KR20090096747A - Storage and dispensing devices for administration of oral transmucosal dosage forms - Google Patents

Abstract

Compositions, methods and systems for oral transmucosal administration of small volume sufentanil-containing drug dosage forms to a subject using a drug dispensing device are disclosed. The drug dispensing device may provide for administration of multiple doses, a single dose at a time or be a single dose applicator (SDA).

Description

STORAGE AND DISPENSING DEVICES FOR ADMINISTRATION OF ORAL TRANSMUCOSAL DOSAGE FORMS

The present invention relates to a drug delivery device, method and system for oral transmucosal administration of a small volume of drug formulation to a subject, the drug formulation comprising serfentanil for pain treatment.

Oral formulations make up about 80% of all drug formulations on the market. Oral formulations are non-invasive, easily administered and have high patient compliance.

Orally administered therapeutics are rapidly delivered to the stomach and small intestine for absorption across the gastrointestinal (GI) mucosa into the blood. Metabolism in the GI region and metabolism in the liver, which are not suitable for controlling acute illness, or because of relatively long onset time or abnormal absorption characteristics, can reduce the effectiveness of drug absorption after oral administration. Most of the oral formulations on the market are designed for GI delivery. Relatively small oral formulations are designed for delivery through the oral mucosa.

However, oral transmucosal delivery offers several advantages, particularly for lipophilic drugs, which may provide shorter onset times of action _up to the maximum plasma concentration (C _max ) than oral delivery. This is because the drug passes rapidly and directly and efficiently through the highly vascularized mucosal tissues to the plasma, reaching the circulatory organ quickly, avoiding slow and often inefficient variable GI absorption. Thus, it is advantageous for the drug to be delivered through the mucosa of the aperture cavity (eg, via the sublingual route) when rapid action, constant T _max and C _max are beneficial.

To effect oral transmucosal drug delivery, the drug is absorbed through the epithelial mucosa of the oral cavity. However, a frequent major risk associated with oral transmucosal delivery is the increased likelihood of swallowing the drug due to continuous production, reflux and saliva swallowing. This is particularly dangerous if the formulation used is large enough to cause a significant saliva reaction, causing swallowing of the drug and / or removal of the formulation from the oral mucosa.

Various solid formulations such as sublingual tablets, pills, lozenges pills, lozenges on sticks, chewing gum, and ball patches have been used to deliver drugs through oral mucosal tissue. Solid dosage forms such as lozenges and tablets have been used for oral transmucosal of drugs such as nitroglycerin sublingual tablets.

The related art does not describe a dispensing device for delivering the drug formulation to the oral mucosa, such as the sublingual space, where the device facilitates proper placement of the drug formulation.

Reproducible and effective drug delivery techniques represent an active research area, particularly when applied to controlled substances such as opioids. Oral transmucosal drug dispensing systems with a controlled approach offer many advantages over conventional drug administration means, such as the oral and intravenous routes, the most important of which are faster and more consistent expression, more consistent and predictable than currently available formulations. With additional benefits such as plasma concentrations, higher and more consistent bioavailability, there is an improvement in safety.

This relates in particular to the treatment of pain, more particularly acute, intermittent and sudden pain.

Thus, there remains a need for devices and systems that can be used to administer controlled substances such as opioids (eg, patient controlled administration) for the treatment of pain while minimizing the potential for drug abuse and / or dedication.

The present invention addresses this need.

The present invention provides drug delivery devices, methods, systems, and kits for oral transmucosal membranes, such as, for example, sublingual administration of bioadhesive small volumes of serpentanyl containing drug formulations to a subject using a device.

The device is portable by hand and includes a cartridge containing one or more drug formulations (typically 1 to about 200 formulations).

Each formulation contains 5 mcg, 10 mcg, 15 mcg, 20 mcg, 30 mcg, 40 mcg, 50 mcg, 60 mcg, 70 mcg, 80 mcg, or 100 mcg of serpentanyl and has a volume of less than 100 microliters or Have a mass of less than 100 mg.

With the device, the dispensing end of the device is inserted into the subject's mouth and the formulation is dispensed through the dispensing end of the device (eg sublingual space) located in the subject's oral mucosa.

The dispensing end of the device has a spout comprising a side plate for positioning the formulation, the side plate comprising means for preventing or delaying the entry of saliva and other moisture into the device such that the formulation remains dry before being placed on the oral mucosa. do.

The device further includes a lockout element for setting the lockout time, wherein the formulation cannot be dispensed from the device during the lockout time. The lockout time is transmitted to a distribution device from a fixed time lockout period, a predetermined lockout period, a predetermined variable lockout period, a programmable lockout period determined by an algorithm or from a remote computer, a docking station or another device. It may be a lockout period.

The cartridge may comprise one or more tablets, wherein at least one tablet is dispensed prior to dispensing the formulation.

The cartridge includes a smart cartridge recognition system, the system comprising a physical major element of the cartridge, an optically detected element or pattern, a bar code of the cartridge, a magnetic tag of the cartridge, an RFID tag of the cartridge, an electronic microchip of the cartridge, or Combinations thereof.

The dispensing device further includes user identification means, wherein the user identification means is a radio frequency identification (RFID) reader configured to be associated with the identified patient's matching RFID tag, wherein the dispensing device is configured to have the dispensing device's RFID reader read the patient's matching RFID. When detecting a tag, it can be released or used.

The dispensing device may comprise means for recording the administration history, the usage history, or both alone or with the means for viewing or downloading the administration and / or usage history.

After placement of the formulation on the subject's oral mucosa, erosion of the formulation is completed in about 30 seconds to about 30 minutes.

In the practice of this method, a single sublingual administration of the formulation to a subject exhibits a bioavailability of at least 50%, an AUC with a coefficient of variation of less than 40%, a T _max with a coefficient of variation of less than 40%, Repeated sublingual administration of the formulation shows better bioavailability than the bioavailability after a single sublingual administration to the subject, and the difference between the T _max after repeated sublingual administration and the time of prior sublingual administration after the single sublingual administration to the subject Shorter than T _max .

When a bioadhesive small volume of serpentanyl containing drug formulation is dispensed into the sublingual cavity of the subject using the device, at least 55%, at least 60%, at least 65%, at least 70%, at least 75 of the total amount of drug in the formulation The amount of drug selected from the group consisting of%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% and at least 99% is absorbed via the oral transmucosal route.

Administration of the serfentanil containing drug formulation using the drug dispensing device can be patient controlled, can be used to treat pain in the subject, and pain relief is apparent after administration of the formulation.

1A-1E are schematic diagrams of representative dispensing devices designed to deliver drug formulations to the oral mucosa of a patient being treated.

2 is a schematic diagram of an exemplary dispensing device showing the elements configured to prevent or delay saliva and moisture ingress.

3A and 3B are schematic diagrams of representative geometries of the dispensing tip.

4A-4D are schematic views of representative spouts of the dispensing device.

5A-5D are a series of flow charts for the use of a representative device illustrating the stages of pushload / purification interaction in the use of the device, FIG. 5A is a load process, FIG. 5B is a calibration process, FIG. 5C is a dispense process, And FIG. 5D shows the decomposition process.

6 is a schematic diagram of an exemplary device showing the stage of pushrod / tablet interaction in use.

7 is a schematic diagram of a schematic structure showing various components that may be included in a drug delivery device or system.

8A is a block diagram illustrating communication of one aspect of a drug dispensing system, the system including an RFID tag, a drug dispensing device, a base station / dock, and a personal computer of a healthcare professional.

8B is a block diagram illustrating communication of another aspect of a drug dispensing system, the system including an RFID tag, a drug dispensing device, a portable docking FOB, and a personal computer from a base station and a healthcare professional.

FIG. 9 is a graph of serpentanyl plasma concentrations after intravenous or sublingual administration of three different strength serpentanyl formulations (n = 12) in healthy human volunteers.

FIG. 10 shows post sublingual administration of Serfentanil Formulation # 44 (equivalent to Human # 47 Formulation; n = 3) compared to intravenous Serfentanil administration (n = 3) in a healthy, conscious Beagle dog model. Schematic diagram of fentanyl plasma concentrations. Error bars represent standard error near the mean (SEM).

FIG. 11 shows after sublingual administration of serfentanil solution (n = 6) or oral of serfentanil (n = 6) compared to intravenous administration of intravenous administration of serfentanil (n = 3) in a healthy, conscious Beagle dog model. A graphical representation of serpentanyl plasma concentrations after ingestion. Error bars represent ± standard error near the mean (SEM).

FIG. 12 is a graphical representation of alfentanil plasma concentrations after sublingual administration of Alfentanil NanoTab ^™ (n = 2) compared to intravenous alfentanil administration (n = 3) in a healthy, conscious Beagle dog model. Error bars represent ± standard error near the mean (SEM).

13 is a graph of the effect of pH of dissolution exercise of serfentanil from a representative oral transmucosal formulation.

14A and 14B are schematic diagrams of representative single dose applicators.

15A-15C illustrate a type of single-dose applicator and show its use in delivering a formulation to a subject.

16A-16F show an additional six single dose applicators.

17 shows a multiple dose applicator stored before multiple single dose applicators are used.

18A-18C show embodiments of additional single dose applicators and multiple dose applicators.

19A-19B show two stages of use of one embodiment of a single dose applicator.

20A-20D are schematic diagrams of additional examples of single dose applicators (SDAs).

21A-21D are schematic diagrams of multiple dose applicators or containers storing multiple SDAs prior to use, and schematic diagrams of the use of SDA for sublingual administration of drug formulations.

I. Introduction

Provided herein are compositions, methods, systems, and kits for oral transmucosal administration of small volumes of formulations containing opioids using a device. Oral transmucosal delivery of the formulation minimizes saliva response and thus minimizes delivery of the drug to the GI tract so that most of the drug is delivered past the oral mucosa. Small volume drug formulations have bioadhesives that facilitate adhesion to oral mucosa, thus minimizing ingestion and inefficient delivery due to swallowing.

The following description shows the formulations, devices, methods, systems, and kits that make up the invention. The invention is not limited to particular formulations, devices, methodologies, systems, kits, or pharmaceutical compositions described herein, but may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.

It should be noted that the appended claims and the singular forms used herein include the plural references unless the context clearly dictates. Thus, for example, "drug formulation" includes a plurality of such formulations, and "drug delivery device" is referred to as including a system comprising a drug formulation and a device for containment, storage and delivery of such formulation.

Otherwise, all technical and scientific terms used herein have the same meaning as terms commonly understood in one of the prior art to which this invention belongs. Although any methods, devices and materials similar or identical to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices and materials are described herein.

The publications discussed herein are provided for publication only prior to the filing date of the present invention. The publications mentioned herein are not meant to acknowledge that the invention should not be preceded by the disclosure of the prior invention.

II. Justice

The term "active agent" or "active" can be used interchangeably with the term "drug" herein and means any therapeutic agent.

The term "adhesion" is used herein with reference to a drug formulation or formulation, which drug formulation or formulation is in contact with a surface, such as a mucosal surface, and remains on the surface without the action of external forces. The term "adhesion" is not meant to imply any degree of adhesion or bonding, nor is it meant to imply any permanent degree.

As used herein, the term "painkiller" includes serpentanyl or serpentanyl homologues such as alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil or mirfentanil, as well as one or more therapeutic compounds. It includes a formulation to make. The use of the phrase “serpentanyl or allomeric” does not mean that it is limited to the use of only one of these selected opioid compounds, or to formulations containing only one. Moreover, references to serpentanyl alone or selected serpentanyl homologs alone, such as to “alfentanil,” are to be understood only as examples of drugs suitable for delivery according to the methods of the invention and in any manner It is not meant to be limited.

The term "AUC" as used herein means "area under the curve" in the concentration graph of the drug in plasma versus time. AUC is generally given for time intervals from zero to infinity, but apparently plasma drug concentrations cannot be measured to 'infinity' for a patient, so using a mathematical approach to estimate AUC from a limited number of concentration measurements do. In practical terms, AUC (infinity from zero) refers to the total amount of drug absorbed by the body regardless of the rate of absorption. This is useful when one wants to determine whether two agents of the same dose release the same dose of drug to the body. The AUC of transmucosal formulation compared to the same dose administered intravenously serves as a criterion for the assessment of bioavailability.

The term "bioadhesion" as used herein refers to adhesion to a biological surface, including mucous membranes.

As used herein, the term "bioavailability" or "F" means "% bioavailability" and, when administered intravenously, refers to the fraction of drug absorbed from the test article compared to the same drug. This is calculated from AUC _∞ of the test article after delivery from the intended route versus AUC _∞ for the same drug after intravenous administration. It is calculated from the formula: Bioavailability (%) = AUC _∞ (Test Product) / AUC _∞ (Intravenous Pathway / Product).

As used herein, the term “abruptive pain” is a temporary explosion up to the intense intensity of controlled pain that occurs in the cause of other controlled pain. "Sudden pain" can be concentrated for as short as 1 or 2 minutes or as long as 30 minutes or more.

The term “cartridge” is used herein with reference to a replaceable single use disposable cartridge configured to receive one or more drug formulations, typically up to 200 drug formulations. A cartridge typically includes a smart cartridge recognition system having physical major elements on the cartridge, a bar code on the cartridge, a magnetic tag on the cartridge, an RFID tag on the cartridge, an electronic microchip on the cartridge, or a combination thereof. The cartridge may comprise one or more tablets, wherein at least one tablet is dispensed prior to dispensing the formulation.

The term "C _max " as used herein refers to the maximum plasma concentration observed after drug administration.

The term “homogen” as used herein refers to one of several variations or configurations of common chemical structures.

As used herein, the term "collapse" is used interchangeably with "erosion" and means a physical method in which the formulation is broken and related to the physical integrity of the tablet alone. This can occur in a number of different ways, including breaking into smaller pieces and ultimately fine and large particulates or, alternatively, eroding from the outside until the tablet disappears.

As used herein, the term “dissolution” refers to the process by which the active ingredient is dissolved from the tablet in the presence of an in vitro solvent or in vivo physiological fluid, eg, saliva, regardless of the mechanism of release, diffusion of erosion. .

The terms "dispensing device", "drug dispensing device", "dispenser", "drug dispenser", "drug dispensing dispenser", "device" and "drug delivery device" are used herein interchangeably with "dispensing device". A device for dispensing a drug formulation. Single dose applicators are considered "drug dispensing devices." Dispensing devices provide a mechanism for the controlled safe delivery of a formulation of a drug for delivery to a patient's oral mucosa, and can be found in lozenges, pills, tablets, capsules, membranes, strips, liquids, patches, films, gels, sprays, etc. Is adapted for storage and / or delivery of the formulations.

The term “dispensing end” as used herein for a device includes a spout and a side plate and means a portion of the device for delivering a drug formulation to the oral mucosa of the subject.

The terms “drug”, “drug,“ pharmacologically active agent ”and the like are used interchangeably herein and refer to any substance that generally alters the physiology of the animal and can be administered effectively by the oral transmucosal route.

The term "erosion time" means the time required for the solid dosage form to break until the formulation disappears.

The term “FOB” refers to a dispenser for uploading data, downloading data, controlling access to drug dispensing devices, controlling access to drug dosage forms, or enhancing or changing the user interface of drug dispensing devices. Refers to a portable electronic docking device that is portable in a small hand that can be used in conjunction with The FOB can communicate or dock with the drug dispensing device in a wired or wireless manner. The FOB may be adapted to be attached to a strap, in particular in a hospital setting, to allow the FOB to be caught in the neck of a healthcare professional, such as a doctor or caregiver. The drug dispensing device may communicate with a physician or caregiver via FOB.

As used herein, the terms "formulation" and "drug formulation" refer to a physical composition that contains at least one therapeutically active substance and can be provided in any of a number of formulations for delivery to a subject. The formulations may be provided in lozenges, pills, capsules, membranes, strips, liquids, patches, films, gums, gels, sprays or in other forms.

As used herein, the term “hydrogel forming agent” refers to a solid that is largely devoid of water capable of absorbing water in such a way as to form a hydrogel in situ when in contact with an aqueous solution, such as a body fluid and especially a body fluid in the oral mucosa. Means formulation. The formation of the gel follows a unique disintegration (or erosion) kinetics, allowing for the regulation of therapeutic drug release over time. Moreover, the term “hydrogel forming agent” refers to a solid preparation that is largely devoid of water, which is transformed into a film that releases the drug upon contact with body fluids, especially body fluids in the oral cavity. Such films can absorb drugs faster by increasing the surface area available for drug release and absorption.

The term "lockout element" is used herein in reference to an element of an apparatus that provides a "lockout time".

The term "lock out time" is used herein with reference to a period during which the device does not allow drug access, ie the formulation cannot be dispensed during the "lock out time". The "lock out time" can be programmed at fixed time intervals, predetermined intervals, predetermined variable intervals, algorithm determined intervals, or variable intervals connected to a device from a remote computer or docking station.

The term "log P" means the logarithm of the ratio of the equilibrium concentrations of the non-ionized compound between octanol and water. P is also called "octanol water partition coefficient" and serves as a means of quantifying the chemical character hydrophobicity or fat affinity of a given drug.

The term “mucoadhesive” is used herein to refer to attachment to mucous membranes covered by mucus, such as those in the oral cavity, and as used herein interchangeably with the term “bioadhesive” to refer to any biological surface. do.

The term "mucosa" generally refers to any biological membrane that is mucus coated in the body. Of particular interest is absorption through the mucous membranes of the oral cavity. Thus, oral mucosa absorption, ie cheek, sublingual, gum and palate absorption, is specifically contemplated by the present invention.

The term "mucosal storage" is used herein in the broadest sense to denote the storage or storage of pharmacologically active substances in or just below the mucosa.

The term “non-sequential particle mixture” or “non-sequential mixture” is used herein to refer to a formulation wherein the mixture is not sequential with respect to the pharmacologically active agent, bioadhesive, or bioadhesion promoter, or other tablet component. Moreover, it is used herein to refer to any formulation produced by a treatment comprising dry mixing, wherein the formulation is not evenly distributed over the surface of the carrier particles with large drug particles. Such “non-sequential” mixing may include dry mixing of the particles in an out-of-order fashion, with respect to the order of addition / mixing of certain additives with drugs, bioadhesives or bioadhesion promoters and / or disintegrants. There is no requirement. Moreover, the size of drug particles in the non-sequential mixing process is not limited. Drug particles may exceed 25 μm. Moreover, the "non-sequential mixture" may include any mixing treatment in which the primary carrier particles do not mix the disintegrant. Finally, "non-sequential mixtures" are prepared by any "wet mixing" treatment, i.e., a solvent or non-solvent added during the mixing treatment, or any mixing treatment in which the drug is added to the solution or suspended form during the mixing treatment. Can be.

As used herein, “operably connected” means that the component is provided to the device to function as intended for any purpose. For example, a memory device that is operatively connected to a CPU that is more operatively connected to a releasing mechanism may be used by the CPU to communicate with the memory device to check the status or history of drug delivery during operation, and then to release and dispense the drug. It may mean indicating communication with a release mechanism (eg, via a solenoid and a switch).

The terms "oral transmucosal formulation" and "drug formulation" can be used interchangeably herein and refer to formulations comprising pharmacologically active substances such as drugs such as serfentanil. Oral formulations are used to deliver pharmacologically active substances to the circulatory system by the oral mucosa, typically a "sublingual formulation", but in some cases other oral transmucosal routes may be used. The formulation controls the formulation from which the point of release of the pharmacologically active substance can be obtained, providing a formulation of the pharmacologically active substance through the oral mucosa, without occurring through GI absorption after swallowing. The formulation includes a pharmaceutically acceptable additive and may be called NanoTab ^™ , as detailed above in US Application Serial No. 11 / 650,174. The formulation comprises a formulation, which formulation is non-foamable and essentially comprises no water-free sequential mixture of microparticles of the drug adhered to the surface of the carrier particles, the carrier particles being substantially the extremes of the drug. It is larger than the fine particles.

As used herein, the terms “oral transmucosal drug delivery” and “oral transmucosal administration” are used to refer to drug delivery substantially occurring through the oral transmucosal route, rather than through GI uptake after swallowing. This includes delivery through the cheek, sublingual, and gum mucosal areas.

The term “spout” is used interchangeably with the terms “dispensing tip” and “delivery tip,” and the dispensing tip and / or positioning tip of a drug dosage form dispenser that delivers the dosage form to the oral mucosa (eg, sublingual space). Say

The term "radio frequency identification device" or "RFID" is used with reference to an automatic identification method that relies on data storage and remote retrieval using a device called an RFID tag, which is applied to a product or an individual for identification using radio waves or Are combined. Some tags may be read several meters away or over a line of sight of the reader.

The term “replaceable cartridge” or “disposable cartridge” is typically used with respect to a cartridge for containing a drug formulation configured to receive up to 200 drug formulations, which cartridge is designed to be discarded when used.

The term “loaded tablet” is used herein with reference to “initial” or “loaded” tablets and has the same size and shape as the drug containing formulation but does not include a therapeutically active substance. “Loaded tablets” can include placebo formulations that do not include a therapeutically active substance and can be made of plastic or other materials. The loaded tablet is the first one dispensed from a new cartridge after insertion into a dispensing device. The device has a means for distinguishing a drug formulation comprising a loaded tablet and a therapeutically active substance.

The term “side plate” is used to describe partially or completely covering the dispensing end of the device, which side plate prevents contact of saliva or other moisture with the delivery port, and forms a barrier between the device and the oral mucosa and tongue. And a relief for formulation delivery, and an interior that is hydrophobic or hydrophilic, which interior serves to minimize or eliminate saliva ingress or moisture ingress. "Side plate" creates a barrier that prevents oral mucosa from contacting the valve area and the formulation, assists in dispensing the formulation, and prevents the formulation from adhering to the side plate. The side plate may have a rounded inner surface or other geometry to mitigate adherence of the formulation to the side plate. The side plates limit saliva or oral mucosa's ability to contact the formulation dispensing area to control saliva contact and entry. The side plates protect the valves from moisture and saliva entry from the mouth and other mucous membranes, and provide an area for the formulation to exit the device without "sticking" to the wet end valve or side plate area. The side plate also includes a cutout / relief to relieve drag in the formulation when the device is removed from the oral cavity. The valve controls saliva and moisture ingress and also works with the side plates to aid in delivery of the formulation.

The term "subject" includes any subject in need of treatment for a disease, generally a mammal (eg, human, canine, feline, horse, bovine, ungulate, etc.), adult or child. The terms "subject" and "patient" can be used interchangeably herein.

As used herein, the term “system comprising drug formulation and dispensing device” refers to a drug dispensing system for the delivery and / or monitoring of drug administration. The system can be used to monitor and deliver therapeutically active substances such as opioids, such as serfentanil, and the efficacy and safety depending on the amount of drug delivered can be improved over currently available systems. The system may have one or more elements that provide improved safety and ease of use compared to currently available systems, which elements are safety elements, controlled drug access that prevents unauthorized access to stored drugs, such as administration lockout elements. Means for identifying an individual user, a dose counting element, storage means for maintaining information about dose delivery, and an interface for bi-directional exchange of information with another device such as a user, drug cartridge or computer.

The term “small volume drug formulation” or “small volume formulation” is used herein for small volume formulations having a volume of less than 100 μl and a mass of less than 100 mg. More specifically, the formulation is 100 mg, 90 mg, 80 mg, 170 mg, 60 mg, 50 mg, 40 mg, 30 mg, 29 mg, 28 mg, 27 mg, 26 mg, 25 mg, 24 mg, 23 Mg, 22 mg, 21 mg, 20 mg, 19 mg, 18 mg, 17 mg, 16 mg, 15 mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg, 9 mg, 8 mg, 7 mg, Has a mass of less than 6 mg, or 5 mg, or 100 μl, 90 μl, 80 μl, 170 μl, 60 μl, 50 μl, 40 μl, 30 μl, 29 mg, 28 mg, 27 μl, 26 μl, 25 Μl, 24 μl, 23 μl, 22 μl, 21 μl, 20 μl, 19 μl, 18 μl, 17 μl, 16 μl, 15 μl, 14 μl, 13 μl, 12 μl, 11 μl, 10 μl, 9 μl, Have a volume of less than 8 μl, 7 μl, 6 μl, or 5 μl. A "formulation" may or may not have bioadhesion and may form a hydrogel upon contact with an aqueous solution.

"Formulation" delivers any drug that can be administered by the oral transmucosal route in an amount that can be administered through the small size of the formulation, i.e. 0.25 μg to 99.9 mg, 1 μg to 50 mg or 1 μg to 10 mg. Can be used to

The term “small volume of serfentanil-containing drug formulation” herein refers to from about 2 micrograms (mcg) to about 200 mcg of serpentanyl, such as 5 mcg, 10 mcg, 15 mcg, 20 mcg, 30 mcg, 40 mcg, 50 mcg It is used with respect to small volume formulations comprising a dose of serfentanil selected from 60 mcg, 70 mcg, 80 mcg, or 100 mcg of serpentanyl.

The term “solid formulation” or “solid drug formulation” is used herein with reference to small volume formulations that are solids such as lozenges, pills, capsules, tablets, membranes, or strips.

As used herein, "sublingual" means literally "under the tongue" and refers to a method of administering the substance through the mouth in such a way that the substance is absorbed faster through the blood vessels below the tongue than through the digestive organs. Absorption occurs through the vascular-rich oral mucosa and provides direct systematic administration regardless of the GI effect, allowing the therapeutically active substance to access blood flow more directly.

The term "Therapeutic Time Ratio" or "TTR" is defined as the time that drug plasma concentration is maintained above 50% of the C _maximum normalized to the elimination half-life of the drug, the mean that the drug is present at the therapeutic level. Time is given and is calculated by the formula: TTR = (over 50% of C _maximum time) / (terminal intravenous elimination half-life of drug). The last term is obtained from literature data on the drug in suitable species.

As used herein, the term "T _max " means the time point of the observed maximum plasma concentration.

As used herein, the term “T _{action expression} ” means “time of action expression” and refers to the time required for the plasma drug concentration to reach 50% of the maximum plasma concentration (C _max ) observed.

The term “therapeutically effective amount” means the amount of therapeutic agent or the rate of delivery of the therapeutic agent (eg, over time) that is effective for promoting the desired therapeutic effect, such as pain relief. The exact desired therapeutic effect (eg, degree of pain relief and alleviated pain source, etc.) depends on the condition being treated, the resistance of the subject, the drug administered and / or the drug formulation (eg, the efficacy of the therapeutic agent (drug), the agent Concentration of drug, etc.), and various other factors recognized by one of ordinary skill in the art.

III. Drug formulation

The small volume oral transmucosal drug formulations claimed result in a reduced saliva response compared to conventional large formulations that deliver drugs in the oral cavity. The formulation includes a pharmacologically active substance and provides a high rate of absorption of the pharmacologically active substance across the oral mucosa and reduced absorption through the gastrointestinal tract active substance, resulting in a more consistent and reproducible pharmacokinetic region and corresponding pharmacokinetic profile. to provide.

The formulation is typically a "sublingual formulation" but in some cases other oral transmucosal routes may be used. The formulation is a substantially homogeneous composition comprising one or more active drugs with pharmaceutically acceptable additives.

In certain embodiments, although it is beneficial to place the drug formulation inside the cheeks or attach it to the mouth ceiling or gums, the preferred location for oral transmucosal drug delivery is the sublingual space.

The formulation provides a higher delivery (and amount) of drug through the oral mucosa and a corresponding reduction in delivery through the gastrointestinal (GI) tract compared to conventional oral formulations and other oral transmucosal formulations.

Typically, formulations are generally adapted to adhere (ie bioadhesive) to the oral mucosa upon drug delivery until most or all of the drug is delivered from the formulation to the oral mucosa.

 The claimed formulations have a mass of less than 100 mg and a volume of less than 100 μl. More specifically, the formulation is 100 mg, 90 mg, 80 mg, 170 mg, 60 mg, 50 mg, 40 mg, 30 mg, 29 mg, 28 mg, 27 mg, 26 mg, 25 mg, 24 mg, 23 Mg, 22 mg, 21 mg, 20 mg, 19 mg, 18 mg, 17 mg, 16 mg, 15 mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg, 9 mg, 8 mg, 7 mg, Have a mass less than 6 mg, or 5 mg, or 100 μl, 90 μl, 80 μl, 170 μl, 60 μl, 50 μl, 40 μl, 30 μl, 29 μl, 28 μl, 27 μl, 26 μl, 25 Μl, 24 μl, 23 μl, 22 μl, 21 μl, 20 μl, 19 μl, 18 μl, 17 μl, 16 μl, 15 μl, 14 μl, 13 μl, 12 μl, 11 μl, 10 μl, 9 μl, Have a volume of less than 8 μl, 7 μl, 6 μl, or 5 μl. Formulations are typically bioadhesive and can form hydrogels upon contact with an aqueous solution.

Formulations typically have an erosion time from 30 seconds to 5 minutes, up to 10 minutes, up to 15 minutes or up to 30 minutes.

Generally, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90 of the total amount of pharmacologically active substance in the formulation administered to the oral mucosa of the subject %, At least 95%, at least 98% or at least 99% are absorbed via the oral transmucosal route.

The formulation may have essentially any shape, including by way of example, a circular disk having ellipsoidal, flat or concave or convex, spherical, three or more blades and a polygon with flat, concave or convex. Drug formulations may be symmetrical or asymmetrical and may have elements or geometries that are controlled, convenient, and easy to store, handle, pack and administer.

Oral transmucosal drug delivery is simply non-invasive and can be administered by a caregiver or patient with minimal discomfort. Formulations for oral transmucosal delivery can be solid or nonsolid. In one preferred embodiment, the formulation may be a solid which is converted to a hydrogel after contact with saliva. In another preferred embodiment, the formulation is a solid which is eroded without forming a hydrogel after contact with saliva.

Oral transmucosal delivery of pharmacologically active substances is generally obtained using specific formulations, such as lozenges or pills, but liquids, sprays, gels, gums, powders and films and the like may also be used.

For certain drugs, such as those with poor bioavailability through the GI tract, such as lipophilic opioids such as serpentanyl and alfentanil, oral transmucosal delivery can provide a more effective route of delivery than GI delivery. For drugs such as lipophilic opioids, oral transmucosal delivery has a shorter onset time (ie, time to therapeutic effect from administration) than oral GI delivery administration, and provides better bioavailability and more consistent pharmacokinetics. .

The drug formulations claimed are designed and adapted to reduce saliva response, thus reducing the amount of drug swallowed, delivering the actual amount of drug to the subject through the oral mucosa. The claimed drug formulations also effectively deliver drugs through the oral mucosa and provide constant plasma levels within the therapeutic range.

The claimed formulations comprise substantially homogeneous formulations comprising at least 0.001% by weight of pharmacologically active substance in combination with pharmaceutically acceptable additives. Commonly claimed formulations comprise 0.01 to 99% or about 0.25 μg to 99.9 mg, about 1 μg to 50 mg, or about 1 μg to 10 mg w / w of pharmacologically active substance.

Formulations for the preparation of the claimed formulations and methods of making the formulations are described in US Application Nos. 11 / 825,251 and 11 / 650,227. Representative agents are bioadhesive and about 0.0004% to about 0.04% are serpentanyl, such as 0.0005%, 0.001%, 0.002%, 0.003%, 0.004%, 0.006%, 0.008%, 0.01%, 0.012%, 0.014% Or 0.016% of serpentanyl. In general, the formulation comprises (a) a non-sequential mixture of pharmacologically active amounts of the drug, (b) a bioadhesive material for attachment to the oral mucosa of the subject, and (c) stearic acid, the formulation of the formulation comprising the formulation Dissolution is independent of pH, for example over a pH range of about 4-8.

Pharmacologically active agents for use in the formulations of the invention are characterized by the logarithm of the octanol-water separation coefficient (LogP) of 0.006 to 3.382.

Pharmaceutical formulations of the invention for oral transmucosal delivery may be solid or nonsolid. In one preferred embodiment, the formulation may be a solid which is converted to a hydrogel after contact with saliva. In another preferred embodiment, the formulation is a solid that is converted into a bioadhesive film upon contact with saliva.

In a preferred embodiment, such formulations are designed to form a membrane visible after tablet digestion. When placed on the oral mucosa, the formulation absorbs water so that, upon complete hydration, the formulation spreads over the mucosal surface to convert it into a bioadhesive film containing the active drug. This modification results in a significant increase in the surface area available for drug release, promoting drug diffusion and releasing the drug from the formulation. Due to the high contact surface area, drug absorption occurs quickly resulting in rapid action expression.

Many suitable non-toxic pharmaceutically acceptable carriers for use in oral formulations can be found in 'Remington's Pharmaceutical Sciences (17th edition, 1985)'.

Those skilled in the art will appreciate that the formulations will be converted into formulations to deliver wet granules and the like to subjects using routinely used procedures such as direct compression. The formulation process of the formulation is optimized for each formulation to achieve high dosage content uniformity.

Without wishing to be bound by theory, in one exemplary embodiment, when the drug formulation is positioned in the sublingual cavity, preferably below the tongue on either side of the plaque tongue organ, the drug formulation is attached upon contact. When the formulation is exposed to moisture in the sublingual space, the formulation absorbs water, resulting in erosion of the formulation and release of the active drug in the subject's circulatory system.

Ⅳ. Serfentanil

Opioids are still widely used for the treatment of pain and are generally delivered intravenously, orally, epidural, transdermal, rectal and intramuscular. Morphine and its analogues are usually delivered intravenously and are effective for severe, chronic and acute pain. However, they also have severe respiratory depression if not used properly and they also suffer from high abuse potential. The main cause of morbidity and mortality from pure opioid overdose is due to respiratory complications.

One example of a representative use of the claimed drug formulation is application to pain-relieving. When the claimed drug formulations are used for the treatment of pain, they include drugs such as opioids or opioid agonists and are useful for treating both moderate to severe intensity acute and chronic pain.

In such drug formulations the active agent is serfentanil, or a serpentanyl homologue such as, for example, alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil. In a preferred embodiment, serfentanil is used as the activator. Serpentanyl may be provided as citric acid serpentanyl, serpentanyl salt, or a combination thereof.

Another preferred embodiment uses serpentanyl homologs as activators. Another preferred embodiment utilizes a combination of serfentanil and at least one additive for treating analgesia, such as a combination of serfentanil and alfentanil as an active agent. Since various opioid drugs have different pharmacokinetic profiles and different interactions with mu opioid receptor splicing variants, they can be used in combination to enhance the therapeutic effect.

Serpentanyl (N-[(4- (methoxymethyl-1- (2- (2-thienyl) ethyl) -4-piperidinyl)]-N-phenylpropanamide) is intended for epidural administration during childbirth. The commercially available form of serfentanil used for IV delivery is SUFENTA FORTE ^® formulation, which is used as a primary anesthetic to produce a balanced general anesthesia in cardiac surgery and in both intranasal and liquid oral formulations. The liquid formulation contains 0.075 mg / ml serpentanyl citrate (equivalent to 0.05 mg serpentanyl base) and 9.0 mg / ml sodium chloride in water, which has a plasma elimination half-life of 148 minutes and is 80% of the administered dose. Is discharged within 24 hours.

Although 200 mcg Actiq ^® doses exhibit varying GI uptake due to swallowing 75% of Fentanyl's (Actiq® package insert) in the range of 20 to 120 minutes, the fentanyl concentration of lozenges by lozenge tablets (eg Actiq ^® ) After transbuccal administration, the bioavailability is 50%. More recent literature on the T _max of Actiq ^® indicates that this original time was skewed for faster onset (Fentora package inserts show the T _maximum range for Actiq ^® extended to 240 minutes). Fentora (fentanyl oral tablet) shows 65% bioavailability due to swallowing 50% of the drug. In contrast to the claimed formulations, both Actiq ^® and Fentora have the disadvantage that a substantial amount of fentanyl administered as a lozenge tablet is swallowed by the patient.

Although serpentanyl and fentanyl have many similarities as potential mu-opioid receptor agonists, it is suggested that they differ in many ways. Several studies have shown that serfentanil is 7 to 24 times more potent than fentanyl (SUFENTA ^® package insert; Paix A, et al. Pain, 63: 263-69, 1995; Reynolds L, et al., Pain, 110: 182-188, 2004). Therefore, serfentanil can be administered using smaller formulations while avoiding increased saliva response of larger formulations, minimizing the amount of drug that is afflicted. This results in minimal GI uptake.

Moreover, fentanyl and other opiate agonists have the potential for harmful side effects, including respiratory depression, nausea, vomiting and constipation. Fentanyl has 30% bioavailability from the GI pathway, so the swallowed drug can contribute to a significant C _maximum plasma level, causing varying C _max and T _max to be observed with these products.

In addition, the liquid solubility (octanol-water separation coefficient) of serfentanil (1778: 1) is greater than fentanyl (816: 1). Fentanyl is also shown a stand fentanyl (80 ~ 85%) (SUFENTA ® ^® and Actiq package inserts, respectively) the protein-coupled (91 to 93%) increased compared to. The pKa of serfentanil is 8.01, while the pKa of fentanyl is 8.43 (Paradis et al., Therapeutic Drug Monitoring, 24: 768-74, 2002). This difference can affect various pharmacokinetic parameters, for example, serfentanil appears to have faster onset of action and faster recovery time than fentanyl (Sanford et al., Anesthesia and Analgesia, 65: 259-). 66, 1986). Compared with fentanyl, the use of serfentanil can lead to faster pain relief with the ability to optimize the effect and avoid overdose.

Importantly, serfentanil is suggested to produce endocytosis of mu-opioid receptors 80,000 times more potentially than fentanyl (Koch et al., Molecular Pharmacology, 67: 280-87, 2005). The result of this receptor internalization suggests that neurons continue to respond more strongly to serpentanyl over time than fentanyl, suggesting that clinically less resistance to serfentanil will develop over repeated doses of fentanyl.

The use of serfentanil has been markedly limited to IV administration clinically in the operating room or intensive care unit. There are several studies on the use of liquid serfentanil formulations for low-dose intranasal administration (Helmers et al., 1989; Jackson K, et al., J Pain Symptom Management 2002: 23 (6): 450-452 ), There is a case report on sublingual delivery of liquid serpentanyl formulations (Gardner-Nix J., J Pain Symptom Management. 2001 Aug; 22 (2): 627-30; Kunz KM, Theisen JA, Schroeder ME, Journal of Pain and Symptom Management, 8: 189-190, 1993). In most of the studies, the minimum dose of serfentanil in adults was 5 mcg in opioid naïve patients. Liquids administered to the oral or nasal mucosa have lower bioavailability and possibly shorter duration of action, as demonstrated in the animal studies (sublingual liquids) of the present invention as well as nasal fluids-Helmers et al., 1989. Experience. Gardner-Nix contains only analgesic data (not pharmacokinetic data) produced by liquid sublingual serpentanil, and the onset of anal sublingual serpentanyl occurred within 6 minutes but duration of pain relief lasted only approximately 30 minutes. It is described as lasting.

Prior to our work, no pharmacokinetic data has been published for any form of sublingual serpentanyl.

The claimed drug formulations contain from about 0.25 to about 200 mcg of serfentanil per formulation for oral transmucosal delivery. In one exemplary embodiment, each formulation contains about 0.25 to about 200 mcg of serfentanil, alone or in combination with one or more other therapeutic or drug species.

Representative drug formulations for administration to children (pediatric patients) contain from about 0.25 to about 120 mcg of serfentanil per formulation. For example, a drug formulation for administration to a child may contain about 0.25, 0.5, 1, 2.5, 4, 5, 6, 8, 10, 15, 20, 40, 60, or 120 mcg of serpentanyl for oral transmucosal delivery. It may contain. For pediatric patients, exemplary dosage ranges are at least about 0.02 mcg / kg to about 0.5 mcg / kg, with a preferred range of about 0.05 to about 0.3 mcg / kg.

Representative drug formulations for administration to adults contain from about 2.5 to about 200 mcg of serfentanil per formulation. For example, a drug formulation for administration to an adult may be about 2.5, 3, 5, 7.5, 10, 15, 20, 40, 60, 80, 100, 120, 140, 180 or 200 mcg oral for oral transmucosal delivery or It may contain more serpentanyl.

Preferably, the serfentanil-containing formulation contains about 2 to about 200 micrograms (mcg) of serpentanyl, such as 5 mcg, 10 mcg, 15 mcg, 20 mcg, 30 mcg, 40 mcg, 50 mcg, 60 mcg, 70 mcg, 80 mcg, or 100 mcg of serpentanyl.

As will be appreciated by those skilled in the art, especially when administered for an extended period of time in an opioid resistant adult, the dose may be the lowest of the range for children and the highest of the range for adults, depending on body weight. Prior to our work, no small volume oral transmucosal drug delivery formulations of serfentanil have been described.

In various embodiments, the claimed formulations provide effective pain relief for both children and adults of all ages who are opioid resistant or do not have medication experience, and patients, including non-human mammals. The present invention has found utility in both inpatient and outpatient settings and in the art.

Iii. Serpentanyl Homologous

The use of homologs of serfentanil is found in the compositions, methods and systems described herein, examples being remifentanil and alfentanil.

In certain embodiments, the formulation comprises at least about 0.005% to up to 99.9% by weight of alfentanil, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil. The percentage of active ingredient (s) will depend on the size of the formulation and the nature of the active ingredient (s) optimized to achieve maximum delivery through the oral mucosal route. In some embodiments, more than one active ingredient can be included in a single dosage form.

Remifentanil is a potent fentanyl homologue that metabolizes much faster than fentanyl or serfentanil, but would be suitable for the treatment of acute pain when delivered through sustained release formulations. Remifentanil containing formulations typically comprise from about 0.25 mcg to 99.9 mg of remifentanil. Dosage ranges for remifentanil formulations may include, for example, 0.1 mcg / kg to 50 mcg / kg over a 20 minute time period for both adult and pediatric patients. Such doses may be repeated at suitable time intervals, which may be shorter than the time intervals for fentanyl or serfentanil.

Alfentanil is also a potential serpentanyl homologue that is rapidly metabolized, but may be suitable for use in sustained release formulations. The formulation contains about 10 to about 10000 mcg alfentanil per formulation for oral transmucosal delivery. As will be appreciated by those skilled in the art, especially when administered for an extended period of time in an opioid resistant adult, the dose may be the lowest of the range for children and the highest of the range for adults, depending on body weight.

Representative formulations for administration to children (pediatric patients) contain from about 10 to about 6300 mcg of alfentanil per formulation. For example, a formulation for administration to a child may be about 10, 25, 50, 130, 210, 280, 310, 420, 600, 780, 1050, 2100, 3000, or 6300 mcg of alfentanil for oral transmucosal delivery. It may contain.

Representative formulations for administration to adults contain about 70 to about 10000 mcg of alfentanil per formulation. For example, formulations for administration to adults may contain about 70, 140, 160, 210, 280, 310, 420, 600, 780, 1050, 2100, 3000, 6300 or 10000 mcg or more eggs for oral transmucosal delivery. May contain fentanyl.

After delivering a single dose of the serpentanyl-, alfentanil-, or remifentanil-containing formulation of the invention to a human subject, the plasma levels of the serpentanyl, alfentanil or remifentanil should be within 60 minutes after administration, such as from 5 to 50 Maximum levels can be reached in minutes or from 10 to 40 minutes.

Ⅵ. Treatment of pain

Patients suffering from a chronic painful condition may also exacerbate their pain, requiring acute use of fast acting breakthrough opioids in addition to the use of slow action time-release opioids for basic chronic pain.

Sudden pain or procedural pain may be as short as 1 or 2 minutes or as long as 30 minutes or more, intensive for short periods of time, resulting in faster clinically effective plasma levels with a more consistent and predictable duration of effect, but also In order to avoid excessive opioids administered during short-term pain events, it would be of significant advantage to provide opioid formulations with limited half-life.

Opioids remain the strongest form of analgesic, but there is a need for improved forms in which side effects are minimized and patient use can be provided in a manner that can be easily followed by a physician.

Using current treatment methods, pain control is attempted using a number of adjustments, which typically include patient-controlled analgesia (PCA), continuous epidural infusion (CEI), other types of acute pain control, relief care pain control , And home health patient pain control. These methods meet varying degrees of success in terms of control period, ease of treatment and stability versus side effects.

The need for rapid treatment of acute pain arises in many different clinical situations, including post-surgical restenosis, rheumatoid arthritis, failed back, terminal cancer, and the like (ie, sudden pain). After surgery, for example, the patient experiences severe pain in the first few days and then mild to moderate pain for several days.

IV morphine is the most common analgesic used to treat severe post-operative pain at moderate levels. This is by IV injection to the patient by the nurse “as needed” or by placing a morphine injection into the PCA pump, whereby the patient self administers the opioid by pressing a button with a lockout element. Other opioids such as hydromorphone and fentanyl can also be used in this manner.

Treatment of acute pain is also necessary for the patient in setting outpatients. For example, many patients have chronic pain, requiring the use of opioids on a weekly or daily basis for their pain treatment. While you may have long-acting oral or transdermal opioid preparations to treat chronically placed pain levels, you often need powerful opioids that are often short-lived to treat extreme sudden pain levels.

Treatment of acute pain is also needed "on the battlefield" under highly suboptimal situations. Practitioners or surgeons often require treatment of extreme acute pain in non-sterile situations where the needles used for IV or IM administration may cause unintended needle bar damage, risk of infection, and the like. Oral opioid tablets often take less than 60 minutes to provide relief, for someone with severe pain.

In many clinical settings, there is a clear need for improved means for drug administration that produce effective pain relief in a reasonable, safe, convenient and non-invasive manner that provides relief from extreme sudden or intermittent pain over a suitable time. .

The claimed methods and systems rely on the administration of a dosage form comprising a pharmacologically active substance, such as serfentanil, which is effective for treating pain (acute, intermittent, or sudden pain) using a dispensing device, the device comprising an element such as a lockout. , Means for identifying the user prior to drug administration, and means for protecting the stored formulation. The claimed method and system thus provide significant advantages over currently available treatment modalities for both safety and efficiency.

Ⅵ. Dispensing device

Dispensing devices, methods and systems for oral transmucosal administration of small volumes of drug formulations are provided. The dispensing device is typically hand-held and includes a housing having a dispensing end, which typically has a spout with side plates, which device provides means for blocking or delaying saliva entry and / or for controlling moisture. The dispensing device further provides safety elements such as means for lockout and means for user identification.

The claimed dispensing devices, methods and systems include delivering a small volume of dosage form to the oral mucosa. The invention is not limited to the specific devices, systems, methodologies and formulations described herein, but may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention.

Blocking / Delaying Saliva and Moisture Ingress

In some embodiments, the claimed dispensing device comprises (1) avoiding the formulation getting wet, (2) isolating saliva entering the dispensing device to keep the formulation dry, and (3) dispensing the formulation into the dispensing device to keep the formulation dry. Enter saliva into the dispensing device for absorbing or adsorbing saliva, (4) preventing saliva and water from entering the device to protect the formulation from vapor and liquid moisture, or (5) any combination thereof And means for minimizing or eliminating moisture ingress.

The dispensing device may have means for preventing and / or controlling moisture ingress due to environmental conditions external to the device.

Means for preventing the entry of other moisture into the dispensing device, or for minimizing or eliminating saliva entry, may include one or more flexible or rigid seals, one or more flexible or rigid wipers, desiccants or pads, manually or automatically Doors or latches that open or close, multistage delivery systems, positive air pressure and airflow, or air gaps or predetermined distances or barriers / sideplates maintained between mucosal tissue and tablet delivery holes in the mouth capable of moving saliva Although it may be, it is not limited to this. The side plates limit the ability of the tongue or oral mucosa to contact the formulation dispensing area, thereby controlling saliva contact and entry. By inhibiting or removing the "wetting" of the inner side of the side plate and the surface of the valve / seal, the formulation is dispensed without sticking between the side plate or valve / seal and the formulation.

In order to protect the drug formulation from moisture, exposure to water from saliva entry, or accidental exposure to other aqueous liquids, the container or cartridge containing the drug form in the dispensing device and the device may include a desiccant.

If saliva or moisture is present in the device, the means for capturing or otherwise isolating the saliva or moisture may be a hydrophilic wicking material or element, an absorbent or adsorbent or element, or a desiccant or element, for collecting moisture. It may include, but is not limited to, individual tracks or channels, individual channels for delivering moisture to the absorbent or absorbent material, or any combination of these materials or materials.

The desiccant is a solvent in the form of a hydrophilic solid, liquid, or gel, and can absorb or adsorb moisture from the surroundings, thereby controlling the moisture in the adjacent environment. Any commercial desiccant may be used. Commercial desiccants typically take the form of pellets, canisters, packets, capsules, powders, solids, paper, boards, tablets, adhesive patches, and films and can be formed for specific applications, including injection moldable plastics. have. There are many types of solid desiccants, including silica gel (sodium silica that is a non-gel solid), alumino-silicate, activated alumina, zeolites, molecular sieves, montmorillonite clay, calcium oxide and calcium sulfide, etc. May be used in the dispensing device. Different desiccants will have different affinities for water or other materials, in addition to different capacities and rates of absorption or adsorption. In addition, different types of desiccants will equilibrate at different relative humidity in adjacent environments. As a means for protecting the interior of the dispensing device and the formulation from moisture, one or more desiccants may be provided in the spout of the dispensing device, in or near the formulation delivery passageway, in or near the formulation tablet magazine or cartridge, or as an injection molded part of the dispensing device. It may be provided at or near other components of the formed dispensing apparatus, and a compressive desiccant pressed into position, or a desiccant at any other location in and outside the apparatus may be used.

In one preferred embodiment, the desiccant snaps into the cavity on the cartridge side. The desiccant cavity has a hole connecting it to the tablet stack, which exposes the tablet to the desiccant and keeps the tablet dry.

The claimed dispensing device may rely on valves, pads, seals, rest positions of the pushrods, spout structures, and side plates to minimize or control saliva entry or moisture into the dispensing device upon administration of the formulation.

Valves used in the claimed device are typically dome / cart-type valves that provide sufficient sealing to prevent saliva and / or moisture from entering the device and close the end orifice during dispensing and when the tablet is dispensed. Minimize or eliminate saliva entry or moisture.

The pads for use with the claimed device have a variety of geometries that assist in contact or communication with the push rod to remove liquid from the push rod face. Such pads are typically hydrophilic and carry liquid away from the tracks and pushrods to minimize or eliminate saliva entry or moisture entry.

The seals and wipers used in the claimed device are designed to maintain a uniform seal around the drug formulation and the push rod upon delivery, imparting a seal around the formulation and the push rod, and prior to, during and after dispensing the orifice and push It features a flexible material that functions to seal and wipe off the rod to minimize or eliminate saliva entry or moisture.

The resting position of the pushrods of the claimed device is characterized by placing the pushrods in an intermediate position remote to the cartridge outlet and close to the dispensing orifice, the channels for drying the pushrods at rest between dose dispenses, or desiccants. In addition, the push rod is present at the position including the absorbent to minimize or eliminate saliva ingress and moisture.

The spout structure used in the claimed device is characterized by a terminal device shape (usually an S shape) that assists in the use of the device and / or placement of the tip on the oral mucosa of the subject. The shape typically has curves, angles, and geometries that may enable proper use of the device and the placement of the formulation on the subject's oral mucosa, for example in the sublingual space.

The side plate of the claimed device has a geometry that forms a barrier between the device and the oral mucosa and tongue, a relief for formulation delivery, a hydrophobic or hydrophilic interior, and creates a barrier that prevents the oral mucosa from contacting the valve area and the formulation. And assists in dispensing the formulation and prevents the formulation from adhering to the side plates to minimize or eliminate saliva ingress or moisture ingress. The side plate may have a rounded inner surface or other geometry to mitigate adherence of the formulation to the side plate. The side plates limit saliva or oral mucosa's ability to contact the formulation dispensing area to control saliva contact and entry.

1A-1E are schematic diagrams illustrating various aspects of one embodiment of a drug dispensing device designed to receive multiple formulations for oral transmucosal delivery. 1A is a schematic diagram of a fully assembled or unitary dispensing device 11 of the present invention. In FIG. 1B, the dispensing device 11 comprises a reusable head 13, and a disposable body 15, in FIG. 1C the dispensing device 11 further comprises a cartridge 17, and in FIG. 1D a dispensing device. 11 includes a valve 33, a spout 31, a latch button 19, a power train coupling 25, a hub lock 21 and a dispense button 23, FIG. 1E being a reassembled complete It is a schematic diagram of the dispensing apparatus 11.

2 is a schematic representation of an exemplary dispensing device, wherein the dispensing tip comprises a side plate 29, the dispensing device comprising a wiping / seal valve 37, an absorption pad 39, a drug drying chamber / moisture communication panel 43. At least one of the desiccant 45 of the channel, the cartridge 17 comprising the formulation 67, and the desiccant 47 of the cartridge.

3A and 3B are schematic representations of representative geometries of the dispensing tip, which dispensing tip prevents the one or more seals 33, 35 from contacting the wet or wet surface of the oral mucosa through the side plate 29.

4A-4D are schematic views of a representative spout 31 of the dispensing device 11, the spout 31 having a side plate 29, a valve 33 for dispensing the formulation 67, a cutout / relief ( 55), wherein the cutout / relief is to position the formulation 67 relative to the oral mucosa and to prevent movement when the device 11 is withdrawn after dispensing.

Means to minimize saliva and water into the claimed device are important for the preservation of the original state of the formulation prior to storage, such as between oral transmucosal administration.

The drug administration dispensing device of the present invention may be used to administer a drug formulation that is sensitive to moisture and / or moisture. In this case, the formulation forms a cartridge to protect the drug formulation from liquid and gaseous moisture, including moisture, liquid moisture, saliva, mucus and the like. The cartridge may be cylindrical, disk-shaped, threaded, straight, irregular, or may take the form of any assembly of drug formulations that allows the dispensing device to dispense the formulation in a controlled manner. In order to prevent unused formulations from absorbing moisture or being exposed to moisture prior to use, the cartridge may provide a means for sealing the drug formulation from exposure to moisture. This results in cartridges containing individually packaged drug formulations separated by thin impermeable foils or impermeable materials such that when one drug formulation is dispensed from the cartridge, the seal protecting the remaining formulation remains intact. May be achieved by use. As an alternative, the formulation may be packaged in a cartridge such that two or more formulations are packaged together in each individual sealed compartment. In some embodiments, all formulations in the cartridge may be packaged together in compartments sealed with foil.

Drug cartridges containing a small volume of drug formulation in a dispensing device may be protected against moisture by partitions, elastic seals or valves, sliding, translation, hinge doors or valves, or by sealing against other components of the drug dispensing device when the formulation is loaded. May provide a seal. In this way, a single resealable seal may be opened independently or by the passage of the formulation outside the cartridge. Once the formulation is delivered from the cartridge, the resealable seal of the cartridge may be resealed to protect moisture or other contaminants from damaging the remaining drug formulation in the cartridge. The cartridge may further have a non-resealable seal that breaks when the cartridge is loaded into the drug dispensing device or the first formulation is delivered from the cartridge.

In another embodiment, the cartridge comprises a desiccant, other absorbent or adsorbent that absorbs or adsorbs moisture entering the cartridge prior to use or during normal use. The cartridge for use in the claimed dispensing device may comprise any combination of individual sealed formulations, multiple sealed formulations, resealed seals, non-resealable seals, desiccants, absorbents, or adsorbents. In one embodiment, the cartridges used in the dispensing device may maintain sufficient drug formulations, such as 40 formulations or sufficient drug formulations for 48 to 72 hours of treatment, for 1 to 5 days of treatment.

Push rod  rescue

5A-5D show a series of flow diagrams of the use of an exemplary device representing pushload logic, FIG. 5A shows the LOAD process, and FIG. 5B shows the device calibration logic flow. Referring to FIG. 6, the push rod 51 is advanced from the position 65, picks up the loading tablet 69 at the position 63, and is further advanced to the position 61. In position 61, the device detects the presence of tablet 69 and / or pushrod 51. The device is then calibrated and locates the end of loading tablet 69 and / or push rod 51, regardless of assembly tolerances, push rod length and push rod end state variations. After such correction, the push rod 51 advances the loading tablet 69 from the position 61 to the position 57 where the loading tablet 69 is discharged from the apparatus. In this operation, the device can distinguish between a loaded tablet 69, a push rod 51, a drug tablet 67. This distinction allows the device to confirm that the cartridge is not used because the loading tablet is the first to be ejected from the new cartridge during device setup. Elements providing a means for differentiating between loaded tablets, push rods, tablets 67 can be optical, physical, RF, electronic (resistive, capacitive, other) or magnetic. The push rod 51 can be continuous or intermittent from position 65 to position 67 as described, and no physical stop at position 61 is required. The push rod 51 is then retracted from position 57 to position 59, the device 11 is in the ready position, and the push rod 51 is located below the remaining formulation 67. In this position, the push rod 51 prevents the formulation 67 from accidentally falling out of the device 11.

5C shows the device distribution logic flow. Referring to FIG. 6, following the dosing instructions, pushrod 51 is retracted from position 59 to position 65, advancing tablet 67 into the pushrod track. The push rod 51 is then advanced from position 65, picks up the tablet at position 63, and administers the formulation 67 from the device at position 57. Between the position 63 and the position 57, the presence of the formulation 67 is detected / identified at the position 61 by the position sensor. The push rod is then retracted from position 57 to position 59, the device is in the ready position, and the push rod 51 is positioned below the remaining formulation 67. In this position, the push rod 51 is dried before the next formulation 67 is dispensed, preventing the formulation 67 from accidentally falling out of the device 11.

5D shows the device disassembly logic flow. According to the "disassembly" command, the push rod 51 moves to the position 65. This allows removal of the remaining formulation 67 without interference of the pushrods.

6 is a schematic of an exemplary dispensing device, illustrating the stage of pushrod / tablet interaction in the use of the device. 6 shows a push rod 51, a formulation 67, a loading tablet 69, a spring 73, and a position sensor 71. In use, the push rod 51 is also shown in FIG. 6 and moves between positions 57, 59, 61, 63, 65, which are described in more detail in FIGS. 5A-5D.

Dosing History / Feedback

Another embodiment of the device The ability to store usage history information and the ability of the device to convey such information. The device can carry unidirectional (downloading) or bidirectional information transfer. For example, this bidirectional exchange of information may be accomplished by downloading information stored on a computer via a physical wired interface, such as USB or any other communication connection. Alternatively, the information may be communicated via a wireless system.

In another embodiment, the dispensing device has a dose counting element that monitors or stores a history of drug use. Such information may include, for example, usage history information such as the number of doses stored and dispensed, and the time of dispensing.

correction

The dispensing device can self-calibrate the dispensing mechanism or can be calibrated manually. This process may use tablets and the element (s) that distinguishes those tablets from tablets or pushrods. These elements can be designed to have higher device calibration accuracy than device calibration accuracy that can be obtained using tablets or pushrods. Differentiating elements can be physical, optical, radio frequency (RF), electronic or magnetic.

User identification element

In one aspect, the dispensing device comprises detection means for identification of a patient, such as a fingerprint reader, optical retina reader, voice recognition system, face recognition system, tooth shape recognition system, visual recognition system, or DNA reader. The dispensing device may utilize one or more means to determine a user, allowing the system to determine whether a dispensing request was made in an authorized or unauthorized manner. It is important for the effective delivery of many drugs that the dispensing device is not accidentally or intentionally used by an unauthorized person to prevent accidental or intentional use of the drug. Such patient identification systems may recognize one or more users. For example, in an inpatient hospital setting, the dispensing device may be programmed to recognize patients who have been prescribed the dispensing device, as well as authorized healthcare professionals such as nurses and doctors. Can be converted. In the home setting of an outpatient, for example, the dispensing device may only respond to the prescribed patient.

The dispensing device is capable of RFID detection, retinal identification, DNA identification, voice recognition, using active or passive RFID tags on means of positioning and securing fingerprints, bracelets, necklaces, clips, belts, straps, attachment patches, implants or tags. Personal area network identification, optical scanner or face recognition, sonic speed, subsonic or ultrasound recognition, or personal identification using a human body or garment as a password or code entry, physical key, electronic key or magnetic key, data or signal conduit; and Any user identification means may be used, including any other means of verifying their identification.

One method of identifying a user is a device such as a bracelet, necklace, attachment patch, garment tag, orthodontic device, belt, strap, some combination thereof, or a short distance ("close up") attached to another location. Passive RFID tag is used. When an RFID tag is used in a "near field" roughly defined as about 16% of the wavelength of the received signal, the tag operates in an inductive mode of operation, magnetically connecting between the reader and the tag antenna. The near field is characterized by at least two factors: the first is a sharp decrease in field strength over distance, and the second is the strong directionality of the signal. In the near field, signal strength drops very rapidly, with a signal strength loss of approximately 60 dB per 10 distances. For good inductive coupling between the transmitting antenna and the RFID tag antenna, the two antennas are oriented in parallel planes with the axes passing through the center of each antenna in close proximity. Strong signal strength (sure patient identification) is provided when the device is very close to an RFID tag. At the same time, a very weak signal is provided when the device is away from the tag, which helps to prevent unauthorized use by anyone other than the patient wishing to use the device. It is desirable to operate in this near field with good antenna alignment. Moreover, since it is desirable to operate at a very near and appropriate signal strength for active identification, it is very difficult to receive signals unless the device is properly oriented and close to the RFID. In order to achieve near and proper alignment between the antennas, the distribution device is characterized in that the RFID readout antenna mounted on the distribution device is for example a garment band on a wristband or bracelet or collar, or an attachment patch such as a hand, arm, ball or neck. It may be designed to be properly positioned adjacent to the RFID tag antenna mounted on the. Moreover, the RFID tag antenna on the wrist band or wristband can be held in proper alignment and position by a small attachment patch that prevents the wristband from moving or rotating on the wrist.

In another embodiment, the dispensing device uses a high frequency RFID reader operating in or near the 13.56 MHz band for use by inpatient (hospital, clinic, etc.) settings, wherein the patient uses a matching RFID on a disposable bracelet or wristband. It has a tag and an antenna, which is designed such that if the bracelet or wristband is removed, the RFID tag, antenna, or related circuitry and other components may be damaged or broken, preventing the bracelet or wristband from functioning. In one embodiment, the RFID communication range is short, preferably 0 inches to 10 inches, more preferably 0 inches to 5 inches, most preferably 0 inches to 3 inches, and may additionally be directional, Appropriate use by the patient is easy and reliable, while at the same time unauthorized use by other individuals is difficult, very difficult or impossible.

Lockout (Lock Out)

The dispensing device provides a lockout, and the patient is required to communicate with a doctor or other authorized caregiver to unlock the device for the next defined period of time. In this way, the device and dock provide safe drug administration due to better physician supervision and treatment management.

The dispensing device provides a means for adjusting both the initial and subsequent doses, as well as the lockout time. The initial dose and lockout time can be adjusted next depending on the patient's response, treatment duration, and the like.

The initial timeout lockout period for the dispensing device of the present invention is typically from about 1 minute to about 60 minutes, from 3 minutes to 40 minutes or from 5 minutes to 30 minutes, in special cases such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 minutes Etc. is set at any one minute interval of 1 to 60 minutes.

In some cases, the dispensing device may have a defined lockout between administrations and may indicate stoppage after a predetermined period of time. In other cases, the lockout time is a programmable lockout time. The lockout time is also transferred to a distribution device from a fixed time lockout period, a predetermined lockout period, a predetermined variable lockout period, a programmable lockout period determined by an algorithm or from a remote computer, docking station or other device. It can be a variable lockout period.

Additional features

The dispensing device is characterized by the ability of the dispensing device to recognize a particular cartridge by mechanical, optical (such as barcode), electronic (such as microchip), magnetic, radio frequency, chemical, or other means for detecting and identifying the cartridge. Can provide. In one exemplary embodiment, the cartridge may include the physical significance of the cartridge that is physically detected by a sensor or switch or a series of sensors or switches in the dispensing device. Moreover, the dispensing device can communicate in one or two directions with the cartridge to exchange information. Such information may include drug name, dosage intensity, usage information, lockout duration, serial number, instructions for use, side effects, drug interactions, date of manufacture, expiration date, serial number, number of doses in the cartridge, or any other relevant information. . The dispensing device may write and read information about the cartridge, such as date of use, health care professional or patient identification, number of doses used, and the like.

The dispensing device provides mechanical protection for the drug form contained in the device, preventing breakage, chipping, hydration, and the like, to dispense the intact drug form contained in the device. This is particularly important for small, light and soft drug forms.

The drug dispensing device may be powered by a battery, capacitor, fuel cell, or other power source, or may be manually operated without requiring power.

In some embodiments, the dispensing device may generate an alarm or other notification if a functional or safety problem occurs. The alarm or notification device may alert the distribution device, the dock or other peripheral device, or the computer by wired or wireless network, or may trigger an alarm on another remote device. The alarm or notification may be auditory, tactile, visual, or other means of notifying one or more individuals.

Docking station

In some embodiments, the device includes a portable or stationary docking station that may query the device, reset the device between doses, lock the device when not in proper access, and control the dosing schedule. The drug dispensing device may communicate with the doctor or manager via the dock or by a wired or wireless communication method.

The dispensing device may utilize one or more interface levels for different types of authorized users, such as, for example, patients, nurses, doctors, pharmacists or other authorized care or healthcare workers. These different interfaces consist of keypads, buttons, graphical icons and commands, light, LEDs, black and white or color graphics or text displays, touch screens, LCDs, sounds, tactile feedback, voice recognition interfaces, and other input and output devices and means. It may also contain elements. The activity, or mode, of the user interface is determined by the mode of operation of the distribution device, by login or access activity by a user such as a password or code entry, by the connection or disconnection of the distribution device from a dock, computer, or network, or by a key. May be determined by detection of an authorized access key, and / or an RFID tag, or similar combination. When changing the interface mode, the functionality of the device may be changed by activating, deactivating or changing the functionality of the various interface components described above. By having the devices have one or more interface modes with different functionality relative to each other, the devices can be optimized for a variety of users.

Base station

In some embodiments, there may be a base station for recharging the drug dispensing device and the portable docking FOB during use. This base station allows simultaneous recharging of multiple distribution devices and / or batteries of a FOB or fuel cell. In addition to recharging the drug dispensing device and the FOB, the base station can provide one or more of the following functions: a wireless or wired connection to a peripheral device, computer, or network; Feedback of the state of charge for the device being recharged; An interface for viewing, adding, deleting or changing data of the drug dispensing device or FOB; Means for synchronizing data between multiple drug dispensing devices and / or FOB; And means for performing a diagnostic test on the drug dispensing device and / or the FOB.

1 dose and Multiple times  administration Applicator

The present invention provides a disposable applicator for delivering a drug formulation comprising serfentanil to the oral mucosa of a patient for application up to a predetermined location (eg mouth, sublingual space, etc.) for drug delivery.

In one approach to the present invention, the formulation is delivered to the oral mucosa using a single dose applicator (SDA). The formulations are provided in drug dispensing devices or packages for child protection and are delivered to the sublingual cavity, for example. The formulation may be administered on its own, alternatively the formulation may be administered with or without a device.

In one embodiment, SDA may be used in drug formulations provided as solid tablets, liquid capsules, gel capsules, liquids, gels, powders, films, strips, ribbons, sprays, mists, patches, or other suitable drug formulations.

SDAs may include drug forms therein, may have attached or fixed drug formulations, and may provide a seal against moisture, moisture, and light. Single dose applicators may be manually operated by a patient, healthcare professional, or other user to position the formulation in an appropriate location for drug delivery.

In the practice of the present invention, single or multi-dose applicators or drug dispensing devices may deliver tablets or other formulations to the hand, mouth, under the tongue, or any other suitable location for specific drug delivery.

In one embodiment, a single or multiple dose applicator or drug dispensing device is used to deliver the formulation to the oral mucosa such as the sublingual space.

The formulation in the dispensing device will remain dry prior to dispensing, at which point a single dosage will be dispensed from the device into the mouth, such as the sublingual space, the patient's saliva will wet the tablet, the tablet will disintegrate / erode and the drug delivered. .

SDA can be used with a pair of tweezers, syringes, sticks or rods, straws, pads, capsules, cups, spoons, strips, tubes, applicators, droppers, patches, adhesive pads, adhesive films, sprayers, sprayers, or single drug formulations. It may be provided in any other form suitable for application to a subject, such as the oral mucosa of the sublingual space. Those skilled in the art will appreciate that the SDA design may vary as long as it is effective to place the drug formulation, such as a tablet, in a manner that protects the integrity of the drug formulation during the dispensing process, eg, at the location required for the oral mucosa in the sublingual space. After use, the SDA is disposed of to eliminate the risk of contaminating the drug distribution device with saliva, or other contaminants.

For sublingual administration, small-sized formulations are generally administered sublingually by placing SDA under the tongue adjacent to the platoon.

The formulation can be provided in a package (called “blister pack” herein) consisting of a molded plastic or laminate having an indentation (“blister”) in which the formulation is located. Covers, typically laminated materials or foils, are used to seal the molded part. The blister pack may or may not have preformed or molded parts and may be used to package any type of SDA.

Such blister packs may be provided in a multi-dose drug dispenser (MDA) that is for child protection and may be provided for dispensing the embedded formulation or used for storage of multiple SDAs.

15A-15C, 16A-16F, 18A-18C, 19A and 19B are schematic diagrams of representative embodiments of SDAs of the present invention.

In one embodiment, the present invention provides a disposable single dose applicator comprising a blister pack 151, the applicator comprising a drug formulation 67 and a handle 131 inside a housing, the foil seal 135 A support such as) covers the formulation 67 and the handle 131.

In one embodiment, the combination of disposable single dose applicator, housing or tube 129 and handle 131 has a spoon shape.

Housing or tube 129 for formulation 67 is a blister pack 151 that receives a unit dose of formulation 67 for administration to a subject. The formulation 67 is sealed in the blister pack 151 by a foil or other type of seal 135.

In some embodiments, the foil or other type of seal 135 is removed prior to administration of the formulation 67, and the handle 131 is formulated in an appropriate position relative to the oral mucosa of the subject such that the formulation 67 adheres to the oral mucosa. Used to locate 67. See, eg, FIGS. 16B, 16D, 16E, and 16F. In another embodiment, the foil or other type of seal 135 is perforated and perforated 149 prior to administration using the handle 131 to position the formulation 67 in a suitable position relative to the oral mucosa of the subject. ), The applicator 123 is folded and removed prior to administration of the formulation 67. See, eg, FIGS. 19A and 19B. This allows handling of only one drug formulation 67 at a time and prevents the other individually sealed drug formulation 67 from being exposed to saliva, moisture, and the like.

The foil or other type of seal 135 of the disposable applicator 123 including the handle 131 is typically made of a single piece of foil stack, paper, plastic, or other cover, i.e., of the housing or tube 129 An applicator tab 147 only rearward or across both housing or tube 129 and handle 131 effectively seals formulation 67 in blister pack 151 or other container.

The handle 131 can properly place the formulation 67 without touching the formulation 67.

Multiple single dose applicators may be provided as a series of individual single dose applicators attached by a support or housed in a multiple dose dispenser 137.

14A and 14B show one embodiment of a single dose applicator 123 of a dispensing device for delivering a drug formulation. The dispensing device shown in FIG. 14A shows a single dose applicator 123 ready to dispense the drug formulation 67. In one aspect of this embodiment, when the user picks up the single dose applicator 125, the applicator opens and the drug formulation 67 is dispensed as shown in FIG. 14B.

15A-15C illustrate one application of a single dose applicator 123 consisting of an applicator with a tube 129, a stopper seal 127, a handle 131 (eg, an ergonomic handle) and a single dosage form 67. An embodiment is shown. 15A shows a single dose applicator 123 in sealed form prior to use. FIG. 15B shows the single dose applicator 123 ready to use with the stopper seal 127 removed to form an opening 133. 15C shows the single dose applicator 123 tilted to dispense the formulation 67 to the oral mucosa, for example in the sublingual space.

16A-16F show some alternative embodiments of a single dose applicator 123. In all these figures, the applicator seal 127 is broken and the applicator is tilted to drop the drug formulation 67 near the oral mucosa of the subject's mouth under the tongue, for example for sublingual formulation placement. 16A shows a tubular applicator 129 with the handle 131 positioned axially under the tube 129. 16B shows an applicator formed of thermoformed or blister package 151, which has a foil seal 135 that peels off to open applicator package 141 before placing formulation 67. 16C shows an applicator with a tube 129 broken to break the seal prior to placement of the formulation 67. 16D shows a blister pack hub 151 with a handle 131, which can be maintained and tilted to place the blister pack 151 on the oral mucosa after the seal 135 is peeled back. ) Is a formulation package 141. 16E and 16F each show a blister pack 151 shaped package with a handle 131 shaped like a flower or animal used for a single dose applicator 123 designed for pediatric use. Other single dose applicator shapes may include cartoon characters, animals, superheroes, or other suitable shapes for use in pediatrics.

18A shows a flat rigid applicator 123 wherein when the applicator end with the formulation is positioned under the tongue, the adhesive dissolves and the formulation 67 is placed on the oral mucosa, such as the sublingual space, and the applicator can be removed. For example, the formulation 67 is adhered to one end by a rapidly dissolving and ingestible adhesive. FIG. 18B shows an applicator 123 made of a water-permeable material, impregnated with the drug, and forming a material / dosage matrix. When the impregnated end of this applicator 123 is located in the mouth oral mucosa, the moisture of saliva dissolves the drug and delivers the drug through the mucosa. 18C shows a formulation package having a soluble membrane formulation 145 and a plurality of soluble membrane formulations 143. The soluble membrane formulation 143 is removed from the package 141, such as located in the oral mucosa in the sublingual space, where the soluble membrane formulation is dissolved and delivers the drug through the mucosa.

19A and 19B show diagrams of two steps of use of one embodiment of a single dose applicator 123. 19A shows a pre-use shape of an applicator 123 with a blister pack 67 comprising two applicator tabs 147, two perforations 149, and a formulation 67. To administer the formulation 67, the two applicator tabs 147 are bent down at the perforations 149 to form the handle 131, and the seal 135 is peeled back so that the blister pack 151 is open. For example, the formulation 67 may fall into the oral mucosa of the sublingual space.

In another embodiment, the drug dispensing device of the present invention may comprise a plurality of SDAs in a cartridge or individually packaged and include a single drug formulation for use by a patient, healthcare professional, or user. To distribute the SDA. The drug dispensing device may dispense a single SDA in the same manner and with the same features as may be advantageous for the dispensing of a single drug formulation described herein.

In another embodiment of the present invention, the multiple dose applicator 137 comprises one or more drug formulations 67 or single dose applicators 123, portable power supply means such as batteries, printed circuit boards, data connectable means, and user interfaces. It includes a device. In this embodiment, the drug dispensing device may include the ability to perform one or more of the following functions: record the drug administration dispensing history, verify user identification by fingerprint identification, RFID, voice recognition, and the like, and other devices. It is made to communicate its administration history (computer or network) and / or provide a lockout period between drug administrations.

FIG. 17 is a schematic diagram of an exemplary multi-dose applicator 137 for dispensing and delivering each individually packaged drug formulation 67 to a single-dose applicator 123.

20A-20D are schematic diagrams of examples of additional SDAs, wherein the SDAs may be retained between both sides 153 of the SDA 123 such that the drug formulation 67 is released when the latches 19 are released. Tweezers or reverse sheared SDA (FIG. 2OA), which is no longer maintained by SDA and can be placed on the oral mucosa by the user; When the user pushes the slider or plunger 159 (155) a syringe-shaped SDA having a circular channel that pushes the drug formulation 67 out of the end of the channel (FIG. 2OB); When the user pushes the slider 159 (155) a pushered SDA having a rectangular channel that the drug formulation 67 is pushed out of the end of the channel (FIG. 2OC); Or drug formulation 67 is retained in pocket 161 and includes a slider-type SDA (FIG. 2OD) that becomes accessible to drug formulation 67 when the user pulls slider 159 (157).

21A-21D are schematic illustrations of multiple dose applicators (MDAs) 137 or containers for storage of multiple SDAs 123 prior to use (FIG. 21A), in which representative embodiments are shown for removal of individual SDAs 123. There is a slot in the top cover of the MDA 137 (FIG. 21B), each individual SDA 123 contains a drug formulation 67 (FIG. 21C), and the SDA 123 is a drug under the tongue in the sublingual space. The placement of formulation 67 is facilitated (FIG. 21D).

Iii. Methods and Systems for Delivering Small Volume Formulations Using Devices

Methods and systems are provided for delivering small volume formulations, such as, for example, serpentanyl containing formulations using a device. 7 is a schematic structural diagram showing various components that may be included in a dispensing device or system for dispensing a small volume of formulation, the components of which are individual head 13 and body 15, cartridge 17. , Portable docking FOB 113, patient RFID tag 115, and base station 117.

A block diagram illustrating one aspect of communication in a drug dispensing system is provided in FIG. 8A, which includes an RFID tag, a drug dispensing device, a base station / dock, and a personal computer of a healthcare professional, the drug dispensing device being wired or wireless. The communication method allows communication with the doctor or caregiver via the dock.

8B is a block diagram illustrating another aspect of communication in a drug dispensing system, including an RFID tag, a drug dispensing device, a portable docking FOB, and a personal computer from a base station and a healthcare professional. The drug dispensing device may communicate with the doctor or caregiver via FOB by wire or wireless communication method to provide the doctor with usage information and information about the patient's respiratory status or blood pressure at regular intervals. The FOB may be adapted to be attached to a strap so that the FOB can be caught by a doctor or caregiver's neck.

Exemplary features of the dispensing device include the following: In one embodiment, the head, body, and cartridge comprise a handholdable portion of the device. The device assembly has a latch to disconnect the head and body and a dispense button for patient use. The device also has light indicating lockout status, error and power. In this embodiment, the cartridge and body containing the drug formulation are used only once.

The system is hand held and includes a portable dock dedicated to healthcare professionals, regardless of the patient device. The dock enables the use of higher level elements such as the use of deeper demanding patient devices, the ability to update device data, the head / body and chains to unlock, lockout turnover for patient administration, and a wide readout display. The dock may be used to set up and disassemble the patient device.

The system may also include an RFID bracelet that operates through the dock and is worn by the patient for administration and control to and from the correct patient. This element prevents the use of the device by others.

The system may further include a recharge base used to charge the dock and head, and is also used to update the head and dock when new software is available, or when a new user is programmed into the system.

Drug formulations are typically provided in single-use disposable cartridges that are loaded into the device prior to administration.

Representative setup instructions for a device include the following steps.

The device head and dock are charged at the recharge station.

The device body and the band are removed from the package.

The device head and dock are removed from the charging station.

The cartridge is loaded into the body by inserting the cartridge into the device as indicative of ensuring a cartridge "click" and is locked in place.

The device body (with cartridge) is assembled on the head.

The power button of the assembled device is pressed to start the system.

The power button on the dock is pressed to activate the dock.

The assembled device is plugged into the dock.

Healthcare professionals scan their fingerprints or enter their own passwords to unlock the dock.

The device reads the label of the cartridge, and the dock displays setting information such as, for example, the name of the drug, the amount of tablet, the drug concentration, the current lockout time, the duration of use (72 hours) and the battery condition of the head.

After the information is read from the cartridge and displayed in the dock, the healthcare professional is asked to confirm that all the information is correct, and evidence is needed to verify the information.

The dock brings the band closer to the device and requires the patient's band to mate with the device.

The device reads the band and requires confirmation of the band number (selection and confirmation of the number).

Patient ID (ie patient medical record number) is entered into the dock.

The band is placed in the hand of the patient and used to operate the device.

The dock then indicates that it is ready to dispense plastic initialized tablets or "loaders".

Upon confirmation, the device dispenses a plastic initialized tablet or "loaded tablet". This step is used by the device to calibrate the dispensing instrument and initializes the cartridge for use, allows the care professional to verify proper use and test the patient with a "load" or placebo type tablet.

Once the plastic initiated tablet or “loaded tablet” is dispensed, the dock requires the healthcare professional to confirm that the plastic tablet has been dispensed.

After confirmation, the display indicates that the device is ready for use.

In some cases, the chain may be connected to the device via a dock. Docks allow health care professionals to fill or unwrap chains as needed.

In order for the patient to administer the drug formulation by themselves using the device, the patient is trained before use.

Representative uses of the claimed apparatus and methods are provided in Examples 6-8.

Human in vivo research

Provided herein are pharmacokinetic data obtained in animals and humans based on studies administered via the sublingual route using small volume formulations for which serpentanyl and alfentanil are claimed.

Human clinical studies were conducted using healthy volunteers. The study described in Example 1 below included sublingual subfentanil containing 3.7 mcg, 7.5 mcg or 15 mcg of serpentanyl citrate, and 2.5 mcg, 5 mcg or 10 mcg of serpentanyl base, respectively (see Table 1). The formulation was used in 12 subjects (6 males and 6 females). All additives have a "pharmaceutically acceptable" (inactive and GRAS or "generally recognized as safe") state.

Serpentanyl formulations designed for sublingual use were compared to IV serfentanil administered via an IV catheter with continuous infusion over 10 minutes. Plasma samples were recovered from different IV catheter at remote locations. The analysis showed good inter-day precision and accuracy at high, medium and poor control sample concentrations.

For this study the formulation was eroded over a period of 10-30 minutes in all subjects. After placing each serfentanil formulation in the sublingual cavity of 12 healthy volunteers, a significantly consistent pharmacokinetic profile was obtained (see FIG. 9 and Table 2). Bioavailability compared to IV administration for a single dose of all three doses averaged 91%, as measured for commercial fentanyl transmucosal preparations, Actiq and Fentora (47% and 65%-Fentora package inserts, respectively) Much better than This high bioavailability may be due to a number of factors, but deficiency of saliva produced by the size of small formulations seems to limit drug swallowing and avoid the low bioavailability typical of drug absorption through the GI pathway. Both Fentora and Actiq package inserts require at least 50% and 75% of the drug dose, swallowed through saliva, and both exhibit lower bioavailability than the claimed formulations.

The formulation used in this clinical trial is a small fraction of the size of an Actiq or Fentora lozenge tablet, approximately 5 microliters (mass 5.5-5.85 mg) in volume. According to the dog studies described in Example 4 and discussed above, when serpentanil has a very poor GI bioavailability (12%), therefore, a high bioavailability of serfentanil formulation is provided (the drug is administered by the oral transmucosal route) Data shows that more than 75% of the drug is absorbed into the transmucosal membrane. Thus, less than 25% of the drug is swallowed, which is a much lower rate than swallowed in the case of Fentora or Actiq.

Importantly, this high bioavailability is also associated with high consistency of the total drug delivered to the patient. For example, the total plasma drug area (AUC 0 to infinity) under the curve for 10 mcg of serfentanil formulation was 0.0705 ± 0.0194 hr * ng / ml (mean ± standard deviation (SD)). The SD is only 27.5% of the total AUC. The coefficient of variation (CV) is a term for indicating the percentage SD of the mean. The coefficient of variation for the fentanyl product (CV), Fentora (45% for AUC) and Actiq (41% for AUC; Fentora package insert), the coefficient of variation for the sublingual serpentanyl formulation claimed is less than 40%. Thus, for serpentanyl formulations, the total dose delivered to the subject is not only more bioavailable but more consistent.

Serpentanyl sublingual formulations are also excellent in consistent drug plasma levels initially after administration. The C _maximum obtained with 10 mcg of serfentanil formulation was 27.5 ± 7.7 pg / ml. Therefore, the coefficient of variation of C _max is only 28%. The C _max for Fentora and Actiq is variable in the GI uptake of the drug. Fentora has a C _maximum of 1.02 ± 0.42 ng / ml, so the coefficient of variation of C _maximum is 41%. The coefficient of variation for various doses of Fentora ranges from 41% to 56% (package insert). C The _maximum Actiq coefficient of variation is 33% (Fentora package insert).

In addition to superior bioavailability and consistency in plasma concentrations, it is also important that the time of the C _{up to a maximum} known as the T so important in the treatment of acute pain, fast and consistent initiation of pain relief. The T _maximum for the 10 mcg sublingual formulation was 40.8 ± 13.2 minutes (range 19.8-60 minutes). The reported average T _maximum for Fentora is 46.8 in the range of 20 to 240 minutes. The T _max for Actiq is 90.8 minutes and ranges from 35 to 240 minutes (Fentora package insert). Therefore, the consistency at the onset of analgesic action on the serfentanil formulation is reduced by 400% at the slowest onset of T _max , which is a significant improvement over Fentora and Actiq.

An important point in the treatment of acute pain, especially acute sudden pain, is the half-life of the drug, which is consistent and relatively short. The plasma elimination half-life of the 10 mcg of serfentanil formulation was 1.71 ± 0.4 hours, which makes the drug titerable for various levels of pain. The patient may be given another formulation if the sudden pain lasts longer than 1.5 hours. Plasma depletion half-lives of Actiq and Fentora are 3.2 hours and 2.63 hours, respectively, for the lowest dose. The half-life for higher doses is substantially increased for these drugs, limiting the adequacy of these drugs.

While still in development, the published data allow for comparison of serpentanyl pharmacokinetic data provided herein with data of Rapinyl, fentanyl sublingual fast-dissolving lozenge tablets. As mentioned previously, the bioavailability observed for the serpentanyl formulations of the present invention averages 91% compared to the published bioavailability for Rapinyl, which is approximately 70% (Bredenberg, New Concepts in Administration of Drugs in Tablet Form, Acta Universitatis Upsaliensis, Uppsala, 2003). The coefficient of variation of AUC (0 to infinity) for Rapinyl ranges from 25 to 42%, depending on the dose, whereas the coefficient of variation for the 10 mcg serpentanyl formulation claimed is 27.5%. High bioavailability will suggest that the serpentanyl formulation will have a consistently low coefficient of variation of AUC, whereas for Rapinyl, regardless of dose. In fact, the coefficient of variation of AUC for all three doses of serfentanil (2, 5, 10 mcg) exemplified herein was on average 28.6%, demonstrating that the low coefficient of variation observed does not depend on the dose.

The coefficient of variation of C _maximum for Rapinyl varies between 34 and 58% depending on the dose administered. As shown in the data presented herein, the _maximum C coefficient of variation was only 28% when the 10 mcg serfentanil formulation was administered and the average coefficient of variation of the C _maximum for 2, 5, 10 mcg doses was 29.4%. However, the minimum variability is in accordance with the dose. Similarly, in the case of Rapinyl T, while in the range of 43-54% based on the _maximum coefficient of variation is administered minutes, the coefficient of variation of T _max for standing fentanyl dosage forms of the present application, on average, just about all three dose minutes strength 29 Was%. This consistent expression of expression achieved with the sublingual serpentanyl formulation allows for a safer redosing window compared to any of the three comparative drugs, as the elevated plasma levels contain up to a shorter period of time.

In addition, as in the case of Fentora and Actiq, Rapinyl exhibits a longer plasma elimination half-life (5.4-6.3 hours, depending on dose) than the claimed serfentanil formulation. Plasma depletion half-life of the serfentanil formulation ranges from 1.5 to 2 hours after single oral transmucosal administration in humans (Table 2), which allows for more titration and avoids overdose. As will be appreciated by those skilled in the art, the half-life described herein for the illustrated formulations can be adjusted by altering the components and relative amounts of the additives in the formulations used to prepare a given formulation. The ability to titrate to higher plasma levels by administering repeated doses of the sublingual subfentanil formulation was also tested in this human study.

Repeated administration of 5 mcg of the formulation every 10 minutes during four administrations resulted in a bioavailability of 96%, indicating that it is possible for the repeated administration to achieve higher plasma levels while maintaining high bioavailability. Regardless of the treatment of postoperative pain or cancerous pain, it is important that it can be effectively titrated to the individual's level of pain relief.

Another aspect of the PK curve generated by sublingual subfentanil formulation is the flat phase, which allows for a consistent period of plasma levels, which is important for both safety and efficacy. Comparing the IV pill administration (see animal studies Examples 2 to 5) or the 10 minute IV infusion in the human studies of the present application (Examples 1 and 9), the PK profile for serfentanil administration is clearly safer. Fast, high C _maximum plasma levels are avoided. It is advantageous to avoid these high peaks in the PK profile if the opioid can cause respiratory depression.

An important modification ratio that represents the extended flat phase of the measured blood plasma levels of serpentanil after administration of the formulation is the> 50% consumption time of C _max divided by the known IV final elimination half-life of the drug.

Treatment time ratio = (C _maximum extinction time / 2-C _maximum onset time / 2) / drug elimination half-life

Elimination half-life is an inherent property of the molecule and is most reliably measured using the IV route to avoid contamination due to continuous ingestion of drugs from the sublingual route. The IV clearance half-life for 5 mcg of serfentanil in the human study of the present invention was 71.4 minutes at this low dose due to the detection limit for the assay. The published IV elimination half-life for serpentanil at much higher doses is 148 minutes, due to the rapid alpha elimination mechanism of redistribution and the detection of both longer elimination beta phases through metabolism and excretion. This published elimination half-life is more accurate and more suitable for use in the above formula. The time spent over 50% of the C _max for 12 volunteers for the 2.5, 5 and 10 mcg dose intensities was on average 110 minutes, 111 minutes and 106 minutes, respectively. Therefore, the treatment time ratio for this particular serfentanil formulation ranged from 0.72 to 0.75. Thus, if the formulation of the formulation is changed, the erosion time of the formulation will decrease or increase, and a range of treatment time ratios of approximately 0.2 to 2.0 can be observed for serfentanil.

The treatment time ratio is a measure of how short-acting drugs have been successfully formulated to increase treatment time and also to increase safety by avoiding high peak plasma C _maximum concentrations. For example, as a comparison, the serpentanyl IV case in human studies showed a treatment time ratio of 10 minutes / 148 minutes = 0.067. This low rate value for the IV case is therefore a measure of the high peak generated by IV infusion of serfentanil, indicating that the formulation does not produce a significant flat phase. There is a 10 times higher treatment time ratio for the serfentanil formulations (doses used in human studies) to IV serfentanil listed in Table 1, showing an extended treatment flat profile for these formulations.

Ingestion of transmucosal medications through small volume drug formulations results in more consistent drug delivery between individual administrations and individual patients compared to the delivery of currently available oral transmucosal formulations where large fractions of drug intake occur via the GI pathway. .

The methods and systems described herein are designed to work effectively so as not to adversely affect the absorption of drugs in the unique oral cavity environment, providing higher levels of drug absorption and pain relief than currently available systems. The claimed method and system are configured to enter the circulatory system through the sublingual mucosa and avoid high peak plasma levels of intravenous administration.

The claimed methods and systems can independently control bioadhesion, tablet disruption (erosion) and drug dissolution and release over time, with administration using a device to provide a safer delivery profile. Oral transmucosal formulations administered by the device provide individual, repeated administrations containing a limited amount of active agent (eg, serfentanil), whereby the patient or caregiver is delivered in a precisely appropriate, safe and effective manner. Adjust the volume accordingly. The lockout element of the dispensing device adds to the safety of the drug dispensing profile.

An advantage of the oral transmucosal formulations described herein is that they exhibit very consistent bioavailability and can maintain plasma drug concentrations in the target therapeutic area with significantly lower variability for longer periods than currently available pharmaceutical or pain treatment systems. High peak plasma levels typically observed for IV formulations become dull after administration of the serfentanil counting formulation. In addition, a large reduction in plasma levels is avoided, as the drug continues to traverse the oral cavity from the oral cavity into the bloodstream during or more than the erosion time of the formulation, providing a plasma pharmacokinetic with an expanded flat phase compared to the IV route of administration. Moreover, treatment with the claimed methods and systems provides improved safety by minimizing the potentially harmful side effects of peaks and bones in plasma drug pharmacokinetics, typical of currently available pharmaceutical or pain treatment systems.

Various liquid forms for sublingual or nasal administration The advantages of the claimed sublingual formulations include controlled local release of the solid formulation over a minimal swallowing time of the liquid drug via the nasal or oral / GI route. Published pharmacokinetic data on nasal serpentanyl liquid administration (15 mcg) in humans demonstrates 78% bioavailability (Helmers et al., Canadian Journal of Anaesthesia 36: 494-497, 1989). Sublingual sublingual serpentanil (5 mcg) administration in beagle dogs (see Example 4 below) resulted in 40% bioavailability. The above mentioned bioavailability data is on average less than 91% obtained in human volunteers using subfentanil administered sublingually in the form of small volume formulations (see Example 1 below).

The small size of the oral transmucosal formulation allows for repeated placement in the sublingual cavity over time. The small size that allows repeated administration over the mouth to days to weeks results in minimal saliva production and minimal physical discomfort. Given the lipid profile of the sublingual cavity, the sublingual pathway also slows the release into the plasma for certain drugs, such as serpentanyl, which is due to the "depot" effect of further stabilizing plasma levels compared to ball delivery. This may be due to use.

Oral transmucosal formulations are designed to fit comfortably under the tongue, causing the drug form to disintegrate slowly enough to avoid immediate peak plasma levels, resulting in a significant reduction seen in prior art formulations as described in US Pat. No. 6,759,059 (Rapinyl). Where fentanyl is administered via a tablet containing 400 mcg of fentanyl, which results in a peak plasma level of 2.5 ng / ml followed by an immediate decrease in plasma levels. Fentora (pentanyl ball tablets) ) Also suffer from a lack of flatness, but followed by a sharp decline in C _max followed by a significant decrease in plasma levels (Pentora package insert).

Animal research

A series of studies in awake, alert beagle dogs was conducted to more fully characterize the properties of small volume oral transmucosal formulations using various drugs and formulations. Comparison of the claimed systems for oral transmucosal administration of serfentanil to liquid sublingual serpentanyl administration or swallowed serpentanyl formulations was made to evaluate various properties of the drug formulation. The results show that the small volume formulations of the present invention are well tolerated under the tongue (as demonstrated using in awake dogs), with higher bioavailability and more consistent pharmacokinetics than other oral transmucosal formulations containing injected liquids. Representing the data supports the claims of the present application.

The first beagle dog study was performed by comparing the sublingual 5 mcg serfentanil formulation with IV serfentanil as described more fully in Example 2 below. A total of three beagle dogs were studied and the results are graphed in FIG. 10 and tabulated in Table 3. The bioavailability of the sublingual serpentanyl formulation was 75% compared to IV. Therefore, similar to human data, the bioavailability data in dogs confirms the properties of the formulation better than the larger formulation. Moreover, similar to human data, the coefficient of variation for AUC was 14%, lower than that of other commercial transmucosal formulations. The ratio of treatment time for sublingual subfentanil formulation is 0.28 while the ratio for IV serfentanil is 0.05 (using 139 min of the published IV elimination half-life of serpentanil in dogs). Therefore, similar to humans, the 5 mcg formulation in Table 1 resulted in a much higher treatment time rate (5.6-fold) compared to IV serfentanil in dogs.

Further studies measured the effect of changing the formulation on the pharmacokinetic profile. This study is described in more detail in Example 3 below. By prolonging the erosion time of the formulation, the plasma half-life was extended from 33 minutes to 205 minutes for the medium disintegration formulation. Treatment time ratio was increased from 0.28 to 1.13 for slow disintegration formulations. This study demonstrates the flexibility of small volume formulations that modify the PK of a drug based on the additive selection. This flexibility is possible due to the small size of the formulation, which shortens or prolongs the contact time with the sublingual submucosa without removing or producing excess saliva that would rinse the drug prematurely into the GI tract.

Another study in Beagle dogs was conducted to evaluate the benefits of sublingual formulations for sublingual liquid administration. This study is described in more detail in Example 4 below. The result is that although drug-infused serpentanil (5 mcg) is delivered to the sublingual cavity, a rapid T _max is observed, this method of drug administration is very low in bioavailability (75%) compared to the sublingual subfentanil formulation (75%). 40%). This is probably due to swallowing of liquid drugs. Moreover, the AUC is very variable as shown by the high coefficient of variation (82%). C _max also varies greatly with this method of drug administration, with a coefficient of variation of 72%. The treatment time ratio for sublingual sublingual liquid serpentanyl was calculated to be 0.06, very similar to the IV serpentanyl case for this study showing a time ratio of 0.03. Therefore, the sublingual sublingual liquid profile does not provide the beneficial therapeutic plateau observed in the sublingual formulation. This finding supports that the high sublingual bioavailability observed in other formulations is not molecular inherent and is a direct result of the unique design of the formulation and its formulation. The strong adhesion of the small formulation to the oral mucosa in the sublingual cavity minimizes the variability of the surface area available for absorption, as in the case of liquid solutions, improving the delivery of molecules to the circulation. Moreover, due to its unique design and small dimensions, the formulation does not lead to significant saliva production, thus reducing the digestive potential of the released drug. Both factors contribute to higher and more uniform drug absorption from the sublingual cavity.

An additional part of the study in Example 4 was the determination of the bioavailability of the swallowed serpentanyl formulation. Since there is little data on serpentanyl GI bioavailability in the literature, it is important to further evaluate the low bioavailability of this route of administration to further support the observation that the drug can not be swallowed from the sublingual formulation and maintain high bioavailability. It was. As indicated in the PK analysis data in Table 7, the oral bioavailability of serfentanil from the swallowed formulation is very low, approximately 12%. In addition, as expected from the known whimsical GI uptake of fentanyl, the swallowed formulation has both the amount of drug absorbed (AUC) and the pharmacokinetics of absorption (C _max , T _max ) as shown in Table 7. Extremely high volatility is shown. These data support the conclusion that bioadhesive sublingual formulations do not fall off and adhere strongly to the sublingual cavity in a way that avoids oral intake and avoids high variability in typical plasma levels when the drug is absorbed through the GI pathway. .

Additional studies to evaluate other alfentanils formulated in small volume formulations were also performed in Beagle dogs, described in more detail in Example 5 below.

Alfentanil formulations have a 94% bioavailability compared to IV alfentanil, with a 5% coefficient of variation for AUC, a 7% coefficient of variation for C _max and a 28% coefficient of variation for T _max . Treatment time ratio was calculated as 0.33, compared to 0.04 for the IV alfentanil case of this study (calculated using 104 min published IV elimination half-life for alfentanil in dogs). Therefore, the alfentanil formulation (as described in Example 5) results in an eight times increased treatment time rate compared to the IV alfentanil case. The high bioavailability of such formulations also supports the claim that minimal swallowing of the drug occurs with the use of the formulation.

Iii. Small volume of oral Transmucosal membrane  Use of the formulation

The claimed formulations find utility in the delivery of any drug that can be administered by the oral transmucosal route. Small volume oral transmucosal formulations provide high bioavailability, low variability of T _max , low variability of C _max and low variability of AUC. The formulation also provides extended plasma levels in the treatment area.

In one exemplary embodiment described in detail herein, the formulation finds utility in treating subjects suffering from pain that may be associated with any of the various identifiable or non-identifiable etiologies. In this embodiment, the formulation finds utility in the inhibition or alleviation of pain. The term “treatment” or “management” of pain is generally used herein to describe the regression, inhibition or alleviation of pain to make the subject more comfortable, for example as measured by pain score.

The present invention finds utility in treatment in both patients with no opioid dosing experience and in opioid resistant patients.

The term "patient with no opioid administration experience" is used herein for a patient who has not received repeated administration of the opioid component over weeks to months.

As used herein, the term “opioid resistant patient” means a physiological condition characterized by the chronic administration of reducing the effect of the opioid component (eg, analgesic, nausea or sedation). Opioid components are drugs, hormones or other chemical components with analgesic, soothing and / or nausea effects similar to those containing opiates or derivatives thereof. When analgesic resistance develops, the dose of opioid component is increased so that the same level of analgesia occurs. The resistance will not extend to side effects, and side effects may not be well tolerated with increasing doses.

The formulation finds particular utility in treating acute pain or other conditions "in the battlefield", ie, under highly suboptimal conditions. Practitioners or surgeons often require treatment of extreme acute pain or other injuries or conditions in a non-sterile situation, where the needle used for IV or IM administration may cause unintended needle bar damage, risk of infection, etc. . Oral opioid tablets often take 60 minutes to provide relief, which is too long for someone suffering severe pain. The claimed formulations find utility in addressing this need.

When formulations are used for the treatment of pain, the claimed methods and systems find utility in the treatment, administration or application of drugs to pediatric and adult populations, and the treatment of patient populations with no experience with opioid resistance and opioid dosing.

The use of the claimed method and system is not limited to any particular therapeutic measure. Thus, the claimed formulations find utility in drug administration to pediatric and adult populations, and treatment of human and non-human mammals.

The formulation finds additional utility in pediatric applications because the comfortable and safe nature of the formulation will make it easier for children to receive this type of therapy and reliably deliver the drug to the transmucosal membrane. Specific examples include the treatment of acute pain in children when the IV approach is not readily available or inconvenient, the treatment of pediatric asthma if the child does not use the inhalation route effectively, the treatment of nausea if the child does not or cannot swallow the pill. Includes, but is not limited to, NPO (no oral intake allowed) or procedural sedation if more rapid onset of action is required.

Formulations find additional utility in veterinary use. Specific examples include, but are not limited to, any treatment of acute conditions such as pain relief, anxiety / stress relief, pre-procedure sedation, etc., where IV administration is not readily available or inconvenient.

The following examples are provided to illustrate the invention and are not intended to limit any aspect of the invention as set forth in the foregoing or following claims.

Formulations for the formulations described above can be tested for in vivo drug pharmacokinetics in both human and suitable animal models after sublingual administration.

The following examples show the ability of the formulation to allow a consistent absorption profile of serfentanil citrate after sublingual administration in human volunteers and in awake, alert beagle dog models.

Example 1. Sublingual Subfentanil formulation administered sublingually to an adult volunteer.

[Table 1] standing fentanyl preparations in human clinical trials

Human clinical studies were conducted using healthy volunteers. The study was prepared with a 5 μl volume, approximately 5.5 mg of mass, and a serpentanyl-containing formulation (Formulation # 46 shown in Table 1) determined to have a uniform size for all dose strengths with dimensions of approximately 3 mm in diameter and 0.8 mm in thickness. # 48), using 12 subjects (6 males and 6 females). The serfentanil formulation contained 2.5 mcg, 5 mcg or 10 mcg of serpentanyl base corresponding to 3.7 mcg, 7.5 mcg or 15 mcg of serpentanyl citrate, respectively. All additives are inert and have a GRAS ("generally recognized as safe") state. Serfentanil formulations have been tested for sublingual use. The study staff used the blunt tweezers to administer the formulation to the subject by placing the formulation directly on the base of the platoon.

For bioavailability calculations, intravenous serpentanyl, 5 mcg, was diluted in 0.9% saline to a total volume of 20 ml and administered via IV catheter as a continuous infusion over 10 minutes. Plasma samples were recovered from different IV catheter at remote locations. This human experiment was a crossover design with a wash period between transitions from high doses to low doses. Subjects were blocked with opioid antagonist naltrexone daily to avoid opioid-induced side effects.

● Day 0: IV Serpentanyl Injection:

O 17 samples were collected:

-5.0 (before injection), 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 45, 60, 90, 120, 160, 320, 480 and 640 minutes

Day 2: Subcutaneous serpentanyl formulation of 2.5 mcg;

○ 17 pieces samples:

-5.0 (prior to administration), 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 45, 60, 90, 120, 160, 320, 480 and 640 minutes

Day 3: 5.0 mcg of sublingual serpentanyl formulation;

○ 17 pieces samples:

-5.0 (prior to administration), 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 45, 60, 90, 120, 160, 320, 480 and 640 minutes

Day 4: Sublingual subfentanyl formulation of 10.0 mcg;

○ 17 pieces samples:

-5.0 (prior to administration), 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 45, 60, 90, 120, 160, 320, 480 and 640 minutes

7 days: 5.0 mcg of sublingual serpentanyl formulation repeated four times at 10 minute intervals;

○ 23 pieces samples:

-5.0 (prior to administration of first formulation), 5, 7.5 min

10 (immediately before administration of the second formulation), 15, 17.5 minutes

20 (immediately before administration of the third formulation), 25, 27.5 minutes

30 (immediately before administration of the fourth formulation), 35, 40, 45, 50, 55, 60, 90, 120, 150, 190, 350, 510 and 670 minutes

The total volume of blood required for pharmacokinetic sampling was approximately 455 ml.

Serpentanyl concentrations in plasma samples were determined using an effective LC-MS / MS serpentanyl human plasma assay. Evaluation showed good date-to-date precision and accuracy at high, medium and poor control sample concentrations.

For this study the formulation was eroded over 10-30 minutes in all subjects. After each serpentanyl sublingual formulation was placed in the sublingual cavity of 12 healthy volunteers, a remarkably consistent pharmacokinetic profile was obtained for three doses (FIG. 9).

[Table 2] 3 kinds administration min strength PK analysis (2.5 mcg = # 46, 5 mcg = # 47, 10 mcg = # 48) human clinical trials when IV (5 mcg) and hyeomit standing fentanyl administration at using

¹ represents the relative time (over 50% of C _max ) at which the drug achieves a treatment level, which is calculated by the formula: TTR = (time spent exceeding 50% of C _max ) / (IV final elimination half-life ). The denominator is obtained from the literature and is 148 minutes in human relative to serfentanil.

Example  2. In dog model Sublingual Serfentanil  In vivo evaluation of the formulation

Examples 2-5 below used the Beagle dog model and formulations for all formulations used a formulation of a total mass of 5.5 mg. In vivo pharmacokinetics (PK) of serfentanil was evaluated in a healthy beagle dog model after sublingual administration of the 5 mcg formulation described above (Formulation # 44 for dogs, which is equivalent to Formulation # 47 in humans). Briefly, a fully awake healthy dog was administered sublingually with a single 5 mcg formulation placed directly in the sublingual cavity. All three dogs were rated. After administration, the position of the formulation in the sublingual cavity was observed visually at 5-15 minute intervals after administration. Sublingual serpentanyl PK was compared to serfentanil administered IV at the same dose level.

All dogs were catheterized through the head vein for blood collection up to 2 hours after dosing. Throughout the blood collection for 2 hours after dosing, all dogs were run with a Elizabethan collar to prevent removal of the catheter. The catheter was removed after 2 hours blood collection. Blood collections were collected from the head vein or other suitable vein after 4-, 8-, and 24-hour administration. Approximately 2 ml of blood was collected in a pre-frozen tube containing potassium EDTA at the following time points: before, and after about 1, 3, 5, 10. 15, 30 minutes, 1, 2, 4, 8 and 24 time. Samples were analyzed by a suitably effective LC / MS / MS method for the determination of serpentanyl citrate in dog plasma. Serpentanyl plasma concentrations and pharmacokinetic results are shown in FIG. 10 and Table 3.

[Table 3] Analysis of the PK fentanyl formulation hyeomit standing compared to intravenous fentanyl standing in the Beagle dog.

¹ represents the relative time (more than 50% of C _max ) at which the drug achieves a treatment level, which is calculated by the following formula: TTR = (time spent _up to more than 50% of C _max ) / (IV final elimination half-life ). The denominator is obtained from the literature and is 139 minutes in beagle dogs for serfentanil.

Example  3: drug release and in vivo Pharmacokinetics  Typical to adjust Serfentanil  Formulation

For illustrative purposes, longer sustained formulations (Formulation # 58) were prepared with serfentanyl citrate to assess slower rates of drug release and in vivo pharmacokinetics of long acting formulations. As shown in Table 4, the slower disintegrating serfentanil formulations were prepared by direct compression and tested as described above. The erosion time in dogs ranged from 35 to 120 minutes and the bioadhesion of the placebo formulation was measured as described above and determined to be 0.18 ± 0.08 N / cm 2.

Sample analysis was performed using an effective LC / MS / MS method for the analysis of serfentanil in dog plasma. Pharmacokinetic analysis was performed using a noncompartmental absorption method. The results of the limited PK analysis are shown in Table 5.

Table 4 fentanyl formulations standing slow decay.

[Table 5] PK analysis for fentanyl formulations standing slow decay hyeomit in beagle dogs.

¹ represents the relative time (more than 50% of C _max ) at which the drug achieves a treatment level, which is calculated by the following formula: TTR = (time spent _up to more than 50% of C _max ) / (IV final elimination half-life ). The denominator is obtained from the literature and is 139 minutes in beagle dogs for serfentanil.

Example  4. In dog models Sublingual Serfentanil  Solution and Serfentanil  In vivo studies of swallowing of formulations

A. solution formulation of hyeomit after administration of fentanyl standing Assessment of Bioavailability

The bioavailability of serfentanil after sublingual administration from solution as compared to the bioavailability to the vein was evaluated in a healthy, conscious Beagle dog animal model, as shown in Table 6. Was used as the commercially available formulation (Sufenta ^® 50 ㎎ / ㎖) of books fentanyl citrate in all cases of the study, the fentanyl base was administered in the same total dose of 5 mcg minutes standing. Through a suitable size needle and syringe sterilization was carried out intravenously (Group 1) by a single administration (n = 3) of Sufenta ^® 50 ㎎ / ㎖ by intravenous bolus injection to two. For sublingual administration (group 2), the test article is prepared from Sufenta ^® 50 mg / ml, diluted appropriately at 0.9% w / w with 5 ml of serpentanyl base in the same final dose, administered twice under the sublingual (Total n = 6), where each dose was separated by at least 2 days wash. Next to the platoon, the dose was slowly applied via a sterile syringe under the tongue. Blood samples were collected from the jugular vein or other suitable vein before and at approximately 1, 3, 5, 10, 15, 30 minutes, 1, 2, 4, 8 and 24 hours. Approximately 2 ml of blood was collected per time point in a pre-frozen tube containing K ₂ EDTA. Samples were centrifuged at 3,000 × g for approximately 10 minutes in a refrigerated centrifuge. Plasma was collected and frozen at approximately −70 ° C. into 20 minutes of centrifugation and kept at the same temperature until analysis. Sample analysis was performed using LC / MS / MS methods effective for the analysis of serfentanil in dog plasma.

Pharmacokinetic analysis was performed using a noncompartmental absorption model. Serpentanyl plasma concentrations are shown in the graph of FIG. 11. The results of the PK analysis are shown in Table 7.

B. of Serfentanil after Oral Ingestion of the Formulation Assessment of Bioavailability

The bioavailability of serfentanil after ingestion of the 5 mcg serfentanil formulation (Formulation # 44, which is the same formulation as # 47 used in the above human studies) compared to intravenous serfentanil administration was determined by healthy, consciousness as described in the previous examples. In a beagle dog animal model. A single 5 mcg formulation was administered twice orally, where each administration was separated by a minimum 2 day wash with a total of n = 6 (Table 6). The formulation was placed as far as possible from the throat and as far back as possible and watered to facilitate the swallowing response in the animals. Pharmacokinetic analysis was performed using a noncompartmental absorption model. Serpentanyl plasma concentrations are shown in the graph of FIG. 11. The results of the PK analysis are shown in Table 7.

TABLE 6 organized in test group

a = expressed as a free base.

b = The same animal will be used for groups 1 to 3 with at least 2 days washout period between administrations.

c = Groups 2 & 3 animals were given two doses with a total of n = 6, with a minimum washout period of two days.

d = Regular (0.9% w / w) saline was used to dilute the test article (Sufenta ^® 50 mg / ml) to the desired concentration.

Table 7 standing PK analysis of fentanyl compared to intravenous administration and a fentanyl solution and stand the intake standing fentanyl formulation implanted under the tongue in the Beagle dog.

¹ represents the relative time (more than 50% of C _max ) at which the drug achieves a treatment level, which is calculated by the following formula: TTR = (time spent _up to more than 50% of C _max ) / (IV final elimination half-life ). The denominator is obtained from the literature and is 139 minutes in beagle dogs for serfentanil.

Example  5: dog model Sublingual Alfentanil HCl  In vivo evaluation of the formulation

For the purpose of illustrating another drug use for the formulation, additional formulations were prepared with alfentanyl HCl to demonstrate the ability of the formulations described herein to effectively improve the PK of alfentanil compared to that of administration of the IV route. . Formulation compositions, medium disintegration formulations are listed in Table 11. The erosion time in the dog of Formulation # 63 was 20 minutes and bioadhesion was measured at 0.056 ± 0.01 N / cm 2 for the placebo formulation.

Dosing parameters for this study are shown in Table 12. Alfentanil plasma concentrations are shown graphically in FIG. 12. PK analysis was performed using a noncompartmental absorption model. The results of the PK analysis are shown in Table 13. Blood collection and storage were similar to the conditions described above; Sample analysis was performed using an effective LC / MS / MS method for the analysis of alfentanil in dog plasma.

[Table 11] Representative formulations alfentanil

[Table 12] hyeomit alfentanil formulation and intravenous administration know parameters for administration of fentanyl in the solution of the beagle dog.

a = expressed as glass base.

b = same animals were used for groups 1 and 2 with a minimum 2 day washout period between administrations.

Table 17 An Al PK analysis of fentanyl compared to intravenous formulations hyeomit alfentanil in a beagle dog.

¹ represents the relative time (more than 50% of C _max ) at which the drug achieves a treatment level, which is calculated by the following formula: TTR = (time spent _up to more than 50% of C _max ) / (IV final elimination half-life ). The denominator is obtained from the literature and is 104 minutes in Beagle dogs.

Example  6: using device Serfentanil  Acute Pain Management in Outpatient Settings by Administering Containing Formulations

The pharmacist loads a drug cartridge containing 40 serfentanil formulations into the drug dispensing device. Each cartridge has two colored initialized tablets (called "loading tablets"), which are arranged to be dispensed first. The device has a means for loading a cartridge, the means being a port, hatch, or door that is safe and inaccessible to an unauthorized user. When the pharmacist loads the cartridge in the device, he locks the device access port, hatch or door. The pharmacist then uses the docking connector to program the device after docking the dispensing device for the first time to a dock connected to an individual or another computer. Programming may include the dosage strength of the formulation, the number of formulations loaded on the device, the prescribed frequency of the formulation use, the number of formulations used per day, the current date and time, the preferred language, a valid thumb fingerprint or other identification to identify the patient. Uploading the information, and identifying information of the doctor in the event that the device is found lost.

Once the dispensing device is programmed, the pharmacist demonstrates proper use and tests the device by dispensing a single tablet. The pharmacist then gives the patient a dispensing device and observes the dispensing of the tablet to ensure the patient is in proper use and function. In conjunction with the dispensing device, the pharmacist provides the user with a radio frequency identification (RFID) key that must be within approximately 5 inches of the device for the dispensing device to operate.

When the patient wishes to administer a single dose of drug, the patient grabs the dispensing device and presses any button to wake up the device from dormant mode. The device will ask the user for a thumb fingerprint reading or personal identification number (PIN). The device will then retrieve the validated RFID key within range. If these conditions are met, the dispensing device will query the internal memory and recording to ensure that the dosing program programmed by the pharmacist has not been violated by the current use request. At this point, the device displays status information such as date and time, number of remaining doses, last time the dose was used, patient's name, etc., and the pharmacist gives the patient the form of the drug by visual and / or audio signals Informs you that you are ready to distribute.

The patient will secure the dispensing end of the device under the patient's tongue and press the dispensing lever. When the formulation is dispensed, a voice will sound to inform the patient that the formulation has been properly dispensed. At this point, the device will lock down to prevent another distribution until the pre-programmed lockout time has passed, and the device will then be ready for use again.

Example  7: using device Serfentanil  Acute Pain Management in Inpatient Settings by Administering Containing Formulations

Postoperative patients require postoperative acute pain treatment. The doctor prescribes oral transmucosal serfentanil, which is used as a drug dispensing device. The attending nurse orders a prescription from a pharmacist or automated pharmaceutical inventory management system (eg, Pyxis) to obtain a serpentanyl containing drug cartridge for sublingual delivery. The cartridge is labeled and equipped with an RFID electronic tag containing drug label information.

The nurse then takes the disposable dispensing of the drug dispensing device from stock and proceeds to the base station to obtain a reusable control of the drug dispensing device that has been refilled and is ready for use. The nurse inserts the drug cartridge into the disposable dispenser, then attaches the drug cartridge to the reusable control of the drug dispensing device, and secures the disposable dispense to the reusable control of the drug dispensing device with a key tool. At this point, the device reads the RFID tag of the drug cartridge and uploads the appropriate drug information, including the drug type, dosage strength, lockout period between administrations, and the like. The nurse confirms that the appropriate drug cartridge information has been read by drug dispensing and hands the drug dispensing device to the patient for patient controlled analgesic dispensing.

If the patient needs analgesics, the patient holds the medication dispensing device with his hand, places the dispensing tip under the tongue in the mouth, and presses the dispense button. The drug dispensing device then checks with an internal check that the appropriate lockout period has elapsed since the last dose dispensing. At this point, the drug dispensing device dispenses the tablet under the patient's tongue and feedback that the administration was successful. The patient removes the drug dispensing device from the mouth and allows the sublingual formulation to dissolve under the patient's tongue. The patient may attempt dispensing as often as desired, but the drug dispensing device may only be successfully administered after the appropriate lockout period has elapsed. The drug dispensing device electronically records the dispensing attempt and successful dispensing in the dispensing history.

On a regular basis, nurses check patients and drug delivery devices. During such patient checks, the nurse examines the drug detection device to confirm that there are no errors in the drug dispensing device and to check the number of remaining tablets and returns to the patient.

When the patient is discharged, the nurse has the drug dispensing device, disassembles the reusable part from the disposable part with the key tool, and disposes the cartridge and disposable part of the drug dispensing device. The nurse then connects the reusable portion to the computer and uploads the patient's usage information from the drug dispensing device to the computer for recording in the patient's medical record. The nurse cleans the reusable control and returns it to the base station for recharging.

Example  8: using device and portable dock Serfentanil  Acute Pain Management in Inpatient Settings by Administering Containing Formulations

After surgery, the patient requires postoperative acute pain treatment. The doctor prescribes oral transmucosal serfentanil to be administered using a drug dispensing device. The attending nurse orders a prescription from a pharmacist or automated pharmaceutical inventory management system (eg, Pyxis) to obtain a serpentanyl containing drug cartridge for sublingual delivery. The cartridge is labeled and equipped with an RFID electronic tag containing drug label information. The cartridge also includes a loaded tablet or an initial tablet at the position to be dispensed first in the formulation stack.

The nurse then takes the disposable dispensing of the drug dispensing device from inventory, proceeds to the base station, and takes the reusable control of the drug dispensing device whose refill cycle has been completed and is ready for use. The nurse inserts the drug cartridge into the disposable dispensing unit and then attaches the drug cartridge to the reusable control unit of the drug dispensing device. Next, the nurse takes a portable dock (or docking FOB) from the refilled base station and docks the assembled drug dispensing device into the portable dock. The portable dock and the assembled drug dispensing device are in electronic communication, and a setup menu appears in the portable dock to set up the drug dispensing device.

At this point, the device holds the reusable and disposable portions together, reads the RFID tag of the drug cartridge, and uploads the appropriate drug information including drug type, dosage strength, lockout period between administrations, and the like. The dispensing device writes the code into the RFID tag of the cartridge that identifies the device as the cartridge to be used. The nurse records her fingerprint in the fingerprint reader of the portable dock to gain secure access and begins to set up the drug dispensing device for use. The setup procedure includes recording patient identification, nurse identification, identifying the appropriate time on the device, and verifying the appropriate drug cartridge information. The nurse then has a disposable RFID wristband, places it near the drug dispensing device, at which point the drug dispensing device reads the tag, and the nurse confirms that the appropriate wristband is read.

The nurse then presses the dispense device once to confirm proper setting of the drug dispense device. The drug dispensing device is activated to dispense the facsimile with the nurse's hand and to ensure proper operation. The drug dispensing device can detect the dispensing of the loaded tablet and check internally the system for proper operation and internal calibration of the newly assembled system. If the internal dispensing check is successful, the portable dock asks the nurse to verify that the tablets are properly dispensed, and confirms the nurse proper setting. The nurse then disconnects the drug dispensing device from the portable dock and goes to the patient for the final setup step.

The nurse places the RFID wristband on the patient's wrist and attaches an anti-theft chain to the other end of the patient's couch and drug delivery device. The nurse then informs the patient of the proper use of the sublingual drug dispensing device and gives the patient a drug dispensing device for patient controlled dispensing of serfentanil.

If the patient needs analgesics, the patient holds the medication dispensing device with his hand, places the dispensing tip under the tongue in the mouth, and presses the dispense button. The drug dispensing device then checks with an internal check that the appropriate lockout period has elapsed since the last dose dispensed and that the patient's RFID wristband is present and readable. At this point, the drug dispensing device dispenses the formulation under the patient's tongue and feedback that the administration was successful. The patient removes the drug dispensing device from the mouth and allows the sublingual formulation to dissolve under the patient's tongue. The patient may attempt dispensing as often as desired, but the drug dispensing device may only be successfully administered after the appropriate lockout period has elapsed. The drug dispensing device electronically records the dispensing attempt and successful dispensing in the dosing history.

On a regular basis, nurses check patients and drug delivery devices. During such patient checks, the nurse brings a portable docking FOB and docks the device to the FOB. The nurse can download information from the drug delivery device to the FOB over an electronic connection. This information includes usage history, drug information, number of remaining tablets, and duration of use after initial setup. The nurse then enters her fingerprint on the fingerprint scanner to access the information and drug dispensing device. Because the patient requires additional drug administration before the lockout period expires, the nurse reverses the lockout period and returns the drug dispensing device to the patient, at which point the patient can take another dose.

The nurse leaves the patient room with a portable docking FOB and returns to the nurse station to record the dosing history in the patient log. Upon completion, the nurse returns the FOB to the base station for recharging.

If the patient has used all of the tablets in the drug dispensing device, the nurse brings the portable docking FOB into the patient room and docks the drug dispensing device in the FOB. The nurse then enters her fingerprint on the FOB's fingerprint scanner to securely access the drug dispensing device. Next, the nurse breaks the security chain and separates the drug delivery device from the bed. Then, she unwinds the drug dispensing device and removes it from the FOB for disassembly. The nurse separates the disposable portion from the reusable portion and removes the cartridge from the disposable portion. The nurse discards the disposable part and cartridge and rubs with a sterile wipe to clean the reusable control before returning the reusable control to the base station. The nurse should return the reusable control to the base station, where the reusable control is recharged and undergoes an internal diagnostic test before it is ready for use again.

The nurse then sets up a new drug dispensing device as described above and provides the device to the patient.

While the invention has been described in detail by the drawings and examples for clarity and understanding, it will be apparent to those skilled in the art that certain changes and improvements may be made. Various aspects of the invention have been accomplished by a series of experiments, some of which are illustrated by the following non-limiting examples. Accordingly, the descriptions and examples should not be construed as limiting the scope of the invention, but are described by the added description of representative embodiments.

Claims (20)

A dispensing device for administering a serpentanyl containing drug formulation to a subject's oral mucosa, A dispensing end for administering the serpentanyl containing drug formulation to the oral mucosa of the subject, and means for preventing or delaying saliva or water ingress, wherein the drug formulation has a volume of less than 100 microliters (mcL) or 100 Administration of serfentanil having a mass less than mg and selected from the group consisting of 5 mcg, 10 mcg, 15 mcg, 20 mcg, 30 mcg, 40 mcg, 50 mcg, 60 mcg, 70 mcg, 80 mcg, and 100 mcg Dispensing device containing minutes. The method of claim 1, And the dispensing device is a handholding device. The method of claim 1, Oral transmucosal administration is a sublingual administration. The method of claim 1, Dispensing device, characterized in that oral transmucosal administration is buccal administration. The method of claim 1, The means for preventing or delaying saliva entry comprises a spout. The method of claim 5, wherein The spout comprises a side plate. The method of claim 1, And the device further comprises a lockout element. The method of claim 7, wherein Wherein said lockout element is effective for setting a lockout time, wherein a formulation cannot be dispensed from said device during said lockout time. The method of claim 8, The lockout time may be a fixed time lockout period, a variable lockout period, a programmable lockout period determined by an algorithm or a lockout period transferred from a remote computer, a docking station or another device to a distribution device. Dispensing device. The method of claim 1, And the device comprises a reusable head and a disposable body. The method of claim 1, The device further comprises a replaceable cartridge. The method of claim 11, The cartridge includes a smart cartridge recognition system, the system comprising a physical key element of the cartridge, an optically detected element or pattern, a bar code of the cartridge, a magnetic tag of the cartridge, an RFID tag of the cartridge, an electronic microchip of the cartridge, And at least one element selected from among the combinations thereof. The method of claim 1, The dispensing device further comprises a user identification means. The method of claim 13, And the user identification means is patient identification means. The method of claim 14, The patient identification means is a radio frequency identification (RFID) reader configured to be associated with a matching RFID tag of the patient to be identified, wherein the dispensing device is capable of being released or usable when the RFID reader of the dispensing device detects the matching RFID tag of the patient. Dispensing device characterized in that. The method of claim 13, And said user identification means comprises means for identification of a health care professional. The method of claim 16, And said health care professional identification means is a radio frequency identification (RFID) reader. The method of claim 1, Wherein said dispensing device is a single dose applicator (SDA). The method of claim 18, Oral transmucosal administration is sublingual administration. The method of claim 18, The oral transmucosal administration is SDA characterized in that the ball administration.

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