WO1994016755A1 - Liberation intrapulmonaire de narcotiques - Google Patents

Liberation intrapulmonaire de narcotiques Download PDF

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Publication number
WO1994016755A1
WO1994016755A1 PCT/US1994/000999 US9400999W WO9416755A1 WO 1994016755 A1 WO1994016755 A1 WO 1994016755A1 US 9400999 W US9400999 W US 9400999W WO 9416755 A1 WO9416755 A1 WO 9416755A1
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WIPO (PCT)
Prior art keywords
patient
drug
valve
analgesic drug
analgesic
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PCT/US1994/000999
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English (en)
Inventor
Reid M. Rubsamen
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Miris Medical Corporation
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Publication date
Application filed by Miris Medical Corporation filed Critical Miris Medical Corporation
Priority to AU60976/94A priority Critical patent/AU6097694A/en
Publication of WO1994016755A1 publication Critical patent/WO1994016755A1/fr

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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
    • A61M15/00—Inhalators
    • A61M15/0065—Inhalators with dosage or measuring devices
    • 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
    • A61M15/00—Inhalators
    • 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
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/0021—Mouthpieces therefor
    • A61M15/0023—Mouthpieces therefor retractable
    • 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
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • A61M15/0046—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier
    • A61M15/0048—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier the dosages being arranged in a plane, e.g. on diskettes
    • 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
    • A61M15/00—Inhalators
    • A61M15/0065—Inhalators with dosage or measuring devices
    • A61M15/0068—Indicating or counting the number of dispensed doses or of remaining doses
    • A61M15/008—Electronic counters
    • 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
    • A61M15/00—Inhalators
    • A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
    • 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
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/0003—Accessories therefor, e.g. sensors, vibrators, negative pressure
    • A61M2016/0015—Accessories therefor, e.g. sensors, vibrators, negative pressure inhalation detectors
    • A61M2016/0018—Accessories therefor, e.g. sensors, vibrators, negative pressure inhalation detectors electrical
    • A61M2016/0021—Accessories therefor, e.g. sensors, vibrators, negative pressure inhalation detectors electrical with a proportional output signal, e.g. from a thermistor
    • 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
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/0003—Accessories therefor, e.g. sensors, vibrators, negative pressure
    • A61M2016/003—Accessories therefor, e.g. sensors, vibrators, negative pressure with a flowmeter
    • A61M2016/0033—Accessories therefor, e.g. sensors, vibrators, negative pressure with a flowmeter electrical
    • A61M2016/0039—Accessories therefor, e.g. sensors, vibrators, negative pressure with a flowmeter electrical in the inspiratory circuit
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/35—Communication
    • A61M2205/3546—Range
    • A61M2205/3569—Range sublocal, e.g. between console and disposable
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/35—Communication
    • A61M2205/3576—Communication with non implanted data transmission devices, e.g. using external transmitter or receiver
    • A61M2205/3592—Communication with non implanted data transmission devices, e.g. using external transmitter or receiver using telemetric means, e.g. radio or optical transmission
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/82—Internal energy supply devices
    • A61M2205/8206—Internal energy supply devices battery-operated

Definitions

  • This invention relates generally to methods of pain management by the administration of narcotics. More specifically, this invention relates to the intrapulmonary delivery of narcotics from a hand-held, self-contained device capable of automatically releasing a controlled amount of narcotics to a patient at an optimal point in the respiratory cycle of the patient.
  • Narcotic therapy forms the mainstay of pain management. These drugs can be administered in many forms to patients with postsurgical and other forms of acute and chronic pain. Morphine, one of the oldest narcotics, is available for administration in tablet or in injectable form. Fentanyl, a synthetic narcotic, was first synthesized in 1960 by Paul Janssen and found to be 150 times more potent than morphine [Theodore Stanley, "The History and Development of the Fentanyl Series," Journal of Pain and Symptom Management (1992) 7 : 3 (suppl . ) , S3 -S7] . Fentanyl and its relatives Sufentanil and Alfentanil are available for delivery by injection.
  • fentanyl is available for administration by a transdermal delivery system in the form of a skin patch [DuragesicTM (fentanyl transdermal system) package insert, Janssen Pharmaceutica, Piscataway, NJ 08855, Jan-Jun 1991] .
  • a feature of the synthetic narcotic fentanyl is that is has a more rapid time to onset and a shorter duration of action than morphine. This makes fentanyl a useful drug for the management of acute pain.
  • fentanyl is typically given by intravenous injection for acute pain management.
  • transdermal delivery of fentanyl is designed for long-term administration of the drug and does not lend itself to achieving a peak level rapidly for a short-term effect.
  • PCA patient-controlled analgesia
  • the first commercial device for automatically providing intravenous patient-controlled analgesia was developed in Wales in the mid-1970s.
  • This device the Cambridge Palliator (Graesby Medical Limited, United Kingdom) is the predecessor of numerous currently available computer-controlled patient-controlled analgesia intravenous pumps [Elizabeth Ryder, "All about Patient-Controlled Analgesia, " Journal of Intravenous Nursing (1991) 14 , 372 - 81] .
  • Studies using these computer controlled intravenous narcotic infusion pumps have shown that small doses of narcotics given on demand by the patient provided superior pain relief when compared with intermittent intramuscular administration of these drugs [Morton Rosenburg, "Patient-Controlled Analgesia, " J. Oral Maxillofac Surg (1992) 50, 386- 89] .
  • These computer-controlled pumps typically allowed for the programming of four different parameters: 1) .basal intravenous narcotic infusion rate; 2) the bolus of narcotic to be delivered on each patient demand; 3) the maximum hourly total dose of narcotic to be allowed; and 4) the lockout period between doses.
  • Typical programming for postoperative pain management with intravenous fentanyl might be a basal infusion rate of 20 ⁇ g/hr, a bolus demand dose of 20 ⁇ g, a maximum hourly does of 180 ⁇ g, and a lockout period between doses of 5 minutes.
  • narcotic for pain management is potentially dangerous because overdoses of narcotics will cause complications such as respiratory depression.
  • the patient's respiratory rate is decreased by the Administration of narcotics. This decrease in respiratory rate may not be associated with a change in respiratory tidal volume [Miller, Anesthesia (2nd ed) , Churchill Livingston, I, 762] .
  • the four programmable parameters available on computer-controlled intravenous patient-controlled analgesia infusion pumps must be selected so as to minimize the likelihood of narcotic overdose.
  • the preferred technique is to set the basal infusion rate at a relatively low rate and increase this rate based on how many times the patient presses the bolus demand button to self-administer supplemental drug.
  • This system incorporated some of the features of computer-controlled programmable PCA infusion pumps such as basal infusion rate and the amount of each bolus.
  • this system which involved the use of an intravenous catheter as seen in larger infusion pumps, incorporated no provision to record accurately the actual dose of Fentanyl administered to the patient over time.
  • fentanyl can be administered by transdermal patch, this method has been found to be suboptimal for postoperative main management [K.A. Lehmann et al., "Transdermal Fentanyl for the Treatment of Pain after Major Urological Operations, Eur. J. Clin Pharmacol (1991) 21 : 17-21] .
  • fentanyl by aerosol used in conjunction with a non-invasively delivered long-acting preparation of narcotic such as slow-release oral morphine or a fentanyl transdermal patch provides a means for non-invasive administration of a basal rate of narcotic and rapid-acting boluses of narcotic to an ambulatory patient.
  • narcotic such as slow-release oral morphine or a fentanyl transdermal patch
  • inefficient, bulky nebulizers must be used for the administration of the drug.
  • these nebulizers work by administering from an open reservoir of the drug in aqueous solution allowing the vapor to be generally distributed and creating the potential for overdosing due to the lack of reproducible aerosol delivery.
  • abuse through theft of the aqueous-phase fentanyl and subsequent unauthorized repackaging of this controlled substance in an aqueous injectable form are possible.
  • a method of pain control is provided by the intrapulmonary delivery of a pharmaceutically active pain relief formulation.
  • the formulation is automatically released from a hand-held, self-contained, portable device comprised of a means for automatically releasing a measured amount of drug into the inspiratory flow path of a patient in response to information obtained from a means for analyzing the inspiratory flow of a patient.
  • Reproducible dosing is obtained by providing for automatic release in response to a measured inhalation profile.
  • Abuse of narcotic formulations is avoided by providing a tamper-resistant device which includes a variety of security features including a pre-programmed microprocessor designed to avoid overdosing.
  • An advantage of the present invention is that it can be used for ambulatory patients.
  • a feature of the invention is that aerosolized potent narcotics can be used in conjunction with a non- invasively delivered baseline infusion rate of narcotic to provide a complete method for patient-controlled analgesia for ambulatory patients.
  • formulations of narcotics such as fentanyl and a highly volatile propellant provide for a fundamentally tamper- resistant package making it difficult for the contained fentanyl to be illicitly repackaged in an injectable form.
  • the device can be programmed to provide a minimum required time interval between doses.
  • Another advantage of the invention is that the device can be programmed so as to control the maximum amount of narcotic delivered within a period of time.
  • Yet another advantage is to provide a device which can be simultaneously programmed to control the maximum amount of narcotic drug delivered within a given period of time and provide for a minimum required time interval between the delivery of doses.
  • a feature of the invention is that it can monitor the amount of aerosolized narcotic delivered to a patient and record amounts and times of delivery for review by a treating physician.
  • Another advantage of the invention is that the apparatus can monitor respiratory rate to ensure that respiratory depression has not supervened prior to further administration of narcotic.
  • Another object of this invention is to provide an apparatus which can analyze the breathing pattern of the patient not only to determine the respiratory rate prior to delivery but also to determine the inspiratory flow profile characteristics so as to determine the optimal point in the inspiratory cycle for delivery of aerosolized potent narcotic.
  • Yet another object of this invention is to further provide aerosolized naloxone which may be administered to counteract the effects of administered potent narcotic in the event of the development of complications such as respiratory depression due to overdose of the narcotic.
  • Another advantage is that the method described provides for reproducible delivery of narcotics such as fentanyl wherein the reproducibility is a critical part of safety causing each dose of narcotic to have the same clinical effect.
  • Another object is to provide an electronic lock-and-key system which can ensure that only the intended authorized patient can inhale aerosolized narcotic from the described apparatus making unauthorized users unable to inhale drug from the system.
  • Figure 1 is a cross-sectional view of a drug delivery device
  • Figure 2 is a cross-sectional view of a more preferred embodiment of a drug delivery device
  • Figure 3 is a perspective view showing a pressurized canister with the canister cover components disconnected
  • FIG. 4 is a perspective view of another embodiment of the cover components connected and the canister held therein. Detailed Description of the Preferred Embodiments
  • dosing event shall be interpreted to mean the administration of analgesic drug to a patient in need thereof by the intrapulmonary route of administration which event may encompass one or more releases of analgesic drug formulation from an analgesic drug disper ing device over a period of time of 15 minutes or less, preferably 10 minutes or less, and more preferably 5 minutes or less, during which period multiple inhalations are made by the patient and multiple doses of analgesic drug are released and inhaled.
  • a dosing event shall involve the administration of analgesic drug to the patient in an amount of about 1 ⁇ g to about 100 mg in a single dosing event which may involve the release of from about 10 ⁇ g to about 1000 mg of analgesic drug from the device.
  • monitoring event shall be interpreted to mean an event taking place prior to a "dosing event” whereby the inspiratory flow of the patient's inhalation is measured in order to determine an optimal inspiratory flow rate and cumulative volume at which to allow the release of a valve so that analgesic drug can be delivered to the patient. It is preferable to carry out a "monitoring event" prior to each "dosing event” so as to optimize the ability to repeatedly deliver the same amount of analgesic drug to the patient at each dosing event.
  • inspiratory flow shall be interpreted to mean a value of airflow calculated based on the speed of the air passing a given point along with the volume of the air passing that point with the volume calculation being based on integration of the flow rate data and assuming atmospheric pressure and temperature in the range of about 18°C to about 30°C.
  • inspiratory flow profile shall be interpreted to mean data calculated in one or more monitoring events measuring inspiratory flow rate and cumulative volume which profile can be used to determine a point within a patient's respiratory cycle which is optimal for the release of analgesic drug to the patient.
  • the optimal point within the respiratory cycle for the release of analgesic drug is not calculated based on a point within the cycle likely to result in the maximum delivery of analgesic drug but rather the point in the cycle most likely to result in the delivery of the same amount of analgesic drug to the patient at each release of analgesic drug from the device.
  • analgesic drug shall be interpreted to mean a drug for treating symptoms of pain.
  • Analgesic drugs may include one of: narcotics, nonsteroidal antiinflammatory drugs and mixed agonist-antagonistic drugs such as butorphanol. Examples of useful narcotics drugs are described and disclosed within the Physicians Desk Reference and the Drug Evaluations Annual 1993, published by the American Medical Association, both of which are incorporated herein by reference.
  • the invention encompasses the free acids, free bases, salts, hydrates in various formulations of analgesic drugs useful for pain control.
  • a non-invasive means of pain management is provided in a manner which makes it possible to maintain tight control over the amount of drug administered to a patient suffering with pain.
  • An essential feature of the invention is the intrapulmonary delivery of analgesic drug to the patient in a controlled and repeatable manner.
  • the device of the invention provides a number of features which make it possible to achieve the controlled and repeatable dosing procedure required for pain management. Specifically, the device is not directly actuated by the patient in the sense that no button is pushed nor valve released by the patient applying physical pressure. On the contrary, the device of the invention provides that the valve releasing analgesic drug is opened automatically upon receipt of a signal from a microprocessor programmed to send a signal when data is received from a monitoring device such as an airflow rate monitoring device.
  • a patient using the device withdraws air from a mouthpiece and the inspiratory rate, and calculated inspiratory volume of the patient is measured one or more times in a monitoring event which determines an optimal point in an inhalation cycle for the release of a dose of analgesic drug.
  • Inspiratory flow is measured and recorded in one or more monitoring events for a given patient in order to develop an inspiratory flow profile for the patient.
  • the recorded information is analyzed by the microprocessor in order to deduce a preferred point within the patient's inspiratory cycle for the release of analgesic drug with the preferred point being calculated based on the most likely point to result in a reproducible delivery event.
  • the flow rate monitoring device continually sends information to the microprocessor, and when the microprocessor determines that the optimal point in the respiratory cycle is reached, the microprocessor actuates the opening of the valve allowing release of analgesic drug.
  • drug is always delivered at a pre- programmed place in the inspiratory flow profile of the particular patient which is selected specifically to maximize reproducibility of drug delivery and peripheral deposition of the drug.
  • the device of the present invention can be used to, and actually does, improve the efficiency of drug delivery.
  • the critical feature is the reproducibility of the release of a tightly controlled amount of drug at a particular point in the respiratory cycle so as to assure the delivery of a controlled and repeatable amount of drug to the lungs of each individual patient.
  • valve release combined with frequent monitoring events in order to calculate the optimal flow rate and time for the release of analgesic drug, combine to provide a repeatable means of delivering analgesic drug to a patient. Because the valve is released automatically and not manually, it can be predictably and repeatedly opened for the same amount of time each time or for the preprogrammed measured amount of time which is desired at that particular dosing event. Because dosing events are preferably preceded by monitoring events, the amount of analgesic drug released and/or the point in the inspiratory cycle of the release can be readjusted based on the particular condition of the patient.
  • the microprocessor which will readjust the amount and/or point of release of the analgesic drug in a manner calculated to provide for the administration of the same amount of analgesic drug to the patient at each dosing event. It has been found that the ability to tightly control the amount of a volatile propellant formulation of drug delivered via the intrapulmonary route can be improved by delivering smaller doses of the propellant/drug formulation with each release of the valve and with each dosing event.
  • an important aspect of the invention is to deliver aerosolized analgesic drug to a patient in a series of interrupted bursts while the patient continues a single inhaled breath, with each burst being delivered while the patient maintains optimal inspiratory flow.
  • Short bursts of the release of analgesic drug can be obtained as two or more bursts but are preferably three or four bursts.
  • the amount of time the valve is opened is generally in the range of about 0.05 seconds to l second but is more preferably 0.1 seconds to 0.25 seconds.
  • the valve it is preferable for the valve to be open a substantially shorter period of time than the valve is closed.
  • the valve might be opened for approximately 0.1 seconds and closed for approximately 0.5 seconds, followed by another opening of 0.1 seconds and another closing of 0.5 seconds, with this pattern being repeated a plurality of times.
  • Repeatability and dosing can be improved by providing for four bursts, wherein each burst allows for the valve to be opened four times, separated by three closings, wherein the amount of closed time is two to eight times longer than the amount of open time for each on/off event.
  • Particularly preferred repeatability can be obtained by allowing for four bursts, wherein the valve is opened for approximately 0.015 seconds, followed by a closing for approximately 0.1 second, which pattern is repeated for four openings, separated by three closings.
  • analgesic drug delivered to the patient will vary greatly depending on the particular drug being delivered.
  • sufentanil which is generally administered to a patient in an amount in the range of about 10 ⁇ g - 100 ⁇ g.
  • sufentanil is approximately ten times more potent than fentanyl so that fentanyl is generally delivered to a patient in an amount of about 100 ⁇ g - 1000 ⁇ g.
  • the differential between the amount of analgesic drug actually released from the device and the amount of analgesic drug actually delivered to the patient varies due to a number of factors.
  • the present device is approximately 20% efficient, however, the efficiency can be as low as 10% and as high as 50% meaning that as little as 10% of the released analgesic drug may actually reach the circulatory system of the patient and as much as 50% might be delivered.
  • the efficiency of the delivery will vary somewhat from patient to patient and must be taken into account when programming the device for the release of analgesic drug.
  • a conventional metered dose inhaling device is about 10% efficient.
  • the entire dosing event can involve the administration of anywhere from 1 ⁇ g to 100 mg, but more preferably involves the administration of approximately 10 ⁇ g to 10 mg.
  • the large variation in the amounts which might be delivered are due to the fact that different drugs have greatly different potencies and may be delivered from devices which vary greatly in terms of the efficiency of drug delivered.
  • the entire dosing event may involve several inhalations by the patient with each of the inhalations being provided with multiple bursts of analgesic drug from the device.
  • the device can be programmed so as to release enough analgesic drug so that approximately 1 mg of analgesic drug is delivered to the patient per inhalation or 0.33 mg of analgesic drug per burst with three bursts being delivered per inhalation. If ten mg are to be delivered, the ten mg are delivered by releasing 33 bursts in ten different inhalations. Such a dosing event should take about 1-2 minutes to deliver 10 mg of analgesic drug. Since only small amounts are delivered with each burst and with each inhalation, even a complete failure to deliver analgesic drug with a given inhalation or burst is not of great significance and will not seriously disturb the reproducibility of the dosing event.
  • analgesic drug sensitivity must be taken into consideration.
  • the present invention makes it possible to vary dosing over time if analgesic sensitivity changes and/or if user compliance and/or lung efficiency changes over time.
  • the dosing or amount of analgesic drug actually released from the device can be changed based on the most immediately prior monitoring event wherein the inspiratory flow of a patient's inhalation is measured. Variations in doses are calculated by monitoring the effect of respiratory rate in response to known amounts of analgesic drug released from the device. If the response in decreasing the patient's respiratory rate is greater than with previous readings, then the dosage is decreased or the minimum dosing interval is increased. If the response in decreasing respiratory rate is less than with previous readings, then the dosing amount is increased or the minimum dosing interval is decreased.
  • the increases and decreases are gradual and are preferably based on averages (of 10 or more readings of respiratory rates after 10 or more dosing events) and not a single dosing event and monitoring event with respect to respiratory rates.
  • the present invention can record dosing events and respiratory rates over time, calculate averages and deduce preferred changes in administration of analgesic drug.
  • the microprocessor can be programmed to take two different criteria into consideration with respect to dosing times.
  • the microprocessor can be programmed so as to include a minimum time interval between doses i.e. after a given delivery another dose cannot be delivered until a given period of time has passed.
  • the timing of the device can be programmed so that it is not possible to exceed the administration of a set maximum amount of drug within a given time.
  • the device could be programmed to prevent dispersing more than 200 micrograms of a narcotic within one hour. More importantly, the device can be programmed to take both criteria into consideration.
  • the device can be programmed to include a minimum time interval between doses and a maximum amount of drug to be released within a given time period.
  • the microprocessor could be programmed to allow the release of a maximum of 200 micrograms of a narcotic during an hour which could only be released in amounts of 25 micrograms with each release being separated by a minimum of five minutes.
  • the dosing program can be designed with some flexibility. For example, if the patient normally requires 25 mg per day of analgesic drug, the microprocessor of the inhalation device can be programmed to prevent further release of the valve after 35 mg have been administered within a given day.
  • the ability to prevent overdosing is a characteristic of the device due to the ability of the device to monitor the amount of analgesic drug released and calculate the approximate amount of analgesic drug delivered to the patient based on monitoring given events such as the respiratory rate.
  • the ability of the present device to prevent overdosing is not merely a monitoring system which prevents further manual actuation of a button.
  • the device used in connection with the present invention is not manually actuated, but is fired in response to an electrical signal received from a microprocessor (which received data from a monitoring device such as a device which monitors inspiratory flow) and allows the actuation of the device upon achieving an optimal point in a inspiratory cycle.
  • each release of the valve is a release which will administer drug to the patient in that the valve is released in response to patient inhalation. More specifically, the device does not allow for the release of analgesic drug merely by the manual actuation of a button to fire a burst of analgesic drug into the air or a container.
  • the microprocessor of applicant's invention will also include a timing device.
  • the timing device can be electrically connected with visual display signals as well as audio alarm signals. Using the timing device, the microprocessor can be programmed so as to allow for a visual or audio signal to be sent when the patient would be normally expected to administer analgesic drug.
  • the device can indicate the amount of analgesic drug which should be administered by providing a visual display.
  • the audio alarm could sound alerting the patient that analgesic drug should be administered.
  • the visual display could indicate "50 ⁇ g" as the amount of analgesic drug to be administered.
  • a monitoring event could take place. After completion of the monitoring event, administration would proceed and the visual display would continually indicate the remaining amount of analgesic drug which should be administered. After the predetermined dose of 50 ⁇ g had been administered, the visual display would indicate that the dosing event had ended. If the patient did not complete the dosing event by administering the stated amount of analgesic drug, the patient would be reminded of such by the initiation of another audio signal, followed by a visual display instructing the patient to continue administration.
  • Patients suffering from pain may be treated solely with analgesic drug as indicated above, i.e. by intrapulmonary delivery.
  • analgesic drug(s) provided by other means of administration.
  • a patient can be provided with a basal level of analgesic drug by a means such as transdermal administration and/or oral administration. This basal level of drug will be sufficient to control the pain of the patient during normal circumstances.
  • an analgesic drug such as sufentanil using the device and methodology of the present invention.
  • the intrapulmonary delivery of analgesic drug provides a pulsalite rate increase over the normal basal rate level maintained by the oral or transdermal administration.
  • the use of the intrapulmonary administration of analgesic drug via the present invention is particularly desirable in that the effects of the drug are felt almost immediately. Such an immediate effect cannot be obtained using oral and/or transdermal administration means.
  • Fentanyl is available for administration by a transdermal delivery system in the form of a skin patch [DuragesicTM (fentanyl transdermal system) package insert, Janssen Pharmaceutica, Piscataway, NJ 08855, Jan-Jun 1991] .
  • narcotics in addition to administering narcotics by transdermal administration it is possible to administer the drugs by other means such as by injection and/or orally.
  • a preferred supplemental means of administration is oral in that oral administration can be carried out on an out- patient basis.
  • the method of the invention may be carried out by administering a long acting orally effective narcotic drug.
  • the oral drug is preferably given in amount so as to maintain a relatively low level of narcotic within the circulatory system which is sufficient to control pain during periods when the pain is less severe. However, this low level of drug to blood ratio must be raised in order to control more severe pain and such can be accomplished by the interpulmonary administration of narcotic using the present invention.
  • a plurality of different treatments and means of administration can be used to treat a single patient.
  • a patient can be simultaneously treated with analgesic drug by injection, analgesic drug via intrapulmonary administration in accordance with the present invention, and drugs, which are orally administered. Should such prove to be ineffective for whatever reason, such as breathing difficulties (not related to the administration of the analgesic drug) , such could be supplemented by administration via injection.
  • the methodologies of the present invention can be carried out using any type of analgesic drug, although they are preferably carried out using potent narcotic such as fentanyl and morphine.
  • potent narcotic such as fentanyl and morphine.
  • the biochemical mechanism of action of such narcotics is known. Further, it is known that the narcotic effect can be blocked by the administration of a narcotic antagonist such as naloxone.
  • Such a device is a hand-held, portable device which is comprised of (a) a means for analyzing the inspiratory flow of a patient and (b) a means for automatically releasing a measured amount of a narcotic into the inspiratory flow path of a patient, e.g. an automatic valve actuation means.
  • the device In order to use the device, the device must be "loaded", i.e. connected to (c) a source of pain relieving drug which, in general, is a potent narcotic drug suspension dispersed within a low boiling point propellant.
  • the entire device is light weight (less than 1 kg loaded) and portable.
  • a formulation of an analgesic drug in a low boiling point propellant is typically contained in a pressurized canister which is connectable to the "unloaded" device, i.e., the device without the container.
  • the container When the container of propellant and analgesic drug is connected to the device, the container will include a valve opening at one end which opening is seated into a flow path within the device.
  • the device preferably includes a mouth piece at the end of the flow path, and the patient inhales from the mouth piece which causes an inspiratory flow to be measured within the flow path. This inspiratory flow causes an air flow transducer to generate a signal.
  • This signal is conveyed to a microprocessor which is able to convert, continuously, the signal from the transducer in the inspiratory flow path to a flow rate in liters per minute.
  • the microprocessor can further integrate this continuous air flow rate signal into a representation of cumulative inspiratory volume.
  • the microprocessor can send a signal to an actuation means.
  • the actuation means When the actuation means is signaled, it releases a valve allowing analgesic drug and propellant to escape into the inspiratory flow path of the device and ultimately into the patient's lungs. After being released, the drug and propellant will preferably pass through -a nozzle prior to entering the inspiratory flow path of the device and thereafter the lungs of the patient.
  • the firing threshold of the device is not based on a single criterion such as the rate of air flow through the device or a specific time after the patient begins inhalation.
  • the firing threshold is based on an analysis of the patient's inspiratory flow profile. This means that the microprocessor controlling the device takes into consideration the instantaneous air flow rate as well as the cumulative inspiratory flow volume when it determines the optimal point in the patient's inspiratory cycle which would be most preferable in terms of reproducibly delivering the same amount of drug to the patient with each release of drug.
  • the device preferably includes a means for recording a characterization of the inspiratory flow profile for the patient which is possible by including a microprocessor in combination with a read/write memory means and a flow measurement transducer.
  • a microprocessor in combination with a read/write memory means and a flow measurement transducer.
  • Figure 1 shows a cross-sectional view of a hand-held, portable, electronic breath-actuated inhaler device which can be used in connection with the present - invention.
  • the device is shown with a holder 1 having cylindrical side walls and a removable cap.
  • the holder l is "loaded” in that it includes the pressurized canister 3.
  • the canister 3 includes a non-metering valve 5 which is held down in the open position when the cap 2 is screwed down, thus setting the valve 5 into a seat 6 which is in connection with a flow path 8.
  • a formulation 4 comprised of a narcotic such as sufentanil or fentanyl and a suitable propellant, such as a low boiling point propellant, is contained within the pressurized canister 3.
  • a narcotic such as sufentanil or fentanyl
  • a suitable propellant such as a low boiling point propellant
  • Propellant and narcotic drug are released from the canister 3 via the electrically controlled solenoid 7.
  • the valve 5 of the canister is continuously open, another valve, contained within solenoid 7, facilitates the release of the drug.
  • the solenoid 7 allows release of propellant and drug, the propellant and drug flows through the flow path 8 and then through the solenoid actuated valve 9 into the flow path 10, out through the nozzle 13 and then into the inspiratory flow path 11 surrounded by walls 12.
  • the device must be capable of allowing the release of a metered amount of analgesic drug based on pre-programmed criteria which are readable by the microprocessor 22.
  • the pre-programmed information is contained within a nonvolatile memory which can be modified via an external device.
  • this pre-programmed information is contained within a "read only" memory which can be unplugged from the device and replaced with another memory unit containing different programming information.
  • microprocessor 22, containing read only memory which in turn contains the pre-programmed information is plugged into the device.
  • the non-volatile memory contains information relevant only to the administration of a specific analgesic drug such as fentanyl.
  • Microprocessor 22 sends signals to solenoid 7 which determines the amount of drug delivered into the inspiratory flow path. Further, microprocessor 22 keeps a record of all drug dosing times and amounts using a read/write non-volatile memory which is in turn readable by an external device.
  • the formulation 4 contained within canister 3 is released into the atmosphere ultimately via nozzle 13 which opens into inspiratory flow path 11.
  • the solenoid 7, and associated valve 9, flow paths 8 and 10, as well as nozzle 13 make up the aerosol delivery system 14 shown by the dotted lines within Figure 1.
  • the system 14 is in connection with the flow sensor 15 which is capable of measuring a flow rate of about 0 to about 300 liters per minute.
  • the flow sensor 15 includes screens 16, 17 and 18 which are positioned approximately 1/4" apart from each other. Tubes 19 and 20 open to the area between the screens 16, 17 and 18 with the tubes 19 and 20 being connected to a conventional differential pressure transducer 21. When the user draws air through inspiratory flow path 11, air is passed through the screens 16, 17 and 18 and the air flow can be measured by the differential air pressure transducer 21.
  • the flow sensor 15 is in connection with the aerosol delivery system 14, and when a threshold value of air flow is reached, the aerosol delivery system 14 allows the release of formulation 4 so that a controlled amount of analgesic drug is delivered to the patient.
  • Solenoid 7 is connected to a microprocessor 22 via an electrical connection.
  • FIG. 2 A cross-sectional view of yet another (and more preferred) embodiment of the hand-held, electronic, breath-actuated inhaler device of the invention is shown in Figure 2.
  • the device of Figure 2 shows all of the components present within the single hand-held, portable device, i.e. the power source not shown in Figure 1 is shown in the device in Figure 2.
  • the device of Figure 2 includes a canister 3 which includes a canister valve 5.
  • the device of Figure 2 does not have the valve continuously open but allows a valve 5 connected to the canister 3 to be opened by the mechanical force generated by a valve actuation mechanism 26 which is a motor driven, mechanical mechanism powered by a power source such as batteries 23 and 23'.
  • the patient inhales through inspiratory flow path 11 which can form a mouth piece in order to obtain a metering event using the differential pressure transducer 21.
  • the microprocessor 24 sends a signal to an actuator release mechanism 25 which actuates the actuation mechanism 26 forcing canister 3 downward so that canister valve 5 releases formulation into the inspiratory flow path 11.
  • an actuator release mechanism 25 which actuates the actuation mechanism 26 forcing canister 3 downward so that canister valve 5 releases formulation into the inspiratory flow path 11.
  • Microprocessor 24 of Figure 2 includes an external non-volatile read/write memory subsystem, peripheral devices to support this memory system, reset circuit, a clock oscillator, a data acquisition subsystem and an LCD annunciator subsystem.
  • the discrete components are conventional parts which have input and output pins configured in a conventional manner with the connections being made in accordance with instructions provided by the device manufacturers.
  • the microprocessor used in connection with the device of the invention is designed and programmed specifically so as to provide controlled and repeatable amounts of analgesic drug to a patient upon actuation. Adjustments can be made in the program so that when the patient's inspiratory flow profile is changed such is taken into consideration.
  • the microprocessor of the present invention can be programmed so as to prevent the release of drug from the canister from occurring more than a given number of times within a given period of time.
  • This feature makes it possible to prevent overdosing the patient with a potent narcotic.
  • the overdose prevention feature can be particularly designed with each individual patient in mind or designed with particular groups of patients in mind.
  • the microprocessor can be programmed so as to prevent the release of more than approximately 200 ⁇ g of fentanyl per day when the patient is normally dosed with approximately 100 ⁇ g of fentanyl per day.
  • the systems can also be designed so that only a given amount of a particular analgesic drug is provided at a given dosing event.
  • the system can be designed so that only approximately 100 ⁇ g of fentanyl is given in a given 15-minute period over which the patient will make approximately 10 inhalations with 10 ⁇ g of fentanyl being delivered with each inhalation.
  • Another feature of the device is that it may be programmed to not release drug if it does not receive a signal transmitted to it by a transmitter worn by the intended user. Such a system improves the security of the device and prevents abuse by unauthorized users.
  • the microprocessor of the invention can be connected to external devices permitting external information to be transferred into the microprocessor of the invention and stored within the non-volatile read/ write memory available to the microprocessor. The microprocessor of the invention can then change its drug delivery behavior based on this information transferred from external devices. All of the features of the invention are provided in a portable, programmable, battery-powered, hand-held device for patient use which has a size which compares favorably with existing metered dose inhaler devices.
  • the microprocessor of the present invention is programmed so as to allow for monitoring and recording data from the inspiratory flow monitor without delivering drug. This is done in order to characterize the patient's inspiratory flow profile in a given number of monitoring events, which monitoring events preferably occur prior to dosing events. After carrying out a monitoring event, the preferred point within the inspiratory cycle for drug delivery can be calculated. This calculated point is a function of measured inspiratory flow rate as well as calculated cumulative inspiratory flow volume. This information is stored and used to allow activation of the valve when the inhalation cycle is repeated during the dosing event.
  • the dry powder would be concealed by a gate, which gate would be opened in the same manner described above, i.e., it would be opened when a predetermined flow rate level and cumulative volume have been achieved based on an earlier monitoring event. Patient inhalation would then cause the dry powder to form a dry dust cloud and be inhaled. Dry powder can also be aerosolized by compressed gas, and a solution can be aerosolized by a compressed gas released in a similar manner and then inhaled.
  • narcotic drugs are subject to drug abuse it is desirable to design devices and methodology so as to hinder abuse to the extent possible.
  • the methodology and devices of the present invention do so in an number of specific ways.
  • the device shown within Figure 2 is designed to be reusable. More specifically, the drug delivery device can be "loaded” with a cassette of the type shown within either of Figures 3 and 4.
  • the cassette is comprised of an outer cover 30, a canister 3 and top nozzle piece 31.
  • the components are shown in a disassembled state in Figure 3. A different embodiment of such components are shown in an assembled state within Figure 4.
  • the cassette shown in Figure 3 is somewhat less secure than the cassette shown within Figure 4.
  • the top portion of the cover 30 is open within Figure 3. This allows one to force the canister 3 downward and open the valve 5 to allow release of drug.
  • the cassette is loaded within the device shown in Figure 2 and a motor driven piston forces the bottom of the canister 3 downward actuating the valve 5 to an open position.
  • a two-pronged fork device is positioned over the end portion of the cover 30' .
  • each prong of the fork protrudes through an opening 34 and 34' allowing the canister 3 to be forced downward so that the valve 5 can be opened.
  • cover 30 when the cover 30 is attached to the top nozzle piece 31, they can be sealed together using a fast-acting glue or any appropriate means making it impossible to separate the components.
  • the narcotic drug is contained within the canister 3 with a low boiling point propellant it is extremely difficult to open the canister without losing all of the contents. Accordingly, the contents of the canister can generally be obtained only by including the canister within components 30 and 31 and attaching such to the device shown within figure 2.
  • the cover 30 can have protuberances such as the protuberance 32 and openings such as the opening 33 thereon. These openings and protuberances can serve as a type of lock and key mechanism which is interactable with receiving protuberances and openings in the device shown in figure 2. Accordingly, unless the cover 30 includes the correct openings and protuberances in the correct position the cover will not fit into the device shown in figure 2 and cannot be -operated.
  • the body of the device as shown within figure 2 is designed so as to be capable of receiving the openings and protuberances on the cover 30.
  • the physical configuration of the device is specific with respect to certain drugs and is particularly specific with respect to narcotic drugs.
  • the cover 30 and receiving body portion on the device of figure 2 are designed so that they can be integrated but are also designed so that they will not integrate with other devices not specific for the delivery of narcotic drugs.
  • the device and methodology of the present invention provides for a physical lock and key interaction.
  • the transmitting and receiving signals can be by any means of signalling and need not be limited to radio signals and thus could include infrared and other types of signals. Further, other interlocking mechanisms with more complex physical shapes could be readily devised in order to enhance the security of the device.
  • valve actuation means can be electronically prevented from allowing the release of valves. As further indicated above, this is generally done for purposes of security. However, such can also be implemented in order to prevent accidental overdosing by a given patient.
  • the monitoring components of the invention can be designed so as to read the patients respiratory rate. If the respiratory rate is below a given value assigned to the particular patient then the electronics can prevent the release of any drug from the device. It is well known that respiratory rates slow when large amounts of narcotics are administered to a patient. Accordingly, if the patients respiratory rate has been slowed to a dangerously low rate it is important to prevent further administration of drug to the patient.

Abstract

La douleur peut être contrôlée par la libération intrapulmonaire d'une composition analgésique pharmaceutiquement active. Ladite composition est libérée automatiquement par un dispositif à main autonome portatif (1) constitué d'un moyen (7) de distribution automatique d'une dose de médicament dans le conduit inspiratoire d'un patient en réponse à des informations provenant d'un moyen (22) d'analyse du débit inspiratoire d'un patient. L'observance médicamenteuse et la précision du dosage sont obtenues par une libération automatique en réponse à un profil d'inhalation mesuré. L'abus de compositions narcotiques est empêché grâce à un dispositif inviolable comportant plusieurs sécurités dont un microprocesseur préprogrammé (22) conçu pour empêcher le surdosage.
PCT/US1994/000999 1993-01-29 1994-01-27 Liberation intrapulmonaire de narcotiques WO1994016755A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU60976/94A AU6097694A (en) 1993-01-29 1994-01-27 Intrapulmonary delivery of narcotics

Applications Claiming Priority (2)

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US1128993A 1993-01-29 1993-01-29
US08/011,289 1993-01-29

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WO (1) WO1994016755A1 (fr)

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EP0759744A1 (fr) * 1994-05-13 1997-03-05 Aradigm Corporation Formulation en aerosol contenant un narcotique
WO1997013553A1 (fr) * 1995-10-10 1997-04-17 Medtrac Technologies Inc. Dispositif electronique d'enregistrement chronologique de medication
FR2740345A1 (fr) * 1995-10-26 1997-04-30 Neftel Frederic Dispositif d'automedication
EP0952866A1 (fr) * 1996-11-06 1999-11-03 Imed Corporation Systeme d'auto-analgesie a la demande avec controle de l'oxymetrie
GB2385845A (en) * 2002-02-22 2003-09-03 G W Pharma Ltd Dose dispensing apparatus
US7537005B2 (en) 2002-02-22 2009-05-26 Gw Pharma Limited Dose dispensing system and apparatus
US9008761B2 (en) 2010-02-01 2015-04-14 Proteus Digital Health, Inc. Two-wrist data gathering system
US9014779B2 (en) 2010-02-01 2015-04-21 Proteus Digital Health, Inc. Data gathering system
US9084566B2 (en) 2006-07-07 2015-07-21 Proteus Digital Health, Inc. Smart parenteral administration system
US9125979B2 (en) 2007-10-25 2015-09-08 Proteus Digital Health, Inc. Fluid transfer port information system

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0759744A1 (fr) * 1994-05-13 1997-03-05 Aradigm Corporation Formulation en aerosol contenant un narcotique
EP0759744A4 (fr) * 1994-05-13 1997-10-29 Aradigm Corp Formulation en aerosol contenant un narcotique
WO1997013553A1 (fr) * 1995-10-10 1997-04-17 Medtrac Technologies Inc. Dispositif electronique d'enregistrement chronologique de medication
FR2740345A1 (fr) * 1995-10-26 1997-04-30 Neftel Frederic Dispositif d'automedication
WO1997015339A1 (fr) * 1995-10-26 1997-05-01 Debiotech S.A. Dispositif d'automedication
EP0952866A1 (fr) * 1996-11-06 1999-11-03 Imed Corporation Systeme d'auto-analgesie a la demande avec controle de l'oxymetrie
EP0952866A4 (fr) * 1996-11-06 2000-05-17 Imed Corp Systeme d'auto-analgesie a la demande avec controle de l'oxymetrie
GB2385845B (en) * 2002-02-22 2006-03-08 G W Pharma Ltd Dose dispensing apparatus
GB2385845A (en) * 2002-02-22 2003-09-03 G W Pharma Ltd Dose dispensing apparatus
US7537005B2 (en) 2002-02-22 2009-05-26 Gw Pharma Limited Dose dispensing system and apparatus
US8061351B2 (en) 2002-02-22 2011-11-22 Gw Pharma Limited Dose dispensing system and apparatus
US9084566B2 (en) 2006-07-07 2015-07-21 Proteus Digital Health, Inc. Smart parenteral administration system
US9125979B2 (en) 2007-10-25 2015-09-08 Proteus Digital Health, Inc. Fluid transfer port information system
US9008761B2 (en) 2010-02-01 2015-04-14 Proteus Digital Health, Inc. Two-wrist data gathering system
US9014779B2 (en) 2010-02-01 2015-04-21 Proteus Digital Health, Inc. Data gathering system
US10376218B2 (en) 2010-02-01 2019-08-13 Proteus Digital Health, Inc. Data gathering system

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