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

Abstract

The invention provides a vitamin K1 injection package preparation method and a vitamin K1 injection package, the vitamin K1 injection package preparation method comprises the steps of filling, nitrogen filling, plug adding and rod screwing, in the nitrogen filling step, sterile nitrogen is filled into a glass needle tube, oxygen in the glass needle tube is removed to be 2.0% or below, in the plug adding step, the glass needle tube is vacuumized, so that a piston is sucked into the glass needle tube, and the rod screwing is performed. The headspace volume is controlled to be 0.1 to 0.2 ml. According to the present invention, the total impurity amount and the maximum single impurity content of the vitamin K1 preparation in the glass needle tube can be maintained at the low level after the long-term placement, and the potential secondary pollution risk is avoided by using the glass needle tube packaging form.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to the field of medical syringes, in particular to a preparation method of a vitamin K1 injection package and the vitamin K1 injection package. BACKGROUND

[0002] Vitamin K1 deficiency can easily lead to 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.

[0003] Most domestic vitamin K1 injections use the method of adding antioxidants in the prescription and controlling the residual oxygen in the headspace to reduce impurities. However, the addition of antioxidants such as sodium pyrosulfite in the prescription often has adverse reactions such as hypersensitivity, and the product has safety risks.

[0004] 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 packaging, and International Medication Systems uses single-dose vials Syringe, the headspace volume of these two kinds of packaging 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 content. During long-term storage, vitamin K1 will still undergo oxidative degradation, resulting in total impurity content exceeding the 2% limit requirement of the Chinese Pharmacopoeia and the maximum single impurity content exceeding the 1% limit requirement of the Chinese Pharmacopoeia.

[0005] In addition, during the transfer process of ampoule packaging in clinical use, the sterile liquid contacts air or a drug delivery device, which has the potential risk of secondary contamination. SUMMARY

[0006] The present disclosure provides a preparation method of a vitamin K1 injection package and the vitamin K1 injection package.

[0007] Specifically, the present disclosure is realized by the following technical solutions:

[0008] In a first aspect, the present disclosure provides a preparation method of a vitamin K1 injection package, comprising the steps of:

[0009] Filling, injecting vitamin K1 injection into a glass needle tube;

[0010] Nitrogen filling, filling the glass needle tube with sterile nitrogen, removing the oxygen in the glass needle tube to 2.0% or less;

[0011] Stoppering, vacuumizing the glass needle tube, thereby sucking the piston into the glass needle tube, and controlling the headspace volume to be 0.1-0.2ml;

[0012] Twist rod, twist in the push rod.

[0013] In some embodiments, in the nitrogen filling step, the oxygen in the needle tube is removed to 0.3%-2.0%.

[0014] In some embodiments, in the stoppering step, the headspace volume is controlled to be 0.01-0.06ml.

[0015] In some embodiments, in the filling step, the vitamin K1 injection solution injected into the glass needle tube is 0.5-1.0ml.

[0016] In some embodiments, in the filling step, the concentration of the vitamin K1 injection solution injected into the glass needle tube is 2-10mg / ml.

[0017] In some embodiments, in the filling step, a ceramic pump is used to inject the vitamin K1 injection solution into the glass needle tube.

[0018] In some embodiments, it further includes the step of labeling, labeling the outer wall of the glass needle tube.

[0019] In a second aspect, the embodiments of the present disclosure provide a vitamin K1 injection solution package, comprising:

[0020] Glass needle tube;

[0021] Vitamin K1 preparation, filled into the glass needle tube, and the oxygen in the glass needle tube is removed to 2.0% or less by filling the glass needle tube with sterile nitrogen,

[0022] Piston, sucked into the glass needle tube by vacuumizing the glass needle tube;

[0023] Push rod, twisted into the glass needle tube and arranged on the piston.

[0024] According to the embodiments of the present disclosure, by reducing the oxygen content in the glass needle tube to 2.0% or less, the total amount of impurities and the maximum single impurity content of the vitamin K1 preparation in the glass needle tube can still be kept at a low level after long-term storage, and the glass needle tube packaging form avoids the potential risk of secondary pollution.

[0025] It should be understood that the above general description and the following detailed description are only exemplary and explanatory, and cannot limit the present application.BRIEF DESCRIPTION OF DRAWINGS BRIEF DESCRIPTION OF DRAWINGS

[0026] The accompanying drawings, which are incorporated herein and constitute part of this specification, illustrate embodiments consistent with the application and, together with the description, serve to explain the principles of the application.

[0027] Figure 1 is a physical diagram of a vitamin K1 injection package in an embodiment of the present disclosure;

[0028] Figure 2 is a flow chart of a preparation method of a vitamin K1 injection package in an embodiment of the present disclosure;

[0029] Figure 3 is an HPLC related substance inspection chromatogram in an embodiment of the present disclosure;

[0030] REFERENCE NUMERALS

[0031] 1: glass syringe; 2: piston; 3: push rod; 4: needle cap. DETAILED DESCRIPTION

[0032] The present disclosure will now be discussed with respect to several embodiments. It should be understood that the discussion of these embodiments is merely meant to provide a better understanding of the present disclosure and thus, the present disclosure should not be limited to these embodiments.

[0033] As used herein, the term "includes" and its variants are to be read to be synonymous with "comprising" and its variants; the terms "a" and "an" are to be read as meaning "at least one" or "one or more"; the term "another" is to be read as meaning "at least one other"; the terms "first", "second", etc. can refer to different or identical objects; the term "set" is not limited to direct or indirect connection, nor to a specific manner of connection. Other explicit and implicit definitions can also be included below.

[0034] 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.

[0035] As described above, the residual oxygen ratio of the prior art vitamin K1 injection package 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 package and the vitamin K1 injection package proposed in the embodiments of the present disclosure at least partially solve the above problems. As shown in the following table, the residual oxygen ratio of the vitamin K1 injection package prepared according to the preparation method of the present disclosure is 0.5% or less, which is much lower than the residual oxygen ratio of the prior art vitamin K1 injection package. Figure 1As shown, the vitamin K1 injection liquid package of the embodiment of the present disclosure generally comprises 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 sleeved 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. The glass syringe 1 is used to store the vitamin K1 injection liquid, the piston 2 is used to block the rear end of the glass syringe 1 and press the vitamin K1 injection liquid out of the front end of the glass syringe 1, and the push rod 3 is used to move the piston 2 in the glass syringe 1.

[0036] 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 fixed 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.

[0037] After the glass syringe 1, the piston 2 and the push rod 3 of the embodiment of the present disclosure are assembled and the vitamin K1 injection liquid is filled, the total amount of oxygen 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 liquid and the front end of the glass syringe is maintained at 0.1-0.2ml. In order to realize this vitamin K1 injection liquid package, the following steps are taken: Figure 2 As shown, the preparation is completed through the steps of filling, nitrogen filling, plugging, rod tightening and labeling.

[0038] In one embodiment, the filling step injects a certain amount of vitamin K1 injection liquid into the glass syringe. For example, the vitamin K1 injection liquid 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 liquid can be injected manually or in batches by using an injection machine for multiple glass syringes.

[0039] In one embodiment, the vitamin K1 injection liquid injected into the glass syringe is 0.5-1.0ml. The vitamin K1 injection liquid occupies a certain space in the glass syringe, which is associated with the internal pressure of the glass syringe under a certain headspace volume, thereby affecting the distribution state of oxygen in the glass syringe.

[0040] In one embodiment, the concentration of the vitamin K1 injection liquid injected into the glass syringe is 2-10mg / ml. The concentration of the injection liquid affects the compressibility of the injection liquid, thereby affecting the distribution state of oxygen in the glass syringe.

[0041] In one embodiment, a certain pressure needs to be maintained during the filling process, so that the vitamin K1 injection liquid can be quickly injected into the glass syringe. For example, a ceramic pump or a metal pump can be used to realize the pressurized injection process.

[0042] In one embodiment, the nitrogen filling step fills the glass syringe with sterile nitrogen gas, and the oxygen gas in the glass syringe is replaced with inert nitrogen gas, so that the oxygen gas is removed to less than 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 vitamin K1 injection under the pressure in the glass syringe.

[0043] In one embodiment, the stoppering step performs vacuumizing on the glass syringe from the front end opening, so that the piston is sucked into the glass syringe from the rear end opening of the glass syringe. During the vacuumizing process, the gas near the front end opening of the vitamin K1 injection is pushed out of the syringe, but the headspace volume needs to be maintained at 0.1-0.2ml. Preferably, the headspace volume is controlled at 0.01-0.06ml. Preferably, the piston can be made of chlorobutyl or bromobutyl.

[0044] 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, the rod twisting and labeling operations can be performed by a labeling and rod twisting machine, or by manual operation.

[0045] The disclosure tests the impurity content under the following examples 1-8 and comparative examples 1-5, wherein the sample conditions are placed in a stability box at a temperature of 40℃ and a relative humidity of 75% for 1 month, 3 months and 6 months, and in a stability box at a temperature of 25℃ and a relative humidity of 60% for 3 months and 6 months:

[0046] Example 1:

[0047] (1) Filling: 0.5ml of vitamin K1 injection with a concentration of 2mg / ml is injected into the glass syringe using a ceramic pump;

[0048] (2) Nitrogen filling: sterile nitrogen gas is filled into the glass syringe to remove the oxygen gas in the syringe to 1.5-2.0%;

[0049] (3) Stoppering: vacuumizing is performed on the syringe to form negative pressure, and the bromobutyl piston is sucked into the glass syringe, and the headspace volume is controlled at 0.1-0.2ml;

[0050] (4) Rod twisting and labeling: a labeling and rod twisting machine is used to attach a label to the outer wall of the glass syringe, and the push rod is twisted in.

[0051] Example 2:

[0052] (1) Filling: 0.5ml of vitamin K1 injection with a concentration of 2mg / ml is injected into the glass syringe using a ceramic pump;

[0053] (2) Nitrogen filling: filling sterile nitrogen into the glass needle tube to remove oxygen in the needle tube to 1.5-2.0%;

[0054] (3) Stopper adding: through 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;

[0055] (4) Labeling and rod screwing: using a labeling and rod screwing machine to paste a label on the outer wall of the glass needle tube and screw in a push rod.

[0056] Example 3:

[0057] (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;

[0058] (2) Nitrogen filling: filling sterile nitrogen into the glass needle tube to remove oxygen in the needle tube to 0.8-1.2%;

[0059] (3) Stopper adding: through 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;

[0060] (4) Labeling and rod screwing: using a labeling and rod screwing machine to paste a label on the outer wall of the glass needle tube and screw in a push rod.

[0061] Example 4:

[0062] (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;

[0063] (2) Nitrogen filling: filling sterile nitrogen into the glass needle tube to remove oxygen in the needle tube to 0.3-0.8%;

[0064] (3) Stopper adding: through 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;

[0065] (4) Labeling and rod screwing: using a labeling and rod screwing machine to paste a label on the outer wall of the glass needle tube and screw in a push rod.

[0066] Example 5:

[0067] (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;

[0068] (2) Nitrogen filling: filling sterile nitrogen into the glass needle tube to remove oxygen in the needle tube to 0.3-0.8%;

[0069] (3) Stopper adding: by vacuumizing the needle tube, the negative pressure is formed, and the butyl bromide piston is absorbed into the glass needle tube, and the headspace volume is controlled to be 0.03-0.06ml;

[0070] (4) Labeling and rod screwing: the label is pasted on the outer wall of the glass needle tube by using a labeling and rod screwing machine, and the push rod is screwed in.

[0071] Example 6:

[0072] (1) Filling: 0.5ml of vitamin K1 injection with a concentration of 10mg / ml is injected into the glass needle tube by using a ceramic pump;

[0073] (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%;

[0074] (3) Stopper adding: by vacuumizing the needle tube, the negative pressure is formed, and the butyl bromide piston is absorbed into the glass needle tube, and the headspace volume is controlled to be 0.03-0.06ml;

[0075] (4) Labeling and rod screwing: the label is pasted on the outer wall of the glass needle tube by using a labeling and rod screwing machine, and the push rod is screwed in.

[0076] Example 7:

[0077] (1) Filling: 1.0ml of vitamin K1 injection with a concentration of 10mg / ml is injected into the glass needle tube by using a ceramic pump;

[0078] (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%;

[0079] (3) Stopper adding: by vacuumizing the needle tube, the negative pressure is formed, and the butyl bromide piston is absorbed into the glass needle tube, and the headspace volume is controlled to be 0.03-0.06ml;

[0080] (4) Labeling and rod screwing: the label is pasted on the outer wall of the glass needle tube by using a labeling and rod screwing machine, and the push rod is screwed in.

[0081] Example 8:

[0082] (1) Filling: 0.5ml of vitamin K1 injection with a concentration of 10mg / ml is injected into the glass needle tube by using a ceramic pump;

[0083] (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%;

[0084] (3) Stopper adding: by vacuumizing the needle tube, the negative pressure is formed, and the butyl bromide piston is absorbed into the glass needle tube, and the headspace volume is controlled to be 0.03-0.06ml;

[0085] (4) Labeling of the push rod: using a labeling push rod machine to label the outer wall of the glass needle tube, and twist into the push rod.

[0086] Comparative Example 1

[0087] Using an ampoule bottle package:

[0088] (1) Filling: using a ceramic pump to inject 0.5 ml of vitamin K1 injection with a concentration of 2 mg / ml into a 1 ml ampoule bottle;

[0089] (2) Nitrogen filling and sealing: filling sterile nitrogen into the ampoule bottle, and sealing after removing oxygen to 1.0-2.0%.

[0090] Comparative Example 2

[0091] Using an ampoule bottle package:

[0092] (1) Filling: using a ceramic pump to inject 1.0 ml of vitamin K1 injection with a concentration of 2 mg / ml into a 1 ml ampoule bottle;

[0093] (2) Nitrogen filling and sealing: filling sterile nitrogen into the ampoule bottle, and sealing after removing oxygen to 1.0-2.0%.

[0094] Comparative Example 3

[0095] Using an ampoule bottle package:

[0096] (1) Filling: using a ceramic pump to inject 1.0 ml of vitamin K1 injection with a concentration of 10 mg / ml into a 1 ml ampoule bottle;

[0097] (2) Nitrogen filling and sealing: filling sterile nitrogen into the ampoule bottle, and sealing after removing oxygen to 0.3-0.8%.

[0098] Comparative Example 4

[0099] Using a penicillin bottle package:

[0100] (1) Filling: using a ceramic pump to inject 0.5 ml of vitamin K1 injection with a concentration of 2 mg / ml into a 2 ml penicillin bottle;

[0101] (2) Nitrogen filling and stoppering: filling sterile nitrogen into the penicillin bottle, and stoppering after removing oxygen to 0.3-0.8%, and sealing with an aluminum cap.

[0102] Comparative Example 5

[0103] Using a penicillin bottle package:

[0104] (1) Filling: using a ceramic pump to inject 1.0 ml of vitamin K1 injection with a concentration of 10 mg / ml into a 2 ml penicillin bottle;

[0105] (2) Nitrogen filling and stoppering: sterile nitrogen is filled into the vial, and after the oxygen is removed to 0.3-0.8%, stoppering is performed, and the aluminum cap is sealed.

[0106] According to the method for checking the related substances in the vitamin K1 injection in the Chinese Pharmacopoeia 2020 edition, as shown in Table 1 and 2, the maximum single impurity content (%) and the total impurity content (%) of the sample were detected by high performance liquid chromatography (HPLC), as shown in Table 1 and 2: Figure 3

[0107] Table 1 Results of related substances under the condition of temperature 40℃, relative humidity 75%

[0108]

[0109]

[0110]

[0111] Table 2 Results of related substances under the condition of temperature 25℃, relative humidity 60%

[0112]

[0113]

[0114] According to the above sample drawing experiment results, it can be seen that the injection packaging obtained by using the preparation method of the vitamin K1 injection packaging of the embodiment of the present disclosure can control the headspace volume and residual oxygen content, and the total impurity content of the vitamin K1 injection is not more than 2% and the single impurity is not more than 1% under the condition of accelerated storage and room temperature environment for 6 months, while using ampoule bottle or vial bottle packaging, the total impurity content and single impurity of the vitamin K1 injection exceed the limit of the pharmacopoeia.

[0115] In the description of the above embodiments, 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.

[0116] The above is only a preferred embodiment of the present application and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall 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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