HK1237249B - Apparatus and methods for sealing a medicament within a medical delivery device - Google Patents

Description

Apparatus and method for sealing a medicament within a drug delivery device

Background Art

The medication may be delivered to the patient via a syringe.

The medicament may be loaded into the syringe at the time of delivery to the patient. The medicament may be "pre-filled" into the syringe before the syringe is packaged for use by the practitioner.

The medicament may be loaded into a syringe in an injectable form.

The medicament may be loaded into the syringe in a form or composition that requires conversion prior to injection. For example, a medicament loaded in a solid, crystal, colloid, paste, slurry, hydrogel, or liquid form may need to be mixed with another substance that is also in a solid, crystal, colloid, paste, slurry, hydrogel, or liquid form.

The syringe may be pre-filled with the medicament during manufacture. Pre-filled syringes are advantageous in terms of safety, precise dosing and ease of use.

Some pharmaceutical agents exhibit low stability in liquid form. Dehydrating these agents, for example through lyophilization, produces a more stable dry form. Syringes manufactured to contain such dry agents, in which the liquid injectable form can be reconstituted for delivery, combine the advantages of prefilled syringes with an extended shelf life.

In order to obtain a dry form of the medicament in situ within a syringe or within a syringe component (e.g., a tube), the interior of the syringe or syringe component containing the medicament is exposed to a drying process. Typically, the drying process is performed within an environment (e.g., a sealed chamber) where the temperature and pressure are carefully regulated. The manufacture of syringes prefilled with dry medicament is complicated by the re-exposure of the medicament to moisture in the air after the drying process and before the interior is sealed from the surrounding environment outside the regulated environment.

Therefore, it would be desirable to provide an apparatus and method for mitigating moisture exposure of a medicament dried within a syringe or syringe components.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a perspective view of an apparatus according to the principles of the present invention;

FIG2 is a perspective view of an apparatus according to the principles of the present invention;

FIG3 is a perspective view of an apparatus according to the principles of the present invention;

FIG4a is another perspective view of the apparatus shown in FIG3;

FIG4b is another perspective view of the apparatus shown in FIG4a;

FIG5 is a partial cross-sectional view of the apparatus shown in FIG3 taken along line 5-5 (shown in FIG4a);

FIG6 a is a partial cross-sectional view of the apparatus shown in FIG3 taken along line 6-6 (shown in FIG4 a );

FIG6 b is another partial cross-sectional view of the apparatus shown in FIG3 taken along line 6-6 (shown in FIG4 a );

FIG7 is an end view of the apparatus shown in FIG3 taken along line 7-7 (shown in FIG4a);

FIG8 is another perspective view of the apparatus shown in FIG3;

FIG9 is a partial cross-sectional view of the apparatus shown in FIG3 taken along line 9-9 (shown in FIG8);

FIG10a is a perspective view of an apparatus according to the principles of the present invention;

FIG10b is another perspective view of an apparatus according to the principles of the present invention;

FIG11 is a partial cross-sectional view of the apparatus shown in FIG10 a;

FIG12 is a partial cross-sectional view of the apparatus shown in FIG10a taken along line 12-12 (shown in FIG11);

FIG13 is a perspective view of an apparatus according to the principles of the present invention;

FIG14a is another perspective view of the apparatus shown in FIG13;

FIG14b is another perspective view of the apparatus shown in FIG14a;

FIG15a is a cross-sectional view of the apparatus shown in FIG13 taken along line 15-15 (shown in FIG14a);

FIG15 b is another cross-sectional view of the apparatus shown in FIG13 taken along line 15-15 (shown in FIG14 a);

FIG16 is another perspective view of the apparatus shown in FIG13;

FIG17 is a cross-sectional view of the apparatus shown in FIG13 taken along line 17-17 (shown in FIG16);

FIG18 is a perspective view of an apparatus according to the principles of the present invention;

FIG19a is another perspective view of the apparatus shown in FIG18;

FIG19b is another perspective view of the apparatus shown in FIG18;

FIG20 a is a cross-sectional view of the apparatus shown in FIG18 taken along line 20 - 20 (shown in FIG19 a );

FIG20 b is another cross-sectional view of the apparatus shown in FIG18 taken along line 20 - 20 (shown in FIG19 a );

FIG21 is another perspective view of the apparatus shown in FIG18;

FIG22 is a cross-sectional view of the apparatus shown in FIG18 taken along line 22-22 (shown in FIG21);

FIG23 is a perspective view of an apparatus according to the principles of the present invention;

FIG24a is another perspective view of the apparatus shown in FIG23;

FIG24b is another perspective view of the apparatus shown in FIG23;

FIG25 is a partial cross-sectional view of the apparatus shown in FIG23 taken along line 25-25 (shown in FIG24a);

FIG26a is a partial cross-sectional view of the apparatus shown in FIG23 taken along line 26-26 (shown in FIG24a);

FIG26 b is another partial cross-sectional view of the apparatus shown in FIG23 taken along line 26-26 (shown in FIG24 a );

FIG27 is another partial cross-sectional view of the apparatus shown in FIG23 taken along line 26-26 (shown in FIG24a);

FIG28 is a perspective view of an apparatus in accordance with the principles of the present invention;

FIG29 is a perspective view of an apparatus in accordance with the principles of the present invention;

FIG30a is a perspective view of an apparatus in accordance with the principles of the present invention;

Figure 30b is another perspective view of the device shown in Figure 30a; and

31 is a perspective view of an apparatus in accordance with the principles of the present invention.

DETAILED DESCRIPTION

An apparatus and method for freeze-drying a pharmaceutical agent and sealing the agent within a drug delivery device are provided. The apparatus can be used to perform one or more method steps. The apparatus and method can be used for reconstitution and delivery of a pharmaceutical agent in a liquid injectable form.

The apparatus may include and the method may relate to a stopper for a drug delivery device. The delivery device may be cylindrical. The stopper may include a base for sealing an opening of the device. The base may include a central axis. The stopper may include a single elongated member. The stopper may include two or more elongated members. One or more of the elongated members may have a length. The length may be the same as or different from the length of the other elongated members. One or more elongated members may extend away from the base in a direction parallel to the axis. One or more members may be arranged radially away from the axis. One or more members may define: (1) a portion of a central recess coaxial with the axis; and (2) a gap extending circumferentially between adjacent portions of a member or between adjacent members. The gap may be one of a plurality of gaps. Each of the plurality of gaps may be similar.

The gap may have a circumferential overlap. The overlap may be a portion of the circumference of the stopper. The circumference of the stopper may be the circumference of the base. The gap, or gaps in general, may span a portion of the circumference. The gap portion may be referred to as a gap partial circumference.

The stop member may have a first operational configuration.The stop member may have a second operational configuration.

In a first operating configuration, the one or more elongate members may engage an interior wall of the device to support the base away from the opening such that the gap provides for gas exchange between the interior and exterior of the device.

In the second operating configuration, the base is engageable with the inner wall to seal the opening.

In a first working configuration, the gas may be a freeze-dried by-product.

In the second working configuration, the stopper can seal the freeze-dried product within the device. The product can be disposed between the stopper and the plunger sealingly engaged with the inner wall of the device.

The operator can move the stopper from the first working configuration to the second working configuration by moving the stopper forward relative to the opening. The operator can be a human, a machine, a robot, or any other suitable operator.

The base may be adjacent to a flange orthogonal to the axis. The base may include a flange. The flange may be configured to abut an end face of the device in the second working configuration. The end face may surround the opening.

The stopper may comprise an elastic material. The stopper may include a lubricious coating. The lubricious coating may be coated with the elastic material. The lubricious coating may be laminated with the elastic material. The lubricious coating may be bonded to the elastic material. The elastic material may carry the lubricious coating.

The stopper may be manufactured by molding an elastic material and a lubricating coating in combination with each other. The molding may be performed by an overmolding process. The molding may be performed by a co-injection process.

The elastic material may include rubber. The rubber may include chlorobutyl rubber. The rubber may include bromobutyl rubber. The rubber may include chromobutyl rubber. The elastic material may include silicone. The silicone may be molded as liquid silicone rubber (LSR). The elastic material may include a thermoplastic elastomer. The elastic material may include a polymer.

The lubricious coating may comprise polytetrafluoroethylene (PTFE). The lubricious coating may comprise tetrafluoroethylene (ETFE). The lubricious coating may comprise a material selected to mitigate interaction between the coated surface and the medicament. The lubricious coating may impart chemical resistance and/or chemical inertness to the coated surface. The lubricious coating may facilitate movement of the stopper into the delivery device. The lubricious coating may facilitate movement of the stopper within the delivery device. The lubricious coating may facilitate sealing and/or sliding engagement of the stopper with the inner wall.

The base may include an area configured to be penetrated by the needle. The area may be self-sealing around the outer wall of the needle.

The central recess may taper toward the base. The central recess may be continuously tapered toward the base.

The base may include a peripheral ridge. The ridge may be configured to sealingly engage an inner wall of the device.

The device may include a tube. The tube may include glass. The tube may include rigid plastic. The tube may include any other suitable material.

The opening of the device may be the opening of a tube. The end surface of the device may be the end surface of the tube surrounding the opening of the tube. The inner wall of the device may be the inner wall of the tube. The interior of the device may be the interior of the tube surrounded by the inner wall of the tube. The exterior of the device may be the exterior of the tube.

The tubing can be part of a syringe. The tubing can be part of a prefilled syringe. The prefilled syringe can be all or part of the device. The tubing can be all or part of the device.

When the stopper is in the first working configuration, the tube may not engage with the rest of the prefilled syringe. When the stopper is in the first working configuration, the tube may engage with the rest of the prefilled syringe. Only when the stopper is in the second working configuration may the tube engage with the rest of the prefilled syringe.

In a first operating configuration, the lyophilized byproduct gas can be transferred from the interior of the device to the exterior of the device. The lyophilized byproduct gas can initially be exchanged with ambient air outside the device (e.g., air within a lyophilization chamber in which the device is placed), and the ambient air can be transferred from the exterior of the device to the interior of the device.

In the second working configuration, the stopper can be moved forward into the device to sealingly engage the inner wall of the device and/or abut against the end face of the device. The stopper sealingly engaging the inner wall of the device and/or abutting against the end face of the device can seal the freeze-dried product within the device between the stopper and the plunger. When the stopper is in the second working configuration, the device can engage with other parts of the prefilled syringe.

The method may include sealingly engaging an inner wall of the device with a plunger. A face of the plunger closest to the opening of the device may be offset from the opening. The method may include orienting the device such that the opening is at least partially directly above the engaged plunger. The method may include placing a medicament within the device. The method may include placing the medicament within the device such that the medicament occupies at least a portion of the internal volume of the device above the plunger, below the opening, and bounded by the inner wall.

The method includes engaging an inner wall of the device with a resilient elongate member or a plurality of resilient elongate members secured to a sealing base of the stopper.

The method may include advancing one or more components into the device until the base is set to be spaced apart from the inner wall by a predetermined offset. The offset may be referred to as "S". The offset may be scaled proportionally to the perimeter of the portion of the gap. For example, the offset may be in the range of approximately 1-5%, 6-10%, 11-15%, 16-20%, 21-25%, 26-30%, 31-35%, 36-40%, 41-45%, 46-50%, 51-55%, 56-60%, 61-65%, 66-70%, 71-75%, 76-80%, 81-85%, 86-90%, 91-95%, or 96-99% of the perimeter of the portion of the gap.

The offset can be scaled proportionally to the length of the one or more components. For example, the offset can be in the range of about 1-5%, 6-10%, 11-15%, 16-20%, 21-25%, 26-30%, 31-35%, 36-40%, 41-45%, 46-50%, 51-55%, 56-60%, 61-65%, 66-70%, 71-75%, 76-80%, 81-85%, 86-90%, 91-95%, or 96-99% of the length of the one or more components.

The base may be held in position relative to the device by one or more components.The base may be held in position relative to the device only by one or more components.

The method may include freeze-drying the medicament to produce a vapor. The vapor may escape between the inner wall, one or more components and the base. The method may include freeze-drying the medicament to produce an at least partially dried form of the medicament.

The method may include advancing one or more components into the device until the base seals against the inner wall of the device. The method may include advancing one or more components into the device until the base seals against the inner wall only after the lyophilized dose is administered. The method may include advancing one or more components into the device until the flange abuts against the end face of the device. The method may include advancing one or more components into the device until the flange abuts against the end face only after the lyophilized dose is administered.

A pharmaceutical agent may include a preparation of one or more compounds. The compound may include a naturally occurring substance. The compound may include a substance derived from a naturally occurring substance. The compound may include an artificially synthesized substance. The compound may include a chimeric substance. The compound may include an engineered substance. The compound may include a humanized substance. The compound may include a substance produced by recombinant technology. The compound may include a substance modified by recombinant technology.

The compound may include a drug suitable for the therapeutic treatment of a patient. The compound may include a substance in a therapeutic protocol. The compound may include a substance in a diagnostic protocol. The compound may include a substance in an experimental protocol. The compound may include a substance compatible with use with the devices and methods of the present invention.

The pharmaceutical agent may include any of the medicinal agents listed herein, alone or in combination with one or more other listed medicinal agents or one or more other unlisted medicinal agents. The medicinal agents may include anti-glaucoma drugs, other ophthalmic agents, neuroprotectants, antimicrobial agents, anti-inflammatory agents (including steroids and non-steroidal compounds) and biologic agents, including hormones, enzymes or enzyme-related components, antibodies or antibody-related components, oligonucleotides (including DNA, RNA, short interfering RNA and other suitable oligonucleotides, such as antisense oligonucleotides), DNA/RNA vectors, viruses or viral vectors, polypeptides and proteins. Medicinal agents may include: anti-angiogenic agents, including angiostatin, anecortave acetate, thrombospondin, vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors and anti-VEGF drugs, such as ranibizumab, bevacizumab, pegaptanib sodium, sunitinib and sorafenib, as well as any of a variety of known small molecules and transcription inhibitors with anti-angiogenic effects; ophthalmic drugs, including glaucoma agents, such as adrenomedullin antagonists, including beta-blockers such as atenolol, propranolol, metipranolol, betaxolol, carteolol, levobetaxolol, levobunolol and timolol. Medicinal agents may include platelet-derived growth factor (PDGF) inhibitors and anti-PDGF drugs. Medicinal agents may include transforming growth factor (TGF) inhibitors and anti-TGF drugs. Medicinal agents may include anti-inflammatory agents, including glucocorticoids and corticosteroids, such as betamethasone, cortisone, dexamethasone, dexamethasone sodium phosphate, methylprednisolone, prednisone sodium phosphate, prednisolone acetate, prednisolone, loteprednol, medrysone, fluocinonide acetate, triamcinolone acetonide, triamcinolone, beclomethasone, budesonide, flunisolide, fluorometholone, fluticasone, hydrocortisone, hydrocortisone acetate, and rimexolone; and nonsteroidal anti-inflammatory agents, including diclofenac, flurbiprofen, ibuprofen, bromfenac, nepafenac, ketorolac, salicylates, indomethacin, Naxopren, naproxen, piroxicam, and nabumetone. The pharmaceutical agent may include an anti-cytokine agent; the medicinal agent may include an interleukin-6 inhibitor, such as tocilizumab. The medicinal agent may include an anti-complement agent, including targeting complement factor D (e.g., an anti-complement factor D antibody or an antigen-binding fragment thereof), and targeting complement factor H (e.g., an anti-complement factor H antibody or an antigen-binding fragment thereof), such as lampalizumab. The medicinal agent may include an angiogenesis-specific agent, such as an angiopoietin 2 antibody or an antigen-binding fragment thereof. The medicinal agent may include human growth hormone. The medicinal agent may include any suitable medicinal agent.

The pharmaceutical agent may include one or more derivatives of any of the above-mentioned medicinal agents. The pharmaceutical agent may include an advanced form of any of the above-mentioned medicinal agents. The pharmaceutical agent may include a mutant form of any of the above-mentioned medicinal agents. The pharmaceutical agent may include a combination of any of the above-mentioned medicinal agents. The combination may be combined in a multispecific molecule. The multispecific molecule may exhibit properties of its components. The multispecific molecule may exhibit properties that are different from any of its components. The pharmaceutical agent may include depots, hydrogels, and pegylated forms of any of the above-mentioned medicinal agents. The pharmaceutical agent may include any of the above-mentioned medicinal agents in any suitable form.

The apparatus and method according to the present invention will now be described with reference to the accompanying drawings. The accompanying drawings show illustrative features of the apparatus and method according to the principles of the present invention. The features are described in the context of selected embodiments. It should be understood that features shown in conjunction with one embodiment can be practiced in accordance with the principles of the present invention in conjunction with features shown in conjunction with other embodiments.

The apparatus and methods of the present invention may include some or all of the features of the illustrative apparatus and/or some or all of the steps of the illustrative methods. The steps of the methods may be performed in an order different from that shown and described herein. Some embodiments may omit steps shown and described in conjunction with the illustrative methods. Some embodiments may include steps not shown and described in conjunction with the illustrative methods.

Illustrative embodiments will now be described with reference to the accompanying drawings, which form a part hereof.

The apparatus and method of the present invention will be described in conjunction with illustrative device embodiments and features. The apparatus will now be described with reference to the accompanying drawings. It is to be understood that other embodiments may be utilized and structural, functional, and procedural modifications may be made without departing from the scope and spirit of the present invention.

Some of the drawings may indicate dimensions of device features. Illustrative values for the indicated dimensions are presented below following the description of all drawings.

1 shows an illustrative drug delivery device 100. The delivery device 100 can include a stopper 102. The delivery device 100 can include a tube 104. The delivery device 100 can include an intermediate plunger 106.

The delivery device 100 is shown in a first operating state.

The stopper 102 may include a sealing base 108. The stopper 102 may include one or more elongated members 110. The elongated members 110 may define one or more voids 112 in the circumferential space between the elongated members 110. The stopper 102 may include a flange 116.

The tube 104 can be cylindrical. The tube 104 can include a distal opening 118. The tube 104 can include an inner wall 120. The tube 104 can include an end face 122. The tube 104 can include one or more bypass passages 124.

The intermediate plunger 106 can be sealingly engaged with the inner wall 120. The intermediate plunger 106 can separate the tube 104 into a medicament chamber 126 and a liquid chamber 128. The medicament chamber 126 can be bounded proximally by the intermediate plunger 106. The liquid chamber 128 can be bounded distally by the intermediate plunger 106. The liquid chamber 128 can be bounded proximally by a proximal plunger (not shown).

In the first operating state, the stopper 102 can be partially inserted into the tube 104 through the distal opening 118. The partial insertion of the stopper 102 into the tube 104 through the distal opening 118 can engage the elongated member 110 with the inner wall 120. The engagement of the elongated member 110 with the inner wall 120 after the partial insertion of the stopper 102 can position the sealing base 108 distally spaced from the distal opening 118. The sealing base 108 can be positioned distally spaced from the distal opening 118 by an offset S.

The void 112 may be in distal communication with the exterior of the tube 104 in the region of the offset S. The void 112 may be in proximal communication with the medication chamber 126. The void 112 may provide for gas exchange between the medication chamber 126 and the region of the offset S. The gas exchange may be provided via an open-ended conduit (not shown distinct from its components) comprising: (1) the void 112 being open proximally and distally; (2) a circumferentially adjacent elongated member 110 defining the void 112 and being joined to the inner wall 120 adjacent the void 112; and (3) a region of the inner wall 120 circumferentially overlying the void 112.

The first operating state can be used to freeze-dry a medication (not shown) placed in medication chamber 126 before stopper 102 is partially inserted into tube 104 through distal opening 118. During freeze-drying, gas exchanged from medication chamber 126 to the exterior of tube 104 via gap 112 can be a freeze-dried byproduct. The freeze-dried byproduct can be a vaporized medicinal solvent (not shown). Freeze-drying can continue until a freeze-dried product (not shown) remains in medication chamber 126. The freeze-dried product can be agglomerated dry medication.

FIG. 2 shows the drug delivery device 100 in a second operating state.

1 , the stopper 102 can be displaced so that the flange 116 abuts the end face 122. The flange 116 abutting the end face 122 can seal the distal opening 118. Displacing the stopper 102 so that the flange 116 abuts the end face 122 can cause the sealing base 108 to sealingly engage the inner wall 120. The sealing base 108 sealingly engages the inner wall 120 can distally seal the medicament chamber 126.

The second working state can be used to seal a lyophilized product (not shown) in the medication chamber 126. The second working state can be used to store the lyophilized product in the medication chamber 126. The lyophilized product in the medication chamber 126 can be sealed between the stopper 102 and the intermediate plunger 106. Sealing the lyophilized product in the medication chamber 126 between the stopper 102 and the intermediate plunger 106 can contribute to the long-term stability of the lyophilized product.

The proximal plunger 230 can be sealingly engaged with the inner wall 120. The liquid chamber 128 can be defined proximally by the proximal plunger 230. A diluent (not shown) can be sealed in the liquid chamber 128 between the intermediate plunger 106 and the proximal plunger 230.

The lyophilized product (not shown) can be reconstituted into a liquid injectable form of a medicament (not shown). The lyophilized product can be reconstituted using a diluent (not shown) stored in the liquid chamber 128. The diluent can be transferred from the liquid chamber 128 to the medicament chamber 126 via the bypass channel 124.

In the delivery device 100, transferring the diluent to the medicament chamber 126 via the bypass passage 124 may involve advancing the proximal plunger 230 distally within the tube 104 toward the intermediate plunger 106. Transferring the diluent to the medicament chamber 126 via the bypass passage 124 may involve advancing the intermediate plunger 106 distally within the tube 104 toward the stopper 102. Transferring the diluent to the medicament chamber 126 via the bypass passage 124 may involve providing a vent (not shown) through the stopper 102 in the second operating state. The vent may be provided through the stopper 102 in the second operating state by a lumen of a needle (not shown) embedded in the stopper 102, the lumen providing fluid communication between the medicament chamber 126 and the exterior of the tube 104. The needle may be inserted through the sealed septum region 611 (shown in FIG. 6 a) of the delivery device 100 at the appropriate time prior to transferring the diluent. The needle may be used to deliver a liquid injectable form of the medication reconstituted from the lyophilized product to a patient (not shown).

3 illustrates the stopper 102. The stopper 102 may include one or more peripheral sealing ridges 301. The peripheral sealing ridges 301 may be integral with the seal base 108. The peripheral sealing ridges 301 may facilitate sealing engagement of the seal base 108 with the inner wall 120 (shown in FIG. 2 ).

The stopper 102 can include a sealing rim 303. The sealing rim 303 can be integral with the flange 116. The sealing rim 303 can extend radially inward from the outer periphery of the flange 116. At its innermost radial extension, the sealing rim 303 can form a circumferential seam between the flange 116 and the sealing base 108. The sealing rim 303 can facilitate sealing of the distal opening 118 (shown in FIG. 2 ) when the flange 116 abuts the end face 122 (shown in FIG. 2 ).

The stopper 102 can include a central recess 305. The central recess 305 can be at least partially defined by the elongated member 110. The elongated member 110 can partially define the central recess 305 by merging/melting into a web surface 307 within the interior of the stopper 102. The central recess 305 can extend within the interior of the stopper toward the seal base 108.

FIG4 a shows a stopper 102 including a sealing base 108, an elongated member 110, a void 112, and a flange 116. ( FIG4 a shows a view relative to the sealing base 108, the elongated member 110, the void 112, and the flange 116.) The stopper 102 can define a longitudinal axis A. The longitudinal axis A can extend through the base 108. The longitudinal axis A can be coaxial with a central axis (not shown) of the base 108.

FIG. 4 b shows the stop 102 in the same view as FIG. 4 a , with associated illustrative dimensions d1 , d2 , d3 , d4 , d5 and d6 shown.

FIG5 shows the stopper 102 in a cross-sectional view taken along line 5-5 (through the seal base 108, as shown in FIG4a). FIG5 shows the sealing rim 303 surrounding the seal base 108.

FIG6 a shows the stopper 102 in a cross-sectional view taken along line 6-6 (through the flange 116, the sealing base 108, and the gap 112, as shown in FIG4 a). FIG6 a shows a septum face 609 associated with the flange 116. The septum face 609 can be the outer surface of a septum region 611. The septum region 611 can extend through the flange 116 and the sealing base 108. The septum region 611 can extend between the septum face 609 and the central recess 305. The septum region 611 can be a self-sealing needle-penetrable region, allowing a needle to be inserted and then extended from outside the drug delivery device 100 (shown in FIG2 ) into the central recess 305 while its outer wall is sealed.

A lubricious coating 613 may coat the surface of the stopper 102. The lubricious coating 613 may be bonded to the coated surface. The lubricious coating 613 may coat the surfaces of the elongated member 110 and the void 112. The lubricious coating 613 may coat the web surface 307. The surface of the stopper 102 may be free of the lubricious coating 613. The surface of the stopper 102 that is used to sealingly engage the inner wall 120 (shown in FIG. 2 )—such as the peripheral sealing ridge 301—may not be coated with the lubricious coating 613. The surface of the peripheral sealing ridge 301 may be selectively coated with the lubricious coating 613. None of the peripheral sealing ridges 301, or all or a portion of one or more than one ridge may be coated with the lubricious coating 613.

FIG. 6 b shows the stop 102 in the same view as FIG. 6 a , with associated illustrative dimensions d7 , d8 , d9 and d10 shown.

FIG7 shows the stopper 102 in an end view taken along line 7-7 (along the direction of the elongated members 110 and the void 112, as shown in FIG4a). FIG7 shows circumferentially adjacent elongated members 110 defining the void 112 therebetween. Adjacent surfaces of the elongated members 110 located outside the stopper 102 may merge to define the void 112. Adjacent surfaces of the elongated members 110 located inside the stopper 102 may merge to form a portion of the web surface 307 of the central recess 305.

FIG8 shows the stopper 102 after being rotated about the longitudinal axis A (shown in FIG4a ) relative to the view of the stopper 102 shown in FIG4a . The rotation may be approximately 45°. FIG8 shows the seal base 108 , the elongated member 110 , and the flange 116 . ( FIG8 shows a view through the stopper 102 relative to the flange 116 , the seal base 108 , and the elongated member 110 .)

9 shows the stopper 102 in a cross-sectional view taken along line 9-9 (through the flange 116, the sealing base 108 and the elongated member 110 as shown in FIG8).

FIG10 a shows tube 104. Tube 104 can include a proximal opening 1036. Proximal opening 1036 can be opposite distal opening 118. Proximal opening 1036 can be parallel to distal opening 118. Inner wall 120 can extend between proximal opening 1036 and distal opening 118. Inner wall 120 can extend from proximal opening 1036 to distal opening 118.

FIG. 10 b shows tube 104 in the same view as shown in FIG. 10 a , with associated illustrative dimensions d11 and d12 shown.

FIG11 shows a cross-sectional view of tube 104. FIG11 shows inner wall 120 and bypass passage 124. (FIG11 shows a line of sight through tube 104, which is associated with inner wall 120 and bypass passage 124.)

12 shows the tube 104 in a cross-sectional view taken along line 12-12 (through the inner wall 120 and the bypass passage 124, as shown in FIG11).

FIG13 illustrates the intermediate plunger 106. The intermediate stop 106 may include an intermediate plunger face 1325. The intermediate stop 106 may include two or more intermediate plunger lateral projections 1327. The intermediate plunger lateral projections 1327 may have a circumference parallel to the intermediate plunger face 1325. Intermediate plunger lateral projections 1327 of varying circumferences may facilitate sealing engagement of the intermediate plunger 106 with the inner wall 120 (shown in FIG1 ). Intermediate plunger 106 may include intermediate plunger lateral grooves 1329.

FIG14a shows a side view of the intermediate plunger 106 including the intermediate plunger face 1325. (FIG. 14a shows a line of sight through the intermediate plunger 106, which is associated with the intermediate plunger face 1325.)

FIG. 14 b shows the intermediate plunger 106 in the same view as shown in FIG. 14 a , with associated illustrative dimensions d13 and d14 shown.

Figure 15a shows the intermediate plunger 106 in a cross-sectional view taken along line 15-15 (through the intermediate plunger face 1325, as shown in Figure 14a). Figure 15a shows the intermediate plunger lateral protrusion 1327 and the intermediate plunger lateral groove 1329.

FIG. 15 b shows the intermediate plunger 106 in the same view as shown in FIG. 15 a , with associated illustrative dimensions d15 , d16 , d17 and d18 shown.

FIG16 shows the intermediate plunger 106 from the front. FIG16 shows the intermediate plunger face 1325 and the intermediate plunger lateral projection 1327. (FIG. 16 shows a view through the intermediate plunger 106, which is associated with the intermediate plunger face 1325 and the intermediate plunger lateral projection 1327.)

FIG17 shows the intermediate plunger 106 in a front cross-sectional view taken along line 17-17 (through the intermediate plunger face 1325 and the intermediate plunger lateral protrusion 1327, as shown in FIG16). FIG17 shows the intermediate plunger face 1325 with a lubricious coating 1713a. FIG17 shows the face of the intermediate plunger 106 opposite the intermediate plunger face 1325 with a lubricious coating 1713b. The lubricious coating 1713b may comprise the same material as the lubricious coating 1713a. The lubricious coating 1713b may not comprise the same material as the lubricious coating 1713a. The material may be the same material as that comprised in the lubricious coating 613 (shown in FIG6a).

Lubricious coating 1713a or lubricious coating 1713b may coat the intermediate plunger side protrusions 1327. Lubricious coating 1713a may selectively coat one, more than one, or none of the intermediate plunger side protrusions 1327. None of the intermediate plunger side protrusions 1327, or one or more of the intermediate plunger side protrusions 1327 may be free of lubricious coating 1713a or lubricious coating 1713b. The thickness t1 of lubricious coating 1713a or the thickness t2 of lubricious coating 1713b may approximate the girth difference between the intermediate plunger side protrusions 1327. The girth of an uncoated intermediate plunger side protrusion 1327 may be greater than that of a coated intermediate plunger side protrusion 1327, with the difference approximating thickness t1 or thickness t2. The coated intermediate plunger side protrusion 1327 may facilitate sliding engagement along the inner wall 120 (shown in FIG. 2 ). The uncoated intermediate plunger side projection 1327 may facilitate sealing engagement with the inner wall 120 (shown in FIG. 2 ).

FIG18 illustrates the proximal plunger 230. The proximal plunger 230 may include a distal side 1825. The proximal plunger 230 may include a proximal plunger lateral projection 1827. The proximal plunger 230 may include a proximal plunger lateral groove 1829. The proximal plunger 230 may include a leading edge 1831. The proximal plunger 230 may include a trailing edge 1833. The proximal stop 200 may include a proximal side 1835.

During engagement of the proximal plunger 230 with the inner wall 120 (shown in FIG. 2 ), the distal-proximal orientation of the proximal plunger 230 within the tube 104 (shown in FIG. 2 and 10 a ) can be parallel to the distal-proximal alignment of the distal opening 118 and the proximal opening 1036 (both openings shown in FIG. 10 a ). The leading edge 1831 can be closer to the distal opening 118 (shown in FIG. 2 and 10 a ) than the trailing edge 1833. The distal side 1825 can be closer to the distal opening 118 (shown in FIG. 2 and 10 a ) than the proximal side 1835. The trailing edge 1833 can be closer to the proximal opening 1036 (shown in FIG. 10 a ) than the leading edge 1831. The proximal side 1835 can be closer to the proximal opening 1036 (shown in FIG. 10 a ) than the distal side 1825. The distal end of a syringe plunger rod (not shown) controlled by a practitioner can act on the proximal face 1835 to advance the proximal plunger 230 distally within the barrel 104 (shown in FIG. 2 ).

FIG19a shows a side view of the proximal plunger 230 including the distal side 1825 and the proximal side 1835. (FIG. 19a shows a line of sight through the proximal plunger 230, which is associated with the distal side 1825 and the proximal side 1835.)

FIG. 19 b shows the proximal plunger 230 in the same view as shown in FIG. 19 a , with an associated illustrative dimension d19 shown.

20a shows the proximal plunger 230 in a cross-sectional view taken along line 20-20 (through the distal face 1825 and the proximal face 1835, as shown in FIG19a). FIG20a shows the distal face 1825, the intermediate plunger lateral protrusion 1827, the intermediate plunger lateral groove 1829, and the proximal face 1835.

FIG. 20 b shows the proximal plunger 230 in the same view as shown in FIG. 20 a , with associated illustrative dimensions d20 , d21 , d22 , d23 , and d24 shown.

FIG21 shows the proximal plunger 230 as viewed from the front. FIG21 shows the distal face 1825 and the proximal plunger lateral projection 1827. (FIG. 21 shows a view through the proximal plunger 230, which is associated with the distal face 1825 and the proximal plunger lateral projection 1827.)

FIG22 shows the proximal plunger 230 in a bottom cross-sectional view taken along line 22-22 (through the distal face 1825 and the proximal plunger lateral projection 1827, as shown in FIG21 ). FIG22 shows the intermediate plunger face 1825 with a lubricious coating 2213. The intermediate plunger face 1825 can optionally be coated with the lubricious coating 2213. The intermediate plunger face 1825 can have no surface, or a portion or all of its surface can be coated with the lubricious coating 2213. FIG22 shows the leading edge 1831 with the lubricious coating 2213. The leading edge 1831 can optionally be coated with the lubricious coating 2213. The leading edge 1831 can have no surface, or a portion or all of its surface can be coated with the lubricious coating 2213. The lubricious coating 2213 can comprise the same material as the lubricious coating 1713a or the lubricious coating 1713b (both shown in FIG17 ).

FIG23 illustrates a non-vented stopper 2350. The non-vented stopper 2350 may have none, one, or more than one feature in common with the stopper 102 (shown in FIG3 ). The non-vented stopper 2350 may include one or more peripheral sealing ridges 2351. The peripheral sealing ridges 2351 may be integral with the sealing base 2358. The non-vented stopper 2350 may include a sealing rim 2353. The sealing rim 2353 may be integral with the flange 2356. The sealing rim 2353 may extend radially inward from the periphery of the flange 2356. At its innermost radial extension, the sealing rim 2353 may form a circumferential seam between the flange 2356 and the sealing base 2358. The non-vented stopper 2350 may include a central recess 2365 within the elongated section 2370.

FIG24a shows a non-vented stopper 2350 including a flange 2356, a sealing base 2358, and an elongated section 2370. (FIG. 24a shows a view through the non-vented stopper 2350, relating to the flange 2356, the sealing base 2358, and the elongated section 2370.)

FIG. 24 b shows a non-vented stop 2350 in the same view as shown in FIG. 24 a , with associated illustrative dimensions d25 , d26 , d27 , d28 , and d29 shown.

25 shows the non-vented stopper 2350 in a cross-sectional view taken along line 25-25 (through the sealing base 2358, as shown in FIG24a). FIG25 shows the sealing rim 2353 surrounding the sealing base 2358.

FIG26 a shows the non-vented stopper 2350 in a cross-sectional view taken along line 26-26 (through the flange 2356, the sealing base 2358, and the elongated section 2370, as shown in FIG24 a). FIG26 a shows a septum face 2369 associated with the flange 2356. The septum face 2369 can be the outer surface of a septum region 2371. The septum region 2371 can extend through the flange 2356 and the sealing base 2358. The septum region 2371 can extend between the septum face 2369 and the central recess 2365. The septum region 2371 can be a self-sealing, needle-penetrable region.

FIG. 26 b shows a non-vented stop 2350 in the same view as shown in FIG. 26 a , with associated illustrative dimensions d30 , d31 , and d32 shown.

FIG27 shows a non-vented stopper 2350 in a cross-sectional view similar to the view shown in FIG26a. FIG27 shows a lubricious coating 2713-coated surface of the non-vented stopper 2350. The surface of the non-vented stopper 2350 may be free of lubricious coating 2713. Lubricious coating 2713 may selectively coat the surface of the elongated section 2370. No surface, or a portion or all of the surface of the elongated section 2370 may be coated with lubricious coating 2713. Lubricious coating 2713 may selectively coat the surface of the central recess 2365. No surface, or a portion or all of the surface of the central recess 2365 may be coated with lubricious coating 2713. Lubricious coating 2713 may comprise the material of lubricious coating 2213 (shown in FIG22).

28 shows an illustrative drug delivery device 2800. Delivery device 2800 may include a tube 104 including an inner wall 120 and a bypass channel 124. Delivery device 2800 may include an intermediate plunger 106 sealingly engaged with inner wall 120 and dividing tube 104 into a medicament chamber 126 and a liquid chamber 128.

The delivery device 2800 can include a non-vented stopper 2350. The non-vented stopper 2350 is shown inserted into the tube 104. The non-vented stopper 2350 can seal the tube 104. The sealing base 2358 of the non-vented stopper 2350 can sealingly engage the inner wall 120. The sealing ridge 2351 can facilitate the sealing engagement of the non-vented stopper 2350 with the inner wall 120. The sealing engagement of the non-vented stopper 2350 with the inner wall 120 and the intermediate plunger 106 with the inner wall 120 can seal a medicament (not shown) within the medicament chamber 126 of the delivery device 2800. The medicament within the medicament chamber 126 of the delivery device 2800 can be in a liquid state.

29 shows a drug delivery device 2800 having a liquid chamber 128 defined at opposite ends by an intermediate plunger 106 and a proximal plunger 230, each of which is sealingly engaged with the inner wall 120. The sealing engagement of the intermediate plunger 106 with the inner wall 120 and the proximal plunger 230 with the inner wall 120 can seal a fluid (not shown) within the liquid chamber 128. The fluid can be transferred from the liquid chamber 128 to the medicament chamber 126 via the bypass passage 124.

In the delivery device 2800, transferring fluid to the medicament chamber 126 via the bypass passage 124 may involve advancing the proximal plunger 230 distally within the tube 104 toward the intermediate plunger 106. Transferring fluid to the medicament chamber 126 via the bypass passage 124 may involve advancing the intermediate plunger 106 distally within the tube 104 toward a non-vented stopper 2350. Transferring fluid to the medicament chamber 126 via the bypass passage 124 may involve providing a vent (not shown) through the non-vented stopper 2350. A lumen of a needle (not shown) embedded in the non-vented stopper 2350 may provide a vent through the non-vented stopper 2350, which provides fluid communication between the medicament chamber 126 and the exterior of the tube 104. The needle may be inserted at the appropriate time through the septum region 2371 (shown in FIG. 26a ) of the sealed delivery device 2800 prior to transferring the fluid.

Transferring the fluid to the medication chamber 126 via the bypass passage 124 can facilitate interaction of the fluid with the medication (not shown) in the medication chamber 126. This interaction can include mixing. This interaction can include dilution. This interaction can include reconstitution. This interaction can include one or more chemical reactions. This interaction can convert the stored form of medication (not shown) stored between the intermediate plunger 106 and the non-vented stopper 2350 into a deliverable form of medication. The deliverable form of medication can be delivered to a patient (not shown) via a needle (not shown) embedded in the non-vented stopper 2350.

FIG30 a shows tube 3004. Tube 3004 may have none, one, or more than one feature in common with tube 104 (shown in FIG10 a). Tube 3004 may include a distal opening 3018. Tube 3004 may include an inner wall 3020. Tube 3004 may include a proximal opening 3036. Proximal opening 3036 may be opposite distal opening 3018. Proximal opening 3036 may be parallel to distal opening 3018. Inner wall 3020 may extend between proximal opening 3036 and distal opening 3018. Inner wall 3020 may extend from proximal opening 3036 to distal opening 3018.

FIG. 30b shows tube 3004 in the same view as shown in FIG. 30a , with associated illustrative dimensions d33 and d34 shown.

FIG31 shows an illustrative drug delivery device 3100. The delivery device 3100 can include a tube 3004. The delivery device 3100 can include a non-vented stopper 2350. The non-vented stopper 2350 can seal the distal opening 3018. The sealing base 2358 can sealingly engage the inner wall 3020 proximal to the distal opening 3018. The delivery device 3100 can include a proximal plunger 230. The proximal plunger 230 can sealingly engage the inner wall 3020 distal to the proximal opening 3036.

The non-vented stopper 2350 and the proximal plunger 230 can seal the medicament (not shown) within the medicament chamber 3026. The medicament chamber 3026 can be defined proximally by the distal face 1825. The medicament chamber 3026 can be defined distally by proximal features of the non-vented stopper 2350.

The medication (not shown) within the medication chamber 3026 may be in a liquid state. The medication within the medication chamber 3026 may be in a deliverable form.

The distal end of a syringe plunger rod (not shown) controlled by a practitioner can act on the proximal surface 1835 to advance the proximal plunger 230 distally within the tube 3004. A lumen of a needle (not shown) embedded in the non-vented stopper 2350 can provide a vent through the non-vented stopper 2350, providing fluid communication between the medicament chamber 3026 and the exterior of the tube 3004. The needle can be inserted through the septum region 2371 (shown in FIG. 26 a) of the sealed delivery device 3100 at the appropriate time prior to drug delivery. The needle can be used to deliver the drug to a patient (not shown).

Table 1 shows illustrative dimensions in millimeters for the dimensions _d shown in and with reference to Figures 4b, 6b, 10b, 14b, 15b, 19b, 20b, 24b, 26b and 30b.

Table 1d Illustrative dimensions of _i

Dimension d _i is illustrative only. Any suitable dimensions may be used for the features of drug delivery device 100 (shown in Figures 1 and 2 ), drug delivery device 2800 (shown in Figures 28 and 29 ), and drug delivery device 3100 (shown in Figure 31 ). Ratios dj:dk of dimensions di and any other suitable ratios may be used.

Thus, apparatus and methods for sealing a medicament within a drug delivery device have been provided. Those skilled in the art will appreciate that the present invention may be practiced with embodiments other than those described, which are presented for purposes of illustration and not limitation. The present invention is limited only by the following claims.

Claims (25)

1. A stop for a drug delivery device, the stop comprising: A base for sealing the opening of the drug delivery device, the base having a central axis; Two or more elongated members extending away from the base in a direction parallel to the central axis, the elongated members being arranged radially away from the central axis and defining: A portion of a central recess coaxial with the central axis, the central recess continuously tapering towards the base, and a material region extending transversely to the central axis between the base and the bottom of the central recess; and A gap between circumferentially adjacent surfaces located outside the central recess, the gap being spaced apart from the central recess, the gap extending circumferentially and parallel to the central axis toward the base; in: In the first working configuration, the elongated member engages with the inner wall of the drug delivery device to support the base away from the opening, such that the gap provides gas exchange between the interior and exterior of the drug delivery device; and In the second working configuration, the base engages with the inner wall to seal the opening. 2. The stop member according to claim 1 further includes a flange orthogonal to the central axis. 3. The stop according to claim 2, wherein the flange is configured to abut against the end face of the drug delivery device surrounding the opening in the second working configuration. 4. The stop member according to claim 3, wherein the base includes the flange. 5. The stop member according to claim 1 further comprises an elastic material. 6. The stop member according to claim 5, wherein the elastic material has a lubricating coating. 7. The stop according to claim 5, wherein the elastic material located between the base and the bottom of the central recess is permeable by the needle and self-sealed around the outer wall of the needle. 8. The stop according to claim 7, wherein, in the second working configuration, the needle extends from the outside of the drug delivery device through the base into the central recess. 9. The stop according to claim 1, wherein the base includes a peripheral ridge configured to sealably engage with the inner wall of the drug delivery device. 10. The stop according to claim 1, wherein, in the first working configuration, the gas comprises freeze-dried byproducts. 11. The stop according to claim 10, wherein, in the second working configuration, the stop seals the freeze-dried product within the drug delivery device between the stop and a plunger that is sealingly engaged with the inner wall of the drug delivery device. 12. A method for lyophilizing a pharmaceutical agent and sealing the agent within a drug delivery device, the method comprising: The drug is placed in the drug delivery device; The inner wall of the drug delivery device engages with a plurality of resilient elongated members fixed to a sealing base, wherein adjacent surfaces of the elongated members in the circumferential direction define a boundary between the elongated members: A portion of the surface of the central recess, which tapers continuously toward the base. The material region extends continuously between the base and the bottom of the central recess; and The gap separated from the central recess; The elongated component is moved forward into the drug delivery device until the sealing base is positioned to be separated from the inner wall by a predetermined offset, the sealing base being held in place only by the elongated component relative to the drug delivery device; Freeze-drying the agent to generate vapor that escapes through the gap between the inner wall, the elongated component, and the sealing base; and Then, the elongated component is moved further forward until the sealing base is sealed against the inner wall. 13. A method for lyophilizing a pharmaceutical agent and sealing the agent within a drug delivery device, the method comprising: The drug is placed in the drug delivery device; The inner wall of the drug delivery device engages with a resilient elongated member fixed to a sealing base through an opening in the drug delivery device, wherein adjacent surfaces of the elongated member define a boundary between the elongated members in the circumferential direction. A portion of the surface of the central recess, which tapers continuously toward the base. The material region extends continuously between the base and the bottom of the central recess; and The gap separated from the central recess; The elongated component is moved forward relative to the opening until the sealing base is positioned to be separated from the opening by a predetermined offset, the sealing base being held in place only by the elongated component relative to the drug delivery device; Freeze-drying the agent to generate vapor that escapes through the gap between the inner wall, the elongated component, and the sealing base; and Then, the elongated component is moved further forward until the sealing base is sealed against the inner wall. 14. A stop for a drug delivery device, the stop comprising: A base for sealing the opening of the drug delivery device, the base having a central axis; One or more elongated members extending away from the base in a direction parallel to the central axis, the one or more elongated members being arranged radially away from the central axis and defining: A portion of a central recess coaxial with the central axis, the central recess continuously tapering towards the base to form a curved bottom of the central recess, and an elastic material region extending continuously transversely to the central axis between the base and the bottom; and A gap located between circumferentially adjacent portions of the one or more elongated components, the gap being spaced apart from the central recess and extending parallel to the central axis toward the base; in: In the first working configuration, the one or more elongated components engage with the inner wall of the drug delivery device to support the base away from the opening, such that the gap provides gas exchange between the interior and exterior of the drug delivery device; and In the second working configuration, the base engages with the inner wall to seal the opening. 15. A stop for a drug delivery device, the stop comprising: A base for sealing the opening of the drug delivery device, the base having a central axis; An elongated member extending away from the base in a direction parallel to the central axis, the elongated member being configured to be radially away from the central axis and defining: A portion of a central recess coaxial with the central axis, the central recess continuously tapering towards the base, a sealing diaphragm extending transversely and continuously along the central axis between the base and the bottom of the central recess, the sealing diaphragm being permeable by a needle and self-sealing around the outer wall of the needle; and A circumferentially extending gap between adjacent portions of the elongated component; in: In the first working configuration, the elongated member engages with the inner wall of the drug delivery device to support the base away from the opening, such that the gap provides gas exchange between the interior and exterior of the drug delivery device; and In the second working configuration, the base engages with the inner wall to seal the opening. 16. The stop member according to claim 15, further comprising a flange orthogonal to the central axis. 17. The stop according to claim 16, wherein the flange is configured to abut against the end face of the drug delivery device surrounding the opening in the second working configuration. 18. The stop according to claim 17, wherein the base includes the flange. 19. The stop member according to claim 15, further comprising an elastic material. 20. The stop according to claim 19, wherein the elastic material has a lubricating coating. 21. The stop according to claim 19, wherein the elastic material of the sealing diaphragm is permeable by the needle and self-seales around the outer wall of the needle. 22. The stop according to claim 21, wherein, in the second working configuration, the needle extends from the outside of the drug delivery device through the base into the central recess. 23. The stop according to claim 15, wherein the base includes a peripheral ridge configured to sealably engage with the inner wall of the drug delivery device. 24. The stop according to claim 15, wherein, in the first working configuration, the gas comprises freeze-dried byproducts. 25. The stop according to claim 24, wherein, in the second working configuration, the stop seals the freeze-dried product within the drug delivery device between the stop and a plunger that is sealingly engaged with the inner wall of the drug delivery device.