or “optional existence” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0019] The expressions "comprising," or similar synonyms such as "including," "containing," and "having," are open-ended and do not exclude additional unlisted elements, steps, or components. The expression "consisting of," excludes any unspecified elements, steps, or components. The expression "substantially consisting of," limits the scope to the specified elements, steps, or components, plus optional elements, steps, or components that do not materially affect the essential and novel features of the claimed subject matter. It should be understood that the expressions "comprising," "covering," "substantially consisting of," and "consisting of" are not synonymous.

[0020] The term "one or more" can mean 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0021] The term "pharmaceutical composition" refers to a substance consisting of an active ingredient and one or more pharmaceutically acceptable excipients. In this invention, it may be simply referred to as a composition; for example, pharmaceutical composition 1-1 may be simply referred to as composition 1-1.

[0022] The term "pharmaceuticalally acceptable excipient" refers to carrier substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceuticalally acceptable excipients" include, but are not limited to, fillers, binders, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, lubricants, dispersants, disintegrants, stabilizers, solvents, emulsifiers, or coating agents. In some embodiments, pharmaceutically acceptable excipients include fillers (e.g., first and second fillers), binders, disintegrants, lubricants, flow aids, and optionally, coating agents.

[0023] The terms "pharmaceutical product," "pharmaceutical dosage form," "dosage form," and "pharmaceutical preparation" refer to a pharmaceutical composition administered to a patient in need of treatment, which can typically take the following forms: powder, granules, pills, capsules, tablets, solutions, suspensions, or patches. In some embodiments, the pharmaceutical dosage form of the present invention is a tablet.

[0024] In this invention, the term "content uniformity calculation value (A+2.2S)" refers to the value of A+2.2S calculated according to the "content uniformity test method" in General Chapter 0941 of Part IV of the Chinese Pharmacopoeia, used to quantify the dispersion of the content of the active ingredient in the preparation. Here, A represents the absolute deviation between the average content of the active ingredient (e.g., vitamin K1) in the test sample and the labeled content; S represents the standard deviation of the content of all test samples.

[0025] The composition of the present invention

[0026] This invention provides a vitamin K1 composition comprising an internal additive and an external additive;

[0027] in,

[0028] The added material comprises, based on the total weight of the vitamin K1 composition:

[0029] 3.0%-4.0% of the active ingredient, Vitamin K1;

[0030] 15.0%-25.0% of lactose as the primary filler;

[0031] 15.0%-25.0% of the second filler, microcrystalline cellulose;

[0032] 4.0%-6.0% of the disintegrant croscarmellose sodium; and

[0033] 1.5%-3.5% hydroxypropyl cellulose binder;

[0034] The added material comprises, based on the total weight of the vitamin K1 composition:

[0035] 15.0%-25.0% of lactose as the primary filler;

[0036] 15.0%-25.0% of the second filler, microcrystalline cellulose;

[0037] 0.5%-1.5% of the flow aid gel silica; and

[0038] 0.5%-1.5% magnesium stearate as a lubricant.

[0039] The composition of the present invention comprises internal and external additives, and through the specific combination of the components therein, not only is it ensured that vitamin K1 reaches an appropriate drug content, but the vitamin K1 preparation therefrom also exhibits excellent performance in terms of drug uniformity, stability and bioavailability, thereby significantly improving the safety and efficacy of the drug.

[0040] Added materials

[0041] The added material is included in the preparation process of vitamin K1 formulations, and the components are prepared into granules by granulation. In this invention, the added material includes the active ingredient vitamin K1, a first filler lactose, a second filler microcrystalline cellulose, a disintegrant croscarmellose sodium, and a binder hydroxypropyl cellulose. In some embodiments, the added material is prepared into granules by a granulation process: an active ingredient solution containing the active ingredient and binder in an organic solvent (such as anhydrous ethanol) is sprayed onto the surface of a substrate material and dried to obtain the granules; wherein the substrate material contains the first filler lactose, the second filler microcrystalline cellulose, and the disintegrant croscarmellose sodium. In other embodiments, the substrate material is granulated using a fluidized bed processor with an active ingredient solution containing the active ingredient and binder in anhydrous ethanol as a solvent, and dried to obtain the granules; wherein the substrate material contains the first filler lactose, the second filler microcrystalline cellulose, and the disintegrant croscarmellose sodium.

[0042] In some embodiments, the content of the active ingredient vitamin K1 in the added material is about 3.0%-4.0% based on the total weight of the vitamin K1 composition, preferably 3.4%-3.8%, more preferably 3.5%-3.7%, for example, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9% or 4.0%.

[0043] In some embodiments, based on the total weight of the vitamin K1 composition, the content of the first filler lactose in the added material is about 15.0%-25.0%, preferably 20.0%-24.0%, more preferably 21.0%-23.0%, for example 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 21.8%, 21.9%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, or 25.0%.

[0044] In some embodiments, the content of the second filler microcrystalline cellulose in the added material is about 15.0%-25.0% based on the total weight of the vitamin K1 composition, preferably 20.0%-24.0%, more preferably 21.0%-23.0%, for example 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 21.8%, 21.9%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, or 25.0%.

[0045] In some embodiments, based on the total weight of the vitamin K1 composition, the content of the disintegrant croscarmellose sodium in the added material is 4.0%-6.0%, preferably 4.5%-5.5%, more preferably 4.8%-5.2%, for example 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%, or 6.0%.

[0046] In some embodiments, the content of the binder hydroxypropyl cellulose in the added material is about 1.5%-3.5% based on the total weight of the vitamin K1 composition, preferably 1.8%-3.2%, more preferably 2.0%-3.0%, for example 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, or 3.5%.

[0047] Added materials

[0048] The additives comprise components that are not granulated during the preparation of the vitamin K1 formulation. In this invention, the additives include a first filler (lactose), a second filler (microcrystalline cellulose), a flow aid (gelatinized silica), and a lubricant (magnesium stearate).

[0049] In some embodiments, based on the total weight of the vitamin K1 composition, the content of the first filler lactose in the additive is about 15.0%-25.0%, preferably 20.0%-24.0%, more preferably 21.0%-23.0%, for example 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 21.8%, 21.9%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, or 25.0%.

[0050] In some embodiments, the content of the second filler microcrystalline cellulose in the additive material is about 15.0%-25.0% based on the total weight of the vitamin K1 composition, preferably 20.0%-24.0%, more preferably 21.0%-23.0%, for example 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 21.8%, 21.9%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, or 25.0%.

[0051] In some embodiments, the content of the flow aid gel silica in the additive material is about 0.5%-1.5% based on the total weight of the vitamin K1 composition, preferably 0.6%-1.4%, more preferably 0.8%-1.2%, for example 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4% or 1.5%.

[0052] In some embodiments, the content of magnesium stearate, a lubricant, in the additive is about 0.5%-1.5% based on the total weight of the vitamin K1 composition, preferably 0.6%-1.4%, more preferably 0.8%-1.2%, for example 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%.

[0053] Preparation method of the present invention

[0054] The present invention also provides a method for preparing a vitamin K1 preparation, comprising:

[0055] a. Providing the vitamin K1 composition of the present invention as described above;

[0056] b. The lactose and croscarmellose sodium cellulose in the added material are sieved separately and then mixed with the microcrystalline cellulose in the added material as the base material;

[0057] c. Prepare a solution of hydroxypropyl cellulose in the added material, and disperse vitamin K1 into it to obtain an active ingredient solution;

[0058] d. Granulate the base material using an active ingredient solution, dry it, and then perform dry granulation to obtain dry granules;

[0059] e. The lactose and gelled silica in the additives are sieved separately, and then mixed with the dry granules in step d and the microcrystalline cellulose in the additives. The sieved magnesium stearate is then added for lubrication to obtain the total mixture.

[0060] f. Compress the total mixture into tablets to obtain vitamin K1 tablets; and

[0061] g. Optionally, package the vitamin K1 tablets.

[0062] In some embodiments, the sieving process in step b is sieving through a 30-mesh sieve. In other embodiments, the mixing in step b includes loading the lactose and croscarmellose sodium from the sieved additives into a fluidized bed processor for mixing with the microcrystalline cellulose from the additives.

[0063] In some implementations, the solvent used for the active ingredient solution in step c is anhydrous ethanol.

[0064] In some embodiments, granulation in step d is performed using a fluidized bed processor. In other embodiments, drying in step d is performed using a fluidized bed processor. In still other embodiments, the drying process in step d is controlled to result in a drying loss of no more than about 3.0%, for example, 3.0%, 2.9%, 2.8%, 2.7%, 2.6%, 2.5%, 2.4%, 2.3%, 2.2%, 2.1%, 2.0%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5%. In some embodiments, the dry granulation process in step d can be performed using any granulation method conventional in the art. For example, granulation can be performed using a granulator.

[0065] In some embodiments, the sieving process in step e is passing through a 30-mesh sieve. In some embodiments, the mixing and / or lubrication in step e can be carried out by any mixing method conventional in the art. For example, mixing and / or lubrication can be performed using a mixer.

[0066] In some implementations, the tableting in step f is performed using a tableting machine.

[0067] In some implementations, the packaging in step g can be performed using any packaging method conventional in the art. For example, using an aluminum-plastic blister packaging machine, a bottling line (counting machine, capping machine), a bagging machine, etc.

[0068] The preparation method of the present invention is simple and convenient to operate, and has good applicability to industrial production.

[0069] The vitamin K1 formulation of the present invention

[0070] The present invention also relates to a vitamin K1 preparation, which is prepared from the vitamin K1 composition of the present invention as described above or by the preparation method of the present invention as described above.

[0071] The vitamin K1 formulation of the present invention exhibits excellent performance in terms of drug content uniformity, dissolution characteristics, bioavailability and drug stability, which not only provides a reliable guarantee for drug production and transportation, but also effectively ensures medication safety.

[0072] In some embodiments, the vitamin K1 formulation of the present invention is a tablet.

[0073] In some embodiments, the vitamin K1 formulation of the present invention, after being placed under long-term stability conditions at 25°C / 60% relative humidity for 3 months, has a total impurity content of no more than about 0.6%, preferably 0.4%, and more preferably 0.2%. In other embodiments, the vitamin K1 formulation of the present invention, after being placed under long-term stability conditions at 25°C / 60% relative humidity for 3 months, has a total impurity content of no more than about 0.5%, preferably 0.3%, and more preferably 0.1%. In still other embodiments, the vitamin K1 formulation, after being placed under accelerated conditions at 40°C / 75% relative humidity for 3 months, has a total impurity content of no more than about 0.6%, preferably 0.4%, and more preferably 0.2%.

[0074] In some embodiments, the vitamin K1 formulation of the present invention, after being placed under long-term stability conditions at 25°C / 60% relative humidity for 6 months, has a total impurity content of no more than about 0.6%, preferably 0.4%, and more preferably 0.2%. In other embodiments, the vitamin K1 formulation of the present invention, after being placed under accelerated conditions at 40°C / 75% relative humidity for 6 months, has a total impurity content of no more than about 0.6%, preferably 0.4%, and more preferably 0.2%.

[0075] In some embodiments, the vitamin K1 formulation of the present invention, after being placed under long-term stability conditions of 25°C / 60% relative humidity for 3 months, exhibits a drug content change of no more than about 0.6%, preferably 0.4%, and more preferably 0.3%. In some embodiments, the vitamin K1 formulation of the present invention, after being placed under accelerated conditions of 40°C / 75% relative humidity for 3 months, exhibits a drug content change of no more than about 0.6%, preferably 0.5%, and more preferably 0.4%.

[0076] In some embodiments, the vitamin K1 formulation of the present invention, after being placed under long-term stability conditions at 25°C / 60% relative humidity for 6 months, exhibits a drug content change of no more than about 0.6%, preferably 0.4%, and more preferably 0.3%. In some embodiments, the vitamin K1 formulation of the present invention, after being placed under accelerated conditions at 40°C / 75% relative humidity for 6 months, exhibits a drug content change of no more than about 0.9%, preferably 0.8%, and more preferably 0.75%.

[0077] In some embodiments, the calculated content uniformity of the vitamin K1 formulation of the present invention does not exceed about 5.0, preferably not more than 3.5, more preferably not more than 2.5, for example 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1 or 1.0.

[0078] In some embodiments, using a 0.1 mol / L hydrochloric acid solution containing 0.5% Triton X-100 as the dissolution medium, and testing by paddle method at a rotation speed of 50 rpm, the vitamin K1 formulation of the present invention exhibits a dissolution rate of not less than about 80% after 15 minutes, preferably not less than 85%, more preferably not less than 87%, for example 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%. In other embodiments, using a 0.1 mol / L hydrochloric acid solution containing 0.5% Triton X-100 as the dissolution medium, and testing by paddle method at a rotation speed of 50 rpm, the vitamin K1 formulation of the present invention exhibits a dissolution rate of not less than 90% after 30 minutes, preferably 91%, more preferably 92%, for example 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, the volume of a 0.1 mol / L hydrochloric acid solution containing 0.5% Triton X-100 as the dissolution medium is 900 mL. In some embodiments, the paddle method for determining dissolution according to the present invention includes Method II of Dissolution Determination in General Chapter 0931 of the Chinese Pharmacopoeia.

[0079] The present invention also relates to the use of the vitamin K1 pharmaceutical composition or vitamin K1 preparation of the present invention in the preparation of a medicament for treating coagulation disorders associated with vitamin K deficiency or impaired activity.

[0080] It should be understood that, within the scope of this invention, the above-described technical features of this invention, as well as the technical features specifically described below (such as in the embodiments), can be combined with each other to form new or preferred technical solutions.

[0081] Beneficial effects

[0082] The vitamin K1 pharmaceutical composition of the present invention comprises internal and external additives. By appropriately proportioning each component, it not only ensures that vitamin K1 reaches an appropriate pharmaceutical content, but also exhibits significant advantages in several key performance aspects, while being easy to industrialize.

[0083] The formulations prepared from the compositions of the present invention exhibit good stability, with impurity levels reduced by more than approximately 60% compared to existing technologies (e.g., US2018 / 0177735A1). Simultaneously, the formulations prepared from the compositions of the present invention demonstrate excellent drug content accuracy, content uniformity, dissolution rate, and bioavailability. For example, after being stored at 40°C / 75% relative humidity for 6 months, the drug content of the formulations of the present invention remains above 98% of the labeled amount; the content uniformity of the formulations of the present invention meets quality requirements; the dissolution rate of the formulations of the present invention reaches above 94%; and the formulations of the present invention exhibit excellent pharmacokinetic characteristics.

[0084] Furthermore, the preparation method of the present invention is simple in process and convenient in operation, and has good applicability to industrial production.

[0085] Example

[0086] The present invention will now be described in further detail with reference to specific embodiments.

[0087] It should be noted that the following embodiments are merely examples to clearly illustrate the technical solutions of the present invention, and are not intended to limit the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here, and obvious variations or modifications derived therefrom are still within the protection scope of this invention. Unless otherwise specified, the instruments, equipment, and reagents used herein are commercially available.

[0088] 1. Methods for testing drug content

[0089] Preparation of the test solution: Take 20 sample tablets, accurately weigh them and grind them into a fine powder using an agate mortar; accurately weigh an appropriate amount of fine powder (approximately equivalent to 20 mg of vitamin K1), transfer it to a 200 mL brown volumetric flask, add about 120 mL of anhydrous ethanol, sonicate for 5 minutes to dissolve vitamin K1, wait for the solution to cool to room temperature, dilute to the mark with anhydrous ethanol, shake well, filter, and collect the filtrate.

[0090] Preparation of reference solution: Take an appropriate amount of vitamin K1 reference standard, accurately weigh it, dissolve it in anhydrous ethanol and dilute it quantitatively to prepare a solution containing approximately 0.1 mg of vitamin K1 per 1 mL.

[0091] Chromatographic conditions: Waters μBondapak C18 column, 3.9 mm × 300 mm, 10 μm; mobile phase: anhydrous ethanol-water (95:5); flow rate: 1.5 mL / min; column temperature: 30 °C; detection wavelength: 254 nm; injection volume: 10 μL.

[0092] Determination method: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the vitamin K1 content based on peak area using the external standard method.

[0093] 2. Test method for drug content uniformity

[0094] Take one sample tablet, crush it completely, and transfer it to a 50mL brown volumetric flask. Add an appropriate amount of anhydrous ethanol and sonicate for 5 minutes to dissolve the vitamin K1. After the solution cools to room temperature, dilute it to the mark with anhydrous ethanol, shake well, filter, and use the filtrate as the test solution. Determine the vitamin K1 content according to the above-described drug content test method.

[0095] 3. Test methods for impurity content

[0096] Preparation of the test solution: Take 10 sample tablets, accurately weigh them and grind them into a fine powder using an agate mortar; accurately weigh an appropriate amount of fine powder (approximately equivalent to 20 mg of vitamin K1), transfer it to a 10 mL brown volumetric flask, add about 6 mL of acetonitrile, sonicate for 10 minutes to dissolve vitamin K1, wait for the solution to cool to room temperature, dilute to the mark with acetonitrile, shake well, centrifuge, and take the supernatant.

[0097] Preparation of reference solution: Take an appropriate amount of vitamin K1 reference standard, accurately weigh it, dissolve it in acetonitrile and dilute it quantitatively to prepare a solution containing approximately 4 μg of vitamin K1 per 1 mL.

[0098] Preparation of sensitivity solution: Accurately measure an appropriate amount of reference solution and dilute quantitatively with acetonitrile to prepare a solution containing approximately 2 μg of vitamin K1 per mL.

[0099] Chromatographic conditions: GL Sciences Inertsil ODS-3V, 4.6 mm × 250 mm, 3 μm column was used; anhydrous ethanol was used as mobile phase A and acetonitrile as mobile phase B, with gradient elution performed according to the table below; flow rate was 1.0 mL per minute; column temperature was 35 °C; detection wavelength was 245 nm; injection volume was 20 μL.

[0100] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0.0 10 90 1.0 10 90 15.0 0 100 60.0 0 100 60.1 10 90 65.0 10 90

[0101] Assay method: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. If impurity peaks are present in the chromatogram of the test solution, calculate the impurity value based on peak area using the external standard method.

[0102] 4. Dissolution test method

[0103] Dissolution conditions: Use 900 mL of 0.1 mol / L hydrochloric acid solution containing 0.5% Triton X-100 as the dissolution medium, rotate at 50 rpm, and operate according to the dissolution test method (such as General Chapter 0931 of the Chinese Pharmacopoeia, for example, Dissolution Test Method II (Paddle Method)), and take samples at the specified time.

[0104] Preparation of the test solution: Take an appropriate amount of the dissolution solution, centrifuge, and take the supernatant.

[0105] Preparation of the reference solution: Accurately weigh an appropriate amount of vitamin K1 reference standard, dissolve it in anhydrous ethanol, and dilute quantitatively to prepare a solution containing approximately 0.56 mg of vitamin K1 per mL, which will serve as the reference stock solution. Accurately measure an appropriate amount of the reference stock solution and dilute it quantitatively with a dissolution medium to prepare a solution containing approximately 5.6 μg of vitamin K1 per mL.

[0106] Chromatographic conditions: An Agilent Zorbax SB-C18 column (4.6 mm × 50 mm, 3.5 μm) was used; anhydrous ethanol-water (95:5) was used as the mobile phase; the flow rate was 1.0 mL per minute; the column temperature was 35 °C; the detection wavelength was 248 nm; and the injection volume was 50 μL.

[0107] Assay method: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the amount of vitamin K1 dissolved in each tablet based on peak area using the external standard method.

[0108] 5. Test methods for pharmacokinetic parameters

[0109] A single-center, open-label, randomized, single-dose, four-cycle, two-sequence, fully replicated crossover trial design was used to study the fasting bioequivalence (with a 7-day washout period). Forty enrolled healthy subjects were randomly assigned to two sequences (1 = TRTR, 2 = RTRT). The grouping scheme is shown in the table below:

[0110] sequence First cycle Second cycle Third cycle Fourth cycle 1(20 cases) T R T R 2(20 cases) R T R T

[0111] Blood sample collection method: Venous blood was collected at 24 time points each cycle: 48, 42, 36, 30, 24, 18, 12, 6, and 0 hours before administration (within 60 minutes before administration) and 1.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, and 24 hours after administration. Approximately 3 mL of blood was collected each time. The blood was transferred to vacuum blood collection tubes containing heparin sodium anticoagulant, pre-cooled for at least 15 minutes and labeled. The tubes were gently inverted and mixed 4-8 times, and then temporarily stored in an ice-water bath until centrifugation. After centrifugation at room temperature, the plasma samples were divided into two aliquots and stored in an ultra-low temperature freezer set at -70°C (freezer temperature range: -60°C to -90°C) for biological sample analysis.

[0112] The concentrations of the [E isomer (trans)] and [Z isomer (cis)] of vitamin K1 in each plasma sample were determined using LC-MS / MS (specific parameters are shown in the table below).

[0113]

[0114]

[0115] Example 1: Preparation of Vitamin K1 Tablets T1 and T2

[0116] (1) Composition of the composition:

[0117]

[0118] (2) Preparation methods of Vitamin K1 tablets T1 and Vitamin K1 tablets T2:

[0119] Internal material loading section:

[0120] ① Pretreatment: Lactose and croscarmellose sodium cellulose are passed through a 30-mesh sieve and then loaded into a fluidized bed processor together with microcrystalline cellulose as base materials;

[0121] ② Preparation of active ingredient solution: Hydroxypropyl cellulose was dissolved in anhydrous ethanol to prepare an adhesive solution, and vitamin K1 was dispersed into it to obtain the active ingredient solution;

[0122] ③ Granulation: The substrate material in the fluidized bed processor is granulated using the above-mentioned active ingredient solution to obtain wet granules;

[0123] ④ Drying: The wet granules are dried, and the drying loss is controlled to be no more than 3.0% to obtain coarse granules;

[0124] ⑤ Dry granulation: The coarse particles are subjected to dry granulation to obtain dry granules;

[0125] Additional materials section:

[0126] ⑥ Pretreatment: Pass the lactose and gelled silica through a 30-mesh sieve respectively;

[0127] ⑦ Preparation of the total mixture: Microcrystalline cellulose, the above-sieving lactose and gelled silica and the above-mentioned dry granules are mixed, and magnesium stearate that has passed through a 30-mesh sieve is added for lubrication to obtain the total mixture;

[0128] ⑧ Tableting: Compress the total mixture into tablets to obtain vitamin K1 tablets (vitamin K1 tablets T1 and vitamin K1 tablets T2);

[0129] ⑨ Package the vitamin K1 tablets (vitamin K1 tablet T1 and vitamin K1 tablet T2).

[0130] Test Example 1: Determination of Drug Content and Impurity Content

[0131] The aforementioned methods for testing drug content and impurity content were used to test vitamin K1 tablets T1 and T2 obtained in Example 1. The results are shown in the table below:

[0132]

[0133] Note: RH represents relative humidity.

[0134] As can be seen from the stability test results in the table above, the vitamin K1 tablets prepared from the vitamin K1 pharmaceutical composition of the present invention have an impurity level of only 0.2% after being placed at 25°C / 60%RH for 6 months; and the impurities are also at a low level of 0.2% after being placed at 40°C / 75%RH for 6 months.

[0135] Further analysis showed that the vitamin K1 tablets prepared from the vitamin K1 pharmaceutical composition of the present invention maintained the drug content at essentially the initial level after being stored at 25°C / 60%RH for 6 months; after being stored at 40°C / 75%RH for 6 months, although the drug content changed slightly, the change was no more than 0.75%, demonstrating excellent stability.

[0136] Test Example 2: Determination of Drug Content Uniformity

[0137] The drug content uniformity test method described above was used to test the vitamin K1 tablets T1 and T2 obtained in Example 1. The results are shown in the table below:

[0138]

[0139] As can be seen from the table above, the vitamin K1 tablets prepared from the vitamin K1 pharmaceutical composition of the present invention have an A+2.2S value, which is much lower than the acceptance limit of 15.0 specified in the Chinese Pharmacopoeia 0941 guideline, indicating that the vitamin K1 tablets of the present invention have excellent content uniformity.

[0140] Test Example 3: Determination of Dissolution

[0141] The dissolution test method described above was used to test the vitamin K1 tablets T1 and T2 obtained in Example 1. The results are shown in the table below:

[0142]

[0143] As can be seen from the table above, the vitamin K1 tablets prepared from the vitamin K1 pharmaceutical composition of the present invention exhibit excellent dissolution characteristics: the dissolution rate is not less than 85% at 15 min, the dissolution rate is more than 90% at 30 min, and the dissolution rate is almost completely dissolved at 60 min.

[0144] Test Example 4: Determination of Pharmacokinetic Parameters

[0145] The pharmacokinetic parameters of Vitamin K1 tablets T1 and T2 obtained in Example 1 were tested using the aforementioned pharmacokinetic parameter testing methods. The main pharmacokinetic parameters of the E isomer (trans) of Vitamin K1 are shown in the table below:

[0146]

[0147] As can be seen from the above pharmacokinetic parameters, the C1 of the T1 and T2 formulations is... max The concentrations were 7.8 ng / mL and 8.8 ng / mL, respectively, falling within the 7-9 ng / mL range; AUC 0-t The values ​​were 55.9 hr·ng / mL and 69.1 hr·ng / mL, respectively, covering the 55-70 hr·ng / mL range; AUC 0-inf The corresponding peak plasma concentrations and total in vivo exposures were 64.0 hr·ng / mL and 72.1 hr·ng / mL, respectively, corresponding to exposure levels of 64-73 hr·ng / mL. These data indicate that both formulations exhibited stable peak plasma concentrations and total in vivo exposures, with formulation T2 showing significantly improved parameters compared to T1, demonstrating superior pharmacokinetic characteristics.

[0148] Furthermore, the pharmacokinetic parameters (C) of the vitamin K1 tablets of the present invention are as follows: max AUC 0-t and AUC 0-inf The coefficient of variation of the drug is significantly lower than that disclosed in the existing technology US2018 / 0177735A1, which greatly improves the safety of clinical drug use.

[0149] The embodiments of the present invention have been described in detail above, but the content described is only a preferred embodiment of the present invention and should not be considered as limiting the scope of the present invention. The true scope and spirit of the present invention are shown in the appended claims, and the description and embodiments are merely exemplary.

Claims

1. A vitamin K1 composition comprising an internal additive and an external additive; wherein, The added material contains 3.0%-4.0% of the active ingredient vitamin K1 based on the total weight of the vitamin K1 composition; 15.0%-25.0% of lactose as the primary filler; 15.0%-25.0% of the second filler, microcrystalline cellulose; 4.0%-6.0% disintegrant croscarmellose sodium; as well as 1.5%-3.5% hydroxypropyl cellulose binder; The additive material comprises, based on the total weight of the vitamin K1 composition, 15.0%-25.0% of a first filler, lactose; 15.0%-25.0% of the second filler, microcrystalline cellulose; 0.5%-1.5% of the flow aid gel silica; and 0.5%-1.5% magnesium stearate as a lubricant.

2. The vitamin K1 composition of claim 1, wherein, The added material comprises, based on the total weight of the vitamin K1 composition, 3.5%-3.7% of the active ingredient vitamin K1; and / or 21.0%-23.0% of the first filler, lactose; and / or 21.0%-23.0% of the second filler, microcrystalline cellulose; and / or 4.8%–5.2% of the disintegrant croscarmellose sodium; and / or 2.0%-3.0% of binder hydroxypropyl cellulose.

3. The vitamin K1 composition of claim 1, wherein, The additive material comprises, based on the total weight of the vitamin K1 composition: 21.0%-23.0% of a first filler, lactose; and / or 21.0%-23.0% of the second filler, microcrystalline cellulose; and / or 0.8%-1.2% of a flow aid gelled silica; and / or 0.8%-1.2% magnesium stearate as a lubricant.

4. A method for preparing a vitamin K1 preparation, comprising: a. To provide the vitamin K1 composition as described in claim 1; b. The lactose and croscarmellose sodium cellulose in the added material are sieved separately and then mixed with the microcrystalline cellulose in the added material as a base material; c. Prepare a solution of the hydroxypropyl cellulose in the added material, and disperse the vitamin K1 therein to obtain an active ingredient solution; d. Granulate the base material using the active ingredient solution, dry it, and then perform dry granulation to obtain dry granules; e. The lactose and gelled silica in the added material are sieved separately, and then mixed with the dry-finished particles in step d and the microcrystalline cellulose in the added material. The sieved magnesium stearate is then added for lubrication to obtain the total mixture. f. Compress the total mixture into tablets to obtain vitamin K1 tablets; as well as g. Optionally, the vitamin K1 tablets are packaged.

5. The method of claim 4, wherein, The sieving process in steps b and e is to pass the material through a 30-mesh sieve.

6. The method of claim 4, wherein, The solvent for the active ingredient solution in step c is anhydrous ethanol; and / or In step d, the drying process is controlled to ensure that the drying loss does not exceed 3.0%.

7. A vitamin K1 preparation, which is prepared from a vitamin K1 composition as described in any one of claims 1-3 or by a method as described in any one of claims 4-6.

8. The vitamin K1 preparation of claim 7, wherein, The vitamin K1 preparation, after being stored under long-term stability conditions of 25°C / 60% relative humidity for 3 months, showed a total impurity content not exceeding 0.2%; and / or The vitamin K1 preparation, after being placed under accelerated conditions at 40°C / 75% relative humidity for 3 months, showed a total impurity content not exceeding 0.2%; and / or The vitamin K1 preparation, after being stored under long-term stability conditions of 25°C / 60% relative humidity for 6 months, showed a total impurity content not exceeding 0.2%; and / or The vitamin K1 preparation, after being placed under accelerated conditions of 40°C / 75% relative humidity for 6 months, showed a total impurity content of no more than 0.2%.

9. The vitamin K1 preparation of claim 7, wherein, Using a 0.1 mol / L hydrochloric acid solution containing 0.5% Triton X-100 as the dissolution medium, the test was conducted using the paddle method at a rotation speed of 50 revolutions per minute. The vitamin K1 preparation has a dissolution rate of not less than 80% at 15 minutes; and / or The vitamin K1 preparation has a dissolution rate of not less than 90% at 30 minutes.

10. Use of the vitamin K1 composition of any one of claims 1-3 or the vitamin K1 preparation of any one of claims 7-9 in the preparation of a medicament for treating coagulation disorders associated with vitamin K deficiency or impaired activity.

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