Preparation method for vitamin k 1 injection package, and vitamin k 1 injection package

Abstract

A preparation method for a vitamin K1 injection package, and a vitamin K1 injection package. The preparation method comprises filling, nitrogen flushing, stoppering and rod screwing; in the nitrogen flushing step, sterile nitrogen is introduced into a glass cartridge (1) to reduce oxygen content inside the glass cartridge (1) to 2.0% or less; in the stoppering step, the glass cartridge (1) is evacuated, thereby drawing a plunger (2) into the glass cartridge (1), and the headspace volume is controlled to 0.1-0.2 ml.

Description

Preparation method of vitamin K1 injection package and vitamin K1 injection package

[0001] This application claims priority to the prior application filed with the China National Intellectual Property Office on September 23, 2024, Patent Application No. 202411327016.3, entitled "Preparation method of vitamin K1 injection package and vitamin K1 injection package". The entire contents of the prior application are incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure relates to the field of medical injectors, in particular to a preparation method of vitamin K1 injection package and vitamin K1 injection package. BACKGROUND

[0003] Vitamin K1 deficiency is easy to cause hemorrhage in newborns (HDN), and the incidence of hemorrhage in newborns can be significantly reduced by routine injection of vitamin K1. Vitamin K1 is a fat-soluble vitamin, which is sensitive to oxygen and light. Especially in the form of preparation in water environment, oxidative degradation is more likely to occur, and light will accelerate oxidative degradation at the same time. Therefore, vitamin K1 in the injection package will degrade and produce impurities during long-term storage.

[0004] Domestic vitamin K1 injection mostly uses the method of adding antioxidants in the prescription and controlling the residual oxygen in the headspace to reduce impurities. However, the antioxidants such as sodium pyrosulfite added in the prescription usually have adverse reactions such as hypersensitivity, and the product has safety risks.

[0005] In other ways of the prior art, the reference preparations of vitamin K1 injection (the licensees are Roche, Hospira and International Medication Systems, respectively) all use the method of reducing the residual oxygen amount in the headspace to reduce impurities. The product packages of Roche and Hospira use ampoule bottles, and International Medication Systems uses single-dose vials + SAF-T-Jet injectors. The headspace volume of these two kinds of packages is large, especially the ampoule bottle. Although the nitrogen filling process is used to reduce the proportion of residual oxygen, the large headspace volume leads to high total oxygen amount, and vitamin K1 will still undergo oxidative degradation during long-term storage, resulting in total impurity amount exceeding the 2% limit requirement of the Chinese Pharmacopoeia and maximum single impurity content exceeding the 1% limit requirement of the Chinese Pharmacopoeia.

[0006] In addition, the ampoule bottle package has the risk of secondary pollution in the transfer process of clinical use, because the sterile liquid medicine contacts with air or drug delivery devices. SUMMARY

[0007] The present disclosure provides a preparation method of a vitamin K1 injection package and the vitamin K1 injection package.

[0008] Specifically, the present disclosure is realized by the following technical solutions.

[0009] In a first aspect, the present disclosure provides a preparation method of a vitamin K1 injection package,

[0010] comprising the steps of:

[0011] filling, injecting vitamin K1 injection into a glass needle tube;

[0012] nitrogen filling, filling sterile nitrogen into the glass needle tube to remove oxygen in the glass needle tube to below 2.0%;

[0013] plugging, vacuumizing the glass needle tube to suck the plunger into the glass needle tube, and controlling the headspace volume to be 0.1-0.2 ml;

[0014] screwing the rod, screwing in the push rod.

[0015] In some embodiments, in the nitrogen filling step, the oxygen in the needle tube is removed to 0.3%-2.0%.

[0016] In some embodiments, in the plugging step, the headspace volume is controlled to be 0.01-0.06 ml.

[0017] In some embodiments, in the filling step, the vitamin K1 injection injected into the glass needle tube is 0.5-1.0 ml.

[0018] In some embodiments, in the filling step, the concentration of the vitamin K1 injection injected into the glass needle tube is 2-10 mg / ml.

[0019] In some embodiments, in the filling step, a ceramic pump is used to inject the vitamin K1 injection into the glass needle tube.

[0020] In some embodiments, the method further comprises the step of labeling, attaching a label to the outer wall of the glass needle tube.

[0021] In a second aspect, the present disclosure provides a vitamin K1 injection package, comprising:

[0022] a glass needle tube;

[0023] a vitamin K1 preparation, filled into the glass needle tube, and by filling sterile nitrogen into the glass needle tube, oxygen in the glass needle tube is removed to below 2.0%,

[0024] a plunger, sucked into the glass needle tube by vacuumizing the glass needle tube;

[0025] A push rod is screwed into the glass syringe and arranged on the piston.

[0026] According to the embodiments of the present disclosure, by reducing the oxygen content in the glass syringe to below 2.0%, the total amount of impurities and the maximum single impurity content of the vitamin K1 preparation in the glass syringe can be kept at a low level after long-term storage, and the potential risk of secondary pollution is avoided by using the glass syringe packaging form.

[0027] It should be understood that the foregoing general description and the following detailed description are only exemplary and explanatory, and are not limiting to the present application. BRIEF DESCRIPTION OF DRAWINGS

[0028] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the present application and serve to explain the principles of the present application, together with the description.

[0029] Fig. 1 is a physical diagram of a vitamin K1 injection package in an embodiment of the present disclosure;

[0030] Fig. 2 is a flow chart of a preparation method of a vitamin K1 injection package in an embodiment of the present disclosure;

[0031] Fig. 3 is an HPLC related substance inspection chromatogram in an embodiment of the present disclosure;

[0032] Reference signs: 1: glass syringe; 2: piston; 3: push rod; 4: needle cap. DETAILED DESCRIPTION

[0033] The present disclosure will now be discussed with reference to several embodiments. It should be understood that the discussion of these embodiments is merely to provide a better understanding of and thus facilitate the implementation of the present disclosure, and is not intended to suggest any limitation of the scope of the present disclosure.

[0034] As used herein, the term "comprising" and variations thereof are to be construed as meaning "including but not limited to"; the terms "embodiment" and "one embodiment" are to be construed as "at least one embodiment"; the term "another embodiment" is to be construed as "at least one other embodiment"; the terms "first", "second", etc. can refer to different or identical objects; the term "arranged" is not limited to direct or indirect connection, nor to a specific connection manner. Other explicit and implicit definitions can also be included below.

[0035] Some specific numerical values or numerical ranges can be involved in the following description. It should be understood that these numerical values and numerical ranges are merely exemplary, which can be beneficial to put the idea of the present disclosure into practice. However, the description of these examples is not intended to limit the scope of the present disclosure in any way. These numerical values or numerical ranges can be set otherwise according to specific application scenarios and requirements.

[0036] As described above, the residual oxygen ratio of the prior art vitamin K1 injection packaging is matched with the headspace volume, which cannot meet the total impurity limit requirement after long-term storage. The preparation method of the vitamin K1 injection packaging and the vitamin K1 injection packaging proposed by the embodiments of the present disclosure at least partially solve the above problems. As shown in FIG. 1, the vitamin K1 injection packaging of the embodiments of the present disclosure generally includes a glass syringe 1, a piston 2, a push rod 3, a stainless steel needle and a needle cap 4, and the stainless steel needle is provided with the needle cap 4. Alternatively, a luer lock, a screw joint or a rubber plug cap can be provided instead of the stainless steel needle and the needle cap 4, and the screw joint is sleeved on the outer surface of the luer lock. Among them, the glass syringe 1 is used to store the vitamin K1 injection, the piston 2 is used to block the rear end of the glass syringe 1 and press the vitamin K1 injection out of the front end of the glass syringe 1, and the push rod 3 is used to operate the movement of the piston 2 in the glass syringe 1.

[0037] In one embodiment, the front end and the rear end of the glass syringe 1 are both formed with openings, the front end opening is used to connect with the stainless steel needle, and the rear end opening is used to operate the push rod 3. The shape of the glass syringe 1 can be any constant cross-sectional shape, so as to at least ensure that the piston 2 can move along the glass syringe 1 and form a seal between the piston 2 and the inner wall of the glass syringe 1 at any moving position.

[0038] After the glass syringe 1, the piston 2 and the push rod 3 of the embodiments of the present disclosure are assembled and the vitamin K1 injection is filled, the total oxygen content should be less than 2.0% of the volume of the glass syringe, and at the same time, the headspace volume between the vitamin K1 injection and the front end of the glass syringe is maintained at 0.1-0.2ml. In order to realize this vitamin K1 injection packaging, as shown in FIG. 2, the preparation is completed through the steps of filling, nitrogen filling, plugging, screwing, and labeling.

[0039] In one embodiment, the filling step injects a certain amount of vitamin K1 injection into the glass syringe. For example, the vitamin K1 injection can be injected from the rear end opening of the glass syringe, or from the front end opening; in another example, the vitamin K1 injection can be injected manually, or a plurality of glass syringes can be batch injected by using an injection machine.

[0040] In one embodiment, the vitamin K1 injection solution injected into the glass syringe is 0.5-1.0 ml, the vitamin K1 injection solution occupies a certain space in the glass syringe, which is associated with the internal pressure of the syringe under a certain headspace volume, thereby affecting the distribution state of oxygen in the glass syringe.

[0041] In one embodiment, the concentration of the vitamin K1 injection solution injected into the glass syringe is 2-10 mg / ml, and the injection solution concentration affects the compressibility of the injection solution, thereby affecting the distribution state of oxygen in the glass syringe.

[0042] In one embodiment, the filling process requires a certain pressure to be maintained, so that the vitamin K1 injection solution is quickly injected into the glass syringe. For example, a ceramic pump or a metal pump is used to realize the pressurized injection process.

[0043] In one embodiment, the nitrogen filling step fills the glass syringe with sterile nitrogen, and uses inert nitrogen to displace the oxygen in the glass syringe, so as to remove the oxygen to below 2.0%. Preferably, the oxygen content in the glass syringe after nitrogen filling can be maintained at 0.3%-2.0%, and the specific content of oxygen is distributed in the headspace and the vitamin K1 injection solution under the internal pressure of the glass syringe.

[0044] In one embodiment, the stoppering step evacuates the glass syringe from the front end opening, so as to suck the piston into the glass syringe from the rear end opening of the glass syringe. During the vacuumizing process, the gas of the vitamin K1 injection solution near the front end opening is pushed out of the syringe, but the headspace volume needs to be maintained at 0.1-0.2 ml. Preferably, the headspace volume is controlled to be 0.01-0.06 ml. Preferably, the piston can be made of chlorobutyl or bromobutyl.

[0045] In one embodiment, the rod twisting step twists the push rod into the glass syringe from the rear end opening until it is fixedly connected with the piston. In another embodiment, the rod twisting step is followed or preceded by a labeling step, which attaches a label to the outer wall of the glass syringe. Preferably, a labeling and rod twisting machine can be used to perform the rod twisting and labeling operations, or the rod twisting and labeling operations can be performed manually.

[0046] The present disclosure tests the impurity content under the following embodiments 1-8 and comparative examples 1-5, wherein the sample is placed in a stability chamber at a temperature of 40°C and a relative humidity of 75% for 1 month, 3 months and 6 months, and in a stability chamber at a temperature of 25°C and a relative humidity of 60% for 3 months and 6 months:

[0047] Example 1:

[0048] (1) Filling: 0.5 ml of vitamin K1 injection solution with a concentration of 2 mg / ml is injected into the glass syringe by using a ceramic pump;

[0049] (2) Nitrogen filling: filling sterile nitrogen into the glass needle tube to remove oxygen in the needle tube to 1.5-2.0%;

[0050] (3) Adding stopper: by vacuumizing the needle tube to form negative pressure, the brominated butyl piston is sucked into the glass needle tube, and the headspace volume is controlled to be 0.1-0.2ml;

[0051] (4) Labeling and rod twisting: using a labeling and rod twisting machine to label the outer wall of the glass needle tube and twist the push rod.

[0052] Example 2:

[0053] (1) Filling: using a ceramic pump to inject 0.5ml of vitamin K1 injection with a concentration of 2mg / ml into the glass needle tube;

[0054] (2) Nitrogen filling: filling sterile nitrogen into the glass needle tube to remove oxygen in the needle tube to 1.5-2.0%;

[0055] (3) Adding stopper: by vacuumizing the needle tube to form negative pressure, the brominated butyl piston is sucked into the glass needle tube, and the headspace volume is controlled to be 0.01-0.03ml;

[0056] (4) Labeling and rod twisting: using a labeling and rod twisting machine to label the outer wall of the glass needle tube and twist the push rod.

[0057] Example 3:

[0058] (1) Filling: using a ceramic pump to inject 0.5ml of vitamin K1 injection with a concentration of 2mg / ml into the glass needle tube;

[0059] (2) Nitrogen filling: filling sterile nitrogen into the glass needle tube to remove oxygen in the needle tube to 0.8-1.2%;

[0060] (3) Adding stopper: by vacuumizing the needle tube to form negative pressure, the brominated butyl piston is sucked into the glass needle tube, and the headspace volume is controlled to be 0.1-0.2ml;

[0061] (4) Labeling and rod twisting: using a labeling and rod twisting machine to label the outer wall of the glass needle tube and twist the push rod.

[0062] Example 4:

[0063] (1) Filling: using a ceramic pump to inject 0.5ml of vitamin K1 injection with a concentration of 2mg / ml into the glass needle tube;

[0064] (2) Nitrogen filling: filling sterile nitrogen into the glass needle tube to remove oxygen in the needle tube to 0.3-0.8%;

[0065] (3) Stoppering: by vacuum suction to the needle tube, a negative pressure is formed, and the brominated butyl piston is sucked into the glass needle tube, with the headspace volume controlled to be 0.01-0.03 ml;

[0066] (4) Labeling and rod screwing: a labeling and rod screwing machine is used to paste a label on the outer wall of the glass needle tube, and a push rod is screwed in.

[0067] Example 5:

[0068] (1) Filling: a ceramic pump is used to inject 1.0 ml of vitamin K1 injection with a concentration of 2 mg / ml into a glass needle tube;

[0069] (2) Nitrogen filling: sterile nitrogen is filled into the glass needle tube, and the oxygen in the needle tube is removed to 0.3-0.8%;

[0070] (3) Stoppering: by vacuum suction to the needle tube, a negative pressure is formed, and the brominated butyl piston is sucked into the glass needle tube, with the headspace volume controlled to be 0.03-0.06 ml;

[0071] (4) Labeling and rod screwing: a labeling and rod screwing machine is used to paste a label on the outer wall of the glass needle tube, and a push rod is screwed in.

[0072] Example 6:

[0073] (1) Filling: a ceramic pump is used to inject 0.5 ml of vitamin K1 injection with a concentration of 10 mg / ml into a glass needle tube;

[0074] (2) Nitrogen filling: sterile nitrogen is filled into the glass needle tube, and the oxygen in the needle tube is removed to 0.8-1.2%;

[0075] (3) Stoppering: by vacuum suction to the needle tube, a negative pressure is formed, and the brominated butyl piston is sucked into the glass needle tube, with the headspace volume controlled to be 0.03-0.06 ml;

[0076] (4) Labeling and rod screwing: a labeling and rod screwing machine is used to paste a label on the outer wall of the glass needle tube, and a push rod is screwed in.

[0077] Example 7:

[0078] (1) Filling: a ceramic pump is used to inject 1.0 ml of vitamin K1 injection with a concentration of 10 mg / ml into a glass needle tube;

[0079] (2) Nitrogen filling: sterile nitrogen is filled into the glass needle tube, and the oxygen in the needle tube is removed to 0.3-0.8%;

[0080] (3) Stoppering: by vacuum suction to the needle tube, a negative pressure is formed, and the brominated butyl piston is sucked into the glass needle tube, with the headspace volume controlled to be 0.03-0.06 ml;

[0081] (4) Labeling and rod screwing: a labeling and rod screwing machine is used to stick a label on the outer wall of the glass needle tube and screw in a push rod.

[0082] Example 8:

[0083] (1) Filling: a ceramic pump is used to inject 0.5 ml of vitamin Kl injection with a concentration of 10 mg / ml into a glass needle tube;

[0084] (2) Nitrogen filling: sterile nitrogen is filled into the glass needle tube to remove oxygen in the needle tube to 0.3-0.8%;

[0085] (3) Stopper adding: a vacuum is applied to the needle tube to form a negative pressure, and a butyl bromide piston is sucked into the glass needle tube, and the headspace volume is controlled to be 0.01-0.03 ml;

[0086] (4) Labeling and rod screwing: a labeling and rod screwing machine is used to stick a label on the outer wall of the glass needle tube and screw in a push rod.

[0087] Comparative Example 1:

[0088] Using an ampoule bottle for packaging:

[0089] (1) Filling: a ceramic pump is used to inject 0.5 ml of vitamin Kl injection with a concentration of 10 mg / ml into a glass needle tube;

[0090] (2) Nitrogen filling and sealing: sterile nitrogen is filled into the ampoule bottle to remove oxygen to 1.0-2.0% and then sealed.

[0091] Comparative Example 2:

[0092] Using an ampoule bottle for packaging:

[0093] (1) Filling: a ceramic pump is used to inject 0.5 ml of vitamin Kl injection with a concentration of 10 mg / ml into a glass needle tube;

[0094] (2) Nitrogen filling and sealing: sterile nitrogen is filled into the ampoule bottle to remove oxygen to 1.0-2.0% and then sealed.

[0095] Comparative Example 3:

[0096] Using an ampoule bottle for packaging:

[0097] (1) Filling: a ceramic pump is used to inject 0.5 ml of vitamin Kl injection with a concentration of 10 mg / ml into a glass needle tube;

[0098] (2) Nitrogen filling and sealing: sterile nitrogen is filled into the ampoule bottle to remove oxygen to 1.0-2.0% and then sealed.

[0099] Comparative Example 4:

[0100] Using a penicillin bottle for packaging:

[0101] (1) Filling: using a ceramic pump to inject 0.5 ml of vitamin K1 injection solution with a concentration of 2 mg / ml into a 2 ml vial;

[0102] (2) Nitrogen filling and stoppering: filling sterile nitrogen into the vial, and after oxygen is removed to 0.3-0.8%, stoppering and sealing with an aluminum cap.

[0103] Comparative Example 5:

[0104] Using a vial for packaging:

[0105] (1) Filling: using a ceramic pump to inject 1.0 ml of vitamin K1 injection solution with a concentration of 10 mg / ml into a 2 ml vial;

[0106] (2) Nitrogen filling and stoppering: filling sterile nitrogen into the vial, and after oxygen is removed to 0.3-0.8%, stoppering and sealing with an aluminum cap.

[0107] Referring to the method for checking related substances in vitamin K1 injection solution specified in the 2020 edition of Chinese Pharmacopoeia, as shown in FIG. 3, the maximum single impurity content (%) and total impurity content (%) of the sample were detected by high performance liquid chromatography (HPLC), as shown in Tables 1 and 2 below:

[0108] Table 1 Results of related substances under the condition of temperature 40℃ and relative humidity 75%

[0109] Table 2 Results of related substances under the condition of temperature 25℃ and relative humidity 60%

[0110] According to the above sample release test results, it can be seen that the injection solution packaging obtained by using the preparation method of the vitamin K1 injection solution packaging of the embodiments of the present disclosure can control the headspace volume and residual oxygen content, and the total impurity content of the vitamin K1 injection solution does not exceed 2% and the single impurity does not exceed 1% of the provisions of Chinese Pharmacopoeia after being stored for 6 months under accelerated conditions and at room temperature. However, using an ampoule or a vial for packaging, the total impurity content and single impurity of the vitamin K1 injection solution both exceed the limits specified in the pharmacopoeia.

[0111] In the description of the embodiments herein, any reference to direction or position is only for the convenience of description and cannot be understood as any limitation on the protection scope of the present application. The description of the preferred embodiments may involve combinations of features, which may exist independently or in combination, and the present application is not particularly limited to the preferred embodiments. The scope of the present application is defined by the claims.

[0112] The above merely preferred embodiments of the present application are not used to limit the present application, any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A method for producing a vitamin Kl injection package, characterized by, The method further comprises the steps of: filling, filling the vitamin K1 injection into the glass syringe; nitrogen filling, filling sterile nitrogen into the glass syringe to remove oxygen in the glass syringe to 2.0% or less; plugging, vacuumizing the glass syringe to suck the piston into the glass syringe, and controlling the headspace volume to be 0.1-0.2ml; screwing, screwing the push rod into the glass syringe.

2. The method of producing a package of vitamin Kl injection according to claim 1, characterized by, In the nitrogen filling step, the oxygen in the syringe is removed to 0.3%-2.0%.

3. The method of producing a vitamin Kl injection package according to claim 1, characterized by, In the plugging step, the headspace volume is controlled to be 0.01-0.06ml.

4. The method of producing a vitamin Kl injection package according to claim 1, characterized by, In the filling step, the vitamin K1 injection filled into the glass syringe is 0.5-1.0ml.

5. The method of producing a vitamin Kl injection package according to claim 1, characterized by, In the filling step, the concentration of the vitamin K1 injection filled into the glass syringe is 2-10mg / ml.

6. The method of producing a vitamin Kl injection package according to claim 1, characterized by, In the filling step, a ceramic pump is used to fill the vitamin K1 injection into the glass syringe.

7. The method of producing a vitamin Kl injection package according to claim 1, characterized by, The method further comprises the steps of: labeling, labeling the outer wall of the glass syringe.

8. A vitamin K1 injection package, comprising: a glass syringe (1); a vitamin K1 preparation, filled into the glass syringe (1), and the oxygen in the glass syringe is removed to 2.0% or less by filling sterile nitrogen into the glass syringe (1), a piston (2), sucked into the glass syringe (1) by vacuumizing the glass syringe (1); a push rod (3), screwed into the glass syringe (1) and arranged on the piston (2).

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