Containers with a gradient lubricant layer for drug packaging

Abstract

This invention generally relates to a container with a gradient lubricant layer for pharmaceutical packaging. More particularly, this invention relates to a container; a kit comprising a container and a piston; an assembly comprising a container, a piston, and a liquid pharmaceutical composition; a method for preparing the container; and the use of a lubricant layer with a gradient thickness.

Description

Technical Field

[0001] This invention generally relates to a container with a gradient lubricant layer for pharmaceutical packaging. More particularly, this invention relates to a container; a kit comprising a container and a piston; an assembly comprising a container, a piston, and a liquid pharmaceutical composition; a method for preparing the container; and the use of a lubricant layer with a gradient thickness. Background Technology

[0002] Pharmaceutical materials can be provided in various forms and contained in a wide variety of containers. In the case of liquid pharmaceutical materials, some common examples are ampoules, vials, cartridges, and syringes. A widely used form employs a sliding plunger within the container to expel the liquid from the opening. One approach is to provide a lubricant layer on the inside of the container to facilitate plunger sliding.

[0003] US 4,767,414 A describes plasma activation of the inner surface prior to coating with a silicone lubricant layer.

[0004] EP 0920879 B1 discloses a formulation for a silicone-based mixture comprising reactive and non-reactive components.

[0005] There is still a need for improved methods to lubricate drug containers, especially for delivering multiple separate doses from a single container. Summary of the Invention

[0006] The purpose of this invention is to at least partially solve one or more of the above-mentioned problems.

[0007] The object of the present invention is to provide an improved container for pharmaceutical packaging, particularly for multi-dose delivery.

[0008] The object of the present invention is to provide an improved kit including a container and a piston, particularly for multi-dose delivery.

[0009] The object of this invention is to provide an improved method for preparing containers for pharmaceutical packaging, particularly for multi-dose delivery.

[0010] The object of the present invention is to provide an improved assembly comprising a container, a piston, and a liquid pharmaceutical composition, particularly for multi-dose delivery.

[0011] The object of the present invention is to provide a container for pharmaceutical packaging with improved static friction properties, particularly for multi-dose delivery.

[0012] The object of the present invention is to provide a kit with improved static friction properties, particularly for multi-dose delivery.

[0013] The object of the present invention is to provide a method for preparing a container for pharmaceutical packaging, the container having improved static frictional properties, particularly for multi-dose delivery.

[0014] The object of the present invention is to provide a component with improved static tribological properties, particularly for multi-dose delivery.

[0015] The following embodiments represent preferred configurations for achieving the objectives of the present invention, wherein the xth embodiment is denoted as |x|.

[0016] |1| A container for drug packaging, the container having an elongated cylindrical portion, wherein:

[0017] a. The slender cylindrical portion has an extension direction and an axis along the extension direction;

[0018] b. Determine the axial position p along the axis;

[0019] c. The slender cylindrical portion at its axial position p A Extending to axial position p B ;

[0020] d. Length L of the slender cylindrical portion B For p A With p B The distance between them;

[0021] e. The container has sidewalls extending on an elongated cylindrical portion, the sidewalls having an inner surface adjacent to the inner cavity, the inner cavity having a diameter;

[0022] f. The lubricant layer is located on at least a portion of the inner surface;

[0023] g. On the axis at p A With p B At a given axial position p, the following terms are determined as the angular average values ​​in the cross section perpendicular to the axis at axial position p:

[0024] i. The thickness of the sidewalls

[0025] ii. Layer thickness, and

[0026] iii. The diameter of the inner cavity;

[0027] h. A portion X of the axis extends from axial position p1 to axial position p2 to meet the following criteria:

[0028] i.p1 and p2 are both located at p A With p B between,

[0029] ii. Partial length L X Let p1 be the distance between p2.

[0030] iii.L X For L B At least one-quarter, preferably L B At least half, more preferably L B At least 80%, most preferably L B At least 90%,

[0031] iv. The layer extends over the entire section X, and

[0032] v. The thickness t1 of the layer at p1 is less than the thickness t2 of the layer at p2;

[0033] i. Meets one or more container criteria selected from the following groups:

[0034] i. Length L B The value is 3 to 20 cm, preferably 4 to 15 cm, more preferably 5 to 12 cm, and most preferably 6 to 8 cm;

[0035] ii. In p A to p B The average diameter of the defined inner cavity is 0.4 to 4 cm, preferably 0.6 to 3 cm, more preferably 0.8 to 2.5 cm, and most preferably 1 to 2 cm;

[0036] iii. In p A to p B The average thickness of the sidewalls within the defined range is 0.3 to 4 mm, preferably 0.7 to 3 mm, more preferably 1.1 to 2 mm, and most preferably 1.4 to 1.8 mm; and

[0037] iv. The volume of the inner cavity is 0.1 to 150 mL, preferably 0.5 to 50 mL, more preferably 1 to 25 mL, more preferably 2 to 10 mL, and most preferably 3 to 5 mL.

[0038] According to various aspects of this embodiment, the following combinations of container standards i to iv are satisfied: i, ii, iii, iv, i+ii, i+iii, i+iv, ii+iii, ii+iv, iii+iv, i+ii+iii, i+ii+iv, i+iii+iv, ii+iii+iv, and i+ii+iii+iv.

[0039] |2|The container according to embodiment|1|, wherein the ratio of thickness t1:t2 is 1:1.1 to 1:100, preferably 1:5 to 1:90, more preferably 1:10 to 1:80, and most preferably 1:15 to 1:70.

[0040] |3|The container according to embodiment|1| or|2|, wherein the lubricant comprises one or more silicone oils. Preferably, based on the total weight of the lubricant layer, the lubricant comprises at least 5% by weight, more preferably at least 15% by weight, and most preferably at least 25% by weight of one or more silicone oils.

[0041] |4|The container according to Example|3|, wherein one or more silicone oils are at least partially contained in a matrix, wherein the matrix is ​​bonded to the inner surface.

[0042] |5|The container according to Example|4|, wherein the matrix is ​​a polymer, preferably a cross-linked polymer.

[0043] |6|The container according to Example|5|, wherein the polymer comprises repeating units containing SiO-. Preferred polymers are polysiloxanes, more preferably crosslinked polysiloxanes.

[0044] |7| According to any of the foregoing embodiments, the inner cavity of the container is cylindrical or truncated conical in the elongated cylindrical portion. Preferably, the cone opening of the truncated cone is 0.04° to 0.4°, more preferably 0.08° to 0.25°, and more preferably 0.1° to 0.2°.

[0045] |8| The container according to any of the foregoing embodiments includes a first opening at a first end and a second opening at a second end. According to one aspect of this embodiment, the area of ​​the first opening is larger than the area of ​​the second opening, preferably at least 50%, more preferably at least 100%, and most preferably at least 200% based on the area of ​​the second opening. In an alternative embodiment, the container includes a first opening at a first end and a closed end at a second end.

[0046] |9| According to any of the foregoing embodiments, the inner diameter at p1 is d1, the inner diameter at p2 is d2, and d1 is greater than d2. Based on diameter d2, d1 is preferably at least 0.05%, more preferably at least 0.1%, and most preferably at least 0.2% larger than d2. Based on diameter d2, d1 is preferably at most 5%, more preferably at most 4%, and most preferably at most 3% larger than d2.

[0047] |10| The container according to any of the foregoing embodiments includes an opening and a securing device at the opening. Preferably, the securing device is located at one end, more preferably at a second end. Preferred securing devices are adapted and configured to secure one or both of a group consisting of a needle and a tube. Some preferred securing devices are threads, pins, Luer joints, and bayonet joints.

[0048] |11| According to any of the foregoing embodiments, the container wherein the minimum thickness t of the layer is determined in portion X. minThe wavelength is at least 60 nm, preferably at least 90 nm, more preferably at least 100 nm, and most preferably at least 110 nm.

[0049] |12| A kit comprising the following kit components:

[0050] a. The container according to any of the foregoing embodiments, and

[0051] b. Piston;

[0052] The piston is fitted and positioned within the inner cavity, such that:

[0053] i. The cross-section of the cavity between the inner surfaces of the piston sealing sidewalls;

[0054] ii. The piston has a position closest to p B The piston is in contact with the layer or inner surface at the front end of the axial position.

[0055] iii. The piston has a position closest to p A The rear end of the piston is located at an axial position, where the piston contacts the layer or inner surface.

[0056] iv. Piston length L C The distance between the front-end and back-end;

[0057] v. The piston has an axial position, which is the axial position of the front end;

[0058] vi. The piston can move in a direction parallel to the axis by static friction s, where s is a function of the piston's axial position.

[0059] The preferred piston comprises an elastomeric material.

[0060] |13|The component according to embodiment|12|, wherein for p1+L C For piston axial positions within the range of p2, static friction s has a maximum value S. max and minimum value S min S min / S max The value is 40% or more, more preferably 50% or more, more preferably 60% or more, more preferably 65% ​​or more, more preferably 70% or more, more preferably 75% or more, and most preferably 80% or more.

[0061] |14|The assembly according to embodiment|12| or|13|, wherein the static friction at piston axial position p2 is less than or equal to piston axial position p1+L. C Static friction at the location. In one aspect of this embodiment, based on the piston axial position p1+L CThe static friction at piston axial position p2 is greater than that at piston axial position p1+L. C The static friction at the point is less than 5%, preferably at least 10%, more preferably at least 15%, and most preferably at least 20%.

[0062] |15| A component comprising a container and a piston according to any one of embodiments |1| to |11|, wherein:

[0063] a. The container has an opening;

[0064] b. The piston is located in the inner cavity, thus sealing the cross-section of the inner cavity;

[0065] c. The cavity contains a liquid drug composition, which is located between the sealed cross-section and the opening; and

[0066] d. The components are adapted and configured to eject the liquid pharmaceutical composition from the opening by means of the movement of the piston in a direction parallel to the axis.

[0067] |16| A method for preparing a container according to any one of Examples |1| to |11|, a kit according to Examples |12| to |14|, or a component according to Example |15|, comprising the step of coating a lubricant layer with a coating tool.

[0068] |17| Application of gradually thickened lubricant layers in drug containers to improve static friction uniformity.

[0069] Diameter, layer thickness and roughness

[0070] The container's axis is used to determine its axial position. At a given axial position, the sidewall is the perimeter of a cross-section perpendicular to the axis, having a thickness, and the same applies to the lubricant layer. The inner diameter, lubricant layer thickness, sidewall thickness, and surface roughness at a given point along the axis are preferably average values ​​determined along the perimeter. These average values ​​along the perimeter are angular averages. The angular averages are preferably determined by measurements taken at eight points along the perimeter, spaced at equal angular intervals.

[0071] Monotonic parameters

[0072] In this paper, when applied to variables dependent on p, the term "monotonicity" preferably ignores abrupt changes in the function with small variations in p; otherwise, it would be called roughness. On a portion of X, the monotonicity of parameter Y is preferably determined by:

[0073] - Part X is divided into n regions of equal length: M1 to M n ;

[0074] -For M1 to M nSort the data, where M1 starts at p1, M... n The process terminates at p2.

[0075] -In areas M1 to M n The average values ​​of Y are Y1 to Y2. n ;

[0076] -For monotonically increasing series Y2 to Y n The average values ​​are respectively greater than the average values ​​of Y1 to Y2. n-1 ;

[0077] -For monotonically decreasing, the series Y2 to Y n The average values ​​are respectively less than the average values ​​of Y1 to Y2. n-1 ;

[0078] -x is an integer of 2 or greater, with preferred values ​​for x being 5, 10, 15, and 20.

[0079] container

[0080] Preferred containers are adapted and configured to contain liquid medications. Some preferred containers are syringes, syringe barrels, cartridges, closed-end containers, and vials.

[0081] The preferred container has one or more openings. The openings are preferably located at one end of the container. In one embodiment, the container has one opening. In another embodiment, the container has two openings.

[0082] The container preferably has two ends, namely a first end and a second end.

[0083] A preferred container has a first opening at its first end. Another preferred container has a second opening at its second end. Yet another preferred container has a closed second end.

[0084] Slender cylindrical part

[0085] The container has an elongated cylindrical portion. This elongated cylindrical portion is called the container part. The container may have other parts outside the elongated cylindrical portion. The elongated cylindrical portion is also called a tubular portion. Preferably, the elongated cylindrical portion is tubular.

[0086] Possible embodiments of the elongated cylindrical portion and axis are described herein in mathematical terms, such as axes of symmetry, axes of rotation or revolution, planes of revolution and bodies of revolution, and shapes such as cylinders and truncated cones. These embodiments are understood to allow for some modifications to these precise mathematical concepts. Suitable modifications that can be made to these mathematical concepts do not prevent the container from being used as a plunger system when mated with a piston.

[0087] The elongated cylindrical portion has an axis. The axis can be the axis of rotation of the elongated cylindrical portion. The axis can also be the axis of revolution of the elongated cylindrical portion. The sidewalls can be bodies of revolution about the axis. The inner surface can be a surface of revolution about the axis. The layers can be bodies of revolution about the axis.

[0088] The axis defines the axial position p. The axial position p is the axial position along the axis. In this article, the symbol p generally represents the axial position, and a specific axial position is indicated by the letter p followed by a subscript.

[0089] The axial position p along the axis is used as a parameter to describe the position of a point or cross-section along a slender cylindrical section (e.g., on a sidewall). The axial position of a point not on the axis can be found by projecting that point onto the axis using a displacement vector perpendicular to the axis. A cross-section is a plane perpendicular to the axis. The axial position of a cross-section is located at the intersection of the cross-section and the axis.

[0090] The slender cylindrical portion from the axial position p A Extending to axial position p B The slender cylindrical portion is contained in p A The cross section at p B Between the cross sections at that location.

[0091] In one embodiment, the container has a first end and a second end, the container being adapted and configured to dispense a liquid pharmaceutical composition from the second end. B p A Closer to the second end.

[0092] In one embodiment, the container has a first end and a second end, the first end being a closed end without an opening, and the second end being an open end with an opening. B p A Closer to the second end.

[0093] The container has sidewalls extending along an elongated cylindrical portion. The sidewalls have an inner surface. The inner surface is adjacent to an inner cavity. Preferred shapes of the sidewalls are hollow cylinders, hollow prisms, and hollow truncated cones. A preferred hollow truncated cone has a diameter starting from p... A to p B Reduce. The preferred shape of the inner cavity is a cylinder, prism, or truncated cone. The preferred truncated cone has a diameter starting from p. A to p B Decrease.

[0094] The inner surface is preferably smooth, but may have a certain degree of roughness.

[0095] The thickness of the sidewall is preferably measured as the difference between the radial distances from the axis to the inner and outer surfaces of the sidewall.

[0096] The thickness of the layer is preferably measured as the difference between the radial distances from the axis to the inner surface of the layer and the inner surface of the sidewall.

[0097] The preferred materials for the sidewalls are polymers and glass.

[0098] In one embodiment, the sidewall comprises a polymer, preferably made of a polymer. The polymer is preferably selected from one or both of the following: one or more cyclic olefin copolymers and one or more cyclic olefin polymers. According to one aspect of this embodiment, the polymer is preferably at least 30% by weight, more preferably at least 50% by weight, more preferably at least 80% by weight, and most preferably about 100% by weight of the sidewall.

[0099] In one embodiment, the sidewall comprises glass, preferably made of glass. Preferred glass herein comprises one or more of the group consisting of silicon, boron, and aluminum. A preferred glass comprises boron and silicon. A preferred glass is borosilicate glass. A preferred glass comprises aluminum and silicon. A preferred glass is aluminosilicate glass. According to one aspect of this embodiment, the glass preferably comprises at least 30% by weight, more preferably at least 50% by weight, more preferably at least 80% by weight, and most preferably about 100% by weight of the sidewall.

[0100] Lubricant layer

[0101] The lubricant layer is located on the inner surface of the sidewall. The lubricant layer may extend over the entire elongated cylindrical portion or only over a portion thereof. The lubricant layer extends over the entire portion X.

[0102] The preferred lubricant is a silicone-based lubricant.

[0103] Preferred lubricants include one or more polysiloxanes.

[0104] Preferred lubricants include one or more silicone oils, preferably, the total content of silicone oil is 10 to 50% by weight, more preferably 20 to 40% by weight, and most preferably 25 to 35% by weight, based on the total weight of the lubricant. A preferred silicone oil is polydimethylsiloxane.

[0105] Preferred lubricants include crosslinked polysiloxanes, and preferably, the total content of crosslinked polysiloxanes is 50 to 90% by weight, more preferably 60 to 80% by weight, and most preferably 65 to 75% by weight, based on the total weight of the lubricant.

[0106] Preferred lubricants may be prepared from a mixture comprising one or more, preferably all of the following:

[0107] -Reactive polysiloxane;

[0108] -Non-reactive polysiloxane;

[0109] -catalyst;

[0110] -Diluent.

[0111] Preferred reactive polysiloxane adaptants are configured to undergo a crosslinking reaction to obtain a crosslinked network. Crosslinking can be catalyzed by a catalyst.

[0112] Preferred non-reactive polysiloxanes do not undergo crosslinking reactions. Preferred non-reactive polysiloxanes comprise one or more alkyl groups. Another preferred non-reactive polysiloxane is completely substituted with alkyl groups.

[0113] The preferred catalyst catalyzes the reaction to crosslink polysiloxane.

[0114] The preferred diluent dissolves one or more other components of the mixture. A preferred diluent is a silicone-based diluent. A preferred diluent is a short-chain polysiloxane, preferably having six or fewer repeating units. A preferred diluent is hexamethyldisiloxane.

[0115] Based on the total weight of the lubricant, the preferred lubricant contains no more than 10% by weight, preferably no more than 5% by weight, and more preferably no more than 1% by weight of water.

[0116] The lubricant layer has a thickness distribution from p1 to p2. The layer thickness at p2 is greater than the layer thickness at p1, preferably at least 100 nm greater, more preferably at least 500 nm, and even more preferably at least 1 μm.

[0117] In one embodiment, the thickness of the lubricant layer increases monotonically from p1 to p2.

[0118] In one embodiment, the thickness of the lubricant layer satisfies the following condition:

[0119] - Part X is divided into n regions of equal length: M1 to M n ;

[0120] -For M1 to M n Sort the data, where M1 starts at p1, M... n The process terminates at p2.

[0121] -In areas M1 to M n The average thickness T of the upper layer is from T1 to T n ;

[0122] - Series T2 to T n The average layer thickness is greater than the average value of the preceding T from T1 to T2. n-1 ;

[0123] -x is an integer of 2 or greater, with preferred values ​​for x being 5, 10, 15, and 20.

[0124] In one embodiment, the layer extends along the length L of the elongated cylindrical portion. B The lubricant extends over at least 70%, more preferably at least 80%, more preferably at least 90%, most preferably at least 94%, most preferably at least 98%, and most preferably about 100%. In another embodiment, the lubricant extends over the length L of the elongated cylindrical portion. B Extending from 20% to 60%.

[0125] In one embodiment, the lubricant layer has a minimum thickness t determined between p1 and p2. min The wavelength is at least 60 nm, preferably at least 90 nm, more preferably at least 100 nm, and most preferably at least 110 nm.

[0126] In one embodiment, the layer has a minimum thickness t determined between p1 and p2. min It is greater than the average roughness of the inner surface of the sidewall between p1 and p2, preferably at least 20 nm, more preferably at least 40 nm, and even more preferably at least 60 nm.

[0127] The lubricant layer can be cured after application. Preferred curing methods include thermosetting, radiation-induced curing, or a combination of both. Some preferred curing methods are the application of UV radiation and the application of IR radiation.

[0128] Liquid pharmaceutical composition

[0129] The container is used for drug packaging. Preferred containers are adapted and configured to contain liquids.

[0130] The liquid pharmaceutical composition preferably contains an active compound.

[0131] The liquid pharmaceutical composition is a fluid.

[0132] The preferred amount of the liquid pharmaceutical composition is 0.1 to 150 ml, more preferably 0.5 to 70 ml, more preferably 0.8 to 40 ml, most preferably 1 to 10 ml, and most preferably 2 to 5 ml.

[0133] piston

[0134] The container is adapted and configured to accommodate the piston. Preferably, the piston is adapted and configured to be accommodated within the container. The container and the piston are preferably complementary, such that the piston can be introduced into the inner cavity of the container and that the piston can move within the inner cavity in a direction parallel to the axis.

[0135] The piston is preferably made of or comprises portions made of an elastic material. The piston is preferably adapted and configured to seal the cross-section of the inner cavity. The piston is preferably adapted and configured to move within the container, preferably along an axis defined by an extension of the container. When inside the container, the movement of the piston is preferably impeded by frictional forces between the piston and the inner surface of the container.

[0136] The piston can be fixed to a slender rod, which is adapted and configured to push and pull the piston in a direction parallel to the axis.

[0137] The preferred piston is a plunger.

[0138] Piston axial position

[0139] When positioned in the container, the piston contacts the layer or inner surface, or both. The piston's tip is where the piston moves from p... A to p B The point that first contacts the layer or inner surface in the direction of the piston. The rear end of the piston is the point where the piston moves from p. A to p B The point in the direction that finally contacts the layer or inner surface. The piston axial position is the axial position of the piston's front end.

[0140] The distance between the front and rear ends of the piston is the piston length L. C .

[0141] kit

[0142] One or more of the above objectives are achieved at least in part by a kit including a container and a piston according to the present disclosure.

[0143] The piston and container are preferably complementary, such that the piston can be housed in the container and can move within the cavity in a direction parallel to the axis.

[0144] friction

[0145] The movement of the piston within the container is accompanied by frictional forces between the piston and the inner surfaces and / or layers of the sidewalls. These frictional forces include static friction, which prevents the piston from moving relative to the container, and kinetic friction, which occurs as the piston moves.

[0146] Static friction depends on the piston's axial position. The static friction at a given piston axial position p is preferably determined by the piston axial position p1+L. C Starting from point L, a constant speed of 100 mm / min is applied from point L+1. C Move the piston to a position p along its axial direction, for example, p1+L. CThe piston is initially stationary at an equidistant point between p2 and p3, and eventually moves towards its axial position p2. The static friction at the axial position p is the force required to move the piston in the final step.

[0147] The static friction towards the second end of the container is less than the static friction towards the first end of the container, preferably satisfying the criteria of Embodiment |14|, more preferably Embodiments |13| and |14|. The static friction at the piston axial position p2 is preferably less than that at the piston axial position p1+L. C Static friction at the point. The static friction s preferably originates from p1+L. C p2 decreases monotonically. The method for determining static friction is shown in the attached figure.

[0148] From p1+L C The static friction of p2 is preferably relatively uniform, preferably meeting the standards of Example |13|, more preferably Example |13| and |14|.

[0149] Components

[0150] At least one of the aforementioned objectives is achieved, in part, by means of an assembly comprising a container, a piston, and a liquid pharmaceutical composition. The piston is located within the container to seal a cross-section of the inner cavity. The liquid pharmaceutical composition is present in the inner cavity between the cross-section sealed by the piston and the opening of the container.

[0151] In one embodiment, the liquid pharmaceutical composition fills at least 50% by volume, preferably at least 70% by volume, and more preferably 80% by volume of the cavity.

[0152] In one embodiment, the liquid pharmaceutical composition fills less than 50% by volume, or less than 30% by volume, or less than 20% by volume of the cavity.

[0153] The component is preferably adapted and configured such that the liquid drug composition can be ejected from the inner cavity by moving the piston toward the second end in a direction parallel to the axis.

[0154] Preferred components are used as plunger systems, in which the liquid pharmaceutical composition can be ejected from the container by the movement of the piston.

[0155] The preferred container has a fixing device, preferably located at one end. The preferred fixing device is adapted and configured to secure a needle or tube. The needle or tube can be secured to the container in the assembly.

[0156] Luer connector

[0157] Preferred containers, whether as the container itself or as part of a kit or assembly, have Luer connectors. Preferred Luer connectors conform to ISO 80369. Preferred Luer connectors are Luer lock connectors and sliding end connectors, preferably Luer lock connectors. In one embodiment, the container has a Luer lock connector. In another embodiment, the container has a sliding end connector. Preferred Luer connectors are male Luer connectors. Preferred Luer lock connectors are one-piece and two-piece Luer lock connectors. In one embodiment, the container has a one-piece Luer lock connector. In another embodiment, the container has a two-piece Luer lock connector.

[0158] Preparation method

[0159] The container according to this disclosure can be prepared by providing a container without a lubricant layer and coating the inner surface of the container's sidewalls with a lubricant layer. Preferred methods for using the coating layer include application by coating and brushing, preferably with suitable tools.

[0160] The components can be prepared using the following steps:

[0161] - Provide a container according to this disclosure;

[0162] - Preferably, the piston is introduced into the container via the first end, preferably via the first opening;

[0163] - Preferably, the liquid pharmaceutical composition is introduced into the cavity of the container via the second end, preferably via the second opening. Attached Figure Description

[0164] The invention is now further illustrated by the accompanying drawings. The drawings are exemplary and do not limit the scope of the invention. Some features of the drawings are shown.

[0165] Figure 1 A cross-sectional view of a container with a lubricant layer on the inner surface of the sidewalls is shown.

[0166] Figures 2a to 2m The diagram shows the piston being pushed repeatedly inside the container.

[0167] Figure 3 A cross-sectional view of the container is shown.

[0168] Figures 4a to 4e The process of preparing components and launching drug products is illustrated.

[0169] Figure 5 The thickness distribution of the lubricant layer is shown.

[0170] Figure 6 The determination of a monotonically increasing thickness distribution is shown.

[0171] Figure 7The static friction curve of the kit in Example 1 is shown. Detailed Implementation

[0172] Figure 1 A cross-sectional view of a container 100 having a lubricant layer 106 on the inner surface 118 of the sidewall 107 is shown. The container 100 has a first end 119 and a second end 120. The first end 119 has a first opening 102 and an outwardly projecting flange 105. The second end 120 has a second opening 103 and a fixing device 104 for securing a pin connector, which in this case is threaded. The container 100 has an axial position p A Extending to axial position p B The elongated cylindrical portion 501. In this case, the elongated cylindrical portion 501 has a hollow truncated cone shape, in p A The diameter at point p is larger than that at point p. B The diameter at that point. The length of the slender cylindrical portion 501 is L. B The axis 101 extends in the direction of extension of the container 100 and is the axis of rotation of the elongated cylindrical portion 501. The sidewall 107 has an inner surface 118 on which a lubricant layer 106 is present. The layer 106 extends over a portion, but not the entirety, of the sidewall 107 and does not reach end p. A and p B A portion X of the elongated cylindrical portion 501 extends between axial positions p1 and p2. Portion X is an abstract portion selected according to the standards presented in the embodiments and claims. End points p1 and p2 are both located within the layer 106. The purpose of selecting the abstract portion X of the elongated cylindrical portion 501 is to ensure that irregularities at both ends of the elongated cylindrical portion 501 are avoided, especially since in this example, layer 106 does not always extend to end p1. A and p B The axial position along axis 101 of container 100 is measured. The axial position can be given with reference to p1 as a reliable zero point. The general axial position p and the inner diameter 113 between the inner surfaces 118 of the sidewall 107 at that axial position are shown. The thickness t1 at axial position p1 and the thickness t2 at axial position p2 are shown. According to this disclosure, t2 is greater than t1. In the case shown, although t1 and t2 are similar, the difference may be more pronounced.

[0173] Figures 2a to 2mThe diagram illustrates multiple pushes of piston 203 within container 100. This series of figures shows how piston 203 is pushed along axis 101 of container 100 during these multiple pushes, with piston 203 coming to a standstill at least once along its path along axis 101 between each push. During the process shown, piston 203 comes to a standstill at at least two intermediate axial positions along its path. The presented process can also be used to construct dynamic and static friction curves for the container / piston assembly as a function of distance along axis 101. This process was performed using a TesT 106.2kN apparatus purchased from TesT GmbH, Germany.

[0174] Figure 2a A container 100 is shown, prepared for multiple actuations of piston 203. In this case, container 100 is a syringe barrel having a predominantly hollow truncated conical portion (the truncated cone has a very small angle of inclination, and for ease of observation, the elongated cylindrical portion is represented as a cylinder). Axis 101 is in the extending direction of container 100. Axis 101 is the axis of rotation of the conical / cylindrical portion. A first opening 102 and an outwardly projecting flange 105 are present at a first end 119 of container 100. A second opening 103 is present at a second end 120 of container 100, which gradually narrows and is adapted and configured to hold a needle. The diameter of the first opening 102 is larger than the diameter of the second opening 103. Container 100 has cylindrical sidewalls 107 and an inner cavity 121. A lubricant layer 106 is present on the inner surface 118 of sidewall 107. The lubricant layer 106 is present on most of sidewall 107. In this case, portion X comprises most of the lubricant layer 106, with p1 and p2 slightly offset from the end positions of layer 106 to avoid end effects. The lubricant layer 106 has a thickness 210, shown in a general axial position along axis 101. For ease of depiction, although layer 106 is shown as generally uniform, the preferred thickness distribution is described elsewhere herein. A piston 203 is present in the cavity 121 toward the first end 119 of the container 100. In this case, the piston 203 is a stop made of elastomeric material with a fixed elongated rod 202. The piston 203 has ribbed sidewalls. The elongated rod 202 can be used to push the piston 203 along axis 101 in a plunger manner. The axial position of the piston 203 is defined as the axial position of the front end of the piston 203. The piston 203 is shown in the initial axial position 201, where the rear end of the piston 203 is located at p1. In the presented initial state, no force is applied to the piston by the elongated rod 202 and the piston 203 is stationary.

[0175] Figure 2b It shows Figure 1The container 100 contains a thrust 207 applied to an elongated rod 202 along axis 101. Force 207 is transmitted to piston 203. In the figure, force 207 is less than the static friction at axial position 201 and piston 203 is stationary; the thrust 207 is counteracted by the static friction between piston 203 and sidewall 207 / lubricant layer 106. The static friction at axial position 201 is defined as the force 207 at which piston 203 begins to move along axis 101.

[0176] Figure 2c It shows Figure 2b The thrust 207 in the container 100 exceeds the static friction at the axial position 201, causing the piston 203 to move. Although the piston 203 is shown at the axial position 201, it moves 208 along the axis 101. The thrust 207 is equal to the dynamic friction at the axial position 201, and the piston 203 is at a constant speed along the axis 101. The piston 203 moves between the stationary axial positions at a constant speed of 100 mm / min.

[0177] Figure 2d Showing Figure 2c The container 100 then contains piston 203, which has moved along axis 101 from 201 to the intermediate axial position 204. Piston 203 continues to move at a constant speed of 100 mm / min 208 by thrust 207.

[0178] Figure 2e The container 100 is shown with thrust 207 released at axial position 204. The piston is stationary at axial position 204.

[0179] Figures 2e to 2i Similar to Figures 2a to 2e Piston 203 is initially stationary at axial position 204. Figure 2e ) and moves by force 207 of static friction at a position exceeding axial 204. Figure 2f Piston 203 begins to move 208 along axis 101 from axial position 204. Figure 2g And in moving 208, it reaches other intermediate axial positions 205. Figure 2h ), here the thrust 207 is released and the piston 203 stops ( Figure 2i The velocity between the stationary axial positions remains constant at 100 mm / min.

[0180] Figures 2i to 2m They are similar to Figures 2a to 2e and Figures 2e to 2i Piston 203 is initially stationary at axial position 205. Figure 2i ) and moves by force 207 of static friction at a position exceeding axial 205. Figure 2jPiston 203 begins to move along axis 101 at axial position 205 (208). Figure 2k And in movement 208, it reaches the final axial position 206. Figure 2l ), here the thrust 207 is released and the piston 203 stops ( Figure 2m Axial position 206 is the position where the piston tip reaches axial position p2 near the end of lubricant layer 106 and is in its final stationary axial position. The speed between the stationary axial positions remains constant at 100 mm / min.

[0181] Static friction was measured at the following points 201, 204, and 205:

[0182] 201 Figure 2b 204 Figure 2f 205 Figure 2j

[0183] Figure 3 A cross-sectional view of container 100 at axial position p along axis 101 is shown. Sidewall 107 and lubricant layer 106 are shown as concentric circular bands. The thickness 301 of sidewall 107 and the thickness 302 of lubricant layer 106 are shown at eight equidistant points around the circle. The thickness of sidewall 107 or lubricant layer 106 at axial position p is the average thickness around the circle. This is measured by averaging multiple (in this case, eight) equally spaced sampling points around the circle.

[0184] Figures 4a to 4e The process of preparing the components and launching the drug product 401 is shown.

[0185] Figure 4a A container 100 prepared for forming an assembly is shown. The container 100 has a rotation axis 101, sidewalls 107, and an inner cavity 121. A lubricant layer 106 is present on the inner side of the container 100. The lubricant layer 106 has been cured by heating at 175°C for 20 seconds. The container 100 includes a first opening 102 and a second opening 103.

[0186] Figure 4b It shows Figure 4a The piston 203 is located in the inner cavity 121 of the container 100. The front end of the piston 203 is located at an axial position 201 near the first opening 102 along the axis. The rear end of the piston 203 is located at p1 near the starting point of the lubricant layer 106.

[0187] Figure 4c This shows the product after the liquid pharmaceutical composition 401 has been filled. Figure 4b The container 100. The liquid drug composition 401 is located in the cavity 121 between the front end of the piston 201 and the second opening. In this form, the container 100, the piston 203, and the liquid drug composition 401 constitute an assembly.

[0188] Figure 4d It shows Figure 4c The component includes an assembly in which a thrust 207 is applied to push a piston 203 along axis 101 in a direction from the first opening 102 toward the second opening 103. The movement 208 of the piston 203 forces the liquid drug composition 401 to be ejected 402 from the container 100.

[0189] Figure 4e This illustrates the piston 203 having moved along axis 101 from the first opening 102 toward the second opening 103 to an axial position p2 near the end of the lubricant layer 106. Figure 4d The components. The liquid pharmaceutical composition 401 has been dispensed through the second opening 103, and only a small amount remains at the end of the container at the second opening 103.

[0190] Figure 5 The thickness distribution 200 of the lubricant layer 106 is shown. The thickness t increases from t1 value 122 at axial position p1 115 to t2 value 123 at axial position p2 117. The gradient of the thickness relative to the axial position is not negative in the range from p1 115 to p2 117. The distribution is monotonic.

[0191] Figure 6 The determination of a monotonically increasing thickness distribution is shown. The range from p1 to p2 is divided into 10 equal-sized regions M1 to M2. 10 Areas M1 to M 10 The average thicknesses are T1 to T 10 Although the thickness distribution varies drastically with roughness over a small range, from T1 to T... 10 The strictly increasing order (without decreasing order) clearly shows the monotonicity of the thickness distribution over a large range, as shown on the t-axis.

[0192] Figure 7 The static friction curves for the kit in Example 1 are shown. The static friction curves use... Figures 2a to 2m The presented process is defined by three intermediate rest points at 15, 30, and 45 mm from the starting point 201. Ten tests were performed using the newly manufactured kit (all 10 rows shown in the figure). A smooth static friction curve was observed in each run, gradually decreasing from approximately 4.8-6.2 N at 201 to a distance of c. α The static friction is approximately 2.8-3.8 N at 45 mm. The gently decreasing static friction curve is well-suited for use with multi-dose syringes. It can be seen that the transition between static and dynamic friction is smooth, allowing for better control of multi-dose delivery.

[0193] Test methods

[0194] Layer thickness

[0195] The thickness of the layer was determined using optical interferometry with the RapID Explorer, purchased from rap.ID Particle Systems GmbH. Measurements were taken from outside the container, through the sidewall. The device was operated with proprietary software and according to the proprietary instruction manual of 2014.

[0196] Surface roughness

[0197] Surface roughness of the inner surface of the sidewall was measured using white light interferometry. A 2 μm x 2 μm sample region was scanned in tapping mode, with 256 rows and 256 points per row per image. The scan rate was 0.7 Hz. The cantilever had an end with a radius ≤10 nm. The morphology of the sample was measured by evaluating the change in the amplitude of the oscillating cantilever while scanning the surface. The raw data were smoothed by line fitting using a third-order polynomial. Root mean square roughness Rm rms Formulas from AFM software The calculation yields n = 256 * 256 = 65536, y i It is the height value at each of the 65,536 measurement locations.

[0198] resistance

[0199] The resistance was measured using a TesT 106.2kN device purchased from TesT GmbH, Germany. The piston moved at a speed of 100 mm / min.

[0200] Example

[0201] The following examples are provided to further illustrate the invention, and not to limit its scope.

[0202] The lubricant was prepared as follows: First, 10g of vinyl-functionalized polydimethylsiloxane was placed in a reactor and mixed with 65g of decamethylcyclopentasiloxane. Under constant stirring at 800 rpm, 0.5g of methylhydrosiloxane / dimethylsiloxane copolymer, 6.25g of liquid polydimethylsiloxane, 10% hexachloroplatinic acid (catalyst) in 0.01g isopropanol, and 0.05g of 2,4,7,9-tetramethyl-5-decyn-4,7-diol (inhibitor) were added to the reaction mixture. The reaction solution was used after stirring for 60 seconds. Figure 1The container shown is a 1 mL 1g TopPac container purchased from Schott AG, Germany. The inner surface of the sidewalls of the elongated cylindrical portion is coated with a lubricant layer, extending at most 1 mm from both ends of the cylindrical portion. The thickness distribution of the coated layer is shown in Table 1. The lubricant layer is cured by heating at 175°C for 20 seconds. This is achieved by introducing a material made of elastomer... Figure 2a The piston with a fixed, slender rod, shown in the figure, was used to test the container. The piston, FM257 / 2, was purchased from Dedecke GmbH, Germany. Similar tests were performed. Figures 2a to 2m The process shown begins 5 mm along the cylindrical section and has three intermediate stopping points at 15, 30, and 45 mm along the cylindrical section to determine the static friction along the cylindrical section. This process is performed using a TesT 106.2 kN device available from TesT GmbH, Germany.

[0203] The root mean square roughness of the inner surface of the sidewall in the region from p1 to p2 is determined to be 62 nm.

[0204] Table 1

[0205]

[0206] Table 2

[0207]

[0208]

[0209] List of reference numerals

[0210] 100 containers

[0211] 101 Axis

[0212] 102 First Opening

[0213] 103 Second opening

[0214] 104 Fixing device at the front end of container

[0215] 105. The outwardly projecting flange of a container.

[0216] 106 Lubricant layer

[0217] 107. Container sidewalls

[0218] 118 Inner surface of the sidewall

[0219] 119 The first end of the container

[0220] The second end of container 120

[0221] 121 The inner cavity of the container

[0222] 201 Initial piston axial position

[0223] 202 Slender rod used to drive the piston

[0224] 203 Piston

[0225] 204 Axial position of the first intermediate piston

[0226] 205 Axial position of the second intermediate piston

[0227] 206 Final Piston Axial Position

[0228] 207 thrust

[0229] 208 Piston movement along the axis

[0230] 210 Layer thickness at typical axial positions

[0231] 301 sidewall thickness

[0232] Thickness of 302 layers

[0233] 401 Liquid Pharmaceutical Composition

[0234] 402 Introduces Liquid Pharmaceutical Compositions

[0235] 501 Slender cylindrical part

Claims

1. A container (100) for packaging a drug, said container (100) having an elongated cylindrical portion (501), wherein: a. The elongated cylindrical portion (501) has an extending direction and an axis (101) along the extending direction. b. Determine the axial position p along the axis (101); c. The elongated cylindrical portion (501) from its axial position p A Extending to axial position p B ; d. Length L of the slender cylindrical portion B For p A With p B The distance between them; e. The container (100) has a sidewall (107) extending on the elongated cylindrical portion (501), the sidewall (107) having an inner surface (118) adjacent to the inner cavity (121), the inner cavity (121) having a diameter; f. A lubricant layer (106) is located on at least a portion of the inner surface (118); g. On the axis (101) at p A With p B At a given axial position p, the following items are determined as the angular average values ​​in the cross section perpendicular to the axis (101) at the axial position p: i. The thickness of the sidewall (107), ii. The thickness of the lubricant layer (106), and iii. The diameter of the inner cavity; h. A portion X of the axis (101) extends from axial position p1 to axial position p2 in order to satisfy the following criteria: i.p1 and p2 are both located at p A With p B between, ii. Partial length L X Let p1 be the distance between p2. iii.L X For L B At least a quarter of, iv. The lubricant layer (106) extends over the entire portion X, and v. The thickness t1 of the lubricant layer (106) at p1 is less than the thickness t2 of the lubricant layer (106) at p2; i. Meets one or more criteria for selection from a group consisting of the following: i. Length L B It ranges from 3 to 20 cm; ii. In p A to p B The average diameter of the defined lumen (121) ranges from 0.4 to 4 cm; iii. In p A to p B The average thickness of the defined sidewall (107) is 0.3 to 4 mm; iv. The volume of the inner cavity (121) is 0.1 to 150 ml. The thickness of the lubricant layer (106) increases monotonically from axial position p1 to axial position p2, and The inner diameter at p1 is d1, and the inner diameter at p2 is d2, with d1 being greater than d2.

2. The container (100) according to claim 1, wherein the thickness ratio t1:t2 is from 1:1.1 to 1:

100.

3. The container (100) according to claim 1 or 2, wherein the lubricant comprises one or more silicone oils.

4. The container (100) according to claim 1 or 2, wherein the inner cavity (121) is cylindrical or truncated conical in the elongated cylindrical portion (501).

5. The container (100) according to claim 1 or 2, comprising a first opening (102) at a first end (119) and a second opening (103) at a second end (120).

6. The container (100) according to claim 1 or 2, comprising an opening and a fixing device (104) at the opening.

7. The container (100) according to claim 1 or 2, wherein the lubricant layer (106) has a minimum thickness t determined in the portion X. min It is at least 60 nm.

8. The container (100) according to claim 3, wherein the one or more silicone oils are at least partially contained in the matrix.

9. A kit comprising the following kit components: a. The container (100) according to any one of claims 1 to 8, and b. Piston (203); in, The piston (203) is adapted and configured to be positioned within the inner cavity (121) such that: i. The piston seals the cross-section of the cavity (121) between the inner surfaces (118) of the sidewall (107); ii. The piston (203) is closest to p B The piston has a front end at an axial position, at which the piston contacts the lubricant layer (106) or the inner surface (118); iii. The piston (203) is closest to p A The piston (203) has a rear end at an axial position, at which the piston (203) contacts the lubricant layer (106) or the inner surface (118); iv. The length L of the piston C The distance between the front end and the back end; v. The piston (203) has a piston axial position, which is the axial position of the front end; vi. The piston (203) can move in a direction parallel to the axis (101) by static friction s, where s is a function of the axial position of the piston.

10. The kit of claim 9, wherein for p1+L C For piston axial positions within the range of p2, static friction s has a maximum value S. max and minimum value S min S min / S max The value is 70% or higher.

11. The kit according to claim 9 or 10, wherein the static friction at the piston axial position p2 is less than or equal to the piston axial position p1+L. C Static friction at the point.

12. A component comprising a container (100) and a piston (203) according to any one of claims 1 to 8, wherein: a. The container (100) has an opening (103); b. The piston (203) is located in the inner cavity (121), thereby sealing the cross-section of the inner cavity (121); c. The inner cavity (121) contains a liquid drug composition located between the sealed cross section and the opening (103); and d. The components are adapted and configured such that the liquid pharmaceutical composition is ejected from the opening (103) by the movement of the piston (203) in a direction parallel to the axis (101).

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