Patent Description:
Generally, syringes are used to inject liquids (e.g. liquid medicines or saline solution) into the body or to extract blood from the body. Syringes include a barrel, a gasket or stopper that forms an air-tight and liquid-tight seal with the barrel, and a piston or plunger that translates the stopper. The barrel includes a tip that is fitted with a hollow hypodermic needle. Syringe barrels can be made of various materials, such as metal, glass, or polymers (plastics).

Some syringes are pre-filled with a single dose of medication. Pre-filled syringes are used to both package and deliver the medication and face certain requirements. For example, the material of the syringe barrel must be free from impurities, so-called extractables and leachables, that affect the stability or efficacy of the medication stored in the barrel. The material of the barrel should also prevent oxygen permeation and form a tight seal with the gasket during storage. High-performance plastics, such as cyclic olefin polymers (COP), can be used to manufacture the barrel of a pre-filled syringe.

Other syringes are manually filled, e.g., from a vial containing a liquid medicine.

Syringes face strict safety and manufacturing requirements, for example, with respect to the materials used for the syringe components. The specific medication administered using a syringe can introduce further requirements, for example, the speed at which the stopper and plunger are moved in order to dispense the medication.

<CIT> discloses a syringe containing a compressible porous matrix, which compressible porous matrix has in it a pharmaceutical in a soluble glass, methods of producing and using the syringe, and compressible porous matrix inserts for insertion into a syringe barrel.

The present invention provides a syringe, a syringe barrel and a method of filling a syringe that can accurately and safely administer liquid. In particular, claim <NUM> provides such a syringe barrel, claim <NUM> provides such a syringe, and claim <NUM> provides a such a method of filling a syringe. Further advantageous embodiments of the present invention are set out in the dependent claims.

According to the present invnention, a syringe barrel includes a hollow body with an opening configured to receive a stopper, a tip configured for connection to a hollow needle, and a compressible spacer arranged inside the hollow body and adjacent to the tip, wherein the spacer comprises an insoluble material configured to displace a liquid filled in the hollow body.

There is a gap between the compressible spacer and the inner surface of the barrel. The compressible spacer is configured to displace but not to absorb or retain the liquid inside of the barrel.

According to the present disclosure, the spacer includes a porous material configured to absorb the liquid.

According to the present disclosure, the porous material includes a foam, in particular a metal, latex, rubber, polymer, or alginate foam.

According to the present disclosure, the porous material includes a polyurethane, polystyrene, or polyolefin foam.

Preferably, the syringe barrel includes a neck portion arranged between the hollow body and the tip. The spacer includes a protrusion, and the neck portion is configured to receive the protrusion.

Preferably, the hollow body is sized for a <NUM>, a <NUM>, or a <NUM> syringe, and the spacer is configured to displace <NUM> to <NUM>µl, in particular <NUM> to <NUM>µl of a liquid.

Preferably, the spacer consists of a single piece of material.

According to the present invention, a syringe including a syringe barrel according to any of the embodiments above and a stopper received in the body of the syringe barrel is provided. The spacer is arranged between the barrel tip and the stopper.

Preferably, the hollow body includes an annular inner shoulder, wherein the spacer rests against the annular inner shoulder, and an end face of the stopper abuts the spacer.

According to the present invention, a method of filling a syringe includes: arranging a syringe barrel in a holder with an open end of the syringe barrel pointing upwards; inserting a compressible spacer that includes an insoluble material configured to displace a liquid into the syringe barrel through the open end; filling the syringe barrel with the liquid, in particular a liquid pharmaceutical composition, through the open end; and inserting a stopper into the syringe barrel through the open end. There is a gap between the compressible spacer and the inner surface of the barrel. The compressible spacer is configured to displace but not to absorb or retain the liquid inside of the barrel.

Preferably, the liquid pharmaceutical composition includes vascular endothelial growth factor (VEGF) inhibitors.

Preferably, the syringe barrel is sized for a <NUM>, a <NUM>, or a <NUM> syringe, and filling the syringe barrel with a liquid includes filling <NUM>µl to <NUM>µl of the liquid into the syringe barrel.

Preferably, inserting the spacer into the syringe barrel through the open end includes: arranging a tube with one end inside of the syringe barrel; inserting the spacer into an opposite end of the tube; and pushing, using a plunger, the spacer through the tube and into the syringe barrel.

Preferably, the syringe barrel is one of a plurality of syringe barrels arranged in a tray, with the open end of each syringe barrel pointing upwards, and a compressible spacer is inserted into each syringe barrel in the tray. The implementation further includes sealing the tray for storage before filling each syringe barrel with the liquid.

Preferably, the method includes using a filling and vent tube stoppering machine to fill multiple syringe barrels with the liquid and insert stoppers into multiple syringe barrels in parallel.

The details of one or more implementations of the subject matter of this specification are set forth in the accompanying drawings and the subsequent description.

Like reference numbers represent corresponding parts throughout the disclosure.

This disclosure relates to syringes for injecting liquids in the body. Injected liquids can serve a therapeutic purpose and include pharmaceutical compositions in some cases. Other examples of injected liquids are saline solution. The following description is not limited with respect to the injected liquid and therefore uses the generic term "liquid.

Referring to <FIG>, a syringe <NUM> is used to introduce liquids, into skin or tissue and includes a barrel <NUM>, a gasket or stopper <NUM> that seals the barrel <NUM>, and a piston or plunger <NUM> that is connected to the stopper <NUM>. The barrel <NUM> is a continuous structure that extends from a tip <NUM> to an opening <NUM>. A flange <NUM> can be provided adjacent to the opening. In the illustrated embodiment, the tip <NUM> of the barrel <NUM> is covered by a cap <NUM>, e.g., a Luer lock-style connector. Prior to use, the cap <NUM> can be replaced by a hollow needle <NUM> (<FIG>). In some embodiments, a needle is integrally molded with the tip <NUM>. The liquid is dispensed by holding the flange <NUM> and depressing the plunger <NUM>. The plunger <NUM> can be stored separately from the stopper <NUM> and connected prior to use.

Generally speaking, syringe barrels are molded, coated, and assembled with a cap in automated systems. Several empty barrels are loaded, tip first, into a tray or nest with the open end of the barrel exposed. Such trays can be loaded into filling and stoppering machines that inject the liquid substance into the barrel and insert the stopper through the opening of the barrel to manufacture a pre-filled syringe. When the stopper is inserted into the barrel, it is aligned with the level of the liquid. Depending on the amount or dose of substance, the stopper will have a different position along the length of the barrel.

Referring again to <FIG>, the barrel <NUM> contains a particular dosage D of a liquid medicine, and the stopper <NUM> is arranged at the liquid level of the dosage D. The dosage D is small relative to the total capacity of the barrel <NUM>, as shown by the empty space behind the stopper <NUM>. An even smaller dosage D<NUM> in the same barrel <NUM> is shown in <FIG>. As the dosage D becomes progressively smaller, a distance X between the stopper <NUM> and the tip <NUM> decreases. As the distance X decreases, it becomes difficult to tell whether the syringe <NUM> is filled, especially for colorless liquid medicines. The drugs also become more difficult to dispense in a smooth manner.

In some cases, a different size of barrel <NUM> can be used to accommodate small dosages D<NUM> and maintain a certain distance X between the stopper <NUM> and the tip <NUM>. However, using different barrel sizes increases the complexity of manufacturing, filling, and stoppering syringes. For example, a given filling and stoppering machine may not be able to accommodate all possible barrel sizes. Such issues particularly arise for dosages in the microliter range, e.g., <NUM> to <NUM>µl, since the capacity of the most common syringes is <NUM> or <NUM>. In some cases, capacity of the syringe ranges from <NUM> to <NUM>. Dosages of liquid medicines in this capacity are used, e.g., in ophthalmological treatments or in gene cell therapies. Example implementations of a standard syringe (e.g. a <NUM> or <NUM> syringe) that is adapted to dosages in the microliter range are shown in <FIG>.

In <FIG>, a compressible spacer <NUM> inserted in the barrel <NUM> prior to filling. For example, the spacer <NUM> can be inserted using an insertion rod or tube that is similar to the equipment used to insert a stopper <NUM>. The spacer <NUM> is sized and shaped so that it can be inserted through the opening <NUM> of the barrel <NUM>. As explained below in more detail, the spacer <NUM> is made of an elastic or compressible material. In some cases, the spacer <NUM> can include a porous material. In this disclosure, "porous" means that the spacer <NUM> has many small holes. In some implementations, liquid medicine can pass through the holes in the spacer's porous material.

For example, a nozzle N of a syringe filling machine can enter the barrel <NUM> through the opening and fill the barrel <NUM> with a predetermined quantity or dosage D<NUM> of a liquid medicine (not shown). The liquid medicine can pass through the pores within spacer <NUM> and come to rest in the space between the spacer <NUM> and, e.g., the cap <NUM>. In such cases according to the present disclosure, the spacer's pores retain and absorb the liquid medicine, while the rest of the spacer displaces the liquid medicine. As described below, according to the present invention, the spacer displaces the liquid medicine without absorbing it.

The nozzle N can be part of an existing filling machine or system that is used to fill other types of syringes. Automated filling machines can be programmed to precisely fill a syringe with a pre-determined dosage of liquid medicine, which is more hygienic and accurate than, e.g., manually filling a syringe from a vial of liquid to a marking on the syringe barrel. The improvement in accuracy becomes more pronounced as the size of the dosage decreases. Additionally, automated filling machines can help to reduce drug-related waste can arise, e.g., when some of the drug remains in a vial after a syringe is manually filled.

In <FIG>, a spacer <NUM> is shown in a relaxed or uncompressed state that is also shown in <FIG>. In this state, the spacer <NUM> is not subjected to external forces and has a size or volume that can be expressed, e.g., in terms of diameter Ø and height H. In this disclosure, "compressible" means that the size or volume of the spacer <NUM> can be reduced by applying pressure, e.g., from the stopper <NUM> and the walls of the barrel <NUM>. Although the spacer <NUM> is shown having a cylindrical shape <NUM>, it can also take the shape of a rectangular or hexagonal block, for example. In <FIG>, the spacer <NUM> is schematically illustrated as having a continuous monolithic shape <NUM>. For example, the spacer <NUM> can consist of a single piece of material cut from a larger piece of material. However, the spacer <NUM> can also include multiple parts. For example, the spacer <NUM> can include an elastic compressible material with a coated or laminated outer surface.

The spacer <NUM> can include a porous material, meaning that it has a structure that includes a plurality of interconnected cells <NUM> or pores, as schematically shown in <FIG>. More specifically, each cell <NUM> has walls, but the walls of the cells are not completely closed. Such an open-cell structure allows the liquid medicine to pass through and fill the spacer, similarly to a sponge absorbing water. In this disclosure, "absorb" means that the material of spacer <NUM> can temporarily retain the liquid medicine within its pores or cells, and the liquid medicine can be expelled from the pores or cell by applying pressure to the spacer <NUM>, e.g., with the stopper <NUM> and the plunger <NUM>. Furthermore, the material of the spacer is "insoluble," meaning that it is incapable of being dissolved in in the liquid medicine.

Although all of the cells <NUM> in <FIG> are shown having open walls, the material of the spacer can include a mixture of open and closed cells <NUM>. The structure of the spacer <NUM> can also depend on the material used for the spacer <NUM>. For example, the spacer <NUM> can include a porous material that comprises a foam, in particular a metal, latex, rubber, polymer, or alginate foam. Polymer foams can include polyurethane, polystyrene, or polyolefin foams. In some implementations, the material of the spacer can be low-particle material that meets the standards of USP <<NUM>> and/or meet the biocompatibility standards of ISO <NUM>. Other criteria for selecting the spacer's material can include compatibility with the liquid medicine, shelf stability, toxicity, extractables and leachables, material elasticity, or material compressibility.

Each material can have a particular density or porosity. The choice of such properties can be adjusted to the dosage D<NUM> of liquid medicine. For example, material of the spacer can be chosen so that the total volume of the pores or cells <NUM> is based on the dosage D<NUM>, e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM>µl. Once part of the dosage D<NUM> has been absorbed by the spacer <NUM>, a stopper <NUM> is inserted to form a pre-filled syringe, as illustrated in <FIG>. Due to the size of the spacer <NUM>, a sufficient distance X between the stopper <NUM> and the barrel tip <NUM> is maintained despite the small volume of dosage D<NUM>. For example, the same filling and stoppering machine that is used for syringes without a spacer can also be used for the syringe <NUM> in <FIG>.

In <FIG>, a first end of the spacer <NUM> rests against an annular inner shoulder <NUM> of the barrel <NUM> that is adjacent to the tip <NUM>. A second end of the spacer <NUM> abuts an end face <NUM> of the stopper <NUM>. In this case, the height H of the spacer <NUM> substantially corresponds to the distance X between the stopper <NUM> and the tip <NUM>. In some cases, the height H of the spacer <NUM> can be chosen to provide a certain distance X or stroke length of the stopper <NUM> and piston <NUM> as the liquid is dispensed. Additionally or alternatively, the diameter Ø of the spacer <NUM> may substantially correspond to the inner diameter of the syringe barrel <NUM>. In this context, "substantially correspond" can include a gap between the spacer <NUM> and the inner surface of the barrel <NUM> that makes it easier to insert the spacer <NUM> during assembly.

The syringe <NUM> and spacer <NUM> shown in <FIG> are similar to the ones shown in <FIG>. However, the spacer <NUM> includes a projection or protrusion <NUM> that extends past the inner shoulder <NUM> and toward the tip <NUM> of the barrel <NUM>. The projection <NUM> is described in more detail below in reference to <FIG>.

In <FIG>, the cap <NUM> is replaced by a hollow needle <NUM> that is attached to the barrel tip <NUM> for injecting the liquid medicine. The drug is injected by moving the plunger <NUM> and stopper <NUM> towards the barrel tip <NUM>. This movement compresses the spacer <NUM> and reduces its size relative to what is shown in <FIG>. When a certain level of compression is reached, the spacer <NUM> prevents the stopper <NUM> from moving any further towards the barrel tip <NUM>. The deformation characteristics of the spacer <NUM> can provide haptic feedback to the user that the intended dosage D<NUM> has been discharged from the syringe. Overall, the described syringe <NUM> may reduce the risk of overdosing that can occur when multiple amounts of the intended microliter dosage are filled in a syringe, and the user must manually control the amount of liquid that is injected into the patient. Such overfilling also leads to increased cost and waste of the pharmacological product. In some cases, the density of the spacer material can be used to estimate an appropriately sized spacer for a particular dosage. Tests, measurements, and pre-clinical trials can be conducted to determine the specific dimensions to ensure an exact dosage of liquid.

In some cases, the spacer's material can be selected to provide a particular mechanical response or deformation. For example, a material can be selected so that pushing the plunger <NUM> and the stopper <NUM> causes plastic deformation of the spacer <NUM>. In this disclosure, "plastic deformation" refers to a permanent deformation or change in the spacer's shape, i.e., the spacer <NUM> does not fully or partially return to its initial size and shape. Alternatively, the spacer may elastically deform, i.e., regain at least part of its initial shape after compression. In such cases, a delay between the compression and re-expansion can prevent the stopper <NUM> from moving away from the tip <NUM> and creating a vacuum in the barrel <NUM> after injection has been completed.

<FIG> illustrates compressed views of the spacers in <FIG>. More specifically, an upper view (I) corresponds to an enlarged version of <FIG>, showing the spacer <NUM> of <FIG> in the compressed state. As the stopper <NUM> presses the spacer <NUM> against the annular inner shoulder <NUM> of the barrel, the end surface may slightly bulge towards the tip <NUM> without extending past the inner shoulder <NUM>. In such cases, a neck portion <NUM> between the inner shoulder <NUM> and the tip <NUM> of the barrel <NUM> may still hold a residual volume R of the liquid. In contrast to this, the lower view (II) shows the spacer <NUM> of <FIG>, which includes the protrusion <NUM>. At the time of compression, the protrusion <NUM> extends into the neck portion <NUM> of the barrel <NUM> and can reduce the residual volume R of liquid that remains in the neck portion <NUM>. Such a reduction may be advantageous for small doses (e.g. microliters) of costly medications. In <FIG> and <FIG>, the protrusion <NUM> is shown as having a tapered or conical shapes. However, other shapes that are adapted to the neck portion <NUM> of the barrel <NUM> can also be used. Furthermore, although the protrusion <NUM> is shown in conjunction with a cylindrical spacer <NUM>, spacers having other shapes may also include a protrusion <NUM>.

As described in <FIG>, the spacer <NUM> occupies a predetermined portion of the syringe barrel <NUM> to more comfortably accommodate small dosages of liquid medicines. The spacer <NUM> also increases the stroke length of the stopper <NUM> and plunger <NUM> (distance X) for injecting the small dosage of liquid medicines, making it possible to gently inject smaller dosages into the patient. For example, dosages of liquid medicines in the range of microliters are injected into the human eye in the treatment of macular degeneration.

In addition to adapting the inner volume of a standard syringe, the spacer described above also resists the movement of the stopper <NUM> towards the tip <NUM>. In some cases, a low-viscosity liquid may require a slow injection speed. One way to slow the injection speed is to increase friction between the outer surface of the stopper <NUM> and the inner surface of the barrel <NUM>, i.e., increase the glide force. However, the spacer <NUM> can also be used to augment increased friction between the stopper and the barrel or to counteract low friction between the stopper and barrel.

This effect of the spacer <NUM> is not limited to dosages of liquid in the microliter range. For example, the material of the spacer <NUM> can be selected based on the compression characteristics to provide a "braking effect" that slows injection. One material property that can influence resistance or this braking effect is the stiffness of the material. In such cases according to the present invention, the spacer <NUM> may include an elastic compressible materials with closed pores that do not absorb or retain the liquid. In other words, spacers according to the present invention displace but do not absorb the liquid inside of the barrel. The spacer <NUM> can also be laminated or include some kind of coating to prevent absorption of the liquid. In such implementations, the likelihood of liquid remaining in the spacer after injection is reduced.

Referring to <FIG>, a method <NUM> of filling a syringe <NUM> is schematically shown. The method <NUM> comprises: arranging <NUM> a syringe barrel in a holder with an open end of the syringe barrel pointing upwards; inserting <NUM> a compressible spacer configured to absorb a liquid into the syringe barrel through the open end; filling <NUM> the syringe barrel with the liquid through the open end; and inserting <NUM> a stopper into the syringe barrel through the open end.

In some implementations of the method <NUM>, the liquid comprises a liquid pharmaceutical composition, such as vascular endothelial growth factor (VEGF) inhibitors that inhibit the activity of VEGF. VEGF stimulate blood vessel formation. VEGF-A plays a role in wet form age-related macular degeneration. VEGF inhibitors can be administered in the form of intravitreal injections.

In some implementations of the method <NUM>, the syringe barrel is sized for a <NUM>, a <NUM>, a <NUM>, <NUM>, <NUM>, or a <NUM> syringe, and filling <NUM> the syringe barrel with a liquid comprises filling <NUM>µl to <NUM>µl, more specifically <NUM>µl to <NUM>µl, and in particular, <NUM>µl, <NUM>µl, <NUM>µl, <NUM>µl, or <NUM>µl, of the liquid into the syringe barrel. In this way, the method <NUM> can use standard syringe sizes to accurately administer microliter dosages of liquids in an ergonomic manner, as described above. The present disclosure includes all combinations of syringe barrel sizes and dosages of liquids described above, e.g. a barrel sized for a <NUM> syringe and <NUM>µl of the liquid. The disclosure also includes ranges between the specific points within the list, e.g. a barrel size ranging from <NUM> to <NUM> combined with a dosage ranging from <NUM> to <NUM>µl.

In some implementations of the method <NUM>, inserting <NUM> the spacer into the syringe barrel through the open end comprises the use of vent tube stoppering, in other words, the tube used to insert the stopper <NUM> into the syringe <NUM>. For example, using a positioning tube can include arranging a positioning tube with one end inside of the syringe barrel <NUM>; inserting the spacer into an opposite end of the positioning tube; and pushing, using a plunger, the spacer through the positioning tube and into the syringe barrel.

Although the method <NUM> can be implemented to fill a single syringe <NUM>, it can also be used to fill a tray or nest that contains multiple identical syringes. In such implementations, the syringe barrel <NUM> is one of a plurality of syringe barrels arranged in a tray, with the open end of each syringe barrel pointing upwards. Trays of syringe barrels <NUM> can be sealed after manufacturing to maintain hygiene and safety standards. In such cases, inserting <NUM> the spacer into each syringe barrel can happen before or after the sealing and packaging step. When it takes place before the sealing step, the tray can be moved at a later time to, e.g., a filling and vent tube stoppering station for filling the syringe barrels and inserting the stoppers.

In implementations that include the use of a filling and vent tube stoppering machine, one part of the machine can fill one syringe barrel with the liquid while another part of the machine simultaneously inserts a stopper into a barrel that has already been filled. This type of parallel processing may reduce the overall manufacturing time for filling the syringe. In such implementations, it is also possible for a third part of the machine to simultaneously insert a compressible spacer in yet further syringe barrel.

The implementations above have been described for pre-filled syringes. Generally speaking, pre-filled syringes are limited to a small number of formats or volumes, and the machines and equipment for filling pre-filled syringes are based on the size and volume of the syringe. Under these circumstances, the implementations of the present disclosure can adapt existing syringes to very small injection volumes, as described above. However, the implementations are not limited to pre-filled syringes and can also be applied to disposable, single-use syringes. For example, single-use syringes are manually filled from a shelf-stable vial of liquid.

While this specification contains many specific details of implementations, these should not be construed as limitations on the scope of any invention or of what may be claimed, but rather as descriptions of features that may be specific to particular implementations. Conversely, various features that are described in the context of a single implementation can also be implemented in multiple implementations separately or in combination with one another. Moreover, although features may be described herein as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination of features.

Moreover, the separation of various system modules and components in the implementations described herein should not be understood as requiring such separation in all implementations.

Claim 1:
A syringe barrel (<NUM>) comprising
a hollow body with an opening (<NUM>) configured to receive a stopper (<NUM>),
a tip (<NUM>) configured for connection to a hollow needle (<NUM>), and
a compressible spacer (<NUM>) arranged inside the hollow body and adjacent to the tip (<NUM>), wherein the spacer (<NUM>) comprises an insoluble material configured to displace a liquid filled in the hollow body, characterized in that
there is a gap between the compressible spacer (<NUM>) and the inner surface of the barrel (<NUM>), and
the compressible spacer (<NUM>) is configured to displace but not to absorb or retain the liquid inside of the barrel (<NUM>).