US20130012875A1 - Drug delivery device - Google Patents
Drug delivery device Download PDFInfo
- Publication number
- US20130012875A1 US20130012875A1 US13/617,579 US201213617579A US2013012875A1 US 20130012875 A1 US20130012875 A1 US 20130012875A1 US 201213617579 A US201213617579 A US 201213617579A US 2013012875 A1 US2013012875 A1 US 2013012875A1
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- US
- United States
- Prior art keywords
- reservoir
- housing
- drug
- drive member
- cartridge
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M5/145—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons
- A61M5/155—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons pressurised by gas introduced into the reservoir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M5/14212—Pumping with an aspiration and an expulsion action
- A61M5/14216—Reciprocating piston type
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M5/14244—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
- A61M5/14248—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/158—Needles for infusions; Accessories therefor, e.g. for inserting infusion needles, or for holding them on the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/22—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M2005/1401—Functional features
- A61M2005/1405—Patient controlled analgesia [PCA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M2005/14204—Pressure infusion, e.g. using pumps with gas-producing electrochemical cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M5/14244—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
- A61M5/14248—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type
- A61M2005/1426—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type with means for preventing access to the needle after use
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M5/145—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons
- A61M5/1452—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons pressurised by means of pistons
- A61M2005/14533—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons pressurised by means of pistons cam actuated
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- A—HUMAN NECESSITIES
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/31—Details
- A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
- A61M5/31511—Piston or piston-rod constructions, e.g. connection of piston with piston-rod
- A61M2005/31518—Piston or piston-rod constructions, e.g. connection of piston with piston-rod designed to reduce the overall size of an injection device, e.g. using flexible or pivotally connected chain-like rod members
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M5/145—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons
- A61M5/1452—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons pressurised by means of pistons
- A61M5/1454—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons pressurised by means of pistons spring-actuated, e.g. by a clockwork
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/20—Automatic syringes, e.g. with automatically actuated piston rod, with automatic needle injection, filling automatically
- A61M5/2046—Media being expelled from injector by gas generation, e.g. explosive charge
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/31—Details
- A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
- A61M5/31533—Dosing mechanisms, i.e. setting a dose
- A61M5/31545—Setting modes for dosing
- A61M5/31548—Mechanically operated dose setting member
- A61M5/3155—Mechanically operated dose setting member by rotational movement of dose setting member, e.g. during setting or filling of a syringe
- A61M5/31551—Mechanically operated dose setting member by rotational movement of dose setting member, e.g. during setting or filling of a syringe including axial movement of dose setting member
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/31—Details
- A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
- A61M5/31565—Administration mechanisms, i.e. constructional features, modes of administering a dose
- A61M5/31566—Means improving security or handling thereof
- A61M5/31571—Means preventing accidental administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/31—Details
- A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
- A61M5/31565—Administration mechanisms, i.e. constructional features, modes of administering a dose
- A61M5/31576—Constructional features or modes of drive mechanisms for piston rods
- A61M5/31583—Constructional features or modes of drive mechanisms for piston rods based on rotational translation, i.e. movement of piston rod is caused by relative rotation between the user activated actuator and the piston rod
- A61M5/31586—Constructional features or modes of drive mechanisms for piston rods based on rotational translation, i.e. movement of piston rod is caused by relative rotation between the user activated actuator and the piston rod performed by rotationally moving or pivoted actuator, e.g. an injection lever or handle
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S128/00—Surgery
- Y10S128/12—Pressure infusion
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T29/00—Metal working
- Y10T29/49—Method of mechanical manufacture
- Y10T29/49826—Assembling or joining
Definitions
- This invention relates to drug delivery devices, and in particular to portable devices designed to be carried by a patient during normal activities.
- a number of drug delivery devices are known in which medicament is driven from a reservoir, under the action of a driving mechanism, through a needle and into the skin of a patient.
- a problem with known devices is that the delivery rate accuracy suffers when the volume of drug is small.
- Such inaccuracies arise in many cases from the driving mechanisms employed which give rise to variations in delivery rates.
- a gas is generated to drive a plunger in a cartridge or vial
- the volume of gas depends in part on the temperature of the environment. The variation in volume will also depend on the total amount of gas already present in the chamber.
- gas generation is preferred over mechanical driving mechanisms
- the design of gas generating cells, such as electrolytic cells' is extremely simple when compared to mechanical equivalents, and this provides significant advantages in terms of reliability and cost-effectiveness.
- Systems are known in which a mechanically driven ratchet is used to incrementally deliver fixed amounts of medicament, but such systems can be expensive to manufacture.
- the accuracy of delivery of small amounts of drug depends on the manufacturing tolerances of the ratchet mechanism. For mass-produced, moulded, cut or pressed ratchets, the tolerances may not be sufficiently accurate to deliver the required small volumes, which means that more expensive manufacturing techniques are required to obtain the necessary tolerances.
- Such considerations are particularly important if the devices are intended to be disposable, in which case a low unit cost is required without compromising accuracy or reliability or system performance.
- a problem with gas driven mechanisms is that it is extremely difficult to ensure that a gas chamber is leakproof without taking elaborate manufacturing and quality control precautions. Even if a leak is minor and relatively slow, this poses a real problem when the mechanism is supposed to accurately deliver small volumes over extended timespans.
- gas generation it is preferred to design a system that is leak free (which is costly and typically more complex) or provide a system that functions accurately in spite of minor or relatively slow leaks.
- gas generation may not be suitable for lower delivery rates.
- mechanical equivalents having the required precision e.g. clockwork mechanisms
- chronotherapeutic drug delivery in which the drug delivery rate varies over time. Most notably, diurnal or circadian rhythms cause variations in the amounts of certain drugs required by a patient during a 24-hour period. This is most notably required to combat variations in disease and/or condition effects throughout a 24-hour cycle.
- the present invention aims to provide improved drug delivery devices in which smaller volumes of liquid can be delivered more accurately than in prior art devices, thereby giving rise to overall more controlled delivery rates.
- the invention also aims to provide such devices which additionally allow higher delivery rates to be provided on demand, up to and including bolus delivery.
- the present invention provides for a drug delivery device wherein the technology used to provide for accurate delivery rates is relatively easy and inexpensive to manufacture.
- the present invention employs designs for the gas generating system and delivery system so that space within the device is minimised and parts used within the device are easy and inexpensive to manufacture while maintaining high tolerances.
- the present invention provides for a certain amount of gas leakage while delivering accurate dosages. This eliminates the need for costly sealing devices and systems which increase cost and decrease reliability in the event of gas leakage.
- the invention provides a drug delivery device having a housing containing a drug reservoir, and means for facilitating the expulsion of drug from the drug reservoir.
- the device also includes a mechanism in communication with the facilitation means, that incrementally advances and thereby drives the drug from the reservoir, and a member associated with the mechanism to cause the incremental advancement of the mechanism as the member moves in a first direction.
- the device also includes a gas generator located within the housing and operable to expand in a chamber. The member is in transmission relation to the chamber. In operation, the member is driven by the movement of the chamber to advance the mechanism and thereby drive the drug from the reservoir in incremental fashion.
- the mechanism in communication with the facilitation means comprises a ratchet.
- the member moves in a reciprocable fashion.
- the movement of the reciprocable member causes the stepwise advancement of the mechanism.
- the reciprocable member is connected to a wall of the chamber, whereby the reciprocation of the reciprocable member is driven by the expansion and contraction of the chamber.
- the preferred devices according to the invention take advantage of the reciprocation of a gas generation chamber to effect a stepwise advancement of a ratchet mechanism.
- Gas generation chambers which expand and contract repeatedly are advantageous over known chambers which simply expand over time.
- a ratchet which has 100 teeth and is driven by a continuously expanding gas chamber will advance one step for every 1% increase in the chamber volume.
- a temperature rise of only 3° C. will increase the volume of a gas at room temperature by 1%.
- a temperature rise of 3° C. will drive the ratchet one step forward independently of the gas generation rate.
- a chamber which reciprocates will undergo a full expansion for each stepwise advance of the ratchet mechanism, and a 1% variation in the volume of this chamber will have no material effect on the fact that the chamber will expand fully and advance the ratchet correctly.
- a ratchet mechanism which undergoes 100 stepwise advances throughout the emptying of a reservoir. If this ratchet is driven by a continuously expanding gas chamber, a 1% increase in the volume of gas towards the end of the delivery period will advance the ratchet by an (undesired) extra step. Such a 1% expansion occurs with a temperature change of only 3° C. (which is approximately 1% of the room temperature when expressed in kelvins). The situation is worse for devices which require several hundred ratchet advances to ensure the necessary sensitivity for accurate delivery over an extended time period.
- devices according to the present invention employ a reciprocating chamber which continually expands and contracts.
- This enables small-volume chambers to be employed such that the difference in volume between the contracted and expanded states is orders of magnitude greater than the change in volume arising from environmental temperature changes.
- a reciprocating chamber less space is needed for the chamber as the volume at maximum expansion is considerably less that what would be required for a continuously expanding chamber at the maximum volume of expansion.
- the chamber is elastically biased to revert to a contracted state, and wherein a venting means is provided to enable contraction of the chamber after gas generation has expanded the chamber.
- One advantage of using a reciprocity chamber to drive a reciprocating mechanism linked to a ratchet is that there is sufficient amplitude of movement in the reciprocation to advance the ratchet by the required number of steps (in many cases only one step), to ensure that venting is sufficiently thorough to relax the system completely, in order to arrive at a device in which the delivery rate is controlled to a high degree of accuracy.
- the gas generator can be designed to deliver a sufficient amount of gas within one minute, and then switch off automatically for four minutes.
- the ratchet will be caused to advance by the required “tooth” (or equivalent), and then the venting means is actuated to relax the system. By the end of four minutes the system will be fully relaxed and the cycle can begin again.
- the gas generator can be designed to deliver e.g. 20% ⁇ 10% more than the required volume of gas (i.e. not a particularly expensive or accurate system), and still to have an extremely accurate delivery for the following reason. If the gas generator generates between 10% and 30% too much gas on each cycle, the ratchet will advance by a single “tooth”, but it is equally certain that it will not be pushed to advance by a second tooth. Thus, when the gas generation ceases, a certain amount of controlled overpressure or stress will be present in the system, but the amount of drug delivered will be precisely known. Then when the gas is vented, the overpressure is released and the system returns to equilibrium. Thus, the accuracy of delivery at the end of the five minute cycle is independent of whether the generator generated 10% or 30% too much gas.
- the accuracy of the system is controlled by the tolerances of the ratchet mechanism, the timer, the reciprocity chamber, the venting system and the gas generator.
- the venting means is passive and allows escape of gas therethrough when the chamber is pressurised relative to atmospheric pressure.
- Such venting means may connect sub-chambers within the gas generating means. The venting means enables the sub-chambers to increase and decrease pressure therein more efficiently.
- the gas generator is adapted to generate gas at a rate higher than the venting rate.
- the venting means causes depressurisation and contraction of the chamber. Minor leaks in the system, provided that they are not so serious as to prevent the chamber from fully pressurising, do not have any significant effect on the operation or accuracy of the device.
- This enables a gas generating system to deliver extremely small volumes of drug in a highly controlled, accurate manner, without employing any elaborate gas generation system, or any special leakproofing of the gas chamber.
- the gas generation rate should exceed the venting rate so that the error of movement of the reciprocator member errs to the side of excessive pressure rather than too little pressure.
- the gas pressure of the gas generator is divided between at least two cells.
- a first cell has a more permeable member and is designed for minimum gas leakage.
- the first cell also has a controllable vent associated therewith. The vent allows excess gas to escape from the first cell but prevents the escape of gas at a stage in the cycle when the member of the first cell is needed to deflect so as to cause forward movement of the ratchet.
- the alternative embodiment is also designed so that the latter part of the cycle allows the re-opening of the first cell vent to enable gas therein to quickly escape and cause the member to return to its initial resting position.
- the venting means comprises a permeable or semi-permeable member.
- a permeable or semi-permeable member is a silicone membrane.
- the less permeable material is preferably bromo-butyl, ethylene propylene or EPDM, and the more permeable member is preferably silicone rubber.
- the mechanism is caused to advance as the chamber undergoes expansion.
- the mechanism may be caused to advance as the chamber undergoes contraction. While it is possible to employ a mechanism which drives the ratchet forward during both expansion and contraction strokes, it is preferred to employ a single driving stroke (either contraction or expansion) during a reciprocation cycle for lower delivery rates.
- the member comprises a lever extending between the chamber and the mechanism.
- the mechanism comprises a rigid ratchet element having spaced formations on a surface thereof.
- the formations have a sawtooth cross section, although the formations may be in the form of grooves on a surface of the rigid ratchet element.
- the mechanism includes a pawl carried on the member, the pawl being adapted to make ratcheting engagement with the formations on the rigid ratchet element.
- the pawl is resiliently biased against the formations on the rigid ratchet element.
- the pawl is in the form of a substantially flat spring an end of which bears against the formations on the rigid ratchet element.
- Such a pawl is adapted to allow the ratchet element to slide with little resistance in one direction but to prevent any movement in the opposite direction.
- the formations are regularly spaced along the rigid ratchet element
- the pawl comprises a pair of pawl members resiliently biased against the rigid ratchet element at different points along the length of the rigid ratchet element, the axial distance between the pair of pawl members being different to the axial distance between successive formations.
- the advantage of this arrangement is that by locating the ratcheting linkage between the pawl and the ratchet teeth, the teeth make alternating contact with either pawl member.
- the ratcheting member advances by increments which are less than the actual difference between successive formations on the ratchet.
- the distance between successive formations is twice the distance between the pawl members. This means that then the ratchet advances in half steps and enables accurate delivery of even smaller incremental volumes of drug (if a full step is counted as equating to the distance between successive ratchet teeth formations.)
- one of the least expensive ratcheting mechanisms is a stamped plastics ratchet bar having a sawtooth surface, against which a pawl in the form of a leaf spring may be biased.
- the main limitation on accuracy in this system is likely to arise from the spacing of adjacent sawtooth formations which may not be able to be made accurately with the required spacing. In such cases the minimum delivery volume, all other things being equal, will be limited by this component.
- accuracy is doubled, and the minimum deliverable volume may be halved.
- the ratchet teeth are regularly spaced along the rigid ratchet element
- the pawl comprises three or more members resiliently biased against the rigid ratchet element at regular intervals along its length.
- the axial distance between each successive pair of pawl members is chosen to be different to the axial distance between successive ratchet teeth.
- the distance between successive ratchet teeth is given by the number of pawl members multiplied by the distance between each successive pair of pawl members.
- three or four pawl members would preferably be spaced at intervals of a third and a quarter, respectively, of the distance between successive ratchet teeth on the ratchet element.
- the pawl is in the form of a resilient member which terminates in a plurality of fingers biased against the ratchet element.
- a preferred embodiment in this regard is a pawl which comprises a flat spring which is partly split to define fingers of different lengths.
- the ratchet element comprises a helical spring and the pawl comprises one or more fingers which engage with the coils of the spring.
- the coils of a helical spring easily engage with the pawl fingers, and the regular spacing of the coils of a helical spring enable it to be used as a ratchet element.
- a further advantage of this embodiment is that the size of the device can be minimised by taking advantage of the flexibility of the spring.
- a rigid ratchet bar protruding from a drug cartridge before use might provide an unacceptably long device for certain applications (after use, the ratchet element might be partly or totally accommodated within the empty cartridge interior)
- a helical spring can be bent to be parallel with the cartridge to reduce the overall length.
- one or more fixed fingers are mounted in fixed position relative to the housing, and one or more reciprocable fingers are mounted on the mechanism, such that when the one or more reciprocable fingers move in a first direction they engage the coils of the helical spring to drive the helical spring in the first direction, and when the one or more reciprocable fingers move in an opposite direction, the one or more fixed fingers engage with and hold the coils of the helical spring preventing it being driven back in the second direction, whereby the fixed and reciprocable fingers co-operate to drive the helical spring in one direction only.
- each finger is inclined in the first direction. This makes it easier for the helical spring coils to slip past the fingers in this direction, and more difficult for the coils to push back in the opposite direction against the fingers.
- the position of the one or more fixed fingers relative to the one or more reciprocable fingers is such that the helical spring is driven by the reciprocable fingers towards the fixed fingers.
- This feature helps prevent a situation which may develop in which a flexible helical spring is pulled by the reciprocable fingers away from the fixed fingers, but rather than slipping past the fixed fingers, the helical spring merely stretches, such that when the reciprocating fingers move back towards the fixed fingers the helical spring simply relaxes, without any net movement having taken place.
- the solution to this problem is achieved in part by pushing the helical spring towards the fixed fingers as the driving step of the delivery action.
- the minimum distance between the fixed and reciprocable fingers, respectively is not greater than ten times the distance between adjacent coils of the helical spring when the helical spring is in a relaxed position.
- this minimum distance between the fixed and reciprocable fingers, respectively is not greater than five times the distance between adjacent coils of the helical spring when the helical spring is in a relaxed position, most preferably not greater than twice the distance between adjacent coils.
- the minimum distance between the fixed and reciprocable fingers, respectively is approximately equal to the distance between adjacent coils of the helical spring when the helical spring is in a relaxed position.
- the mechanism comprises a flexible ratchet element which is sufficiently stiff to drive medicament from the chamber when driven by the member, and sufficiently flexible to be bent before it meets the member, whereby the overall length of the device is reduced relative to a device in which a rigid ratchet element protrudes linearly from the mechanism before use.
- the flexible member may be, for example, a piece of bendable thermoplastics stamped or molded with a ratchet sawtooth profile.
- the flexible member should have a degree of flexibility which allows it to be bent sufficiently to reduce the overall dimensions of the device. Furthermore, it must nevertheless be sufficiently stiff to transmit the driving force of the ratcheting mechanism without buckling or distorting to any great extent. This can be achieved by restraining the degree of freedom of movement of the member.
- the mechanism comprises two or more co-operating flexible ratchet elements which are individually sufficiently flexible to be bent before they meet the member but when joined together are together sufficiently stiff to drive medicament from the chamber when driven by the member.
- the two or more co-operating flexible ratchet elements are bent away from one another before they meet the member.
- the device according to the invention further comprises electronic control means for controlling the delivery rate.
- the electronic control means comprises a timing mechanism which alternately energises and de-energises the gas generating mechanism for controlled periods.
- the amount of drug delivered in this overall cycle is accurately controllable independently of variations (within reason) in the gas generation rate.
- timer allows the overall cycle length to be varied in a controlled manner over time, thereby providing an accurately controllable device which delivers at a time-varying rate.
- Such devices find a particular application in the field of chronotherapeutics.
- the electronic control means is programmable for different delivery programs.
- the control means may be user-programmable or a single unit may be factory-programmable for different delivery regimes (e.g. for different drugs.
- the device according to the invention further comprises means for manually adjusting the delivery rate. This allows for a certain degree of flexibility which might be desirable where the user can safely have an amount of control over the treatment. Alternatively, it can be set by the physician or pharmacist and disabled to prevent patient interference.
- the member reciprocates to cause the incremental advancement of the mechanism and the means for manually adjusting the delivery rate comprises means for limiting the travel of the member, whereby the volume of drug delivered on each reciprocating stroke is controllable.
- a simple advancing screw can control a stop against which any reciprocating element ends its travel. If this is used, adjustment of the screw will provide a control mechanism.
- a device could be designed with three delivery rates, namely low, medium and high, corresponding respectively to one, two and three ratchet advancements per reciprocation. A simple mechanism would determine how far the reciprocating mechanism is allowed to advance on each stroke, to determine the delivery rate.
- more sophisticated embodiments could also be achieved. Devices having the ability to deliver bolus doses of drug are preferred in therapies such as patient controlled analgesia.
- the means for manually adjusting the delivery rate provides the user with the ability to deliver a bolus dose of drug. It is advantageous if the bolus dose can be delivered without this interfering with the normal basal delivery rate.
- the means for manually advancing the mechanism comprises means for manually advancing the lever extending between the chamber and the mechanism, operable from the exterior of the housing. Any suitable mechanism, such as a knob, button or lever can be used to operate the lever.
- the mechanism comprises a ratchet and wherein the means for manually advancing the mechanism comprises a pawl which is manually reciprocable from the exterior of the housing.
- the mechanism for manually advancing said lever is provided with gradations corresponding to a number of stepwise advances of the ratchet mechanism.
- the advancing means could be marked in units which would be understood by the patient, and the scale would be calibrated to correspond to the delivery of the correct dose.
- the present invention provides a method of delivering drug to a patient.
- the method includes affixing a drug delivery device to the surface of the patient's skin.
- the drug delivery device having a housing containing a drug reservoir, means for facilitating expulsion of drug from the drug reservoir, a mechanism in communication with the facilitation means, operable to undergo incremental advancement and thereby drive the drug from the reservoir, a member operatively associated with the mechanism to cause the incremental advancement of the mechanism as the member moves in a first direction, and a gas generator located within the housing and operable to expand in a chamber, the member being in transmission relation to the chamber.
- the method further includes activating the device whereby the member is driven by the movement of the chamber to advance the mechanism and thereby drive the drug from the reservoir in incremental fashion.
- FIG. 1 is a sectional plan view of a first embodiment of a drug delivery device according to the invention
- FIGS. 2-5 are schematic views of a detail of the embodiment of FIG. 1 shown at successive points in the operating cycle;
- FIG. 6 is a sectional plan view of the embodiment of FIG. 1 , in use;
- FIGS. 7-11 are sectional side views of a second embodiment of a device according to the invention, shown at successive points during its use;
- FIG. 12 is a simplified sectional plan view of a third embodiment of a drug delivery device according to the invention.
- FIG. 13 is a cross sectional side view of the embodiment of FIG. 12 , taken along the line XIII-XIII;
- FIG. 14 is a sectional plan view of a fourth embodiment of a drug delivery device according to the invention.
- FIG. 15 is a cross sectional side view of the embodiment of FIG. 12 , taken along the line XV-XV;
- FIG. 16 is a graph showing the test results of an 80 hour test which plots delivery pressure and amount of drug delivered against time
- FIG. 17 is an enlarged detail of a portion of the graph of FIG. 16 ;
- FIG. 18 is a sectional plan view of a fifth embodiment of a drug delivery device according to the invention.
- FIG. 19 is a sectional side view of the embodiment of FIG. 18 ;
- FIG. 20 is a sectional plan view of the embodiment of FIG. 18 , as it is being prepared for use;
- FIG. 21 is a sectional side view of the embodiment of FIG. 18 when ready for use;
- FIG. 22 is a sectional plan view of a sixth embodiment of the drug delivery device according to the invention.
- FIG. 23 is a sectional plan view of the embodiment of FIG. 22 when ready for use;
- FIG. 24 is a cross-sectional view along line A-A of the embodiment of FIG. 22 ;
- FIG. 25 is a cross-sectional view along line B-B of the embodiment of FIG. 22 ;
- FIG. 26 is a schematic drawing representing the various parts of the gas generation sub-assembly of the embodiment of FIG. 22 .
- FIG. 1 a drug delivery device according to the invention.
- the device 10 comprises a housing 11 containing a cartridge 12 filled with a drug 13 .
- the cartridge 12 is provided with a needle 14 extending from a first end 15 of the cartridge for delivery of drug 13 to a patient.
- a piston 16 is slidably received in the cartridge 12 , such that when the piston 16 is pushed towards the first end 15 , drug is forced from the cartridge 12 out through the needle 14 .
- the piston 16 is mounted on a ratchet bar 17 which is driven by a pawl 18 mounted on a reciprocable lever 19 .
- Lever 19 is mounted on an axis 20 at one side 21 and is connected to a driving rod 22 at the other side 23 , whereby reciprocation of the driving rod 22 causes pawl 18 to reciprocate with respect to the ratchet bar 17 .
- this causes the ratchet bar 17 to advance stepwise towards the first end 15 of cartridge 12 and thereby drive the drug 13 from the cartridge.
- the driving rod 22 is in connection with a flexible diaphragm 24 which defines a wall of a gas generation chamber 25 .
- a battery 26 is connected via a microprocessor 27 to an electrolytic cell 28 which is operable to generate a gas into chamber 25 .
- the chamber expands and causes the diaphragm 24 to move. This movement pushes the driving rod 22 in the direction away from the first end 15 of cartridge 12 .
- the movement is opposed by a return spring 29 which biases the lever 19 towards the first end 15 .
- the chamber 25 is fully expanded and the supply of current from the battery 26 to the electrolytic cell 28 is switched off by the microprocessor 27 .
- a silicone membrane 30 defines a wall of the chamber 25 .
- the membrane 30 is slightly permeable and thus allows a controlled leakage of gas from the chamber 25 .
- the force of return spring 29 will act to decompress the chamber 25 by gas leaking through membrane 30 .
- the lever 19 and hence the pawl 18 will have made one complete reciprocation thereby advancing the ratchet bar 17 by a fixed step.
- the cycle might be chosen to allow the delivery of a quantity of drug corresponding to the advancement of a single step of the ratchet bar 17 every five minutes.
- the electrolytic cell 28 could be switched on for one minute and then switched off for four minutes. As long as the timing of the microprocessor is accurate, this will ensure that precisely one stepwise advance is made in that five minute period.
- the precision of device 10 is to a certain extent independent of the exact quantity of gas generated because the ratchet bar 17 is quantised, i.e. it can only move by a fixed step (or number of steps) at a time.
- the membrane 30 provides a controlled constant leakage from the system even during gas generation, other minor leaks which might affect the accuracy of conventional gas driven delivery devices are not important (although of course if the leak is bad enough the chamber will be unable to pressurise fully when the gas is generating).
- pawl 18 is split in two halves, i.e. a longer half 31 , and a shorter half 32 .
- the pawl 18 is a leaf spring which is biased down onto ratchet bar 17 .
- the halves 31 , 32 of the pawl 18 are of unequal length.
- FIG. 2 shows a cross-sectional enlarged view of a portion of the ratchet bar 17 which has a series of evenly spaced steps or teeth 33 , 34 .
- the difference in length between the halves 31 , 32 of the pawl 18 is exactly half of the distance between adjacent teeth 33 , 34 on the ratchet bar 17 .
- each tooth 33 , 34 has a sloped surface 35 having a peak 36 and a trough 37 , as shown in detail in FIG. 2A .
- the longer half 31 of the pawl 18 presses against the sloped surface 35 of tooth 33 , midway between the peak 36 and trough 37 , and the shorter half 32 presses against the trough 37 of the adjacent tooth 34 .
- FIG. 6 shows the device of FIG. 1 in operation at the completion of gas generation, and before the lever 19 has begun its return stroke.
- gas generation chamber 25 has expanded by pushing the diaphragm 24 outwards, and the lever 19 is thus pivoted on its axis 20 against the force of the return spring 29 .
- the lever 19 is driven back to the FIG. 1 position, a small volume of liquid drug 13 will be forced from the cartridge 12 .
- the device of FIG. 1 delivers small volumes in a stepwise fashion, it is possible to achieve an extremely low delivery rate.
- the gas generator 25 could be activated for 1 minute as previously described and then switched off for 59 minutes to give cycles of one hour duration.
- the device 10 of the present invention does not require a system pressure to be maintained above atmospheric pressure.
- the volume of the gas generation chamber 25 is small relative to the size of the device. This minimises variations in the volume of gas per stroke, and helps ensure a constant delivery rate.
- the device 10 will generate in excess of 10-30% volume of gas over the required amount on each stroke so that the device can compensate of variations due to temperature, atmospheric pressure, materials used, etc. (The device will never drive the ratchet 10-30% further than necessary, since the ratchet can only move in fixed steps.) This extra gas is stored as an overpressure in the system and is of course released during the venting part of the cycle.
- FIG. 7 shows a cross-sectional side view of a second alternative embodiment of the present invention, indicated generally at 50 .
- the device 50 is similar in most respects to the first embodiment shown in FIG. 1 .
- the pawl 51 is not split into two halves, so that it advances the ratchet bar 52 by full steps equal to the tooth length (“L”).
- the device 50 is identical to the device 10 of FIG. 1 . It can be seen from FIG. 7 that the needle 53 of the device 50 (as with the FIG. 1 device) is bent at 90° to the axis of the cartridge 54 .
- the device 50 of FIG. 7 is shown before use.
- a protective sheath 55 is provided on the needle 53 and a displaceable lower cover 56 is hinged to the main housing 57 by a hinge (not shown).
- the displaceable lower cover 56 and the main housing 57 are prevented from moving relative to one another by a safety tab 58 .
- the lower surface 61 of the displaceable cover 56 is covered by a contact adhesive which is protected before application to the user by a protective liner 60 .
- the liner 60 has a pull tab 59 to ease removal of the liner by the user immediately before application of the device 50 .
- the protective sheath 55 is removed as indicated in FIG. 8 by grasping and pulling the pull tab 59 . This also causes the release liner 60 to be pulled away revealing the contact adhesive on the lower surface 61 of the displaceable cover 56 . The lower surface 61 is adhered to the user's skin. Then, the safety tab 58 is pulled away from the device 50 as shown in FIG. 9 .
- the main housing 57 is then pressed towards the skin whereupon it snaps towards the displaceable cover 56 .
- the needle 53 projects beyond the lower surface 61 to penetrate into the skin for subcutaneous drug delivery.
- the delivery mechanism is then actuated, either by the user, or more preferably, in automatic fashion by the microprocessor.
- the ratchet bar 52 is advanced by the pawl 53 in stepwise manner as described above with regard to the operation of the first embodiment as shown in FIG. 1 .
- the main housing 57 is then pulled away from the skin whereupon it snaps away from the displaceable cover 56 and locks in this position by a locking mechanism (described in more detail in our U.S. Provisional Application No. 60/045,745) which prevents further actuation of the device, i.e. prevents the needle 53 from projecting beyond the displaceable cover 56 due to further relative movement of the main housing 57 and the displaceable cover 56 .
- a locking mechanism described in more detail in our U.S. Provisional Application No. 60/045,745
- FIG. 12 there is indicated, generally at 70 , a further embodiment of a device according to the invention.
- a further embodiment of a device according to the invention In the illustration of this embodiment, only those details necessary to understand the differences relative to the devices of the first and second embodiments are shown, and thus the gas generation mechanism, for example is not shown.
- the ratchet bar has been replaced by a helical spring 71 .
- a lever 72 is caused to reciprocate in identical manner to that previously described.
- a pair of resilient reciprocable fingers 73 are mounted on the lever 72 and reciprocate as the lever reciprocates. These reciprocable fingers 73 are inclined in the direction of movement of the piston 74 as it empties the cartridge 75 . Thus, when they move in the direction in which they are inclined they tend to grip and push the coils of the helical spring 71 forward. As the helical spring 71 moves forward it slips past a pair of resilient fixed fingers 76 mounted directly in front of the reciprocable fingers 73 , and inclined in identical manner.
- FIG. 13 shows a sectional side view of the device taken along the line XIII-XIII (in FIG. 12 ), in which the fixed fingers 76 and helical spring 71 are visible.
- the arrangement of reciprocable fingers 73 and fixed fingers 76 act as a pawl and the helical spring 71 acts as a ratchet, such that on each reciprocation of the lever 72 , the helical spring 71 advances by an amount equal to a set number of coil diameters. Accordingly, as with previously described embodiments, precisely controlled delivery rates are achievable, and in particular, extremely low volume delivery rates are possible with this invention.
- One advantage of this embodiment is that because the helical spring 71 is curved within the device 70 , it does not have to project directly out of the cartridge 75 and thus a shorter device can be realised, or the shape of the device can be varied as required.
- FIG. 14 A further embodiment of the present invention is shown in cross-sectional plan view in FIG. 14 .
- the device, indicated generally at 80 is in many respects identical to the device of FIG. 1 but differs in that as well as the gas-driven lever 81 , a second manual lever 82 is provided.
- Manual lever 82 is mounted on a common axis 83 with gas-driven lever 81 , as can be seen referring additionally to FIG. 15 .
- Manual lever 82 passes under the ratchet bar 84 and also carries a second pawl 85 .
- Both the upper surface 86 and lower surface 87 of ratchet bar 84 are provided with ratchet teeth, so that either gas-driven lever 81 or manual lever 82 can drive the ratchet bar 84 forward.
- gas-driven lever 81 will drive the drug from the cartridge 88 , and in this mode, the ratchet bar 84 simply slides past the pawl member 85 on manual lever 82 as described previously.
- the manual lever 82 can be actuated to advance the ratchet bar 84 by a pre-determined number of teeth.
- the manual lever 82 can be seen to have an adjustable threaded locking member 89 which determines the extent of travel of the manual lever 82 , and hence the volume of the bolus delivery.
- FIG. 14 the manual lever 82 can be seen to have an adjustable threaded locking member 89 which determines the extent of travel of the manual lever 82 , and hence the volume of the bolus delivery.
- the lever 82 is prevented from travelling because the threaded member 89 is fully torqued, and this locks the lever 82 preventing it from being actuated.
- the lever 82 is free to move inwards by an amount equal to the distance of axial travel of the threaded member 89 .
- the lever 82 can then be actuated by depressing the threaded member 89 .
- the degree of travel of the lever 82 is determined by the extent to which the threaded member 89 is turned, and by providing marked gradations on the threaded member 89 one can give the user visual control over the volume delivered in such a bolus dosage.
- the movement of the ratchet bar 84 under the action of the second pawl 85 is independent of the primary pawl-and ratchet mechanism.
- the second pawl 85 will, when actuated manually, advance the ratchet bar 84 by a whole number of steps.
- the ratchet bar 84 slides under the pawl member 90 on gas-driven lever 81 , but this has no effect on the basal delivery rate or on the operation of the gas-driven delivery mechanism 80 .
- each individual ratchet mechanism is independent of the other, and bolus delivery can take place against the background basal rate without complication.
- FIG. 16 is a graph of typical results achieved in a test of a device according to the invention, of the design shown in FIG. 1 .
- the graph shows two lines, namely the cumulative delivery of drug against time (the stepwise steadily ascending line), and the delivery pressure against time (the line consisting of a succession of sharp peaks and troughs).
- the device was tested over an 80 hour period (more than 3 days) and delivered just under 1.35 grams of drug solution in this time. This gives a delivery rate of less than 17 ⁇ g/hour. Furthermore, this delivery rate is absolutely constant, i.e. shows no deviation from a straight line. Accordingly, the device of FIG. 1 has a delivery rate whose accuracy is unmatched in the prior art, particularly for extremely slow delivery rates.
- FIG. 17 shows a portion of the graph of FIG. 16 in greater detail, over a five hour period in the middle of the test. It can be seen that the pressure on each cycle immediately shoots up to a maximum, and then slowly falls off as gas is released through the silicone membrane.
- the delivery overpressure reaches over 400 mbar (0.4 atm or 40 kPa) on each cycle, and this assists in providing a constant delivery rate, since any minor needle blockages will be forced out, and variations in blood pressure (when intravenous delivery is effected will have a negligible effect on the delivery rate. This is to be contrasted with other low volume pumps which generally achieve low delivery rates with low delivery pressures.
- FIG. 18 A further alternative embodiment is illustrated in FIG. 18 .
- the device indicated generally at 100 , has a housing 101 containing an internal needle 102 connected via a length of flexible tubing 103 to a delivery needle 104 (seen in sectional side view in FIG. 19 ).
- delivery needle 104 is protected by a sheath 105 before use.
- Internal needle 102 is also protected by a sheath 106 which is provided with a tab 107 extending the length of an internal bore 108 to the exterior of the housing 101 .
- Flexible tubing 103 is carried on a ratchet bar 109 which can be driven to move the internal needle 102 in the direction of the internal bore 108 .
- a leaf spring 110 acting as a pawl is carried on a lever 111 to drive the ratchet bar in the manner previously described.
- the lever 11 is driven by the expansion and contraction of an electrolytic cell 112 which is powered by batteries 113 .
- FIG. 20 shows a step in the preparation of device 100 for use.
- the internal sheath 106 has been removed and is no longer visible, thereby exposing internal needle which is in the centre of a cylindrical cup 114 .
- a drug cartridge 115 is provided in the form of a cylindrical container 116 sealed at its open end 117 by a piston 118 slidably received in the container 116 .
- Bore 108 is dimensioned to receive cartridge 115 , and a pair of resilient projections 119 inside the bore 108 hold the cartridge in place when it is pushed home within the bore.
- FIG. 21 shows the device 100 when the cartridge 115 has been pushed home.
- Internal needle 102 penetrates piston 118 , such that the internal needle 102 is in fluid communication with the drug inside the cartridge 115 .
- movement of the ratchet bar 109 into the cartridge 115 causes the piston 118 to be pushed along the length of the cartridge 115 , and thereby pump drug through the internal needle 102 and flexible tubing 103 to the delivery needle 104 .
- the flexible tubing 103 is pulled behind, thereby maintaining communication between internal needle 102 and delivery needle 104 .
- flexible tubing 103 Another advantage of flexible tubing 103 is that it enables delivery needle 104 to be mounted at any point on the device, and thus the placement of the delivery needle in this embodiment is not constrained by the design of the other features.
- the configuration of lever 111 and the pivot 119 on which it is mounted causes pawl 110 to advance ratchet bar 109 during the gas generation step rather than during the venting step.
- FIGS. 22-26 A further embodiment is shown in FIGS. 22-26 .
- the embodiment 120 comprises a housing 121 containing a cartridge 122 filled with a drug 123 .
- the cartridge 122 is provided with a needle 124 for delivery of drug 123 to a patient.
- the cartridge 122 includes a piston 125 which is slidably received in the cartridge 122 .
- the piston has an outer recess 126 for receiving a needle sterility cover 127 .
- the needle sterility cover 127 covers a first end 128 of the needle 124 and prevents contamination thereto.
- a second end 129 of the needle 124 is connected to a length of tubing 130 .
- the tubing 130 has a first end 131 and a second end 132 , as shown in FIG. 24 .
- the tubing 130 second end 132 is secured within an activation assembly 163 .
- a second needle 134 is also secured to the activation assembly 163 .
- a drug pathway 133 is machined into the activation assembly 163 , and the tubing 130 and second needle are secured within the activation assembly by means of an adhesive, preferably an ultra-violet bonding agent.
- a second needle sterility cover 135 is slidably received on the exterior end 136 of the second needle 134 . Prior to use, the second needle sterility cover 135 is manually removed so as to uncover the exterior end 136 of the second needle 134 so that it is ready for penetration into the user's skin.
- the piston 125 and needle 124 are mounted on a ratchet bar 137 having a multitude of stepped increments 138 thereon.
- the ratchet bar 137 is moved by a leaf spring 139 integral with a reciprocating lever 140 .
- the lever 140 is mounted on an axis 141 and has a return spring 142 that applies constant pressure to the lever 139 in a single direction.
- the lever 139 rests against a gas generator sub-assembly 144 and moves in response to pressure differentiation created therein.
- the gas generation sub-assembly 144 includes a pair of electrolytic cells 145 , 146 , as shown in FIG. 26 .
- the first cell 145 is the propulsion cell.
- the propulsion cell 145 has a first diaphragm 147 made of a low permeability material, such as bromo-butyl, ethylene propylene, or EPDM.
- the lever 140 rests against the first diaphragm 147 .
- the second cell 146 has a second diaphragm 148 thereon.
- the second diaphragm 148 is made of a high permeability material, such as silicone rubber.
- the first cell 145 has a hose 149 extending from the side of the first cell 145 to above the surface of the top of the second cell 146 .
- a gap 143 is created between the end of the hose 149 and the top surface of the second cell 146 .
- the cells 145 , 146 are activated with electrical energy from batteries 150 .
- Additional components in the present embodiment 120 include a drug cartridge recess 151 , as shown in FIG. 23 .
- the drug cartridge has a sleeve 152 for receiving and supporting the cartridge 122 and ensuring safe and accurate operation of the device 120 .
- the sleeve 152 is slidably received into the recess 151 .
- the sleeve 152 has a lip 153 on the exterior at the insertion end 154 of the sleeve.
- the recess 151 has a shelf 155 for receiving the lip 153 of the sleeve when the cartridge 122 is fully inserted, as shown in FIG. 21 .
- a cartridge receiving channel 156 is located within the housing 121 and is proximate to the recess 151 .
- the channel provides further support for the cartridge when it is inserted within the device 120 .
- the channel includes an outer edge 157 , an inner edge 158 and an arched portion 159 .
- the outer and inner edges are parallel and align with the cartridge recess to guide and support the cartridge 122 upon insertion and during use.
- the arched portion 159 of the channel is integral with the inner edge 158 and is curved away from the cartridge and ratchet assembly. Prior to operation, the arched portion 159 rests against a depressable button 160 that is part of the gas generating sub-assembly 137 .
- the button 160 has a puncturing device on the inner surface thereof.
- the puncturing mechanism breaks a seal 161 of the compartment 162 containing the chemical entity used in the electrolytic cells 145 , 146 of the gas generating sub-assembly 144 , as shown in FIG. 22 .
- the chemical entity is typically potassium chloride, and in the present embodiment, it is preferably in a less viscous form so as to enable the liquid to move to gaseous form more quickly.
- FIG. 24 shows a cross-sectional view of manual activation assembly 163 along line A-A.
- the activation assembly 163 includes a spring loaded start button 164 which is slidably received within a button channel 165 .
- the button 164 is maintained in an outward position by means of a helical spring 166 , located and supported in the button channel 165 .
- the helical spring 166 is loaded both axially and torsionally within the button channel 165 .
- 25 is a cross-sectional view of the activation assembly along line B-B, which shows a pin 169 which moves within a groove 170 in the button channel 165 from a first, pre-operational position [shown as position 169 A], to a second, operational position [ 169 B], to a third, locked position [ 169 C].
- the button 164 has a finger 167 extending therefrom.
- the finger 167 is located directly above a deflectable electrical contact 168 .
- the finger 167 contacts the electrical contact 168 and causes it to deflect, thus causing electrical communication between the contacts and initiating operation of the device 120 .
- the embodiment 120 is supplied with a drug cartridge 122 .
- the cartridge 122 filled with drug 123 is fully inserted into the cartridge recess 151 .
- the lip 153 of the sleeve 152 lockably engages with the shelf 155 and prevents the cartridge 122 from being removed.
- the needle sterility cover 127 engages with the piston outer recess 126 , and the tip of the needle pierces the needle sterility cover 127 and piston 125 and moves into the interior of the cartridge, as shown in FIG. 23 .
- the travel of the cartridge ends when the sleeve lip engages with the shelf and the inner and outer edges of the channel.
- the cartridge edge contacts the arched portion of the channel 156 causing it to deflect away from the cartridge.
- Such deflection applies pressure to the depressable button which depresses and pierces the container of chemical used to generate the gas within the electrolytic cells.
- the device 120 is then applied by the user or health care worker to the skin.
- the device is then activated when the start button 164 is depressed causing the finger 167 to contact the electrical contact 168 thus closing an electrical circuit which initiates gas generation in the sub-assembly.
- the button 164 is depressed, the torsional force of the helical spring 166 prevents the button from springing back up and locks the button, and second needle 134 in position [ 169 B] during operation, as shown in FIG. 25 .
- both cells When the cells 145 , 146 are activated with electrical energy from the batteries 150 , both cells begin to generate gas.
- the first cell 145 builds pressure quickly because of the low permeability of the first diaphragm 147 , as shown in FIG. 26A . However, pressure is released through the hose and exits into the atmosphere within the housing 121 .
- the second diaphragm 148 deforms outwardly, closing the gap 143 between the hose and the top surface of the second cell, as shown in FIG. 26B . When this is closed, the gas from the first cell can no longer escape into the atmosphere, causing the first diaphragm to elastically deform outwardly.
- This deformation applies pressure to the lever 140 , as shown in FIG. 26C .
- pressure When pressure is applied on the lever, it causes the leaf spring to move from a first stepped increment 138 A to a second increment 138 B. This movement causes the piston 125 to move further along the length of the drug cartridge 122 , decreasing the volume of drug 123 in the cartridge and moving such drug into the patient via the needle 124 .
- the gas-generation sub-assembly is designed in such a way so as to provide maximum efficiency in the cycle of moving the leaf spring from a first increment 138 A to a second increment 138 B.
- the low permeability of the first diaphragm 147 allows the pressure to build in the first cell 145 and thus results in quick deformation of the diaphragm and movement of the reciprocating piston 143 .
- the integration between the first and second cells, 145 , 146 is important in order to quickly release the pressure within the first cell 145 after the leaf spring has been moved forward.
- the hose 149 between the first and second cell connects the two cells during deflection and provides first for the build up of pressure.
- the electrical connection to the batteries 150 is disconnected, or decreased.
- the second diaphragm looses height and recreates the gap 143 , thus allowing gas from the first cell to quickly bleed off and return to a low pressure state to begin the next cycle. It should be noted that it is possible to maintain a minimum current level within the cells in order to keep a minimum level of pressure in the cells so as not to start the build up of pressure from a lower point than necessary, thus maximizing the efficiency of the cycle time.
- the current needed during the gas generation portion of the cycle may range from 5-7 milliampers, and the current to maintain the minimum level of pressure may range from 30-50 microampers.
- This cell design has enabled the cycle time to decrease from 20 minutes to 5 minutes in the present embodiment.
- the length between activating and deactivating the electrolytic cells may be controlled by means of a microprocessor, along with the use of different diaphragm materials.
- the cycle time to move the leaf spring a single increment may be adjusted depending upon the delivery rate desired.
- the number and size of increments may be altered to provide further flexibility in the delivery rate.
- the helical spring 166 which is torsionally loaded, forces the pin 169 to move from the operation position [ 169 B] to a locked post-operational position [ 169 C]. This causes the entire activation assembly to retract and the exterior end 136 of the second needle 134 to be recessed into the housing, thereby avoiding any accidental injury or attempted further use of the device 120 .
- the number of sterile components has been minimized so as to eliminate the need to sterilize the entire device.
- the following components are sterilized as an assembly prior to being assembled into the device.
- the sterilized sub-assembly includes the needle sterility cover 127 , the needle 124 , the tubing 130 , the start button 164 , the drug pathway 133 , the second needle 134 , and the penetrating needle sterility protector 135 .
- drug used herein includes but is not limited to peptides or proteins, hormones, analgesics, anti-migraine agents, anti-coagulant agents, narcotic antagonists, chelating agents, anti-anginal agents, chemotherapy agents, sedatives, anti-neoplastics, prostaglandins, antidiuretic agents, anti-sense agents, oligonucleotides, mucosal vaccines, gene-based medicines and permeability and enhancing agents.
- Typical drugs include peptides, proteins or hormones such as insulin, calcitonin, calcitonin gene regulating protein, atrial natriuretic protein, colony stimulating factor, betaseron, erythropoietin (EPO), interferons such as a, ⁇ , ⁇ or ⁇ interferon, somatropin, somatotropin, somastostatin, insulin-like growth factor (somatomedins), luteinizing hormone releasing hormone (LHRH), tissue plasminogen activator (TPA), growth hormone releasing hormone (GHRH), oxytocin, estradiol, growth hormones, leuprolide acetate, factor VIII, interleukins such as interleukin-2, and analogues thereof; analgesics such as fentanyl, sufentanil, butorphanol, buprenorphine, levorphanol, morphine, hydromorphone, hydrocodone, oxymorphone, methadone,
- antiulcer agents such as but not limited to cimetidine, and ranitidine; antibiotics; anticonvulsants; anti inflammatories; antifungals; antipsychotics; corticosteroids; immunosuppressants; electrolytes; nutritional agents and vitamins; general anesthetics; antianxiety agents, such as but not limited to compazine; and diagnostic agents.
Abstract
A drug delivery device having a housing containing a gas generator controlled by an electronic controller. The gas generator generates gas into a reciprocable chamber, whereby reciprocation of the chamber causes a lever to reciprocate a pawl, and this action causes a ratchet to The device may also be provided with manually control for delivering a bolus dose of drug when necessary.
Description
- This invention relates to drug delivery devices, and in particular to portable devices designed to be carried by a patient during normal activities.
- A number of drug delivery devices are known in which medicament is driven from a reservoir, under the action of a driving mechanism, through a needle and into the skin of a patient. A problem with known devices is that the delivery rate accuracy suffers when the volume of drug is small. Such inaccuracies arise in many cases from the driving mechanisms employed which give rise to variations in delivery rates. For example, where a gas is generated to drive a plunger in a cartridge or vial, the volume of gas depends in part on the temperature of the environment. The variation in volume will also depend on the total amount of gas already present in the chamber.
- The reason that gas generation is preferred over mechanical driving mechanisms is that the design of gas generating cells, such as electrolytic cells' is extremely simple when compared to mechanical equivalents, and this provides significant advantages in terms of reliability and cost-effectiveness. Systems are known in which a mechanically driven ratchet is used to incrementally deliver fixed amounts of medicament, but such systems can be expensive to manufacture. In particular, the accuracy of delivery of small amounts of drug depends on the manufacturing tolerances of the ratchet mechanism. For mass-produced, moulded, cut or pressed ratchets, the tolerances may not be sufficiently accurate to deliver the required small volumes, which means that more expensive manufacturing techniques are required to obtain the necessary tolerances. Such considerations are particularly important if the devices are intended to be disposable, in which case a low unit cost is required without compromising accuracy or reliability or system performance.
- A problem with gas driven mechanisms, however, is that it is extremely difficult to ensure that a gas chamber is leakproof without taking elaborate manufacturing and quality control precautions. Even if a leak is minor and relatively slow, this poses a real problem when the mechanism is supposed to accurately deliver small volumes over extended timespans. Thus, for gas generation systems, it is preferred to design a system that is leak free (which is costly and typically more complex) or provide a system that functions accurately in spite of minor or relatively slow leaks. In the alternative, gas generation may not be suitable for lower delivery rates. As mentioned above, mechanical equivalents having the required precision (e.g. clockwork mechanisms) are overly expensive and complex for incorporation into inexpensive devices which may be disposable.
- For many drug delivery regimes, it is desirable to provide both steady state delivery (“basal delivery”) and instantaneous bursts of drug (“bolus delivery”) as required. In particular, in patient controlled analgesia or PCA, it may be advantageous to provide a continuous basal infusion of drug for chronic pain treatment, supplemented to a certain extent by bolus delivery. The bolus delivery would be activated by the patient to deal with increased temporary pain levels (“break-through pain”), with safeguards being incorporated to prevent overdosing.
- Another area in which precisely controlled dosing can be particularly indicated is in chronotherapeutic drug delivery, in which the drug delivery rate varies over time. Most notably, diurnal or circadian rhythms cause variations in the amounts of certain drugs required by a patient during a 24-hour period. This is most notably required to combat variations in disease and/or condition effects throughout a 24-hour cycle.
- For example, hypertension crises, angina, and sudden cardiac death are most likely to occur in the morning, whereas sickle cell crises and perforated ulcer crises are most likely to occur in the afternoon. The concept of chronotherapeutics is discussed in more detail in an article by Smolensky & Labrecque, Pharmaceutical News 4, No. 2, 1997, pp. 10-16. The discussion in this article is principally in terms of conventional oral dosing of drugs to take account of chronotherapeutic variations in drug uptake, effects, and requirements, but many of the principles are applicable to other delivery routes. Circadian rhythm applications would also apply to hormonal therapies.
- Accordingly there is a need to provide a drug delivery device capable of regulating drug delivery dosages to provide increased dosages at the times when such dosages are more likely to be required. This gives rise to a need for a device in which the delivery rate is accurately controllable over a wide range of delivery rates. In general, devices which are designed to deliver small amounts of drug are not particularly suitable for high drug delivery rates without being specifically adapted in this regard, and vice versa. Moreover there is a need to provide such a device that is relatively compact so that it is fixed to the user during use and disposed of when the treatment is finished. Such a device must be also relatively inexpensive to manufacture yet maintain accurate and reliable delivery rates
- The present invention aims to provide improved drug delivery devices in which smaller volumes of liquid can be delivered more accurately than in prior art devices, thereby giving rise to overall more controlled delivery rates. The invention also aims to provide such devices which additionally allow higher delivery rates to be provided on demand, up to and including bolus delivery. Moreover, the present invention provides for a drug delivery device wherein the technology used to provide for accurate delivery rates is relatively easy and inexpensive to manufacture. Further, the present invention employs designs for the gas generating system and delivery system so that space within the device is minimised and parts used within the device are easy and inexpensive to manufacture while maintaining high tolerances. In addition, the present invention provides for a certain amount of gas leakage while delivering accurate dosages. This eliminates the need for costly sealing devices and systems which increase cost and decrease reliability in the event of gas leakage.
- The invention provides a drug delivery device having a housing containing a drug reservoir, and means for facilitating the expulsion of drug from the drug reservoir. The device also includes a mechanism in communication with the facilitation means, that incrementally advances and thereby drives the drug from the reservoir, and a member associated with the mechanism to cause the incremental advancement of the mechanism as the member moves in a first direction. The device also includes a gas generator located within the housing and operable to expand in a chamber. The member is in transmission relation to the chamber. In operation, the member is driven by the movement of the chamber to advance the mechanism and thereby drive the drug from the reservoir in incremental fashion.
- Preferably, the mechanism in communication with the facilitation means comprises a ratchet.
- Further, preferably, the member moves in a reciprocable fashion.
- Further, preferably, the movement of the reciprocable member causes the stepwise advancement of the mechanism.
- Further, preferably, the reciprocable member is connected to a wall of the chamber, whereby the reciprocation of the reciprocable member is driven by the expansion and contraction of the chamber.
- The preferred devices according to the invention take advantage of the reciprocation of a gas generation chamber to effect a stepwise advancement of a ratchet mechanism. Gas generation chambers which expand and contract repeatedly are advantageous over known chambers which simply expand over time. For example, a ratchet which has 100 teeth and is driven by a continuously expanding gas chamber will advance one step for every 1% increase in the chamber volume. According to basic gas laws, a temperature rise of only 3° C. will increase the volume of a gas at room temperature by 1%. Thus, towards the end of the chamber expansion, a temperature rise of 3° C. will drive the ratchet one step forward independently of the gas generation rate. In contrast, a chamber which reciprocates will undergo a full expansion for each stepwise advance of the ratchet mechanism, and a 1% variation in the volume of this chamber will have no material effect on the fact that the chamber will expand fully and advance the ratchet correctly.
- For example, a ratchet mechanism which undergoes 100 stepwise advances throughout the emptying of a reservoir. If this ratchet is driven by a continuously expanding gas chamber, a 1% increase in the volume of gas towards the end of the delivery period will advance the ratchet by an (undesired) extra step. Such a 1% expansion occurs with a temperature change of only 3° C. (which is approximately 1% of the room temperature when expressed in kelvins). The situation is worse for devices which require several hundred ratchet advances to ensure the necessary sensitivity for accurate delivery over an extended time period.
- In contrast, devices according to the present invention employ a reciprocating chamber which continually expands and contracts. This enables small-volume chambers to be employed such that the difference in volume between the contracted and expanded states is orders of magnitude greater than the change in volume arising from environmental temperature changes. Moreover, by employing a reciprocating chamber, less space is needed for the chamber as the volume at maximum expansion is considerably less that what would be required for a continuously expanding chamber at the maximum volume of expansion.
- Preferably, the chamber is elastically biased to revert to a contracted state, and wherein a venting means is provided to enable contraction of the chamber after gas generation has expanded the chamber.
- One advantage of using a reciprocity chamber to drive a reciprocating mechanism linked to a ratchet is that there is sufficient amplitude of movement in the reciprocation to advance the ratchet by the required number of steps (in many cases only one step), to ensure that venting is sufficiently thorough to relax the system completely, in order to arrive at a device in which the delivery rate is controlled to a high degree of accuracy.
- For example, if the delivery volume is low (equivalent to a single stepwise ratchet advance) every five minutes, then the gas generator can be designed to deliver a sufficient amount of gas within one minute, and then switch off automatically for four minutes. In the first minute, the ratchet will be caused to advance by the required “tooth” (or equivalent), and then the venting means is actuated to relax the system. By the end of four minutes the system will be fully relaxed and the cycle can begin again.
- This design automatically compensates for any inaccuracies in the performance of its driving mechanism. Thus, the gas generator can be designed to deliver e.g. 20%±10% more than the required volume of gas (i.e. not a particularly expensive or accurate system), and still to have an extremely accurate delivery for the following reason. If the gas generator generates between 10% and 30% too much gas on each cycle, the ratchet will advance by a single “tooth”, but it is equally certain that it will not be pushed to advance by a second tooth. Thus, when the gas generation ceases, a certain amount of controlled overpressure or stress will be present in the system, but the amount of drug delivered will be precisely known. Then when the gas is vented, the overpressure is released and the system returns to equilibrium. Thus, the accuracy of delivery at the end of the five minute cycle is independent of whether the generator generated 10% or 30% too much gas.
- It should be noted that the accuracy of the system is controlled by the tolerances of the ratchet mechanism, the timer, the reciprocity chamber, the venting system and the gas generator.
- In some embodiments, the venting means is passive and allows escape of gas therethrough when the chamber is pressurised relative to atmospheric pressure. In other embodiments, there is designed to be venting means within the gas generator. Such venting means may connect sub-chambers within the gas generating means. The venting means enables the sub-chambers to increase and decrease pressure therein more efficiently.
- In some embodiments, the gas generator is adapted to generate gas at a rate higher than the venting rate. When the gas generator is active, the chamber becomes pressurised and expands, and when the gas generator is inactive, the venting means causes depressurisation and contraction of the chamber. Minor leaks in the system, provided that they are not so serious as to prevent the chamber from fully pressurising, do not have any significant effect on the operation or accuracy of the device. This enables a gas generating system to deliver extremely small volumes of drug in a highly controlled, accurate manner, without employing any elaborate gas generation system, or any special leakproofing of the gas chamber. Also, the gas generation rate should exceed the venting rate so that the error of movement of the reciprocator member errs to the side of excessive pressure rather than too little pressure. If there is insufficient pressure (i.e. caused by the leakage rate exceeding the pressurisation rate, the force needed to move the reciprocating member will be insufficient and the pawl on the ratchet will not move. Thus, the volume of drug wilt not be advanced through the cartridge and delivered to the user.
- In alternative embodiments, the gas pressure of the gas generator is divided between at least two cells. A first cell has a more permeable member and is designed for minimum gas leakage. The first cell also has a controllable vent associated therewith. The vent allows excess gas to escape from the first cell but prevents the escape of gas at a stage in the cycle when the member of the first cell is needed to deflect so as to cause forward movement of the ratchet. The alternative embodiment is also designed so that the latter part of the cycle allows the re-opening of the first cell vent to enable gas therein to quickly escape and cause the member to return to its initial resting position.
- In some preferred embodiments, the venting means comprises a permeable or semi-permeable member. Currently one of the most preferred member is a silicone membrane. In another embodiment, there are at least two members with varying permeability. The less permeable material is preferably bromo-butyl, ethylene propylene or EPDM, and the more permeable member is preferably silicone rubber.
- Suitably, the mechanism is caused to advance as the chamber undergoes expansion. Alternatively, the mechanism may be caused to advance as the chamber undergoes contraction. While it is possible to employ a mechanism which drives the ratchet forward during both expansion and contraction strokes, it is preferred to employ a single driving stroke (either contraction or expansion) during a reciprocation cycle for lower delivery rates.
- Suitably, the member comprises a lever extending between the chamber and the mechanism.
- The use of a lever mechanism enables the amplitude of movement of the expanding chamber to be accurately converted to the correct amplitude of movement to drive the ratchet.
- In certain preferred embodiments, the mechanism comprises a rigid ratchet element having spaced formations on a surface thereof.
- Preferably, the formations have a sawtooth cross section, although the formations may be in the form of grooves on a surface of the rigid ratchet element.
- Preferably, the mechanism includes a pawl carried on the member, the pawl being adapted to make ratcheting engagement with the formations on the rigid ratchet element.
- Further, preferably, the pawl is resiliently biased against the formations on the rigid ratchet element.
- Suitably, the pawl is in the form of a substantially flat spring an end of which bears against the formations on the rigid ratchet element.
- Such a pawl is adapted to allow the ratchet element to slide with little resistance in one direction but to prevent any movement in the opposite direction.
- In preferred embodiments, the formations are regularly spaced along the rigid ratchet element, and the pawl comprises a pair of pawl members resiliently biased against the rigid ratchet element at different points along the length of the rigid ratchet element, the axial distance between the pair of pawl members being different to the axial distance between successive formations.
- The advantage of this arrangement is that by locating the ratcheting linkage between the pawl and the ratchet teeth, the teeth make alternating contact with either pawl member. The ratcheting member advances by increments which are less than the actual difference between successive formations on the ratchet.
- In particularly preferred embodiments, the distance between successive formations is twice the distance between the pawl members. This means that then the ratchet advances in half steps and enables accurate delivery of even smaller incremental volumes of drug (if a full step is counted as equating to the distance between successive ratchet teeth formations.)
- The definitions of “half steps” and “full steps” is not as arbitrary as it may appear, since one of the main constraints on the accuracy of delivery of small volumes, as explained above, is the manufacturing tolerances of the ratcheting teeth.
- It is envisaged that one of the least expensive ratcheting mechanisms, and therefore one of the most suitable for large scale production, is a stamped plastics ratchet bar having a sawtooth surface, against which a pawl in the form of a leaf spring may be biased. The main limitation on accuracy in this system is likely to arise from the spacing of adjacent sawtooth formations which may not be able to be made accurately with the required spacing. In such cases the minimum delivery volume, all other things being equal, will be limited by this component. However, by employing a specially designed pawl or leaf spring (which can be made to much higher tolerances from metal materials at relatively low cost), accuracy is doubled, and the minimum deliverable volume may be halved.
- In alternative embodiments, the ratchet teeth are regularly spaced along the rigid ratchet element, and the pawl comprises three or more members resiliently biased against the rigid ratchet element at regular intervals along its length. The axial distance between each successive pair of pawl members is chosen to be different to the axial distance between successive ratchet teeth.
- Suitably, in such cases, the distance between successive ratchet teeth is given by the number of pawl members multiplied by the distance between each successive pair of pawl members.
- Thus, by analogy with the two pawl members spaced at half of the distance between successive ratchet teeth, three or four pawl members would preferably be spaced at intervals of a third and a quarter, respectively, of the distance between successive ratchet teeth on the ratchet element.
- Suitably, the pawl is in the form of a resilient member which terminates in a plurality of fingers biased against the ratchet element.
- A preferred embodiment in this regard is a pawl which comprises a flat spring which is partly split to define fingers of different lengths.
- In another preferred embodiment, the ratchet element comprises a helical spring and the pawl comprises one or more fingers which engage with the coils of the spring. The coils of a helical spring easily engage with the pawl fingers, and the regular spacing of the coils of a helical spring enable it to be used as a ratchet element.
- A further advantage of this embodiment is that the size of the device can be minimised by taking advantage of the flexibility of the spring. Thus, whereas a rigid ratchet bar protruding from a drug cartridge before use might provide an unacceptably long device for certain applications (after use, the ratchet element might be partly or totally accommodated within the empty cartridge interior), a helical spring can be bent to be parallel with the cartridge to reduce the overall length.
- Preferably, in embodiments which employ a helical spring in lieu of a ratchet element, one or more fixed fingers are mounted in fixed position relative to the housing, and one or more reciprocable fingers are mounted on the mechanism, such that when the one or more reciprocable fingers move in a first direction they engage the coils of the helical spring to drive the helical spring in the first direction, and when the one or more reciprocable fingers move in an opposite direction, the one or more fixed fingers engage with and hold the coils of the helical spring preventing it being driven back in the second direction, whereby the fixed and reciprocable fingers co-operate to drive the helical spring in one direction only.
- The operation of this embodiment will become clearer from the description below. The fingers are generally arranged such that the helical spring is forced to alternately slip past the fixed fingers and the reciprocable fingers, which gives rise to a uni-directional driving movement. Suitably, each finger is inclined in the first direction. This makes it easier for the helical spring coils to slip past the fingers in this direction, and more difficult for the coils to push back in the opposite direction against the fingers.
- Preferably, the position of the one or more fixed fingers relative to the one or more reciprocable fingers is such that the helical spring is driven by the reciprocable fingers towards the fixed fingers.
- This feature helps prevent a situation which may develop in which a flexible helical spring is pulled by the reciprocable fingers away from the fixed fingers, but rather than slipping past the fixed fingers, the helical spring merely stretches, such that when the reciprocating fingers move back towards the fixed fingers the helical spring simply relaxes, without any net movement having taken place. The solution to this problem is achieved in part by pushing the helical spring towards the fixed fingers as the driving step of the delivery action.
- Suitably, the minimum distance between the fixed and reciprocable fingers, respectively, is not greater than ten times the distance between adjacent coils of the helical spring when the helical spring is in a relaxed position. Preferably, this minimum distance between the fixed and reciprocable fingers, respectively, is not greater than five times the distance between adjacent coils of the helical spring when the helical spring is in a relaxed position, most preferably not greater than twice the distance between adjacent coils.
- The reason for this again relates to the problem of using a flexible spring which is likely to stretch rather than be displaced. While the problem could be overcome by using a sufficiently stiff spring, this would defeat the purpose of using this type of spring, which is to allow the ratchet element to be bent within the housing to reduce overall dimensions. While even a stiff spring can be bent under sufficient force, this tends to generate frictional forces which would prevent the spring from sliding past the ratchet fingers.
- Instead, setting the two sets of fingers close together allows even a relatively very flexible spring to be used without much stretching, since for a given overall amount of stretching, a greater stiffness is achieved by concentrating this stretching over just a few coils.
- Thus, in certain preferred embodiments, the minimum distance between the fixed and reciprocable fingers, respectively, is approximately equal to the distance between adjacent coils of the helical spring when the helical spring is in a relaxed position.
- Suitably, the mechanism comprises a flexible ratchet element which is sufficiently stiff to drive medicament from the chamber when driven by the member, and sufficiently flexible to be bent before it meets the member, whereby the overall length of the device is reduced relative to a device in which a rigid ratchet element protrudes linearly from the mechanism before use. Thus, the flexible member may be, for example, a piece of bendable thermoplastics stamped or molded with a ratchet sawtooth profile.
- In order for this embodiment to be useful, the flexible member should have a degree of flexibility which allows it to be bent sufficiently to reduce the overall dimensions of the device. Furthermore, it must nevertheless be sufficiently stiff to transmit the driving force of the ratcheting mechanism without buckling or distorting to any great extent. This can be achieved by restraining the degree of freedom of movement of the member.
- For example, by driving a flexible member into a conduit in which the flexible member makes a good fit, the flexible member is prevented by the conduit walls from bowing or buckling sideways. Thus, when driven by the ratchet mechanism the flexible member is constrained to transmit the driving force to the piston, and despite its flexibility it acts as a drivable piston rod. Other mechanisms not requiring a restraining conduit are also possible, as described below.
- Preferably, the mechanism comprises two or more co-operating flexible ratchet elements which are individually sufficiently flexible to be bent before they meet the member but when joined together are together sufficiently stiff to drive medicament from the chamber when driven by the member.
- Further, in a preferable embodiment, the two or more co-operating flexible ratchet elements are bent away from one another before they meet the member.
- Suitably, the device according to the invention further comprises electronic control means for controlling the delivery rate. Preferably, the electronic control means comprises a timing mechanism which alternately energises and de-energises the gas generating mechanism for controlled periods.
- As explained above, by choosing an energized period long enough to always guarantee complete advancement of the ratchet mechanism by a predetermined number of steps, and by providing a de-energised period (e.g. for venting) which allows relaxation of the system, the amount of drug delivered in this overall cycle is accurately controllable independently of variations (within reason) in the gas generation rate.
- Furthermore, the use of a timer allows the overall cycle length to be varied in a controlled manner over time, thereby providing an accurately controllable device which delivers at a time-varying rate. Such devices find a particular application in the field of chronotherapeutics.
- Further, preferably, the electronic control means is programmable for different delivery programs. The control means may be user-programmable or a single unit may be factory-programmable for different delivery regimes (e.g. for different drugs. Preferably, the device according to the invention further comprises means for manually adjusting the delivery rate. This allows for a certain degree of flexibility which might be desirable where the user can safely have an amount of control over the treatment. Alternatively, it can be set by the physician or pharmacist and disabled to prevent patient interference.
- In preferred embodiments, the member reciprocates to cause the incremental advancement of the mechanism and the means for manually adjusting the delivery rate comprises means for limiting the travel of the member, whereby the volume of drug delivered on each reciprocating stroke is controllable. Thus, a simple advancing screw can control a stop against which any reciprocating element ends its travel. If this is used, adjustment of the screw will provide a control mechanism. For example, a device could be designed with three delivery rates, namely low, medium and high, corresponding respectively to one, two and three ratchet advancements per reciprocation. A simple mechanism would determine how far the reciprocating mechanism is allowed to advance on each stroke, to determine the delivery rate. Clearly, more sophisticated embodiments could also be achieved. Devices having the ability to deliver bolus doses of drug are preferred in therapies such as patient controlled analgesia.
- In a preferred embodiment, the means for manually adjusting the delivery rate provides the user with the ability to deliver a bolus dose of drug. It is advantageous if the bolus dose can be delivered without this interfering with the normal basal delivery rate.
- When the reciprocating mechanism comprises a lever arrangement, it is preferred that the means for manually advancing the mechanism comprises means for manually advancing the lever extending between the chamber and the mechanism, operable from the exterior of the housing. Any suitable mechanism, such as a knob, button or lever can be used to operate the lever.
- Preferably, the mechanism comprises a ratchet and wherein the means for manually advancing the mechanism comprises a pawl which is manually reciprocable from the exterior of the housing.
- Further, preferably, the mechanism for manually advancing said lever is provided with gradations corresponding to a number of stepwise advances of the ratchet mechanism.
- For example, in delivering insulin, the advancing means could be marked in units which would be understood by the patient, and the scale would be calibrated to correspond to the delivery of the correct dose.
- In a further aspect, the present invention provides a method of delivering drug to a patient. The method includes affixing a drug delivery device to the surface of the patient's skin. The drug delivery device having a housing containing a drug reservoir, means for facilitating expulsion of drug from the drug reservoir, a mechanism in communication with the facilitation means, operable to undergo incremental advancement and thereby drive the drug from the reservoir, a member operatively associated with the mechanism to cause the incremental advancement of the mechanism as the member moves in a first direction, and a gas generator located within the housing and operable to expand in a chamber, the member being in transmission relation to the chamber. The method further includes activating the device whereby the member is driven by the movement of the chamber to advance the mechanism and thereby drive the drug from the reservoir in incremental fashion.
- Other objects, features and advantages of the present invention will become apparent upon reading the following detailed description, when taken in conjunction with the drawings and appended claims.
- The invention will be now be described with reference to the accompanying drawings, which illustrate the preferred embodiments of the present invention and in which:
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FIG. 1 is a sectional plan view of a first embodiment of a drug delivery device according to the invention; -
FIGS. 2-5 are schematic views of a detail of the embodiment ofFIG. 1 shown at successive points in the operating cycle; -
FIG. 6 is a sectional plan view of the embodiment ofFIG. 1 , in use; -
FIGS. 7-11 are sectional side views of a second embodiment of a device according to the invention, shown at successive points during its use; -
FIG. 12 is a simplified sectional plan view of a third embodiment of a drug delivery device according to the invention; -
FIG. 13 is a cross sectional side view of the embodiment ofFIG. 12 , taken along the line XIII-XIII; -
FIG. 14 is a sectional plan view of a fourth embodiment of a drug delivery device according to the invention; -
FIG. 15 is a cross sectional side view of the embodiment ofFIG. 12 , taken along the line XV-XV; -
FIG. 16 is a graph showing the test results of an 80 hour test which plots delivery pressure and amount of drug delivered against time; -
FIG. 17 is an enlarged detail of a portion of the graph ofFIG. 16 ; -
FIG. 18 is a sectional plan view of a fifth embodiment of a drug delivery device according to the invention; -
FIG. 19 is a sectional side view of the embodiment ofFIG. 18 ; -
FIG. 20 is a sectional plan view of the embodiment ofFIG. 18 , as it is being prepared for use; -
FIG. 21 is a sectional side view of the embodiment ofFIG. 18 when ready for use; -
FIG. 22 is a sectional plan view of a sixth embodiment of the drug delivery device according to the invention; -
FIG. 23 is a sectional plan view of the embodiment ofFIG. 22 when ready for use; -
FIG. 24 is a cross-sectional view along line A-A of the embodiment ofFIG. 22 ; -
FIG. 25 is a cross-sectional view along line B-B of the embodiment ofFIG. 22 ; and -
FIG. 26 is a schematic drawing representing the various parts of the gas generation sub-assembly of the embodiment ofFIG. 22 . - Referring now in more detail to the drawings, in which like numerals indicate like parts throughout the several views, in
FIG. 1 there is indicated, generally at 10, a drug delivery device according to the invention. Thedevice 10 comprises ahousing 11 containing acartridge 12 filled with adrug 13. Thecartridge 12 is provided with aneedle 14 extending from afirst end 15 of the cartridge for delivery ofdrug 13 to a patient. Apiston 16 is slidably received in thecartridge 12, such that when thepiston 16 is pushed towards thefirst end 15, drug is forced from thecartridge 12 out through theneedle 14. - The
piston 16 is mounted on aratchet bar 17 which is driven by apawl 18 mounted on areciprocable lever 19.Lever 19 is mounted on anaxis 20 at oneside 21 and is connected to a drivingrod 22 at theother side 23, whereby reciprocation of the drivingrod 22 causes pawl 18 to reciprocate with respect to theratchet bar 17. As will be explained in greater detail below, this causes theratchet bar 17 to advance stepwise towards thefirst end 15 ofcartridge 12 and thereby drive thedrug 13 from the cartridge. - The driving
rod 22 is in connection with aflexible diaphragm 24 which defines a wall of agas generation chamber 25. Abattery 26 is connected via amicroprocessor 27 to anelectrolytic cell 28 which is operable to generate a gas intochamber 25. When gas is generated, the chamber expands and causes thediaphragm 24 to move. This movement pushes the drivingrod 22 in the direction away from thefirst end 15 ofcartridge 12. The movement is opposed by areturn spring 29 which biases thelever 19 towards thefirst end 15. After a certain period of time thechamber 25 is fully expanded and the supply of current from thebattery 26 to theelectrolytic cell 28 is switched off by themicroprocessor 27. - A
silicone membrane 30 defines a wall of thechamber 25. Themembrane 30 is slightly permeable and thus allows a controlled leakage of gas from thechamber 25. When thechamber 25 is in its expanded state, the force ofreturn spring 29 will act to decompress thechamber 25 by gas leaking throughmembrane 30. After thechamber 25 has fully decompressed in this manner, thelever 19 and hence thepawl 18 will have made one complete reciprocation thereby advancing theratchet bar 17 by a fixed step. - For example, the cycle might be chosen to allow the delivery of a quantity of drug corresponding to the advancement of a single step of the
ratchet bar 17 every five minutes. In such a case theelectrolytic cell 28 could be switched on for one minute and then switched off for four minutes. As long as the timing of the microprocessor is accurate, this will ensure that precisely one stepwise advance is made in that five minute period. - The precision of
device 10 is to a certain extent independent of the exact quantity of gas generated because theratchet bar 17 is quantised, i.e. it can only move by a fixed step (or number of steps) at a time. Similarly, because themembrane 30 provides a controlled constant leakage from the system even during gas generation, other minor leaks which might affect the accuracy of conventional gas driven delivery devices are not important (although of course if the leak is bad enough the chamber will be unable to pressurise fully when the gas is generating). - It will be noted from the first embodiment shown in
FIG. 1 thatpawl 18 is split in two halves, i.e. alonger half 31, and ashorter half 32. Thepawl 18 is a leaf spring which is biased down ontoratchet bar 17. Thehalves pawl 18 are of unequal length. -
FIG. 2 shows a cross-sectional enlarged view of a portion of theratchet bar 17 which has a series of evenly spaced steps orteeth halves pawl 18 is exactly half of the distance betweenadjacent teeth ratchet bar 17. It can be seen that eachtooth surface 35 having apeak 36 and atrough 37, as shown in detail inFIG. 2A . At the point of the cycle illustrated inFIG. 2 , thelonger half 31 of thepawl 18 presses against the slopedsurface 35 oftooth 33, midway between the peak 36 andtrough 37, and theshorter half 32 presses against thetrough 37 of theadjacent tooth 34. - When gas is generated to drive the driving
rod 22 in the direction away from thefirst end 15 of cartridge 12 (seeFIG. 1 ), the twohalves FIG. 1 ) move left as viewed inFIG. 2 . This results in the situation shown inFIG. 3 , in which theshorter half 32 has been pushed back up the slopedsurface 35 oftooth 34, and thelonger half 31 has passed thepeak 36 oftooth 33 to rest in thetrough 37 ofadjacent tooth 34 formerly occupied by theshorter pawl half 32. In practice, the distance travelled by thepawl 18 will be slightly further than the minimum necessary so as to allow for any variations between components. This does not affect the operation of the invention as a whole since thepawl 18 when making its return stroke will press against the correct tooth as it begins its travel. - After the
gas generation chamber 25 is pressurised fully and thedevice 10 is in theFIG. 3 position, gas generation ceases and the controlled leakage from thechamber 25 allows thereturn spring 29 to push thelever 19 back to its starting position, leading to the configuration shown inFIG. 4 . - In
FIG. 4 , thelonger pawl half 31 when being driven forward (i.e. - to the right) has abutted against
tooth 33 and pushed theratchet bar 17 forward. This completes one reciprocation of thepawl 18, and when theelectrolytic cell 26 again fills thegas generation chamber 25 to drive thepawl 18 to the left (as seen inFIG. 5 ), theshort pawl half 32 passes over thepeak 36 oftooth 34 as shown inFIG. 5 , ready to push againsttooth 34 and thereby once again advance theratchet bar 17. - The reason for using a pawl in two halves of unequal length is seen by observing the movement of a
point 38 on the ratchet bar. After a complete cycle has been completed, i.e. fromFIG. 2 toFIG. 5 , thepoint 38 has moved by a distance ½ L. This is exactly half of the length L of one of theteeth ratchet bar 17, as can be seen with reference toFIG. 2A . - In effect this means that although the manufacturing quality and tolerances are such that the tooth length is not as small as what would be desired (perhaps because the manufacturing technique, chosen for its cost effectiveness, is incapable of achieving a smaller length of adjacent teeth), it is nevertheless possible to deliver amounts of drug corresponding to an advance of half of the length of one of the
teeth -
FIG. 6 shows the device ofFIG. 1 in operation at the completion of gas generation, and before thelever 19 has begun its return stroke. Thus, it can be seen thatgas generation chamber 25 has expanded by pushing thediaphragm 24 outwards, and thelever 19 is thus pivoted on itsaxis 20 against the force of thereturn spring 29. When thelever 19 is driven back to theFIG. 1 position, a small volume ofliquid drug 13 will be forced from thecartridge 12. - Because the device of
FIG. 1 delivers small volumes in a stepwise fashion, it is possible to achieve an extremely low delivery rate. For example instead of operating in 5-minute cycles, thegas generator 25 could be activated for 1 minute as previously described and then switched off for 59 minutes to give cycles of one hour duration. Unlike other gas-driven devices which cannot achieve these long-term low-volume rates because of pressure losses in the system, thedevice 10 of the present invention does not require a system pressure to be maintained above atmospheric pressure. - As can be seen from
FIGS. 1 and 6 , the volume of thegas generation chamber 25 is small relative to the size of the device. This minimises variations in the volume of gas per stroke, and helps ensure a constant delivery rate. Preferably, thedevice 10 will generate in excess of 10-30% volume of gas over the required amount on each stroke so that the device can compensate of variations due to temperature, atmospheric pressure, materials used, etc. (The device will never drive the ratchet 10-30% further than necessary, since the ratchet can only move in fixed steps.) This extra gas is stored as an overpressure in the system and is of course released during the venting part of the cycle. -
FIG. 7 shows a cross-sectional side view of a second alternative embodiment of the present invention, indicated generally at 50. Thedevice 50 is similar in most respects to the first embodiment shown inFIG. 1 . In the device ofFIG. 7 , however, thepawl 51 is not split into two halves, so that it advances theratchet bar 52 by full steps equal to the tooth length (“L”). In all other respects thedevice 50 is identical to thedevice 10 ofFIG. 1 . It can be seen fromFIG. 7 that theneedle 53 of the device 50 (as with theFIG. 1 device) is bent at 90° to the axis of thecartridge 54. - The
device 50 ofFIG. 7 is shown before use. Aprotective sheath 55 is provided on theneedle 53 and a displaceablelower cover 56 is hinged to themain housing 57 by a hinge (not shown). The displaceablelower cover 56 and themain housing 57 are prevented from moving relative to one another by asafety tab 58. Thelower surface 61 of thedisplaceable cover 56 is covered by a contact adhesive which is protected before application to the user by aprotective liner 60. Theliner 60 has apull tab 59 to ease removal of the liner by the user immediately before application of thedevice 50. - Before use, the
protective sheath 55 is removed as indicated inFIG. 8 by grasping and pulling thepull tab 59. This also causes therelease liner 60 to be pulled away revealing the contact adhesive on thelower surface 61 of thedisplaceable cover 56. Thelower surface 61 is adhered to the user's skin. Then, thesafety tab 58 is pulled away from thedevice 50 as shown inFIG. 9 . - As shown in
FIG. 10 , themain housing 57 is then pressed towards the skin whereupon it snaps towards thedisplaceable cover 56. Theneedle 53 projects beyond thelower surface 61 to penetrate into the skin for subcutaneous drug delivery. - The delivery mechanism is then actuated, either by the user, or more preferably, in automatic fashion by the microprocessor. Upon activation either manually or automatically, the
ratchet bar 52 is advanced by thepawl 53 in stepwise manner as described above with regard to the operation of the first embodiment as shown inFIG. 1 . - When delivery is completed (see
FIG. 11 ) the user can see thepiston 62 through anaperture 63 in themain housing 57 as shown in FIG. - 11. The
main housing 57 is then pulled away from the skin whereupon it snaps away from thedisplaceable cover 56 and locks in this position by a locking mechanism (described in more detail in our U.S. Provisional Application No. 60/045,745) which prevents further actuation of the device, i.e. prevents theneedle 53 from projecting beyond thedisplaceable cover 56 due to further relative movement of themain housing 57 and thedisplaceable cover 56. - In
FIG. 12 there is indicated, generally at 70, a further embodiment of a device according to the invention. In the illustration of this embodiment, only those details necessary to understand the differences relative to the devices of the first and second embodiments are shown, and thus the gas generation mechanism, for example is not shown. - In the device of
FIG. 12 , the ratchet bar has been replaced by ahelical spring 71. Alever 72 is caused to reciprocate in identical manner to that previously described. A pair of resilientreciprocable fingers 73 are mounted on thelever 72 and reciprocate as the lever reciprocates. Thesereciprocable fingers 73 are inclined in the direction of movement of thepiston 74 as it empties thecartridge 75. Thus, when they move in the direction in which they are inclined they tend to grip and push the coils of thehelical spring 71 forward. As thehelical spring 71 moves forward it slips past a pair of resilient fixedfingers 76 mounted directly in front of thereciprocable fingers 73, and inclined in identical manner. - When the
lever 72 moves away from the piston 74 (as the gas generator generates the gas) thehelical spring 71 is prevented from moving back because it is gripped by the fixedfingers 76. Thereciprocable fingers 73 thus slip over the coils of thehelical spring 71. When thelever 72 reverses its travel again thehelical spring 71 is again gripped and pushed forward by thereciprocable fingers 73. -
FIG. 13 shows a sectional side view of the device taken along the line XIII-XIII (inFIG. 12 ), in which the fixedfingers 76 andhelical spring 71 are visible. - Thus, the arrangement of
reciprocable fingers 73 and fixedfingers 76 act as a pawl and thehelical spring 71 acts as a ratchet, such that on each reciprocation of thelever 72, thehelical spring 71 advances by an amount equal to a set number of coil diameters. Accordingly, as with previously described embodiments, precisely controlled delivery rates are achievable, and in particular, extremely low volume delivery rates are possible with this invention. - While there is a tendency for the
helical spring 71 simply to stretch between thereciprocable fingers 73 and the fixedfingers 76, this tendency can be overcome by choosing the correct stiffness (for both sets of fingers). Furthermore, the closer together thereciprocable fingers 73 andfingers 74 are mounted, the less likely thehelical spring 71 is to stretch, since the force is spread over fewer coils. - One advantage of this embodiment is that because the
helical spring 71 is curved within thedevice 70, it does not have to project directly out of thecartridge 75 and thus a shorter device can be realised, or the shape of the device can be varied as required. - A further embodiment of the present invention is shown in cross-sectional plan view in
FIG. 14 . The device, indicated generally at 80, is in many respects identical to the device ofFIG. 1 but differs in that as well as the gas-drivenlever 81, a secondmanual lever 82 is provided.Manual lever 82 is mounted on acommon axis 83 with gas-drivenlever 81, as can be seen referring additionally toFIG. 15 .Manual lever 82 passes under theratchet bar 84 and also carries asecond pawl 85. Both theupper surface 86 andlower surface 87 ofratchet bar 84 are provided with ratchet teeth, so that either gas-drivenlever 81 ormanual lever 82 can drive theratchet bar 84 forward. - Thus, in normal operation, gas-driven
lever 81 will drive the drug from the cartridge 88, and in this mode, theratchet bar 84 simply slides past thepawl member 85 onmanual lever 82 as described previously. However, if a bolus dosage of drug is required at any point in time, themanual lever 82 can be actuated to advance theratchet bar 84 by a pre-determined number of teeth. Referring toFIG. 14 , themanual lever 82 can be seen to have an adjustable threaded lockingmember 89 which determines the extent of travel of themanual lever 82, and hence the volume of the bolus delivery. InFIG. 14 , thelever 82 is prevented from travelling because the threadedmember 89 is fully torqued, and this locks thelever 82 preventing it from being actuated. However, if the threadedmember 89 is partially torqued and thereby partially withdrawn from the housing in the axial direction, thelever 82 is free to move inwards by an amount equal to the distance of axial travel of the threadedmember 89. Thelever 82 can then be actuated by depressing the threadedmember 89. The degree of travel of thelever 82 is determined by the extent to which the threadedmember 89 is turned, and by providing marked gradations on the threadedmember 89 one can give the user visual control over the volume delivered in such a bolus dosage. - The movement of the
ratchet bar 84 under the action of thesecond pawl 85 is independent of the primary pawl-and ratchet mechanism. Thus, thesecond pawl 85 will, when actuated manually, advance theratchet bar 84 by a whole number of steps. When advanced in this way, theratchet bar 84 slides under thepawl member 90 on gas-drivenlever 81, but this has no effect on the basal delivery rate or on the operation of the gas-drivendelivery mechanism 80. Thus, each individual ratchet mechanism is independent of the other, and bolus delivery can take place against the background basal rate without complication. -
FIG. 16 is a graph of typical results achieved in a test of a device according to the invention, of the design shown inFIG. 1 . The graph shows two lines, namely the cumulative delivery of drug against time (the stepwise steadily ascending line), and the delivery pressure against time (the line consisting of a succession of sharp peaks and troughs). - It can be seen that the device was tested over an 80 hour period (more than 3 days) and delivered just under 1.35 grams of drug solution in this time. This gives a delivery rate of less than 17 μg/hour. Furthermore, this delivery rate is absolutely constant, i.e. shows no deviation from a straight line. Accordingly, the device of
FIG. 1 has a delivery rate whose accuracy is unmatched in the prior art, particularly for extremely slow delivery rates. -
FIG. 17 shows a portion of the graph ofFIG. 16 in greater detail, over a five hour period in the middle of the test. It can be seen that the pressure on each cycle immediately shoots up to a maximum, and then slowly falls off as gas is released through the silicone membrane. - It can be seen that the delivery overpressure reaches over 400 mbar (0.4 atm or 40 kPa) on each cycle, and this assists in providing a constant delivery rate, since any minor needle blockages will be forced out, and variations in blood pressure (when intravenous delivery is effected will have a negligible effect on the delivery rate. This is to be contrasted with other low volume pumps which generally achieve low delivery rates with low delivery pressures.
- A further alternative embodiment is illustrated in
FIG. 18 . The device, indicated generally at 100, has ahousing 101 containing aninternal needle 102 connected via a length offlexible tubing 103 to a delivery needle 104 (seen in sectional side view inFIG. 19 ). As with previously illustrated embodiments,delivery needle 104 is protected by asheath 105 before use.Internal needle 102 is also protected by asheath 106 which is provided with atab 107 extending the length of aninternal bore 108 to the exterior of thehousing 101. -
Flexible tubing 103 is carried on aratchet bar 109 which can be driven to move theinternal needle 102 in the direction of theinternal bore 108. It can be seen fromFIG. 19 that aleaf spring 110 acting as a pawl is carried on alever 111 to drive the ratchet bar in the manner previously described. Referring back toFIG. 18 , thelever 11 is driven by the expansion and contraction of anelectrolytic cell 112 which is powered bybatteries 113. -
FIG. 20 shows a step in the preparation ofdevice 100 for use. Theinternal sheath 106 has been removed and is no longer visible, thereby exposing internal needle which is in the centre of acylindrical cup 114. Adrug cartridge 115 is provided in the form of acylindrical container 116 sealed at itsopen end 117 by apiston 118 slidably received in thecontainer 116.Bore 108 is dimensioned to receivecartridge 115, and a pair ofresilient projections 119 inside thebore 108 hold the cartridge in place when it is pushed home within the bore. -
FIG. 21 shows thedevice 100 when thecartridge 115 has been pushed home.Internal needle 102 penetratespiston 118, such that theinternal needle 102 is in fluid communication with the drug inside thecartridge 115. Thus, movement of theratchet bar 109 into thecartridge 115 causes thepiston 118 to be pushed along the length of thecartridge 115, and thereby pump drug through theinternal needle 102 andflexible tubing 103 to thedelivery needle 104. As theinternal needle 102 moves with the piston into thecartridge 115, theflexible tubing 103 is pulled behind, thereby maintaining communication betweeninternal needle 102 anddelivery needle 104. - Another advantage of
flexible tubing 103 is that it enablesdelivery needle 104 to be mounted at any point on the device, and thus the placement of the delivery needle in this embodiment is not constrained by the design of the other features. - Although the
electrolytic cell 112 indevice 100 operates in exactly the same manner as the cells in previously described embodiments, the configuration oflever 111 and thepivot 119 on which it is mounted causes pawl 110 to advanceratchet bar 109 during the gas generation step rather than during the venting step. - A further embodiment is shown in
FIGS. 22-26 . InFIG. 22 , theembodiment 120 comprises ahousing 121 containing acartridge 122 filled with adrug 123. Thecartridge 122 is provided with aneedle 124 for delivery ofdrug 123 to a patient. Thecartridge 122 includes apiston 125 which is slidably received in thecartridge 122. The piston has anouter recess 126 for receiving aneedle sterility cover 127. Theneedle sterility cover 127 covers afirst end 128 of theneedle 124 and prevents contamination thereto. Asecond end 129 of theneedle 124 is connected to a length oftubing 130. Thetubing 130 has afirst end 131 and asecond end 132, as shown inFIG. 24 . Thetubing 130second end 132 is secured within anactivation assembly 163. Asecond needle 134 is also secured to theactivation assembly 163. Adrug pathway 133 is machined into theactivation assembly 163, and thetubing 130 and second needle are secured within the activation assembly by means of an adhesive, preferably an ultra-violet bonding agent. A secondneedle sterility cover 135 is slidably received on theexterior end 136 of thesecond needle 134. Prior to use, the secondneedle sterility cover 135 is manually removed so as to uncover theexterior end 136 of thesecond needle 134 so that it is ready for penetration into the user's skin. - Returning now to
FIG. 22 , thepiston 125 andneedle 124 are mounted on aratchet bar 137 having a multitude of steppedincrements 138 thereon. Theratchet bar 137 is moved by aleaf spring 139 integral with areciprocating lever 140. Thelever 140 is mounted on anaxis 141 and has areturn spring 142 that applies constant pressure to thelever 139 in a single direction. Thelever 139 rests against a gas generator sub-assembly 144 and moves in response to pressure differentiation created therein. - The gas generation sub-assembly 144, includes a pair of
electrolytic cells FIG. 26 . Thefirst cell 145 is the propulsion cell. Thepropulsion cell 145 has afirst diaphragm 147 made of a low permeability material, such as bromo-butyl, ethylene propylene, or EPDM. Thelever 140 rests against thefirst diaphragm 147. Thesecond cell 146 has asecond diaphragm 148 thereon. Thesecond diaphragm 148 is made of a high permeability material, such as silicone rubber. Thefirst cell 145 has ahose 149 extending from the side of thefirst cell 145 to above the surface of the top of thesecond cell 146. Agap 143 is created between the end of thehose 149 and the top surface of thesecond cell 146. Thecells batteries 150. - Additional components in the
present embodiment 120 include adrug cartridge recess 151, as shown inFIG. 23 . The drug cartridge has asleeve 152 for receiving and supporting thecartridge 122 and ensuring safe and accurate operation of thedevice 120. Thesleeve 152 is slidably received into therecess 151. Thesleeve 152 has alip 153 on the exterior at theinsertion end 154 of the sleeve. Therecess 151 has ashelf 155 for receiving thelip 153 of the sleeve when thecartridge 122 is fully inserted, as shown inFIG. 21 . Acartridge receiving channel 156 is located within thehousing 121 and is proximate to therecess 151. The channel provides further support for the cartridge when it is inserted within thedevice 120. The channel includes anouter edge 157, aninner edge 158 and anarched portion 159. The outer and inner edges are parallel and align with the cartridge recess to guide and support thecartridge 122 upon insertion and during use. Thearched portion 159 of the channel is integral with theinner edge 158 and is curved away from the cartridge and ratchet assembly. Prior to operation, thearched portion 159 rests against adepressable button 160 that is part of thegas generating sub-assembly 137. Thebutton 160 has a puncturing device on the inner surface thereof. When depressed, the puncturing mechanism breaks aseal 161 of thecompartment 162 containing the chemical entity used in theelectrolytic cells FIG. 22 . The chemical entity is typically potassium chloride, and in the present embodiment, it is preferably in a less viscous form so as to enable the liquid to move to gaseous form more quickly. - With this design, in the event the electrical connection is made prior to use, gas generation in the sub-assembly 144 is not possible because the gas generating chemical is sealed within its
compartment 162. In addition, this design prevents operation of the device unless the drug cartridge is fully engaged. Thearched portion 159 is located so as to only be deflectable by the drug cartridge when the cartridge is in its fully inserted position. Thus, ensuring that the full dosage of the drug will be delivered. -
FIG. 24 shows a cross-sectional view ofmanual activation assembly 163 along line A-A. Theactivation assembly 163 includes a spring loadedstart button 164 which is slidably received within abutton channel 165. Thebutton 164 is maintained in an outward position by means of ahelical spring 166, located and supported in thebutton channel 165. Thehelical spring 166 is loaded both axially and torsionally within thebutton channel 165.FIG. 25 is a cross-sectional view of the activation assembly along line B-B, which shows apin 169 which moves within agroove 170 in thebutton channel 165 from a first, pre-operational position [shown asposition 169A], to a second, operational position [169B], to a third, locked position [169C]. - Returning to
FIG. 24 , thebutton 164 has afinger 167 extending therefrom. Thefinger 167 is located directly above a deflectableelectrical contact 168. When thebutton 164 is depressed, thefinger 167 contacts theelectrical contact 168 and causes it to deflect, thus causing electrical communication between the contacts and initiating operation of thedevice 120. - In operation, the
embodiment 120, shown inFIG. 22 , is supplied with adrug cartridge 122. Thecartridge 122, filled withdrug 123 is fully inserted into thecartridge recess 151. When thecartridge 122 is fully inserted, thelip 153 of thesleeve 152 lockably engages with theshelf 155 and prevents thecartridge 122 from being removed. As thecartridge 122 is inserted, theneedle sterility cover 127 engages with the pistonouter recess 126, and the tip of the needle pierces theneedle sterility cover 127 andpiston 125 and moves into the interior of the cartridge, as shown inFIG. 23 . The travel of the cartridge ends when the sleeve lip engages with the shelf and the inner and outer edges of the channel. As the cartridge is fully inserted, the cartridge edge contacts the arched portion of thechannel 156 causing it to deflect away from the cartridge. Such deflection applies pressure to the depressable button which depresses and pierces the container of chemical used to generate the gas within the electrolytic cells. Thedevice 120 is then applied by the user or health care worker to the skin. - The device is then activated when the
start button 164 is depressed causing thefinger 167 to contact theelectrical contact 168 thus closing an electrical circuit which initiates gas generation in the sub-assembly. Once thebutton 164 is depressed, the torsional force of thehelical spring 166 prevents the button from springing back up and locks the button, andsecond needle 134 in position [169B] during operation, as shown inFIG. 25 . - When the
cells batteries 150, both cells begin to generate gas. Thefirst cell 145 builds pressure quickly because of the low permeability of thefirst diaphragm 147, as shown inFIG. 26A . However, pressure is released through the hose and exits into the atmosphere within thehousing 121. As pressure builds in thesecond cell 146, thesecond diaphragm 148 deforms outwardly, closing thegap 143 between the hose and the top surface of the second cell, as shown inFIG. 26B . When this is closed, the gas from the first cell can no longer escape into the atmosphere, causing the first diaphragm to elastically deform outwardly. This deformation applies pressure to thelever 140, as shown inFIG. 26C . When pressure is applied on the lever, it causes the leaf spring to move from a first steppedincrement 138A to asecond increment 138B. This movement causes thepiston 125 to move further along the length of thedrug cartridge 122, decreasing the volume ofdrug 123 in the cartridge and moving such drug into the patient via theneedle 124. - Once pressure has built sufficiently in the
first cell 145 so as to move the leaf spring incrementally forward, gas generation in the cells is deactivated so as to begin to decrease pressure within the cells. As the pressure in the second cell decreases, the second diaphragm flattens out, thereby re-creating thegap 143 and allowing air to bleed quickly from the first cell, as shown inFIG. 26D . - The gas-generation sub-assembly is designed in such a way so as to provide maximum efficiency in the cycle of moving the leaf spring from a
first increment 138A to asecond increment 138B. The low permeability of thefirst diaphragm 147 allows the pressure to build in thefirst cell 145 and thus results in quick deformation of the diaphragm and movement of thereciprocating piston 143. However, the integration between the first and second cells, 145, 146, is important in order to quickly release the pressure within thefirst cell 145 after the leaf spring has been moved forward. Thehose 149 between the first and second cell connects the two cells during deflection and provides first for the build up of pressure. After the pressure within the first cell builds sufficiently move the reciprocating piston, the electrical connection to thebatteries 150 is disconnected, or decreased. This causes a rapid decrease in the pressure of thesecond cell 146 because much of the gas created escapes through the second diaphragm. As the pressure in thesecond cell 146 declines, the second diaphragm looses height and recreates thegap 143, thus allowing gas from the first cell to quickly bleed off and return to a low pressure state to begin the next cycle. It should be noted that it is possible to maintain a minimum current level within the cells in order to keep a minimum level of pressure in the cells so as not to start the build up of pressure from a lower point than necessary, thus maximizing the efficiency of the cycle time. In one application, the current needed during the gas generation portion of the cycle may range from 5-7 milliampers, and the current to maintain the minimum level of pressure may range from 30-50 microampers. This cell design has enabled the cycle time to decrease from 20 minutes to 5 minutes in the present embodiment. - The length between activating and deactivating the electrolytic cells may be controlled by means of a microprocessor, along with the use of different diaphragm materials. Thus, the cycle time to move the leaf spring a single increment may be adjusted depending upon the delivery rate desired. Moreover, the number and size of increments may be altered to provide further flexibility in the delivery rate.
- When the delivery is complete, the
helical spring 166 which is torsionally loaded, forces thepin 169 to move from the operation position [169B] to a locked post-operational position [169C]. This causes the entire activation assembly to retract and theexterior end 136 of thesecond needle 134 to be recessed into the housing, thereby avoiding any accidental injury or attempted further use of thedevice 120. - It should also be noted that in the
present embodiment 120, the number of sterile components has been minimized so as to eliminate the need to sterilize the entire device. The following components are sterilized as an assembly prior to being assembled into the device. The sterilized sub-assembly includes theneedle sterility cover 127, theneedle 124, thetubing 130, thestart button 164, thedrug pathway 133, thesecond needle 134, and the penetratingneedle sterility protector 135. - It will be appreciated that the embodiments discussed above are preferred embodiments, falling within the scope of the appended claims, and that various alternative embodiments are contemplated. For example, while leaf and coil springs were discussed in the preferred embodiments, it is anticipated that other types of springs may also be used.
- The term “drug” used herein includes but is not limited to peptides or proteins, hormones, analgesics, anti-migraine agents, anti-coagulant agents, narcotic antagonists, chelating agents, anti-anginal agents, chemotherapy agents, sedatives, anti-neoplastics, prostaglandins, antidiuretic agents, anti-sense agents, oligonucleotides, mucosal vaccines, gene-based medicines and permeability and enhancing agents.
- Typical drugs include peptides, proteins or hormones such as insulin, calcitonin, calcitonin gene regulating protein, atrial natriuretic protein, colony stimulating factor, betaseron, erythropoietin (EPO), interferons such as a, α,β or γ interferon, somatropin, somatotropin, somastostatin, insulin-like growth factor (somatomedins), luteinizing hormone releasing hormone (LHRH), tissue plasminogen activator (TPA), growth hormone releasing hormone (GHRH), oxytocin, estradiol, growth hormones, leuprolide acetate, factor VIII, interleukins such as interleukin-2, and analogues thereof; analgesics such as fentanyl, sufentanil, butorphanol, buprenorphine, levorphanol, morphine, hydromorphone, hydrocodone, oxymorphone, methadone, lidocaine, bupivacaine, diclofenac, naproxen, paverin, and analogues thereof; anti-migraine agents such as sumatriptan, ergot alkaloids, and analogues therof; anti-coagulant agents such as heparin, hirudin, and anlogues therof; anti-emetic agents such as scopolamine, ondansetron, domperidone, metoclopramide, and analogues thereof; cardiovascular agents, anti-hypertensive agents and vasodilators such as diltiazem, clonidine, nifedipine, verapamil, isosorbide-5-mononitrate, organic nitrates, agents used in treatment of heart disorders, and analogues thereof; sedatives such as benzodiazepines, phenothiozines, and analogues thereof; chelating agents such as deferoxamine, and analogues thereof; anti-diuretic agents such as desmopressin, vasopressin, and analogues thereof; anti-anginal agents such as nitroglycerine, and analogues thereof; anti-neoplastics such as fluorouracil, bleomycin, and analogues thereof; prostaglandins and analogues thereof; and chemotherapy agents such as vincristine, and analogues thereof.
- Other drugs include antiulcer agents, such as but not limited to cimetidine, and ranitidine; antibiotics; anticonvulsants; anti inflammatories; antifungals; antipsychotics; corticosteroids; immunosuppressants; electrolytes; nutritional agents and vitamins; general anesthetics; antianxiety agents, such as but not limited to compazine; and diagnostic agents.
Claims (21)
1-55. (canceled)
56. A wearable drug delivery device, comprising:
a housing with an adherent patient surface for placing on a patient, and a reservoir disposed within the housing;
a cannula in fluid communication with the reservoir and movable relative to the patient surface between a retracted position within the housing and an exposed position in which at least a portion of the cannula extends through the patient surface outside of the housing;
a piston slidably supported within the reservoir and operable to expel a drug from the reservoir; and
a drive system coupled to the piston, the drive system being operable to advance the piston linearly and intermittently in a series of increments to expel a drug from the reservoir.
57. The drug delivery device according to claim 56 , wherein the drive system comprises:
a first drive member disposed to be rotatably moveable within the housing; and
a second drive member linearly displaceable within the housing, rotation of the first drive member causing the second member to linearly displace and advance the piston in a first linear direction.
58. The device according to claim 57 , wherein the second drive member has an irregular surface defined by a series of peaks and troughs along a direction of its linear displacement.
59. The device according to claim 58 , wherein the first drive member continuously engages the irregular surface of the second drive member.
60. The device according to claim 58 , wherein the first drive member slidably engages the irregular surface of the second drive member.
61. The device according to claim 57 , wherein the first drive member is rotationally moveable about an axis that is substantially perpendicular to a direction of the linear displacement of the second drive member.
62. The device according to claim 57 , wherein the first drive member comprises a reciprocable lever.
63. The drug delivery device according to claim 56 , wherein a patient end of the cannula is substantially perpendicular to a longitudinal axis of the reservoir.
64. The drug delivery device according to claim 56 , further comprising an electronic controller for controlling a delivery rate of a drug from the reservoir.
65. The drug delivery device according to claim 64 , wherein the electronic controller comprises a timing mechanism.
66. The drug delivery device according to claim 64 , wherein the electronic controller is programmable for different delivery programs.
67. The drug delivery device according to claim 56 , wherein the reservoir comprises a prefilled cartridge.
68. The drug delivery device according to claim 67 , wherein the prefilled cartridge comprises a columnar cartridge having a longitudinal axis and an interior serving as the reservoir for a drug, and which is disposed within the drug delivery device such that in use the longitudinal axis of the cartridge is disposed substantially parallel to the patient surface.
69. A wearable drug delivery device, comprising:
a housing with an adherent patient surface for placing on a patient, and a reservoir disposed within the housing;
a cannula in fluid communication with the reservoir and movable relative to the patient surface between a retracted position within the housing and an exposed position in which at least a portion of the cannula extends through the patient surface outside of the housing;
a piston slidably supported within the reservoir and operable to expel a drug from the reservoir; and
a drive system coupled to the piston, the drive system being operable in a plurality of cycles to linearly and intermittently advance the piston to expel the a drug from the reservoir.
70. A method of manufacturing a wearable drug delivery device, comprising:
providing a housing having a reservoir disposed therein, the reservoir having a piston slidably supported therein that is operable to expel a drug from the reservoir;
providing an adherent patient surface on the housing for adhering the device to the patient;
providing a movable a cannula in the housing, the cannula being movable from a retracted position within the housing to an exposed position in which at least a portion of the cannula extends through the patient surface outside of the housing;
fluidly connecting the cannula to the reservoir;
providing a drive system coupled to the piston, the drive system having a controller and being operable to advance the piston linearly and intermittently in a series of increments to expel a drug from the reservoir.
71. The method according to claim 70 , wherein providing the drive system comprises:
providing a first drive member to be rotatably moveable within the housing, the first drive member having an engaging portion;
providing a second drive member at least partially within the reservoir, the second drive member having a helical portion that is slidingly engageable with the engaging portion of the first drive member;
wherein providing the first and second drive members comprises:
operatively connecting the first and second drive members to cooperate to slidably displace the second drive member and the piston in the reservoir in a first linear direction to expel a drug from the reservoir; and
engaging the first drive member with the second drive member so that the rotation of the first drive member causes the linear displacement of the second drive member.
72. The method according to claim 70 , wherein the reservoir comprises a prefilled cartridge, and the method further comprises prefilling the cartridge and subsequently placing the prefilled cartridge into the housing.
73. The method according to claim 72 , wherein placing the prefilled cartridge into the housing comprises linearly sliding the prefilled cartridge in the first linear direction into an opening in the housing.
74. The method according to claim 73 , wherein placing the prefilled cartridge into the housing fluidly connects the prefilled cartridge with the movable cannula.
75. The method according to claim 71 , wherein the first drive member is rotatably moveable about an axis that is substantially perpendicular to the first linear direction.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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Also Published As
Publication number | Publication date |
---|---|
WO1999048546A1 (en) | 1999-09-30 |
US20080215005A1 (en) | 2008-09-04 |
US7998117B2 (en) | 2011-08-16 |
US20130079747A1 (en) | 2013-03-28 |
US7384413B2 (en) | 2008-06-10 |
US20130012874A1 (en) | 2013-01-10 |
EP1064035B1 (en) | 2003-11-26 |
US20130012872A1 (en) | 2013-01-10 |
JP2002507459A (en) | 2002-03-12 |
DE69913111D1 (en) | 2004-01-08 |
TW426531B (en) | 2001-03-21 |
US20160106912A1 (en) | 2016-04-21 |
ATE254938T1 (en) | 2003-12-15 |
US20030236498A1 (en) | 2003-12-25 |
US9132231B2 (en) | 2015-09-15 |
US8361028B2 (en) | 2013-01-29 |
CA2325004A1 (en) | 1999-09-30 |
US20110275999A1 (en) | 2011-11-10 |
US6595956B1 (en) | 2003-07-22 |
US20110270218A1 (en) | 2011-11-03 |
AU3050499A (en) | 1999-10-18 |
DE69913111T2 (en) | 2004-06-03 |
US20130012873A1 (en) | 2013-01-10 |
JP4425465B2 (en) | 2010-03-03 |
US8361027B2 (en) | 2013-01-29 |
EP1064035A1 (en) | 2001-01-03 |
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