WO2015153728A1

WO2015153728A1 - Polar aprotic solvent-compatible infusion sets, components, and methods

Info

Publication number: WO2015153728A1
Application number: PCT/US2015/023820
Authority: WO
Inventors: Steven J. Prestrelski
Original assignee: Xeris Pharmaceuticals, Inc.
Priority date: 2014-04-02
Filing date: 2015-04-01
Publication date: 2015-10-08

Abstract

Infusion sets and/or infusion set components that are compatible with one or more polar aprotic solvents (e.g., dimethyl sulfoxide (DMSO), N-Methyl-2-pyrrolidone (NMP), ethyl acetate, propylene carbonate, and/or the like), as well as related methods.

Description

DESCRIPTION

POLAR APROTIC SOLVENT-COMPATIBLE INFUSION SETS, COMPONENTS,

AND METHODS

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Patent Application No.

61/973,939 filed April 2, 2014, which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

[0002] The present inventions relate generally to delivery of one or more peptides

(e.g., peptide hormones) to a patient, more particularly, but not by way of limitation, to infusion sets and components for the delivery of one or more peptides (e.g., peptide hormones) in liquids that contain polar aprotic solvents (e.g., dimethyl sulfoxide (DMSO)), as well as related methods.

BACKGROUND

[0003] Due to their general chemical inertness, plastics are widely used during the manufacturing and packaging of pharmaceutical products. Examples of plastics that have been employed in medical device applications include polyethylene, polypropylene, polystyrene, polyvinylchloride (PVC), polyamides, nylons, polyesters, polycarbonates, polyurethanes, acrylics, acetals, polyamides, polyether imides, polysulfones, polyether ether ketone (PEEK), polyphenylene sulfide, fluoropolymers, liquid crystalline polymers, biopolymers, and thermosets and adhesives. Examples of medical device applications in which at least some of these plastics have been used include tubing, films, packaging, connectors, lab-ware, IV bags, catheters, face masks, drug-delivery components, housings, luer fittings, connectors, membranes, sutures, syringes, surgical instruments, balloons, blood- set components, blood bowls, blood oxygenators, syringes, implants, dental implants, bone implants, and bioresorbable sutures.

[0004] However, due to the intimate and often prolonged contact with the plastics, plastic-related extractables and/or leachables may in certain circumstances enter the pharmaceutical product and, in sufficient quantities, could potentially expose a consumer or patient to toxicity of the extractable or leachable itself, and/or potentially alter the active pharmaceutical ingredient such that the effect of the drug/biologic could be attenuated, eliminated, or possibly converted into an unintended metabolite. Accordingly, plastic-related extractables and/or leachables may be undesirable due to possible toxicity of an extractable or leachable, and/or due to changes in stability of a contacted therapeutic agent.

[0005] Unintended plastic-related additives may be categorized as either extractables or leachables, where extractables generally include substances that may be released from the plastic under aggressive conditions, and leachables generally include substances that may be spontaneously released under nominal (i.e. typical operating) conditions. Accordingly, the experimental approach for determining potential extractables and/or leachables from a medical device is often divided into two steps: (1) a controlled extraction study to identify potential extractables released by the plastic component, followed by (2) development of appropriate analytical methods to evaluate leachables that enter the drug product through normal contact/use. In the first step, an exaggerated extraction study is performed to generate a thorough extractable profile for identification which is intended to produce a much greater amount of plastic-derived extractables than would be generated under conditions of simulated use. The second step includes a simulated-use experiment to identify leachable materials that may be encountered by the patient during normal-use conditions.

[0006] It is noted that there are different entry routes for leachables into the patient, where leachables from a medical device may enter the drug product which then carries the leachable into a patient, or where the leachable enters via direct migration due to direct tissue contact between the plastic component and the patient. Examples of the former include syringes, syringe filters and infusion sets, while the latter encompasses dental implants, artificial joints, stents, bandages, and contact lenses. Both routes of entry may be possible for certain medical devices, such as drug-releasing implants and stents. SUMMARY

[0007] This disclosure includes embodiments of infusion sets and/or infusion set components that are compatible with one or more polar aprotic solvents (e.g., dimethyl sulfoxide (DMSO), N-Methyl-2-pyrrolidone (NMP), ethyl acetate, propylene carbonate, and/or the like), as well as related methods. For example, at least some of the present embodiments are suitable for use with non-aqueous solutions of, or with, glucagon and/or insulin, such as described in U.S. Patent Application No. 134/417,073 (published as US 2012/0232001) and/or International Patent Application No. PCT/US2012/062816 (published as WO 2013/067022). [0008] Some embodiments of the present infusion sets comprise: a conduit comprising polymer; and a connector configured to couple the conduit to an infusion device; where the polymer of the conduit is compatible with a polar aprotic solvent. In some embodiments, the polymer of the conduit is compatible with one or more of dimethyl sulfoxide (DMSO), N-Methyl-2-pyrrolidone (NMP), ethyl acetate, propylene and carbonate. Some embodiments further comprise: a needle disposed in a distal end of the conduit, the needle configured to facilitate insertion of a distal end conduit through the skin of a patient and to be removed while the distal end of the conduit remains below the skin of the patient. Some embodiments further comprise: a hub coupled to a distal end of the conduit and configured to stabilize the distal end of the conduit relative to the patient. Some embodiments further comprise: an adhesive coupled to the hub. In some embodiments, the connector comprises a polymer, and the polymer of the connector is compatible with DMSO. In some embodiments, the polymer of the conduit comprises one or more of polyethylene, polypropylene, cyclic olefin polymers, cyclic olefin copolymer, pvc, ptfe, polystyrene, Halar ECTFE (ethylene-chlorotrifluoroethylene copolymer), Tefzel ETFE (ethylene - tetrafluoroethylene) Polypropylene copolymer (PPCO), Nylon, Teflon (ETFE). In some embodiments, the polymer of the connector comprises one or more of polyethylene, polypropylene, cyclic olefin polymers, cyclic olefin copolymer, pvc, ptfe, polystyrene, Halar ECTFE (ethylene-chlorotrifluoroethylene copolymer), Tefzel ETFE (ethylene - tetrafluoroethylene) Polypropylene copolymer (PPCO), Nylon, Teflon (ETFE). In some embodiments, the conduit comprises an additive including one or more of a sugar, an amino acid, a buffer, and/or a surfactant. In some embodiments, the connector comprises an additive including one or more of a sugar, an amino acid, a buffer, and/or a surfactant.

[0009] Some embodiments of the present methods comprise: inserting the distal end of a conduit of one of the present infusion sets through the skin of a patient. Some embodiments further comprise: injecting through the conduit a therapeutic composition comprising a polar aprotic solvent. In some embodiments, the polar aprotic solvent comprises one or more of dimethyl sulfoxide (DMSO), N-Methyl-2-pyrrolidone (NMP), ethyl acetate, propylene and carbonate.

[0010] The term "coupled" is defined as connected, although not necessarily directly, and not necessarily mechanically; two items that are "coupled" may be unitary with each other. The terms "a" and "an" are defined as one or more unless this disclosure explicitly requires otherwise. The term "substantially" is defined as largely but not necessarily wholly what is specified (and includes what is specified; e.g., substantially 90 degrees includes 90 degrees and substantially parallel includes parallel), as understood by a person of ordinary skill in the art. In any disclosed embodiment, the terms "substantially," "approximately," and "about" may be substituted with "within [a percentage] of what is specified, where the percentage includes 0.1, 1, 5, and 10 percent.

[0011] Further, a device or system that is configured in a certain way is configured in at least that way, but it can also be configured in other ways than those specifically described.

[0012] The terms "comprise" (and any form of comprise, such as "comprises" and

"comprising"), "have" (and any form of have, such as "has" and "having"), "include" (and any form of include, such as "includes" and "including"), and "contain" (and any form of contain, such as "contains" and "containing") are open-ended linking verbs. As a result, an apparatus that "comprises," "has," "includes," or "contains" one or more elements possesses those one or more elements, but is not limited to possessing only those elements. Likewise, a method that "comprises," "has," "includes," or "contains" one or more steps possesses those one or more steps, but is not limited to possessing only those one or more steps.

[0013] Any embodiment of any of the apparatuses, systems, and methods can consist of or consist essentially of - rather than comprise/include/contain/have - any of the described steps, elements, and/or features. Thus, in any of the claims, the term "consisting of or "consisting essentially of can be substituted for any of the open-ended linking verbs recited above, in order to change the scope of a given claim from what it would otherwise be using the open-ended linking verb.

[0014] The feature or features of one embodiment may be applied to other embodiments, even though not described or illustrated, unless expressly prohibited by this disclosure or the nature of the embodiments.

[0015] Details associated with the embodiments described above and others are described below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The following drawings illustrate by way of example and not limitation. For the sake of brevity and clarity, every feature of a given structure is not always labeled in every figure in which that structure appears. Identical reference numbers do not necessarily indicate an identical structure. Rather, the same reference number may be used to indicate a similar feature or a feature with similar functionality, as may non-identical reference numbers. The figures are drawn to scale for at least the embodiments shown.

[0017] FIG. 1 depicts a perspective view of one example of an infusion set. DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0018] The present embodiments are configured to reduce leachables derived from disposable medical devices; for example, infusion sets such as those that are used in conjunction with hormonal pumps (e.g., insulin pumps and/or pumps for other therapeutics, including glucagon for the treatment of hypoglycemia). In particular, the present embodiments of infusion sets and components can comprise materials that are selected to reduce and/or eliminate unintended additives that might otherwise leach from traditional infusion sets, especially unintended additives that would otherwise enter the drug (or therapeutic agent) product upstream of the patient and then be delivered into the patient along with the drug product or therapeutic agent. To prioritize the types of leachable(s) that should be most reduced, both the potential toxicity of the leachable and the potential impact of the leachable on the drug product must be considered. More particularly, the present embodiments can comprise materials that minimize the leachables that are derived from the present infusion sets and other components through contact with polar aprotic solvents (e.g., dimethyl sulfoxide (DMSO)), which can function as a solvent in pharmaceutically- acceptable formulations. Examples of formulations that include DMSO as the primary solvent in a therapeutic solution include formulations of glucagon and insulin, which are peptide hormones that may be delivered to a patient from electromechanical pumps via plastic infusion sets. Accordingly, infusion sets that are fully compatible with DMSO may be beneficial for delivery of these formulations without introducing plastic-related unintended additives.

[0019] At least some of the present embodiments of infusion sets and components are configured to provide a constant connection between a patient's body and an electromechanical hormonal pump (e.g. insulin or glucagon pump). For example, FIG. 1 depicts one exemplary embodiment 10 of the present DMSO-compatible infusion sets. In the embodiment shown, infusion set 10 comprises: a conduit 14 having a proximal end 18 and a distal end 22; and a connector 26 configured to couple conduit 14 to an infusion device (e.g., an infusion pump, a syringe, and/or the like). In the embodiment shown, infusion set 10 also comprises a needle 30 disposed in distal end 22 of the conduit. In this embodiment, needle 30 is configured to facilitate insertion of distal end 22 through the skin of a patient and to be removed while the distal end of the conduit remains below the skin of the patient. In this embodiment, infusion set 10 also comprises a hub 34 coupled to distal end 22 of conduit 14 (e.g., conduit 14 can extend through a portion of hub 34, as shown) and configured to stabilize the distal end of the conduit relative to the patient. In some embodiments, conduit 14 can include a primary portion 38 and a smaller distal portion 42. Distal portion 42 can, for example, comprise a cannula having a smaller diameter than primary portion 38, and can be flexible or rigid. Distal portion 42 can, for example, be coupled to primary portion 38 within hub 34 such that hub 34 protects the connection between distal portion 42 and primary portion 38 (e.g., during use). In some embodiments, such as the one shown, the infusion set can also include an adhesive 46 coupled to hub 34 to secure the hub to the skin of a patient. For example, in the embodiment shown, the adhesive is carried by a flexible (e.g., fabric) tab 50 that is secured to the hub. In this embodiment, tab 50 includes a transparent window through which distal end 22 of the conduit and the tip of needle 30 can be viewed during insertion. In addition to and/or incorporated within these described components, infusion set 10 can comprise various seals and/or lubricants. Further, each of the components may be made from a unique plastic depending on the specific function of the component. Accordingly, there are multiple sites where plastic-related extractables and/or leachables can be introduced to the formulation as it flows from the pump cartridge into the patient.

[0020] Plastics, though comprised primarily of an essential polymer (e.g. vinyl chloride in PVC, propylene in PP), are often a complex blend in which an essential polymer is mixed with a variety of materials that may be referred to as additives (generally intended in a plastic composition to vary certain properties of the plastic composition). Such additives may serve a diverse array of functions, but are generally intended to improve one or more properties of the final plastic product, either structurally or cosmetically. For example, many of the plastics that are employed in disposable medical devices may be brittle and/or hard, such that the inclusion of plasticizers to enhance flexibility and thereby produce a viable product (i.e. for medical tubing it is necessary to have product that is readily flexible yet sufficiently rigid to ensure the tubing does not rupture or leak). Such plasticizers may not be chemically bound to the plastic polymer, and thus may be released (i.e., leached) from the polymer under certain conditions, such as during prolonged, or even transient, contact with a pharmaceutically- acceptable solvent. One example is di(2-ethylhexyl)phthalate (DEHP), which is often incorporated as a plasticizer into PVC plastics that are found in medical devices. Because DEHP is not covalently (i.e. chemically) attached to the PVC polymer, it has been reported to be leached from the plastic. The FDA has issued warnings for patients using infusion sets containing PVC, informing them that they may be exposed to health risks arising from DEHP due to indications that DEHP may have hepatotoxic, carcinogenic, teratogenic, and/or mutagenic properties. [0021] In addition to plasticizers, other examples of additives that may be commonly incorporated into plastics include: antimicrobial agents that can resist deterioration of a plastic material by microbial interaction; antioxidants that can resist oxidation of the polymer(s); antistatic agents that can help dissipate static charge, as plastics are typically insulators and have the capacity to build up electrostatic charge; blowing agents that can assist with producing a foamed material by forming gases in the plastic; internal lubricants that can lower viscosity and heat dissipation, thus improving the melt flow of the material; light stabilizers that can resist chemical degradation of the plastic when exposed to UV light; pigments that can alter the color of the plastic; processing aids that can include slip agents, which provide surface lubrication to the polymer both during and after conversion, antiblocking (or anti-slip) additives, which reduce the tendency of plastic film layers to stick together when processed into films and sheets, and/or release agents for use when molding thermosetting resins; and/or reinforcement agents that can improve tensile strength, stiffness, and integrity of the plastic material. Often, design considerations and/or requirement for specific properties in the end-product may necessitate the use of different additives (e.g., light stabilizers, anti-blocking additives, pigments, etc.) for each specified purpose, further increasing the potential sources of unintended additives to a therapeutic agent delivered through the medical device (e.g., infusion set).

[0022] DMSO has found extensive use in the medical and pharmaceutical industries due to its biocompatibility, although even brief exposure of some plastics to DMSO can release potentially bioactive leachables (e.g., even transient contact of pipette tips and disposable plasticware with DMSO may release leachables). DMSO is currently believed to interact with certain functional polymers, and certain sources list polymers that may be soluble in DMSO. For example, a DMSO product information sheet from Total Petrochemicals USA, Inc. (formerly Atofina) lists that the following polymers may be soluble in DMSO: polyacrylonitrile, bismaleimide copolymers, epoxy resins, polyether sulfones, phenoplasts, and aminoplasts. A more extensive listing of materials that may be soluble in DMSO is provided in Bulletin #102B published by Gaylord Chemical Co. and includes: organics, active pharmaceutical agents, inorganics, gases, resins and polymers (e.g., PVC, which is indicated to have some solubility in DMSO). Product information from MP Biomedicals, LLC further indicates that flexible and rigid PVC tubing may be soluble in DMSO, thereby posing a risk of producing leachables. This is particularly relevant as a listing of the materials contained in certain insulin pumps may, if not equipped with a PVC- free infusion kit, include PVC tubing that is compatible with aqueous-based insulin formulations.

[0023] While DMSO has long been used as solvent for storage and handling of drug product samples in the pharmaceutical industry, DMSO has recently emerged as a solvent for non-aqueous-based formulations that can promote enhanced stability of highly-concentrated solutions of certain therapeutic agents relative to traditional aqueous formulations. These therapeutic agents can include peptide hormones such as insulin and glucagon, which can be delivered to a patient through an electromechanical pump via an infusion set. However, and as noted above, infusion sets for currently- available hormonal pumps are designed to be compatible with aqueous formulations and are not designed for compatibility with DMSO- based formulations. Given the considerable physicochemical differences between water and DMSO, many plastics that produce little or no leachables when exposed to water may produce considerable levels of leachables when exposed to DMSO. Accordingly, delivery of non-aqueous DMSO-based therapeutic formulations from an electromechanical pump may be beneficially accomplished with DMSO-infusion sets that comprise materials that are insoluble or less-soluble in DMSO.

[0024] In some embodiments, conduit 14 (e.g., primary portion 38 and/or distal portion 42), connector 26, hub 34, and/or various other seals and/or internal components of infusion set 10 (and/or other embodiments of the present infusion sets) comprises one or more polymers and/or additives that are compatible (insoluble or less-soluble that other materials that are commonly used in polymeric medical devices and components, such as those listed above) with Dimethyl Sulfoxide (DMSO). For example, such polymers can include polyethylene, polypropylene, cyclic olefin polymers, cyclic olefin copolymer, polyvinyl chloride (PVC), polytetrafluoroethylene (PTFE), polystyrene, Halar ECTFE (ethylene-chlorotrifluoroethylene copolymer), Tefzel ETFE (ethylene-tetrafluoroethylene), polypropylene copolymer (PPCO), Nylon, Teflon (ETFE). By way of further example, such DMSO-compatible additives can include: sugars, amino acids, buffers, and/or surfactants.

[0025] The above specification and examples provide a complete description of the structure and use of illustrative embodiments. Although certain embodiments have been described above with a certain degree of particularity, or with reference to one or more individual embodiments, those skilled in the art could make numerous alterations to the disclosed embodiments without departing from the scope of this invention. As such, the various illustrative embodiments of the devices are not intended to be limited to the particular forms disclosed. Rather, they include all modifications and alternatives falling within the scope of the claims, and embodiments other than the one shown may include some or all of the features of the depicted embodiment. For example, components may be omitted or combined as a unitary structure, and/or connections may be substituted. Further, where appropriate, aspects of any of the examples described above may be combined with aspects of any of the other examples described to form further examples having comparable or different properties and addressing the same or different problems. Similarly, it will be understood that the benefits and advantages described above may relate to one embodiment or may relate to several embodiments.

[0026] The claims are not intended to include, and should not be interpreted to include, means-plus- or step-plus-function limitations, unless such a limitation is explicitly recited in a given claim using the phrase(s) "means for" or "step for," respectively.

Claims

An infusion set comprising: a conduit comprising polymer; and a connector configured to couple the conduit to an infusion device; where the polymer of the conduit is compatible with a polar aprotic solvent.

The infusion set of claim 1, where the polymer of the conduit is compatible with one or more of dimethyl sulfoxide (DMSO), N-Methyl-2-pyrrolidone (NMP), ethyl acetate, propylene and carbonate.

The infusion set of claim 1, further comprising: a needle disposed in a distal end of the conduit, the needle configured to facilitate insertion of a distal end conduit through the skin of a patient and to be removed while the distal end of the conduit remains below the skin of the patient.

The infusion set of any of claims 1-3, further comprising: a hub coupled to a distal end of the conduit and configured to stabilize the distal end of the conduit relative to the patient.

The infusion set of claim 4, further comprising:

an adhesive coupled to the hub.

The infusion set of claim 5, where the connector comprises a polymer, and the polymer of the connector is compatible with DMSO.

The infusion set of any of claims 1-6, where the polymer of the conduit comprises one or more of polyethylene, polypropylene, cyclic olefin polymers, cyclic olefin copolymer, pvc, ptfe, polystyrene, Halar ECTFE (ethylene-chlorotrifluoroethylene copolymer), Tefzel ETFE (ethylene-tetrafluoroethylene) Polypropylene copolymer (PPCO), Nylon, Teflon (ETFE).

8. The infusion set of any of claims 1-7, where the polymer of the connector comprises one or more of polyethylene, polypropylene, cyclic olefin polymers, cyclic olefin copolymer, pvc, ptfe, polystyrene, Halar ECTFE (ethylene-chlorotrifluoroethylene copolymer), Tefzel ETFE (ethylene-tetrafhioroethylene) Polypropylene copolymer (PPCO), Nylon, Teflon (ETFE).

9. The infusion set of any of claims 1-8, where the conduit comprises an additive including one or more of a sugar, an amino acid, a buffer, and/or a surfactant.

10. The infusion set of any of claims 1-9, where the connector comprises an additive including one or more of a sugar, an amino acid, a buffer, and/or a surfactant.

11. A method comprising: inserting the distal end of a conduit of an infusion set of any of claims 1-10 through the skin of a patient.

12. The method of claim 11, further comprising: injecting through the conduit a therapeutic composition comprising a polar aprotic solvent.

13. The method of claim 12, where the polar aprotic solvent comprises one or more of dimethyl sulfoxide (DMSO), N-Methyl-2-pyrrolidone (NMP), ethyl acetate, propylene and carbonate.