CN101621994B - For treating a small amount of oral transmucosal dosage forms containing sufentanil of pain - Google Patents

Abstract

Discuss the compositions of pharmaceutical dosage form, the method and system for giving to comprise sufentanil in a small amount to individual oral mucosa.

Description

For treating a small amount of oral transmucosal dosage forms containing sufentanil of pain

The related application quoted

The application is the part continuation case of the U.S. Patent Application Serial Number 11/650,174 of the U.S. Patent Application Serial Number submission on January 5th, 11/985,162 and 2007 submitted on November 14th, 2007, hereby both is incorporated by by way of reference.

Invention field

The present invention relates to the pharmaceutical dosage form (smallvolumesufentanil-containingdrugdosageforms) in a small amount containing sufentanil, and for the method and system to individual oral transmucosal administration.

Background of invention

Peroral dosage form accounts on market about the 80% of all pharmaceutical dosage forms. They be noninvasive, be prone to administration and have height patient compliance. But, the therapeutic agent of oral administration must be transported to stomach and small intestinal, enters in blood through gastrointestinal (gastrointestinal, GI) mucosa absorption. After oral administration, the efficiency of drug absorption is in low-level due to the metabolism in GI road and the first pass metabolism in liver (first-passmetabolism), causes the characteristic of relatively tediously long onset time (onsettime) or the unstable absorption being unsuitable for controlling acute illness. On market, most of peroral dosage forms are designed for GI and send and pass. Being designed to oral mucosa send the peroral dosage form passed relatively fewer.

Oral transmucosal send to pass and provides many advantages because which provide than oral send to pass shorter reach maximal plasma concentration (C_max) onset time, especially for lipophilic medicine. This is because medicine arrives blood plasma through the mucosal tissue epithelial cell of very vascular quickly, directly and efficiently, therefore arrive rapidly blood circulation, thus avoid more slowly, often insufficient and variable GI absorbs. Therefore as quick acting, consistent T_maxAnd C_maxTime favourable, drug delivery is sent to be advantageous for by oral mucosa.

Sending in the process of passing at oral transmucosal medicine, medicine absorbs through the epithelial cell membrane in oral cavity. But give to oral transmucosal and pass relevant key risk and may often be such that, due to the continuously generating of saliva, reflux and the probability swallowing and make medicine be swallowed increases. When the dosage form adopted is even as big as producing significant ptyaloreaction and when described ptyaloreaction causes medicine to swallow in turn and/or dosage form is lost by oral mucosa adhesiveness (adherence), this becomes special hazard.

Utilize various solid dosage forms such as sublingual tablet, tablet, lozenge, lozenge rod (lozenges-on-a-stick), chewed and send drug delivery with chewing gum (chewinggums) and mouth paster via oral mucosas tissue. Solid dosage forms, such as lozenge and tablet, has been used for sending, across mucosa, the medicine passing such as nitroglycerin Sublingual tablet (nitroglycerinsublingualtablets).

Can reproduce and effectively drug delivery technology is active research field, particularly, when it is applied to controlled substance such as opioid such as sufentanil.

Association area does not describe send the solid pharmaceutical dosage formulation being handed to oral mucosa such as sublingual space (sublingualspace) by sufentanil.

Usual manner relative to administration, such as oral route and intravenous route, use controlled oral transmucosal pharmaceutical Dispensing System, provide many advantages, most important of which is that, safety improves, and other advantages are the onset effect of fast and stable, and predictable plasma concentration more more stable than existing dosage form and higher and more stable bioavailability.

This is particularly relevant with the treatment of pain, relevant with acute (i.e. Post operation), intermittent and explosive pain (breakthroughpain) specifically.

Therefore, need to give the opioid pharmaceutical dosage form of such as sufentanil, method and system (as being administered) by patient-controlled for what treat pain, device is wherein utilized to give pharmaceutical dosage form, described device provides and send pass via safety and the controlled medicine of oral mucosa, and makes drug dependence and/or the minimizing possibility diverted from one use to another.

The invention solves these demands.

Summary of the invention

Give to individual single Sublingual disclosed sufentanil dosage form cause following one or more: the bioavailability more than 50%, the coefficient of variation (coefficientofvariation) AUC less than 40%_inf, the coefficient of variation T less than 40%_max��C_maxAnd linear relationship between the amount of sufentanil in dosage form, and AUC_infAnd linear relationship between the amount of sufentanil in dosage form.

Repeat to individual Sublingual to give disclosed sufentanil dosage form cause following one or more: than the bioavailability higher to the bioavailability after individual single sublingual administration; Repeat the T after sublingual administration_maxAnd the difference between the time of previous sublingual administration, the described time is less than the T after being administered at present to individual single_max; And the T that the coefficient of variation is less than 40%_max��

Disclosed sufentanil dosage form has purposes in the method for the treatment of pain.

Disclose for the distributor that sufentanil dosage form is positioned over sublingual space treatment pain method in purposes, wherein, place/administration can be patient-controlled.

Disclosed hand-held dispensing device includes one or more following parts (features): having the housing (housing) of distribution end (dispensingend), this distribution end has preventing or the component (means) hindering saliva to enter; Locking parts (lock-outfeature); User identification component (identificationfeature); The disposable cartridge case of configured one or more pharmaceutical dosage form of accommodation.

Locking parts can provide, with the interval of minimum 20 minutes, the sufentanil sublingual administration repeated.

Cartridge case can provide intelligence cartridge recognition system, keys in the electronic microchip on the bar code on parts (physicalkeyedfeature), photodetector or pattern, cartridge case, the magnetic labels on cartridge case, the RFID tag on cartridge case, cartridge case or its combination including the physics on cartridge case.

Brief Description Of Drawings

Fig. 1 is that Sublingual gives healthy human volunteer 2.5,5,10 and 20mcg (every 10 minutes 5mcg, 4 doses) after sufentanil dosage form (slowly-corrosion), the schematic diagram of sufentanil mean plasma concentrations �� standard deviation (SD) and time.

Fig. 2 is after Sublingual gives healthy human volunteer 2.5,5,10 or 4 �� 5mcg sufentanil dosage form (slowly-corrosion), C_maxThe linear schematic diagram of (meansigma methods �� SD) and sufentanil dosage.

Fig. 3 is after Sublingual gives healthy human volunteer 2.5,5,10 or 4 �� 10mcg sufentanil dosage form (slowly-corrosion), AUC_infThe linear schematic diagram of (meansigma methods �� SD) and sufentanil dosage.

Fig. 4 is compared with 10 minutes infusion 5mcg sufentanils of intravenous (IV), after 10 minutes repetition Sublingual give 4 5mcg sufentanil dosage forms of healthy human volunteer (slowly-corrosion), the schematic diagram of sufentanil plasma concentration (meansigma methods �� SD) and time.

Fig. 5 A and Fig. 5 B is within the time period of 12 hours (Fig. 5 A) or 2.5 hours (Fig. 5 B) after 10 minutes repetition Sublingual give healthy human volunteer's 4 �� 5mcg sufentanil dosage form (slowly-corrosion), the observed diagram with the sufentanil dosage form plasma concentration (meansigma methods �� SD) predicted with time.

Fig. 6 is after Sublingual gives healthy human volunteer 10,40 (every 20 minutes 10mcg, 4 doses) and 80mcg sufentanil dosage form (faster-corrosion), the schematic diagram of sufentanil plasma concentration (meansigma methods �� SD) and time.

Fig. 7 A and Fig. 7 B be 12 hours (Fig. 7 A) or 2.5 hours (Fig. 7 B) in the time period every within 20 minutes, repeating after Sublingual gives healthy human volunteer's 4 �� 10mcg sufentanil dosage form (very fast-corrosion), the sufentanil plasma concentration (meansigma methods �� SD) of observed and prediction and the schematic diagram of time.

Fig. 8 is after Sublingual gives healthy human volunteer 10,4 �� 10 or 80mcg sufentanil dosage form (faster-corrosion), C_maxThe linear diagram of (meansigma methods �� SD) and sufentanil dosage (mcg).

Fig. 9 is after Sublingual gives healthy human volunteer 10,4 �� 10 or 80mcg sufentanil dosage form (faster-corrosion), AUC_infThe linear schematic diagram of (meansigma methods �� SD) and sufentanil dosage.

Figure 10 A and Figure 10 B gives the sufentanil (Figure 10 A) of 10mcg dosage or every within 20 minutes, repeating after Sublingual gives the sufentanil (Figure 10 B) of 10mcg dosage every within 20 minutes, repeating Sublingual, the diagram of the stable state sufentanil plasma concentration predicted by superposition and time.

Figure 11 A-11E is illustrative of the schematic diagram of distributor, and the oral mucosa of the designed patient in treatment of wherein said device send drug delivery dosage form. Figure 11 A-11E illustrates the process (progression) (Figure 11 A) of intact drug distributor 11; The reusable head (head) 13 of drugs distribution apparatus (11B) and disposable main body (body) 15; The reusable head 13 of drugs distribution apparatus (Figure 11 C), disposable main body 15 and cartridge case 17, distribution button 23 and nose body (proboscis) 31; The various aspects of drugs distribution apparatus 11, including reusable head 13, disposable main body 15 and cartridge case 17, nose body 31 and open the door bolt (latch) 19 of this device, hub lock (hublock) 21, distal seal (distalseal) 33,35 and power coupler (powertraincoupling) 25 (Figure 11 D); And the complete drugs distribution apparatus 11 (Figure 11 E) re-assemblied.

Figure 12 is the schematic diagram of exemplary allocations of communication resources device, shows designed blocking-up or the parts hindering saliva and moisture to enter. Preferred embodiment includes the dispensing head (dispensingtip) with guard shield (shroud) 29, and this distributor has one or more: wiper seal/valve (wipingseal/valve) 33,35, absorption pad (absorbentpad) 39, push rod (pushrod) 51, hothouse/moisture circulation passage 43, the desiccant 45 in passage, desiccant 47 in the cartridge case 17 containing dosage form 67 and cartridge case.

Figure 13 A and 13B is the schematic diagram of dispensing head exemplary geometric arrangement.

Figure 14 A-14D is the schematic diagram of the exemplary nose body 31 of distributor 11, and wherein nose body 31 has the 53 of S shape and comprises guard shield 29 and valve. Nose body protection valve exempts from the entrance of the moisture from tongue and other mucosas and saliva, and is not adhere to, for dosage form separating device, the far-end valve or the offer space, guard shield district that moisten. When apparatus for removing from gap, oral cavity, in order to alleviate dragging of dosage form, nose body also comprises breach/depression (cut-out/relief) 55. Valve works together with nose body, controls the entrance of saliva and moisture, and auxiliary is sent and passed dosage form.

Figure 15 A-15D provides the flow chart that a series of exemplary means uses, and is shown in device use procedure, and in the stage that push rod/tablet (pushrod/tablet) interacts, wherein Figure 15 A represents loading performance; Figure 15 B represents calibration performance; Figure 15 C represents allocation performance; And Figure 15 D represents dismantling property.

Figure 16 is the schematic diagram of exemplary means, in exhibiting device use procedure, and the stage that push rod/tablet interacts. In figure 16, it is shown that push rod 51, dosage form 67, transport tablet (shippingtablet) 69, spring 73 and position sensor 71. In use, move between the push rod 51 position 57,59,61,63,65 and 67 in being also shown in Figure 16.

Figure 17 is structure connection diagram, explanation can be included in the various assemblies in drugs distribution apparatus or system, including the device with separate medical distributor head 13, drugs distribution apparatus main body 15, cartridge case 17, portable docking FOB (portabledockingFOB) 113, patient's FRID label 115 and base station (basestation) 117.

Figure 18 A, the structure chart of one aspect of communication in pharmaceutical Dispensing System, the personal computer of described pharmaceutical Dispensing System RFID tag, drugs distribution apparatus, base station/base (basestation/dock) and medical personnel (healthcareprovider) are described.

Figure 18 B illustrates the structure chart of the another aspect of communication in pharmaceutical Dispensing System, and described pharmaceutical Dispensing System includes the personal computer of FRID label, drugs distribution apparatus, portable docking FOB, base station and medical personnel.

Figure 19 A and B is the schematic diagram of exemplary single dose applicator.

Figure 20 A-20C be a type of single dose applicator and its pass the diagram of purposes in dosage form sending to individuality.

Figure 21 A-21F is the diagram of 6 kinds of other single dose applicator.

Figure 22 is the diagram of multiple dose giver, wherein before the use, stocks multiple single dose applicator.

The diagram of other single dose applicator of Figure 23 A-23C and multiple dose giver embodiment.

Figure 24 A-24B is two stages that diagram single dose applicator one embodiment uses.

The schematic diagram of Figure 25 A-25D single dose applicator (singledoseapplicator, SDAs) other examples.

Figure 26 A-26D is multiple dose giver or the container storing multiple SDAs before use and uses SDAs Sublingual to give the schematic diagram of pharmaceutical dosage form.

The detailed description of invention

I. introduce

Provide and give the compositions of a small amount of dosage form containing sufentanil, method, system, test kit and drugs distribution apparatus for oral transmucosal such as Sublingual. Oral transmucosal gives dosage form, makes ptyaloreaction minimize, thus makes medicine sending to pass and minimize to GI road, so that most drug is obtained through oral mucosa and send and pass. Dosage form has the bio-adhesive properties promoted to oral mucosa adhesion in a small amount, thus makes the digestion caused owing to swallowing and poor efficiency send and pass risk minimization.

The a small amount of being claimed comprises the dosage form of sufentanil, and some of which embodiment is also referred to as " Sublingual sufentanil NanoTabs^TM(SublingualSufentanilNanoTabs^TM) ", compared with being currently available that Pain treatment, in safety and efficiency, both provide many advantages.

Following disclosure provides the description of the composition dosage form of the present invention, drugs distribution apparatus, method, system and test kit. Do not limit the invention to concrete dosage form as herein described, device, method, system, test kit or medical condition, because they are it is of course possible to change. It will also be appreciated that term used herein, it is only for the purpose describing specific embodiments, is not meant to limit the scope of the present disclosure.

It must be noted that as used by this paper and appended claims, singulative " a ", " and " and " the " includes plural reference, unless the context. It is therefoie, for example, the implication of " pharmaceutical preparation " includes this type of preparation multiple, system that the implication of " drug delivery devices " includes comprising pharmaceutical dosage form and for holding, store and send the drug delivery devices passing this type of dosage form.

Except as otherwise noted, all technology used herein and scientific terminology generally and general technical staff of the technical field of the invention be generally understood there is identical implication. Although similar with as herein described or that be equal to any method, device and material may be used to implement and the inspection present invention, but presently described be preferred method, drug delivery devices and material.

Provide only the disclosure of publication discussed in this article before the present patent application day. In this article, can be construed to without any content, admit due to the fact that formerly invention and disqualification prior in this type of disclosure.

II. define

Term " activating agent (activeagent) " or " (active) of activity " can use with " medicine (drug) " exchange in this article, it is intended that any curative activating agent.

Term used herein " adheres to (adhere) " and relates to contacting and remain in this surface with surface such as mucomembranous surface without application external strength pharmaceutical dosage form or preparation. Term " adhesion " is not intended to imply deadlocked (sticking) of any degree or combine, and neither be intended to imply the persistency of any degree.

Term used herein " analgesic (analgesicdrug) " includes sufentanil or sufentanil congener and the preparation comprising one or more therapeutic compounds, described congener such as alfentanil (alfentanil), fentanyl (fentanyl), lofentanil (lofentanil), carfentanil (carfentanil), remifentanil (remifentanil), trefentanil (trefentanil) or mirfentanil (mirfentanil). Use a kind of of the opioid compound that phrase " sufentanil or congener " is not intended to be limited to only to use these selected or comprise only these selected opioid compound a kind of. Additionally, only mention sufentanil or only mention a kind of selected sufentanil congener, for instance mention alfentanil it should be appreciated that be only adapted for sending according to the inventive method the example of the medicine passed, not limit by any way.

Term used herein " AUC " means " area under a curve (areaunderthecurve) ", in the plasma drug level chart with the time, also referred to as " AUC_inf". Generally provide zero-time interval to unlimited AUC, it may be evident, however, that plasma drug level can not be measured as " to unlimited " for patients, therefore assessed AUC with mathematical formulae by a limited number of concentration measurement.

AUC_inf=AUC_t+C_last/��_z, wherein C_lastIt it is last plasma concentration.

In the meaning of practice, AUC_infRepresent the total amount of the medicine of health absorption, unrelated with absorption rate. When whether the two kinds of preparations attempting to measure same dose discharge the medicine of same dose to health, it is useful. With the AUC that intravenous gives same dose_infCompare, the AUC of transmucosal dosage forms_infAct the effect on the basis measuring bioavailability.

Term used herein " bioadhesion " refers to biological surface is included the adhesion of mucosa.

Term used herein " bioavailability " or " F " mean " percentage ratio bioavailability ", and represent compared with same medicine intravenous administration, the share (fraction) of the medicine absorbed from detection article (testarticle). Its by send via given path pass after detect the AUC of article_infWith the AUC of same medicine after intravenous administration_infCalculate. The absolute bioavailability of sublingual administration is measured by following formula.

F (%)=AUC_inf ^Sublingual/AUC_INF ^IV�� dosage_IV/ dosage_Sublingual

Term used herein " explosive pain " be the moderate of prompt explosion to severe pain, it betides under otherwise controlled pain background. At short notice, being as short as 1 or 2 minute or long to 30 minutes or more, " explosive pain " can be violent.

Term used herein " cartridge case " relates to the one or more pharmaceutical dosage form of configured accommodation and is generally up to about the disposable cartridge case of 200 pharmaceutical dosage forms. Cartridge case can comprise the physics having on cartridge case and key in the intelligent cartridge recognition system of the electronic microchip on the bar code on parts, cartridge case, the magnetic labels on cartridge case, the RFID tag on cartridge case, cartridge case or its combination. Cartridge case can also comprise one or more shipping tablet, wherein before distribution dosage form, distributes at least one shipping tablet.

Term " C used herein_max" mean maximal plasma concentration observed after giving medicine.

Term used herein " congener " refers to the one in many variants of total chemical structure or configuration.

Term " disintegrate (disintegration) " uses with " corrosion " exchange in this article, it is intended that dosage form decomposes passed physical process, and it is only relevant to the physical integrity of dosage form. This can occur in a number of different ways, including splitting into less fragment, and eventually becomes trickle and big granule, or alternatively, corrosion from outside to inside, until dosage form disappears.

Term used herein " dissolving " means such a process, namely by this process, solvent or body physiological liquid such as saliva are deposited in case in vitro, lytic activity composition from tablet, and unrelated with the mechanism of release, the combination of diffusion, corrosion or corrosion and diffusion.

Term " distributor ", " drugs distribution apparatus ", " allotter ", " pill dispenser ", " drug dose allotter (drugdosagedispenser) ", " device " and " drug delivery devices " exchange use in this article, refer to the device of distribution pharmaceutical dosage form. Distributor provides controlled and safe the sending of the pharmaceutically active substance (such as, the opioid of such as sufentanil) of preparation in dosage form and passs. The storage and/or send of the dosage form that device is suitable for such as lozenge, pill, tablet, capsule, diaphragm (membrane), band (strip), liquid, paster (patch), thin film (film), gel (gel), spraying (spray) or other forms is passed.

Term about device used herein " distribution end " means a part for device, and described part comprises nose body and guard shield, and its effect is to send drug delivery dosage form to individual oral mucosa.

Term " medicine ", " medicine (medication) ", " pharmaceutically active agents ", " therapeutic agent " etc. exchange use in this article, are often referred to the physiological function changing animal and can pass through any material that Oral Mucosal Route effectively gives.

Term " erosion time " refers to that solid dosage forms is decomposed until this solid dosage forms disappears the required time.

Term " FOB " refers to the hand-held electric power docking facilities of small portable, its cooperative drug distributor is for the data that upload data, download, the user interface controlling the use of drugs distribution apparatus, the use controlling pharmaceutical dosage form or raising drugs distribution apparatus, or changes this interface on the contrary. FOB can in a wired or wireless manner with drugs distribution apparatus communication or dock. FOB can be made to be suited for attachment to rope, in order to allow FOB to hang on the neck of health care professional of such as doctor or care-giver (caregiver), particularly in hospital environment. Drugs distribution apparatus can via FOB and doctor or care-giver's communication.

Term used herein " preparation (formulation) " and " pharmaceutical preparation " refer to, containing the physical composition of at least one pharmaceutically active substance, it can provide with any one in many dosage forms, is used for sending and passs in individuality. Dosage form can with lozenge, nine doses, capsule, diaphragm, band, liquid, paster, thin film, chewing gum, spraying or other forms, it is provided that to patient.

Term " forms the preparation (hydrogel-formingpreparation) of hydrogel " and means, anhydrous solid preparation to a great extent, it is once contact with aqueous solution, such as the body fluid of body fluid and particularly oral mucosa, just form the form of hydrated gel (hydratedgelinsitu) with original position and absorb water. Disintegrate (or corrosion) kinetics of uniqueness is followed in the formation of gel, allows to discharge therapeutic agent over time simultaneously. " form the preparation of hydrogel " it addition, term and describe anhydrous solid preparation to a great extent, itself once with body fluid and particularly intraoral bioresorbable, then be changed into the thin film of release medicine. This type of thin film adds drug release and absorbs surface area used, therefore can absorb the drug quickly.

Term used herein " locking parts " relates to the parts providing the device of " locking time (lock-outtime) ".

Term used herein " locking time " time period, within this time period, device does not allow drug use, namely within " locking time ", it is impossible to distribution dosage form. " locking time " can be can arrange, fixed time interval, predetermined interval, predetermined variable interval, the algorithm interval measured or be conveyed to the variable interval of device from far-end computer or Docking station (dockingstation).

Term used herein " LogP " means the logarithm of the equilibrium concentration ratio of the compound of unionization between pungent alcohol and water. P is also referred to as " octanol-water partition coefficient ", and acts the effect of hydrophobicity and the lipotropy means quantifying given pharmaceutical chemistry feature.

Term used herein " mucosal adhesive (mucoadhesion) ", refers to the adhesion to the mucus such as mucosa that intraoral mucus covers, and it can exchange with the term " bioadhesion " referring to any biological surface is adhered to and use.

Term " mucosa (mucosalmembrane) " is often referred to the raw coated any biomembrane of internal mucus. By oral mucosal absorption, advantageous particularly. Therefore, oral mucosal absorption, namely cheek, Sublingual, gingiva and palate absorb is consider especially.

Adopt the most broad sense of term " mucosa storehouse (mucosal-depot) " herein, refer in mucosa or the stock (reservoir) of lucky SM pharmaceutically active substance or or deposit (deposit).

Term used herein " unordered granulate mixture " or " disordered conglomeration " relate to preparation, and wherein for pharmaceutically active agents and bioadhesive material or adhesion promoter or other preparation composition, this mixture is unordered. It addition, this term further relates to, by including any preparation prepared by dry mixed process, use this term herein, it it not wherein the surface that drug particles is uniformly distributed in more larger vector granule (carrierparticles). This " unordered " mixing can include dry blending granule in the way of unordered, wherein for adding/mix the order no requirement (NR) of concrete excipient and bioadhesive material or bioadhesion accelerator and/or disintegrating agent. Additionally, in unordered mixed process, the unbounded size system to drug particles. Drug particles can more than 25 ��m. It addition, " disordered conglomeration " includes any mixed process, in this process, main carriers granule (primarycarrierparticles) is not incorporated to disintegrating agent in inside. Finally, " disordered conglomeration " can be prepared by any " wet-mixed " process, and namely described wet blending process adds the process of solvent or non-solvent in mixed process, or adds any mixed process of medicine with the form of solution or suspension. ,

Term used herein " is operably connected " and means to provide and in device assembly, in order to play a role by intention, it is achieved target. Such as, memory is operably connected CPU, the latter is further operable to Connection Release mechanism (releasemechanism) and means, once exciting, CPU just with memory communication, check that medicine send the state or history passed, and subsequently with relieving mechanism communication (as via solenoid and switch), release and distribution medicine; Term used herein " patient (the opioid that opioid is not testedPatient) " relate to not repeating to give opioid patient within the period of several weeks to several months.

Term used herein " opioid intolerant patient " means to be characterized as owing to (such as analgesia, feeling sick or calm) physiological status reduced to, the opioid effect of medicine for a long time. Opioid be have with those material types comprising Opium or derivatives thereof like analgesia, calm and or the medicine of hypnotic effect, hormone or other chemical substances. If gradually forming analgesic tolerance, then increase opioid dosage to reach the analgesia of phase same level. This toleration is likely to may not extend to side effect, along with the increase of dosage, it is possible to cannot stand side effect fully.

Term " oral transmucosal dosage forms " and " pharmaceutical dosage form " can exchange use in this article, and refer to containing pharmaceutically active substance such as the dosage form of the medicine of such as sufentanil. Peroral dosage form is for sending drug delivery active substance by the mode of oral mucosa to blood circulation, and is usually " sublingual dosage forms ", but in some cases, it is possible to use other oral transmucosal approach. This dosage form provides send drug delivery active substance through oral mucosa, and by controlling formula, it is possible to achieve time-releasable medications active substance. This dosage form comprises pharmaceutically acceptable excipient, and is properly termed as NanoTab^TM, this is had detailed description by U.S. Patent Application Serial Number 11/650,174. This dosage form comprises preparation, described preparation neither effervescent tablet does not comprise the substantially anhydrous ordered mixture of the drug microparticles adhering to carrier particle surface yet, much bigger than the microgranule of medicine of wherein said carrier granular.

Term used herein " oral transmucosal medicine send and passs " and " oral transmucosal administration " refer to substantially send not via the medicine swallowing the generation of GI absorption subsequently via oral transmucosal approach pass. It includes via cheek, Sublingual and gums across mucosa district.

Term " nose body " uses with term " dispensing head ", " send and pass head " exchange, points to oral mucosa (such as sublingual space) and send distribution and/or the positioning head of the pharmaceutical dosage form allotter passing dosage form.

Term " rfid device (radiofrequencyidentificationdevice) " or " RFID " are used to refer to the recognition methods of automatization, described method depends on and utilizes the device being called RFID tag store and fetch data at a distance, wherein in order to utilize radio wave to be identified, RFID is applied to or is incorporated to product or people. Some labels can read from several meters and outside readers line of vision.

Term " replaceable cartridge case " or " disposable cartridge case " are used to refer to the cartridge case holding pharmaceutical dosage form, and it is generally formulated maximum 200 pharmaceutical dosage forms of accommodation, and wherein cartridge case is designed instant abandons.

Term used herein " shipping tablet " relates to identical with the dosage form size containing medicine and shape but does not comprise " preset (initialization) " or " transport " tablet of pharmaceutically active substance. " shipping tablet " can comprise the placebo formulation not containing pharmaceutically active substance, or can be made up of plastics or other materials. It is first article of distribution from new cartridge after inserting distributor. Device has the component distinguishing shipping tablet and the dosage form containing pharmaceutically active substance.

Term " guard shield " is for describing the part or all of covering of device distribution end; its protection is sent and is passed mouth (deliveryport) and avoid and intraoral saliva or other contact with moistures; and between device, oral mucosa and tongue, form barrier, have and send the depression (relief) passed for dosage form and make saliva enter or moisture entrance minimizes or by the hydrophobic of its eliminating or hydrophilic inside. " guard shield " is formed barrier by the oral mucosa in contact valve district and dosage form, and formulation auxiliary distributes and hinders the dosage form adhesion to nose body. Nose body has inner surface or other the surface configuration of circle, makes dosage form can not adhere to nose body. Nose body restriction tongue or oral mucosa distribute, with dosage form, the ability that district contacts, and thus control saliva contacts and entrance.

Term " individuality " includes expecting sanatory any individuality, it is common that mammal (such as people, Canis animals, felid, equine species, bovid, ungulate etc.), adult or child. Term " individuality " and " patient " can exchange use in this article.

Term used herein " includes the system of pharmaceutical dosage form and distributor " and refers to send passing and/or monitor the pharmaceutical Dispensing System that medicine gives. Described system may be used for monitoring and send drug delivery active substance, for instance, the opioid of such as sufentanil, wherein, send the amount of the medicine passed, corresponding efficiency and safety all to improve than currently available system. Described system can have provides improved safety than currently available system, be easy to one or more parts of operation, send the memory organization packets of the information of passing including the parts of the medicine preventing unauthorized use from storing, dosage locking parts, the component of the indivedual user of drug use identification for controlled, Rapid Dose Calculation parts, retained dose, and carry out the interface of bi-directional exchanges of information with another device of user, cartridge case or such as computer.

Term " small quantities of drugs dosage form " or " in a small amount dosage form " is used to relate to volume less than 100 �� l's with the quality a small amount of dosage form less than 100mg herein. specifically, the quality of dosage form is less than 100mg, 90mg, 80mg, 70mg, 60mg, 50mg, 40mg, 30mg, 29mg, 28mg, 27mg, 26mg, 25mg, 24mg, 23mg, 22mg, 21mg, 20mg, 19mg, 18mg, 17mg, 16mg, 15mg, 14mg, 13mg, 12mg, 11mg, 10mg, 9mg, 8mg, 7mg, 6mg or 5mg, or volume is less than 100 �� l, 90 �� l, 80 �� l, 70 �� l, 60 �� l, 50 �� l, 40 �� l, 30 �� l, 29 �� l, 28 �� l, 27 �� l, 26 �� l, 25 �� l, 24 �� l, 23 �� l, 22 �� l, 21 �� l, 20 �� l, 19 �� l, 18 �� l, 17 �� l, 16 �� l, 15 �� l, 14 �� l, 13 �� l, 12 �� l, 11 �� l, 10 �� l, 9 �� l, 8 �� l, 7 �� l, 6 �� l or 5 �� l. " dosage form " can have or can not have bioadhesive characteristics, and once contact with aqueous solution, just can form hydrogel.

" dosage form " may be used for sending that pass can according to the amount of the amount via a small amount of dosage administration i.e. 0.25 �� g-99.9mg, 1 �� g-50mg or 1 �� g-10mg any medicine by oral transmucosal administration.

Term used herein " in a small amount the pharmaceutical dosage form containing sufentanil " relates to a small amount of dosage form containing sufentanil dosage, described sufentanil dosage is selected from about 2mcg (micrograms, microgram)-Yue 200mcg sufentanil, such as 5mcg, 10mcg, 15mcg, 20mcg, 30mcg, 40mcg, 50mcg, 60mcg, 70mcg, 80mcg or 100mcg sufentanil.

Term used herein " solid dosage forms " or " solid pharmaceutical dosage formulation " are related to a small amount of dosage form of solid such as lozenge, pill, tablet, diaphragm or band.

Term " Sublingual " refers to " under tongue " according to letter, refers to give pharmaceutical dosage form via mouth in the way of via the blood vessel in Sublingual rather than the active substance that quickly absorbs the drug via digestive tract. Absorb and occurred by the hypoglossis mucous membrane of very vascular, and allow pharmaceutically active substance more directly to enter blood circulation, it is provided that not by the GI direct Formulations for systemic administration affected.

Term " t1/2 (terminalhalf-life) " defined herein or " t_1/2[h] " it is calculated as In (2)/��_Z(the one-level last speed constant (firstorderterminalrateconstant) eventually that the time that is defined as is assessed with the linear regression of log concentration curve, and also in repeated doses research, measure after last medication.

Term " T used herein_max" mean the time point of observed maximal plasma concentration.

Term " T used herein_onset" mean observed " onset time ", represent that plasma drug level reaches observed maximal plasma concentration and C_max50% needed for time.

Term " therapeutically effective amount " means to effectively facilitate the amount of the therapeutic agent of desirable therapeutic effect such as pain relief or therapeutic agent send and passs speed (amount as in time). Ideal treatment (the degree such as pain relief accurately, alleviating of pain source), other factors multiple of understanding generally according to state to be treated, individual toleration, medicine to be administrated and/or pharmaceutical preparation (concentration etc. such as the usefulness of therapeutic agent (medicine), preparation of Chinese medicine) and those of ordinary skill in the art and change.

" across the mucosa " of term medicine send the meaning passed, and passs including sending of the form of ownership across or through mucosa.

III. pharmaceutical dosage form

Compared with being intended to send medicine conventional, the bigger dosage form passed in oral cavity, a small amount of oral transmucosal being claimed makes ptyaloreaction reduce.

Oral transmucosal medicine send the preferred sites passed to be sublingual area, although in certain embodiments, is positioned in cheek by dosage form or adheres to the top of mouth or gums is advantageous for.

Compared with Conventional oral dosage forms and other oral transmucosal dosage forms, dosage form provides the medicine of greater percentage (amount) and send via oral mucosa and pass, and send via gastrointestinal (GI) road and passs corresponding minimizing.

Generally, send the phase of passing, dosage form to be suitable to adhere to oral mucosa (being namely bioadhesion) at medicine, and until most of or all medicines have sent from dosage form and have been handed to oral mucosa.

Specifically, the quality of dosage form is less than 100mg, 90mg, 80mg, 70mg, 60mg, 50mg, 40mg, 30mg, 29mg, 28mg, 27mg, 26mg, 25mg, 24mg, 23mg, 22mg, 21mg, 20mg, 19mg, 18mg, 17mg, 16mg, 15mg, 14mg, 13mg, 12mg, 11mg, 10mg, 9mg, 8mg, 7mg, 6mg or 5mg or volume are less than 100 �� l, 90 �� l, 80 �� l, 70 �� l, 60 �� l, 50 �� l, 40 �� l, 30 �� l, 29 �� l, 28 �� l, 27 �� l, 26 �� l, 25 �� l, 24 �� l, 23 �� l, 22 �� l, 21 �� l, 20 �� l, 19 �� l, 18 �� l, 17 �� l, 16 �� l, 15 �� l, 14 �� l, 13 �� l, 12 �� l, 11 �� l, 10 �� l, 9 �� l, 8 �� l, 7 �� l, 6 �� l or 5 �� l.

In preferred embodiments, the quality of the dosage form being claimed less than 30mg and volume less than 30 �� l.

Dosage form is generally of bio-adhesive properties, and once contacts with aqueous solution and just can form the hydrosol.

Dosage form is generally of the erosion time of about 6 minutes or maximum 25 minutes, but, erosion time can change. Specifically, dosage form is generally of the erosion time of about 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes or 25 minutes.

Generally, in the dosage form giving individual oral mucosa, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least the 99% of pharmaceutically active substance total amount absorbs via oral transmucosal approach.

In general, dosage form can have any shape, and the example includes the disk of tool flat horizontal surface, concave surface, convex surface, oval, spherical, has three or more limit and the polygon of plane, concave surface or convex surface. Dosage form can be symmetrical or asymmetric, and can have allow controlled, easily, be easy to store, process, the feature of packaging or medication or shape.

Oral transmucosal send and passs is simple, noninvasive, and can be completed in the way of sense of discomfort is minimum by care-giver or patient. Sending the dosage form passed for oral transmucosal can be solid or non-solid. In a preferred embodiment, dosage form be with saliva contacts after become the solid of the hydrosol. In another preferred embodiment, dosage form be with saliva contacts after corrosion and be formed without the solid of the hydrosol.

Generally, the oral transmucosal of pharmaceutically active substance send to pass and utilizes solid dosage forms such as lozenge or tablet to realize, but, liquid, spraying, gel, chewing gum, powder and thin film etc. can also use.

For some drugs, as having the medicine of very poor bioavailability via GI road, for instance, the lipotropy opioid of such as sufentanil, oral transmucosal send and passs is send than GI to pass more effective to send the approach of passing. For lipophilic drugs, oral transmucosal send the oral GI of ratio of two term to send to pass and have shorter onset time (namely from the time being administered into therapeutic effect), and provides better bioavailability and more stable pharmacokinetics.

The small quantities of drugs dosage form being claimed is suitable to reduce ptyaloreaction, thus reduces the amount of medicine swallowed, and thus, send to individuality via oral mucosa and passs high amount of drug. The pharmaceutical dosage form being claimed provides sufentanil and passs via effectively sending of oral mucosa, and blood plasma level stable in treatment window (therapeuticwindow).

The preparation of the dosage form that preparation is claimed and their preparation method, be described in U.S. Patent Application Serial Number 11/825,251 and 11/650, in 227. Exemplary preparation is bioadhesion, and comprise the sufentanil of about 0.0004%-about 0.04%, for instance the sufentanil of 0.0005%, 0.001%, 0.002%, 0.003%, 0.004%, 0.006%, 0.008%, 0.01%, 0.012%, 0.014% or 0.016%. Generally, preparation comprises the disordered conglomeration of (a) pharmaceutical effective amount medicine; B () provides the bioadhesion material adhered to individual oral mucosa; And (c) stearic acid, wherein comprise the dissolving of dosage form of preparation independent of pH, for instance within the scope of the pH of about 4-8.

It is characterized by for the pharmaceutically active agents in invention formulation, the logarithm (LogP) of the octanol-water partition coefficient between 0.006 and 3.382.

The pharmaceutical dosage form sending the present invention passed for oral transmucosal can be solid or non-solid. In a preferred embodiment, dosage form be with saliva contacts after be transformed into the solid of the hydrosol. In another preferred embodiment, dosage form be with saliva contacts after be changed into the solid of bioadhesion thin film.

In preferred embodiments, this type of preparation is suitable to form visible thin film after disintegration of tablet. Once be positioned on oral mucosa, dosage form just absorbs water, in order to after it is fully hydrated, launches along mucomembranous surface, thus being transformed into the bioadhesion thin film comprising active medicine. This transformation make drug release can surface area dramatically increase, hence speeded up medicine diffusion from dosage form and release. Due to higher contact surface area, drug absorption occurs faster, causes quick release action.

The many suitable pharmaceutically acceptable carrier of non-toxic for peroral dosage form, it is seen that in Remington ' sPharmaceuticalSciences (Lei Mingdun materia medica), 17thEdition (17 editions), 1985.

It is appreciated that the method utilizing those skilled in the art conventionally used, such as directly concentration, wet granulation (wetgranulation) etc., preparation is transformed into for sending the dosage form being handed to individuality. In order to realize homogeneous high dose content, optimize the process of the preparation dosage form of every kind of preparation.

Although being not intended to be limited to theory, but in an exemplary embodiment, when pharmaceutical dosage form being positioned over chamber, Sublingual, it is preferable that during the Sublingual of lingual frenum either side, namely adhere to after its contact. When the moisture of dosage form contacts sublingual space, dosage form absorbs water, causes that the corrosion of dosage form and medicine are to the release of individual systemic circulatory system.

IV. sufentanil

Opioid is widely used in the treatment of pain, and generally send pass with intravenous, oral cavity, dura mater, transdermal, rectum and intramuscular mode. Morphine and its analog generally send in intravenous mode to be passed, and is effective against severe chronic and acute pain. But, if improper use, they also have Severe Respiratory Failure effect (respiratorydepressiveeffects), and also suffer from height abuse potential. Pure opioid causes the main cause of M & M, is caused by respiratory complication.

Sufentanil (N-[(4-(methoxy-1-(2-(2-thienyl) ethyl)-4-piperidyl)]-N-Phenylpropionamide) as main anesthetis, cardiac operation produces comprehensive anesthesia smoothly, for dura mater administration in stages of labor and birth process, and carry out experimental administration with the form of intranasal and liquid oral medicine. The sufentanil sending the commercial form passed for IV isPreparation. This liquid preparation comprises 0.075mg/ml sufentanil citrate (sufentanilcitrate) (being equal to 0.05mg sufentanil alkali (sufentanilbase)) and 9.0mg/ml sodium-chloride water solution. It has the plasma clearance half-life of 148 minutes, and drains the dosage of 80% in 24 hours.

Clinically, the purposes of sufentanil is limited primarily to the IV administration in operating room or intensive care unit. Have the liquid sufentanil product formulation use for low dosage intranasal administration study (Helmersetal., 1989; JacksonK, etal., JPainSymptomManagement2002:23 (6): 450-452) and Sublingual send the case report (Gardner-NixJ., the JPainSymptomManagement.2001Aug that pass liquid sufentanil preparation; 22 (2): 627-30; KunzKM, TheisenJA, SchroederME, JournalofPainandSymptomManagement, 8:189-190,1993). In these researchs of great majority, the minimum dose of sufentanil in adult, do not test in patient at opioid, for 5mcg. Give the liquid of oral cavity or nasal mucosa, there is less bioavailability, and it is likely to shorter acting duration, this can be proved by zooscopy as herein described (sublingual liquid) and document (nasal drop (nasalliquiddrops)-Helmersetal., 1989). Gardner-Nix provides the analgesia data (not being pharmacokinetic data) that liquid Sublingual sufentanil produces, and the onset of pain control describing liquid Sublingual sufentanil occurred in 6 minutes, but the persistent period of pain relief is only about 30 minutes.

For the treatment of pain, can utilizing many opioid dosage forms at present, many of which comprises sufentanil.

Adopt lozenge across cheek give fentanyl (as) after, bioavailability is 50%, although 200mcg dosageT_maxRange for 20-120 minute, the fentanyl due to 75% swallowed (Package insert) the fact that, cause that the GI of instability absorbs. T about Actiq_maxNew publication show, these initial times, (fentanyl buccal tablet (Fentora) package insert showed, the T of Actiq to onset deflection faster_maxExtend maximum 240 minutes). Fentanyl buccal tablet (fentanyl cheek tablet) it is reported that the medicine of 50% is swallowed, and which show the bioavailability of 65%. It is contrary with the dosage form being claimed,And fentanyl buccal tablet both has inferior position, the fentanyl namely given with lozenge in a large number is swallowed by patient.

As effective [mu agonist, sufentanil and fentanyl have many similaritys, but, it has proved that they are different at many critical aspects. Multinomial research it has been proved that sufentanil than fentanyl effective 7-24 times (Package insert; PaixA, etal.Pain, 63:263-69,1995; ReynoldsL, etal., Pain, 110:182-188,2004). Therefore, sufentanil can utilize less dosage form to give, it is to avoid the increase of the ptyaloreaction of bigger dosage form, thus makes the amount of medicine swallowed minimum. It is minimum that this causes that GI absorbs.

It addition, fentanyl and other opioid agonist have the probability of harmful side effect, described side effect includes respiratory failure, Nausea and vomiting and constipation.

Evidence suggests, the sufentanil of clinical dosage than fentanyl and other opioids have less respiratory failure effect (Vedetal., 1989; Baileyetal., 1990; Contietal., 2004).

Owing to being had the bioavailability of 30% by GI approach fentanyl, therefore, the medicine swallowed can significantly influence C_maxBlood plasma level, and cause with the viewed unstable C of these products_maxAnd T_max. On the contrary, by GI approach, the bioavailability of sufentanil is 10-12%, and therefore, the medicine swallowed will not interfere significantly on C_maxBlood plasma level.

And, the lipid solubility (octanol-water partition coefficient) of sufentanil is more than fentanyl (816:1) (vandenHoogenandColpaert, Anesthes.66:186-194,1987). Compared with fentanyl (80-85%), sufentanil also show protein bound increase (91-93%) (respectivelyWithPackage insert). The pKa of sufentanil is 8.01, and the pKa of fentanyl is 8.43 (Paradisetal., TherapeuticDrugMonitoring, 24:768-74,2002). These differences can affect various pharmacokinetic parameter, such as, it has proved that sufentanil has onset effect faster and convalescent period (Sanfordetal., AnesthesiaandAnalgesia faster than fentanyl, 65:259-66,1986). Compared with fentanyl, sufentanil is used to may result in pain relief faster, and can with titrimetry measurement effect with avoid excessive medication.

It is essential that it has been proved that the endocytosis of sufentanil [mu of strong 80,000 times than fentanyl (Kochetal., MolecularPharmacology, 67:280-87,2005). This receptor internalization as a result, as time go by, neuron continues ratio fentanyl and more strongly responds sufentanil, it was shown that compared with the fentanyl of repeated drug taking, gradually form the probability to sufentanil toleration clinically less.

Before the work of the present inventor, it does not have any type of pharmacokinetic data about Sublingual sufentanil is published. Send across mucosa based on the relevant eye of dog and the mankind and intranasal that the pharmacokinetic data passing sufentanil is existing to be delivered. (the AnesthAnalg such as Farnsworth, 1998,86:138-140) describe the eye of sufentanil in dog and, across mucosa absorption and toxicity, wherein 50mcg sufentanil was given within the time period of 2.5 minutes 5 conjunctivas (conjuctiva) through the dog of anesthesia. After 5 minutes, T occurs_max, with the C of 0.81ng/mL_maxAnd the t of about 18 minutes_1/2. In 16 example people, intranasal and intravenous give the research report of 15mcg sufentanil, it is provided that pharmacokinetic characteristic compares, wherein, intranasal sufentanil by dripping by 2.5mcg/, 3, each nostril send and passs. Send compared with passing with intravenous, based on the AUC of 0-120 minute, the bioavailability of intranasal sufentanil was 78%. Intranasal send passs the T causing 10 minutes_maxAnd the C of 0.08ng/mL_max��t_1/2For about 80 minutes. Consult Helmersetal., CanJAnaesth.6:494-497,1989. The Section 3 research carried out in pediatric patients describes, and before surgical operation, via nasal drop, by 2mcg/kg sufentanil, 15 children is carried out Nasacort, and starts to measure sufentanil blood plasma level over the course of 15 mins, and described measurement too late, does not obtain T_max. Based on the deduction of these data, C_maxFor about 0.3ng/ml, t_1/2For about 75 minutes (Haynesetal., CanJAnaesth.40 (3): 286,1993).

Sufentanil dosage form

Activating agent in the dosage form being claimed is independent sufentanil, or with the combination of sufentanil congener such as alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil or mirfentanil. In preferred embodiments, sufentanil is separately as activating agent. Can by sufentanil with in any dosage form being provided in be claimed in many preparations. Sufentanil can provide with the form of sufentanil citrate, sufentanil alkali or its combination.

Sending for Sublingual and pass, sufentanil pharmaceutical dosage form can comprise about 0.25-and is about 200mcg sufentanil/dosage form. In an exemplary embodiment, each dosage form individually comprises about 0.25-200mcg sufentanil or the combination of one or more other treatment agent or medicine.

Give the illustrative drug dosage form of child's (pediatric patients) to contain about 0.25-and be about 120mcg sufentanil/dosage form. Such as, the dosage form giving child can send, containing about 0.25,0.5,1,2.5,4,5,6,8,10,15,20,40,60 or 120mcg oral transmucosal, the sufentanil passed. For pediatric patients, exemplary dosage form ranges at least about 0.02mcg/kg-and is about 0.5mcg/kg, it is preferred that ranges for about 0.05to-and is about 0.3mcg/kg.

The illustrative drug dosage form giving to be grown up contains about 2.5-and is about 200mcg sufentanil/dosage form. Such as, the pharmaceutical dosage form giving to be grown up can contain about 2.5,3,5,7.5,10,15,20,40,60,80,100,120,140,180 or 200mcg or more oral transmucosal and send the sufentanil passed.

Preferably, the dosage form containing sufentanil comprises the sufentanil of about 5-about 100 �� g, for instance 5mcg, 10mcg, 15mcg, 20mcg, 30mcg, 40mcg, 50mcg, 60mcg, 70mcg, 80meg or 100mcg sufentanil.

It will be apparent to a skilled person that and depend on body weight, dosage is low side for child, for high-end for adult, particularly, when giving the adult of opioid tolerance for a long time. Before the work of the present inventor, the dosage form that a small amount of passed comprises sufentanil is sent not to be described for oral transmucosal medicine.

In various embodiments, the dosage form being claimed includes all types of patients in child, opioid tolerance or the adult of all age brackets not tested and non-human mammal, both provides effective pain relief. The present invention in inpatient and outpatient settings and field have purposes.

Sufentanil congener has purposes, the example to include alfentanil, lofentanil, carfentanil, remifentanil, trefentanil or mirfentanil in compositions as herein described, method and system.

In certain embodiments, dosage form comprise at least 0.005% up to 99.9% alfentanil by weight, lofentanil, carfentanil, remifentanil, trefentanil or mirfentanil. The percentage ratio of active component depends on the size of dosage form and the characteristic of active component and changes, and optimized acquisition is passed via maximum the sending of Oral Mucosal Route. The present invention some in, more than one active component can be included in single dosage form.

V. the treatment of pain

Utilize current Therapeutic Method, trial utilizes many intervention means control pains, it generally includes: Patient Controlled Analgesia (patient-controlledanalgesia, PCA), continuous dura mater infusion (continuousepiduralinfusion, CEI) or other kinds of acute pain control, relax nursing Pain management (palliativecarepaincontrol) and family health care patient pain control (homehealthpatientpaincontrol). These methods achieve success in various degree in controlling persistence, being easy to treatment and the safety relative with side effect.

Fast treating acute pain need to betide in many different clinical settings, including pain (failedback) after surgical site infections recovery, rheumatic arthritis, back surgery, terminal cancer (i.e. explosive pain) etc. Surgical site infections, for instance, patient is subject to the pain of the light to moderate level of severe pain a couple of days subsequently of initial several days.

It is IV morphine for treating moderate to the most common analgesic of severe post-surgical pain. This utilizes to send based on IV injection on demand by nurse passs patient, or is generally placed in PCA pump by injection of morphia device, and patient gives opioid by extruding the button oneself with sticking department part. Other opioid, as hydromorphone (hydromorphone) and fentanyl can also be administered by this way.

The treatment of acute pain is also necessary for the patient in ambulatory settings. Such as, many patients suffer from chronic pain and need weekly or daily use their pain of opioid therapy. Although they have long-acting oral or transdermal opioid formulation to treat their chronic underlying pain level, they are also required to their severe burst pain level of fugitive effective opioid therapy.

" field " under highly sub-ideal conditions (highlysub-optimalconditions), the treatment of acute pain is also necessary. It is frequently necessary to the medical worker of airborne troop and medical officer and treat severe pain under ambient non-sterile, the pin that wherein IV or IM administration is used may result in unconscious acupuncture, infection risk etc. Oral opioid tablet provides alleviation to it is frequently necessary to 60 minutes, and this is oversize for the people being in severe pain.

In many clinical settings, have clearly a need for producing with titratable, safety and convenient and noninvasive mode the component of the improvement of the medicine of effective pain relief, described in reasonable time section, provide acute, severe is explosive or the alleviation of intermittent pain.

The compositions, the method and system that are claimed depend on giving of the pharmaceutically active substance dosage form comprising such as sufentanil; described pharmaceutically active substance utilizes distributor effectively to treat acute pain (i.e. post-surgical pain), intermittent pain or explosive pain, described device includes such as locking, give medicine before be stored in distributor for component and the protection of user identification the parts of component of dosage form. Accordingly, for safety and two aspects of effect, the method and system being claimed provides the significant advantage being better than existing form of therapy.

VI. people's In vivo study

Based on utilizing a small amount of dosage form being claimed via the research of sublingual routes of administration, there is provided herein the pharmacokinetic data obtained in the mankind.

Healthy human volunteer has been carried out two Human clinical's researchs. Section 1 research, it has described in detail in embodiment 1, with the 10 of 5mcg sufentanil minutes IV infusions or compared with administration in 10 minutes, slow corrosion Sublingual sufentanil dosage form containing 5mcg sufentanil 4 these repeated doses (table 1), utilize slow corrosion Sublingual sufentanil dosage form, 12 individualities (6 male 6 female) are carried out Section 1 research, described dosage form contains 2.5mcg, 5mcg or 10mcg sufentanil alkali, corresponds respectively to 3.7mcg, 7.5mcg or 15meg sufentanil citrate. Section 2 research, it has described in detail in example 2, compared with and the 10 of 10mcg sufentanil minutes IV infusion solution or 20 minutes IV infusions of 50mcg sufentanil, the administration in 20 minutes of the sublingual-dosage of 5mcg sufentanil solution or interval, the quick corrosion Sublingual sufentanil dosage form that comprises 10mcg sufentanil 4 administrations (table 2), utilize the Sublingual sufentanil dosage form of faster corrosion, 11 individualities are carried out, described dosage form comprises 10mcg or 80mcg sufentanil alkali, corresponds respectively to 15mcg or 120mgc sufentanil citrate. All excipient are " acceptable on materia medica " (inactive), and have GRAS or " being commonly referred to be safe (generallyrecognizedassafe, GRAS) " state.

Will be suitable for the sufentanil dosage form of Sublingual use and compared as the IV sufentanil of continuous infusion by catheter drug delivery. At remote location, from different IV conduits, take plasma sample. High, in and low quality control, under sample concentration, to analyze and all show excellent day to day precision and accuracy (inter-dayprecisionandaccuracy).

The dosage form of Section 1 research is corrosion in 15-25 minute in all individualities, and is called " slow corrosion " in the text. The dosage form of Section 2 research is corrosion in 6-12 minute in all individualities, and is referred to herein as " faster corrosion ". After the sublingual space that each sufentanil dosage form is placed in healthy volunteer, it is thus achieved that significantly stable pharmacokinetic characteristic. With single-dose and repeatedly compared with IV administration, the bioavailability utilizing the in a small amount sufentanil of sublingual dosage forms administration is high, and mobility scale is 60.9% (10mcg dosage; Faster corrosion)-97.2% (4 �� 5mcg dosage (slow corrosion). Utilize the bioavailability of the in a small amount sufentanil of the sublingual dosage forms administration bioavailability than fentanyl product A ctiq and Fentora (respectively 47% and 65%, Fentora package insert) higher. It is essential that bioavailability is relevant with the concordance sending the total medicine being handed to patient. Such as, under the curve of 10mcg sufentanil dosage form, total drug plasma area (AUC0-is unlimited) is 0.0705 �� 0.0194hr*ng/ml (meansigma methods+standard deviation (SD)). This standard deviation is only the 27.5% of total AUC. The coefficient of variation (coefficientofvariation, CV) is to describe the term of the percentage ratio that SD accounts for meansigma methods. The coefficient of variation of fentanyl product, (AUC is 41% to Fentora (AUC is 45%) and Actiq; Fentora package insert), and utilize the bioavailability coefficient of variation of the in a small amount sufentanil of sublingual dosage forms administration less than 40%. Therefore, for sufentanil dosage form, send and pass in individual accumulated dose not still more bioavailable, and be more stable.

Although this high bioavailability is due to include but not limited to that erosion time is in interior many factors, but being likely to, what in a small amount the shortage of the saliva that dosage form produces limited medicine swallows and avoids the low bioavailability into the drug absorption feature via GI approach. The package insert of Fentora and Actiq all claims the drug dose swallowing at least 50% and 75% via saliva respectively, and both shows the bioavailability lower than the dosage form being claimed.

The volume of dosage form used in clinical experiment is about 5 �� l (quality of 5.5-5.85mg), i.e. the fraction of Actiq or Fnetora lozenge size. Therefore, the medicine less than 25% is swallowed, and this is more much lower than Fentora or the Actiq percentage ratio swallowed.

Administration early stage, for the stability of drug blood plasma level, sufentanil sublingual dosage forms is also higher. The C obtained by 10mcg sufentanil dosage form_maxIt is 27.5 �� 7.7pg/ml. C_maxThe coefficient of variation thus be only 28%. The C of Fentora and Actiq_maxImpaired because of the fluctuation of GI drug absorption. The C of Fentora report_maxIt is 1.02 �� 0.42ng/ml, therefore C_maxThe coefficient of variation be 41%. The excursion of the various dose variation coefficient of Fentora is 41%-56% (package insert). It is reported, the C of Actiq_maxThe coefficient of variation be 33% (Fentroa package insert).

Except higher bioavailability and plasma concentration concordance, the T of 10mcg sufentanil dosage form_maxIt is 40.8 �� 13.2 minutes (ranging for 19.8-60 minute). The average T of the Fentora of report_maxIt is 46.8, ranges for 20-240 minute. The T of Actiq_maxIt is 90.8 minutes, ranges for 35-240 minute (package insert of Fentora). Therefore onset stability in sufentanil dosage form analgesic is significantly better than the onset stability of Fnetora and Actiq.

It addition, the T obtained after repeating the sufentanil dosage form that Sublingual is claimed_maxValue is significantly smaller than and gives viewed value after the sufentanil dosage form of single Sublingual. It should be noted that most the T that 10 �� g (4 �� 10 �� g) sufentanil dosage form repeated drug taking (quick corrosion) obtains_maxWithin after former (the 4th) dosage 24.6 minutes, occur. Around T_maxThe coefficient of variation be only 18%, it was shown that repeat the T of sufentanil dosage form that Sublingual is claimed_maxHighly stable and measurable.

After the sufentanil dosage form that Sublingual is claimed, the linearity of sufentanil blood plasma level from the dosage of 2.5mcg to the dosage of 80mcg be stable.

Entirely so still in research and development, but disclosed data allow comparing sufentanil pharmacokinetic data provided herein and Rapinyl (the instant lozenge in fentanyl Sublingual). The coefficient of variation average out to 28.6% around AUC of all three sufentanil dosage exemplified here (2,5 and 10mcg), it was demonstrated that the viewed low coefficient of variation does not rely on dosage. On the contrary, the bioavailability of disclosed Sublingual fentanyl product Rapinyl is about 70% (Bredenberg, NewConceptsinAdministrationofDrugsinTabletForm (gives the new concept of tablet form medicine), ActaUniversitatisUpsaliensis, Uppsala, 2003). The excursion of the coefficient of variation (0-is unlimited) of the AUC of Rapinyl is 25-42%, and is dose dependent.

It addition, the C of Rapinyl_maxThe coefficient of variation depend on that dosage changes between 34-58%. Shown by data as provided herein, give 10mcg sufentanil dosage form and cause that the coefficient of variation is only the C of 28%_max, and 2,5 and the average C of 10mcg dosage_maxThe coefficient of variation is 29.4%, represents the minimal ripple depending on dosage. Equally, the T of Rapinyl_maxThe coefficient of variation depend on dosage, change between 43-54%, and for our sufentanil dosage form, T_maxThis coefficient of variation under all three dose intensity, be on average only 29%. This stable onset effect realized by Sublingual sufentanil dosage form, compared with any in three kinds of comparative drug, allow the safer window of medication repeatedly (redosingwindow), because the rising of blood plasma level was limited in shorter period.

It addition, the same with Fentora and Actiq, Rapinyl shows that the blood plasma more longer than the sufentanil dosage form being claimed gets rid of the half-life (5.4-6.3 hour, depend on dosage). After single oral transmucosal gives people, it is 1.5-2 hour that the blood plasma of sufentanil dosage form gets rid of the excursion of half-life, and this allows better titration and is avoided over-medication. As understood by those skilled in the art, the half-life of exemplified dosage form mentioned herein, can pass through to change the relative quantity of component and excipient in the formula for producing set dosage form, be adjusted. In this human research, also have detected the ability that by the Sublingual sufentanil dosage form giving repeated doses, it is titrated to higher blood plasma level.

Method described herein and system are designed, effectively play a role in the unique environments in oral cavity, it is provided that than the higher levels of drug absorption of existing system and pain relief. The method and system being claimed, designed, by entering circulation via hypoglossis mucous membrane, it is to avoid the high peak plasma level of intravenous administration.

The method and system being claimed additionally provides the release in time of bioadhesion, dosage form disintegrate (corrosion) and medicine and administration, and device administration provides safety to send and passs characteristic (profile). Device gives sublingual dosage forms and provides independent, the repeated dosage including limited amount activating agent (such as sufentanil), allows patient or care-giver's titration exactly to send the amount of the medicine passed and with safely effectively mode suitably adjustment amount accordingly. The locking parts of distributor add medicine and send the safety passing feature.

Additionally, treat with the compositions being claimed, method and system, by making the potentially harmful side effect of plasma pharmacokinetics peak value and valley minimize, improving safety, described harmful side effect is the feature of the medicine of Current therapeutic pain or system.

The sublingual dosage forms being claimed includes relative to the advantage in Sublingual or the various liquid forms of intranasal administration, and from dosage form, local discharges medicine, and minimally swallows liquid medicine via nose or oral cavity/GI approach.

Due to the small size of oral transmucosal dosage forms, over time, repeat to place in chamber, Sublingual (sublingualcavity), be possible. Giving the credit to small size, occur that minimum saliva produces and minimum uncomfortable, this allows repeated drug taking in a few days to several weeks to the period of several months. In view of the lipid characteristic in chamber, Sublingual, epidural route allows also to some drugs such as sufentanil and is more slowly released into blood plasma, and this is attributable to the performance that " storehouse " acts on, and send with cheek compared with passing, and this effect stabilizes blood plasma level further.

Designed, oral card transmucosal dosage forms cosily can be placed in Sublingual, so as pharmaceutical dosage form effectively corrosion lentamente, viewed peak plasma level immediately in existing preparation (Rapinyl) as described in U.S. Patent No. 6,759,059 is avoided to significantly reduce subsequently, wherein by the tablet containing 400mcg fentanyl, giving fentanyl, this causes the peak plasma level of 2.5ng/ml, and blood plasma level reduces immediately subsequently. Fentanyl (fentanyl cheek tablet) also lacks plateau, but has through C_maxAbrupt slope, be followed by significantly reducing of blood plasma level.

VII. the purposes of a small amount of oral transmucosal dosage forms

The dosage form that is claimed, method and system for treat pain, send via the sufentanil of oral transmucosal such as epidural route pass in there is purposes. The bioavailability of a small amount of oral transmucosal dosage forms is high, T_maxFluctuate low, C_maxFluctuate low and AUC fluctuation is low. This dosage form also provides the prolongation of blood plasma level in treatment window.

Specifically, the dosage form, the method and system that are claimed provide following advantage:

In a sufentanil blood plasma level that () is individual after the sufentanil dosage form being claimed and dosage form between the amount of sufentanil, there is linear relationship;

B sufentanil dosage form that () is claimed to individual single Sublingual, causes the coefficient of variation AUC less than 40%_inf;

C () is to individual single or repeat the sufentanil dosage form that Sublingual is claimed, and causes the coefficient of variation T less than 40%_max;

D () repeats, to individuality, the sufentanil dosage form that Sublingual is claimed, cause the ratio bioavailability higher to the bioavailability after described individual single sublingual administration;

E () repeats the T after the sufentanil dosage form that Sublingual is claimed_maxAnd the difference between the time of previous sublingual administration, than to the T after the previous single sublingual administration of described individuality_maxShorter;

F () is at C_maxAnd in dosage form between the amount of sufentanil, there is linear relationship;

G () is at AUC_infAnd in dosage form between the amount of sufentanil, there is linear relationship;

H () repeatedly gives the highest prediction stable state sufentanil concentration after 10 or 15mcg Sublingual sufentanil dosage form, be foreseeable, and this allows measure safe locking time exactly and therefore safely and effectively treat pain.

In an exemplary detailed in this article, dosage form suffers from treatment in the individuality of any relevant pain in possibility and the multiple certifiable or not certifiable cause of disease and has purposes. " treatment " or " disposing (management) " of term pain is in this article for describing disappearing, suppress or alleviating of pain in general manner, in order to make patient more comfortable, and this can pass through such as pain scores and measure.

The present invention had not only tested patient at opioid but also had had purposes in the treatment of opioid intolerant patient.

Dosage form treatment of pain under acute pain such as postoperative pain and other pain are such as " field " i.e. high order ideal conditions is particularly useful.

It is frequently necessary to the medical worker of airborne troop or medical officer and treat severe acute pain or other injury or situation when non-sterile, the pin that wherein IV or IM administration is used can cause unconscious acupuncture infection risk etc. Oral opioid tablet provides alleviation to it is frequently necessary to 60 minutes, and this is oversize for the people being in severe pain.

When dosage form is used for treating pain, the method and system being claimed is not tested and is had purposes in PATIENT POPULATION in being administered to department of pediatrics and Adult group and in the treatment of the mankind and non-human mammal and in opioid tolerance and opioid.

The application of the method and system being claimed is not limited to any concrete treatment indication. Equally, the dosage form being claimed is giving there is purposes in sufentanil and in the treatment of the mankind and non-human mammal to department of pediatrics and Adult group.

Dosage form has purposes in paediatric applications, because the comfortable and safe characteristic of dosage form allows child to be prone to accept the treatment of this pattern, and reliably send across mucosa and passs. Instantiation includes but not limited to, the treatment of Pediatric Acute pain when approach IV (IVaccess) is unavailable or inconvenient, the treatment that the treatment of pediatric asthma is felt sick when child can not or be unwilling to swallow pill when child can not effectively utilize inhalation approach, when child be the pre-operative analgesia (pre-proceduralsedation) during NPO (oral absorption without allowing) or when needing more rapid onset.

Dosage form also has purposes in veterinary applies. Instantiation includes but not limited to, it is impossible to easily or be inconvenient to any treatment carrying out the acute condition of IV administration, as calm etc. before pain relief, anxiety/stress reduction, preposition program.

VIII. distributor

Provide oral transmucosal and give distributor and the system of small quantities of drugs dosage form. Distributor is hand-held, portable, and comprises the housing with distribution end, and described distribution end has the nose body with guard shield, and described guard shield provides the component blocking or stoping saliva entrance and/or moisture Control. Distributor additionally provides safety component, such as locking component and user identification means.

The distributor, the method and system that are claimed include sending a small amount of dosage form being handed to oral mucosa. The present invention is not limited to concrete device as herein described, system, method and dosage form, because they are it is of course possible to change. It is to be further understood that term used herein is merely for the sake of the purpose describing specific embodiments, is not meant to limit the scope of the present disclosure.

Block/hinder the entrance of saliva and moisture

In some embodiments, the distributor being claimed comprises makes saliva entrance and moisture entrance distributor be reduced to Min. or by the component of its eliminating: (1) is to avoid making dosage form therein moisten; (2) in the way of dosage form therein maintenance is dry, isolation enters any saliva of distributor; (3) in the way of dosage form maintenance is dry, absorb or absorb into the saliva of distributor; (4) block saliva or moisture enters device, to protect dosage form to exempt from steam and liquid phase moisture or (5) its any combination.

Distributor can have preventing and/or the component controlling the ambient condition outside due to device and making moisture enter.

Make moisture enter minimize or get rid of moisture entrance or prevent the component that other moisture enters distributor from including but not limited to, one or more toughness or rigid seal, one or more toughness or rigidity scraper (wipers), utilize one or more absorbing material composition such as desiccant or liner, can the door of manual or automatic switch or door bolt, multistage send delivery system (multiplestagedeliverysystems), positive air pressure and air-flow or be maintained at dosage form and send the air gap (airgap) of transport saliva between the mucosal tissue passed in mouth and mouth or the distance specified or barrier/guard shield. the ability in guard shield restriction tongue or oral mucosa contact dosage form distribution district, controls saliva contacts and entrance accordingly. by suppressing or getting rid of in guard shield and moisture on valve/sealing member, dosage form is assigned with when not occurring between dosage form and guard shield or valve/sealing member and adhering to.

In order to protect pharmaceutical dosage form avoid contact wetting or avoid moisten, saliva enter or unexpected contact other based on liquid of water, distributor and device context receive the container of dosage form or cartridge case comprises desiccant.

If saliva or moisture enter device, for trapping or otherwise isolation saliva or the component of moisture include but not limited to, hydrophilic wick material (wickingmaterials) or component, absorption or adsorbing material or component, drying material or component, split tunnel for collecting the separation track of moisture or passage (separatetrackorchannel), making moisture communicate with the combination in any of absorbent or adsorbent or these materials or component.

Desiccant is the adsorbent of solid, liquid or gel form, and it has hydrophilic, and absorbs or absorption moisture about, therefore controls the moisture closest to environment. Any commercial dryness agent can be used. Commercial dryness agent generally adopts the form of granule (pellets), cylinder (canisters), bag (packets), capsule (capsules), powder (powders), solid material, paper, plate (board), tablet (tablet), bioadhesive patch (adhesivepatches) and thin film (films), and can shape by concrete application, including injection mould (injectionmoldableplastics). There is many types of solid drier; including silica gel (sodium silicate; it is solid rather than gel), aluminosilicate, activated alumina, zeolite, molecular sieve, illiteracy unsticking soil (montmorilloniteclay), calcium oxide, calcium sulfate or other, any of which may be used in the distributor being claimed. Moisture or other materials are had different affinitys and different capacity by different desiccant, and different absorptions and the rate of adsorption. And, the different types of desiccant different relative humidity in its immediate environment are to balancing. Avoid the component of moisture as the dosage form and interior section of protecting distributor, one or more desiccant may be used for: nose body place; In dosage form or contiguous dosage form; Send in the approach of passing or vicinity send the approach of passing; In dosage form, tablet cassette (tabletmagazine) or cartridge case or contiguous dosage form, tablet cassette or cartridge case; In other assemblies of distributor or other assemblies of contiguous distributor; Form the injection-molded components (injectionmoldedcomponent) as distributor; It is pressed on the compression drying agent of specific region; Or the desiccant in any other specific region in device or outside device.

In a preferred embodiment, desiccant is stuck in the cavity of cartridge case side. In the cavity of desiccant porose, described hole makes desiccant and dosage form pile (dosageformstack) to be connected, make dosage form contacts desiccant and make them keep drying.

The distributor being claimed depends on valve, liner, sealing member, the position of rest of push rod, nose body design and guard shield, makes saliva in the process give dosage form enter and moisture minimizes or gets rid of it and enters distributor.

The valve of the device for being claimed is usually dome/set needle valve; it provides the enough sealing forces (sealingforce) stoping saliva and/or moisture to enter device; and by assigning process and dosage form distribute after close remote stomidium, make saliva enter and moisture minimize or got rid of.

For the liner in the device that is claimed, there is various surface configuration, its auxiliary contacts push rod or communicate therewith, in order to remove liquid from push rod surface. This kind of liner generally comprises water-wet behavior, effect be by from track and push rod transport liquid make saliva enter or moisture enter minimize or got rid of.

Designed for the sealing member in the device that is claimed and scraper; in sending the process of passing; homogeneous sealing is maintained around pharmaceutical dosage form and push rod; they are characterized by toughness material; described toughness material seals around dosage form and push rod; effect be by before dispensing, seal in assigning process and after distribution and wiping pings QI KOU and push rod, make saliva enter or moisture minimize or got rid of.

In the device being claimed, the position of rest of push rod is characterized by; push rod is positioned over away from cartridge outlet hole and from the centre position close to distal portion distribution; by allowing push rod to reside at the position containing desiccant, absorbent or the passage dried when dosage form distribution is stopped, play and make saliva entrance and moisture minimize or by the effect of its eliminating.

Being characterized by that far end device shape is normally s-shaped for the nose body design in the device that is claimed, its auxiliary device uses and/or is placed in by dispensing head on individual oral mucosa. This shape has bending, angle and geometric figure, in order to it can correctly use device and dosage form is positioned on individual oral mucosa such as sublingual space.

The guard shield of the device being claimed have between device and oral mucosa and tongue, form barrier surface configuration, send the depression passed, hydrophobic or hydrophilic inside for dosage form; and by distributing from generation barrier, formulation auxiliary between the oral mucosa in contact valve district and dosage form and stop the dosage form adhesion to guard shield, make saliva enter or moisture enters and minimizes or get rid of. Guard shield can have rounded internal surface or other surface configurations, to reduce the dosage form adhering to guard shield. Guard shield limits tongue or the ability in oral mucosa contact dosage form distribution district, controls saliva contacts and entrance accordingly.

Figure 11 A-E provides the schematic diagram of the multiple aspect of an embodiment of drugs distribution apparatus, and described distributor is configured, holds multiple oral transmucosal and send the dosage form passed. Figure 11 A is that the present invention assembles completely or the schematic diagram of single-piece distributor (singlepiecedispensingdevice) 11. In Figure 11 B, distributor 11 includes head 13 and the disposable main body 15 that can reuse; In Figure 11 C, distributor 11 also includes cartridge case 17; In Figure 11 D, distributor 11 includes valve 33, nose body 31, door bolt button 19, power coupler 25, hub lock 21 and distribution button 23; Figure 11 E re-assemblies and the schematic diagram of complete distributor 11.

Figure 12 provides the schematic diagram of exemplary allocations of communication resources device, wherein dispensing head comprises described guard shield 29, and described guard shield 29 has one or more: the desiccant 47 in the desiccant 45 in wiping/sealing valve 37, absorbent pad 39, pharmaceutical drying room/exchange of moisture passage 43, passage, the cartridge case 17 containing dosage form 67 and cartridge case.

Figure 13 A and 13B is the schematic diagram of dispensing head exemplary geometric arrangement, and described dispensing head prevents one or more sealing member 33,35 from contacting with tide or the wet structure of oral mucosa via guard shield 29.

Figure 14 A-D is the schematic diagram of the exemplary nose body 31 of distributor 11, and wherein nose body 31 comprises guard shield 29, distributes the valve 33 of dosage form 67 and breach/the depression 55 for dosage form being placed relative to oral mucosa and make when device 11 is recalled after dispensing dosage form not move.

Making saliva enter and moisture enters the component that the device being claimed minimizes, the integrity for preserving dosage form in storing process as before oral transmucosal administration and between oral transmucosal administration is extremely important.

The distributor being claimed may be used for the pharmaceutical dosage form given moisture or moisture-sensitive. In the case, the cartridge case of pharmaceutical dosage form play protect this pharmaceutical dosage form to avoid including moistening, liquid moisture, saliva, mucus etc. the effect of liquid and gas moisture. Cartridge case can be cylindrical, discoidal, spiral, straight line, random, maybe can adopt any form of gathering of pharmaceutical dosage form, and described form allows drugs distribution apparatus to distribute them in a controlled manner. In order to prevent unworn pharmaceutical dosage form from absorbing moisture before use or becoming contact wetting in other manners, cartridge case can provide sealing pharmaceutical dosage form to avoid the component of contact wetting. This can pass through to use the pharmaceutical dosage form containing individual packaging to realize; the pharmaceutical dosage form of described individual packaging; separated by thin impermeable paillon foil or impermeable material, in order to when a kind of pharmaceutical dosage form send from cartridge case and passs, the sealing member of protection residue dosage form keeps complete. Alternatively, dosage form can be packaged in cartridge case in the way of two or more dosage forms are packaged in each single closed chamber together. In some embodiments, all dosage forms in cartridge case are packed together in the indoor of foil seal.

The drug cartridge holding small quantities of drugs dosage form in distributor can seal the mode of another kind of assembly of drugs distribution apparatus when in the way of barrier film, elastic sealing element or valve, slip, translation, hinged door or valve or by loading, seals moisture. In this manner, single re-sealable sealing member can be opened independently or open in the way of dosage form leaves cartridge case. Dosage form is passed, it is possible to make the again sealable sealing member on cartridge case seal, to prevent water from dividing or other pollutant destroy the residual drug dosage form in cartridge case once send from cartridge case. Cartridge case can also have non-sealable sealing member again, when described non-sealable sealing member again is filled in drugs distribution apparatus or send from cartridge case pass first pharmaceutical dosage form time, it is damaged.

In other embodiments, cartridge case comprises desiccant or absorption or absorption and before use or permeates other of moisture of cartridge case in normal use procedure and absorb or adsorbing materials. Any combination of the individually dosage form of sealing, multiple sealing dosage form, re-sealable sealing member, non-re-sealable sealing member, desiccant, absorbent or adsorbent can be comprised for the cartridge case in the distributor that is claimed. In one embodiment, the cartridge case for distributor holds pharmaceutical dosage form such as 40 pharmaceutical dosage forms treated for enough 1-5 days, or holds the pharmaceutical dosage form enough providing 48-72 hours treatment.

Putter design

Figure 15 A-D provides a series of flow charts that show push rod principle, that exemplary allocations of communication resources device uses, and wherein Figure 15 A shows load characteristic; Figure 15 B show device calibrating principle flow process. With reference to Figure 16, push rod 51 moves forward from position 65, obtains shipping tablet 69 at position 63 place, and moves forward to position 61 further. At position 61 place, device experiences shipping tablet 69 and/or the existence of push rod 51. In doing so, shipping tablet 69 and/or the position of push rod 51 end are calibrated and known to device, regardless of the situation of build-up tolerance (assemblytolerance), the change of push rod length and push rod end. After calibration, shipping tablet 69 is advanced to position 57 from position 61 by push rod 51, and there, shipping tablet 69 is distributed from device. In this operating process, device can distinguish shipping tablet 69, push rod 51 and pharmaceutical dosage form 67. This differentiation can make device confirmation cartridge case be unworn, because in device equipment process, shipping tablet is first and is distributed from new cartridge. There is provided the parts of the component distinguishing shipping tablet, push rod and dosage form 67, it is possible to be light, physics, RF, electronics (ohmic, capacitive or other) or magnetic. Push rod 51 mentioned above is from the reach of position 65 and position 57, it is possible to be continuous print or interruption, and need not stop by physics in position 61. Push rod 51, subsequently from position 57 home position 59, makes device 11 be in standby position, and push rod 51 is positioned under remaining dosage form 67 simultaneously. In this position, push rod 51 prevents dosage form from falling down from device 11 because of carelessness.

Figure 15 C represents device distribution principle flow process. With reference to Figure 16, it then follows dosage order, push rod 51 is from position 59 home position 65, it is allowed to move up into push rod track before dosage form 67. Push rod 51 moves forward from position 65 subsequently, obtains dosage form in position 63, distributes dosage form 67 at position 57 place subsequently from device. Between position 63 and 57, the existence of dosage form 67 can by position sensor in position 61 perception/confirmation. Push rod is subsequently from position 57 home position 59 so that it is be in the position awaited orders, and push rod 51 is positioned under residue dosage form 67 simultaneously. In this position, it is allowed to push rod 51 is dry before upper once dosage form 67 is distributed, and prevents dosage form 67 from falling down from device 11 because of carelessness.

Figure 15 D represents device dismounting principle process. Follow " dismounting " order, push rod 51 is elapsed to position 65. This permission removes any remaining dosage form 67 without push rod when disturbing.

Figure 16 is the schematic diagram of exemplary allocations of communication resources device, represents the place that in device use procedure, push rod/dosage form interacts. In figure 16, push rod 51, dosage form 67, shipping tablet 69, spring 73 and position sensor 71 are illustrated. In use, push rod 51 moves between position 51,59,61,63 and 65, is also shown in Figure 16, and is described above in detail further in Figure 15 A-D.

Medication history (dosinghistory)/feedback

Other embodiments of device include storing history and use the ability of information and transmit the ability of this type of information. Device can carry out unidirectional (download) or bidirectional information transfer. Such as, information exchange can be passed through to connect interface such as USB via physical connection of the information of storage or any other communication and is downloaded to computer and realizes. Alternatively, via wireless system, information communication can be carried out.

In another embodiment, distributor has Rapid Dose Calculation parts, and it can monitor and store drug use history. This type of information can include history use information, for instance, store and distribution dosage quantity and distribution number of times.

Calibration

Distributor gear can be carried out self-calibrating by distributor, or can this device of manual calibration. This process can utilize the shipping tablet with or several parts, and described parts can make shipping tablet make a distinction for physically with pharmaceutical dosage form or push rod. These parts can be designed, in order to device calibration accuracy is higher than the degree of accuracy utilizing dosage form or push rod to reach. It can be physics, optics, radio frequency (radiofrequency, RF), electronics or magnetic that parts are made a distinction.

User identification feature

On the one hand, distributor comprises user recognition detection component, such as finger-printer reader (fingerprintreader), optical retina reader (opticalretinalreader), sound recognition system, facial-recognition security systems, teeth mark identification system (dentalimprintrecognitionsystem), visual identifying system or DNA reader. Distributor can use one or more component identification user, and whether distribution request is that authorized or undelegated mode is made to make system determine. Guarantee that distributor unexpectedly or is not intentionally used by undelegated individuality, to prevent medicine from accidentally or intentionally being diverted from one use to another, for many possible medicines or pharmaceutical dosage form effectively send pass extremely important. This kind of user identification system may identify which one or more user, for instance when inpatient, distributor is programmed, and has opened the patient of this device prescription to identify, and the medical personnel authorized or doctor. When outpatient, for instance, distributor has only been split the patient of this device prescription and has been responded.

Distributor can adopt any component of user identification, including fingerprint recognition, utilize hands bracelet, necklace, clip, belt, belt, adhesive patches (adhesivepatch), the RFID detection of the actively or passively RFID tag on the component of implant or location or adhered labels, retina identification, DNA identifies, voice recognition, password or code enter, Physical key (physicalkey), electronics or magnetic key, human body or clothes is utilized to identify (personalareanetworkidentification) as the personal area network of data or signal pipe line (conduit), optical scanner or facial recognition, velocity of sound subsonic speed or supersonic speed identification, or identify any other component that is individual and that confirm their identity.

A kind of method of identification user is to utilize the passive RFID tag of short distance (near field (nearfiled)), and it is attached to bracelet, necklace, adhesive patches, clothing labels, is placed in the device retainer such as orthodontic in oral cavity, belt, belt or their some combination or its another locations. When RFID tag uses near field, it is defined to accept about the 16% of signal wavelength roughly, the drive manner operating of label sensing, magnetically couple between reader and label antenna. Near field has at least two feature: first is just as distance, and magnetic field intensity declines rapidly, and second is the highly directive of signal. In near field, signal intensity declines rapidly, and every decade distance, the loss of signal strength is about 60dB. In order to bring out good coupling between transmitting antenna and RFID label antenna, two antennas are all located in parallel plane, and axle is the middle part of each antenna of traverse in the way of being very close to. When device closely RFID tag, it is provided that strong signal intensity (forcing user to identify). Meanwhile, when device from label distant time, it is provided that weak signal, this contributes to preventing attempting beyond except with person from using some unauthorized use of device. Operate preferably in this near field region with good antenna alignment. Furthermore it is preferred that, with the very short distance operating that initiative recognition signal intensity is enough, because if device is not correctly position and near RFID tag, it is difficult to accept signal. In order to obtain short distance and correct arrangement between antenna, distributor can be designed correctly to position RFID reader antenna, it is placed in distributor, contiguous RFID label antenna, for instance be placed on label or hands, arm, cheek, neck or the bioadhesive patch elsewhere of wrist strap (wristband) or bracelet or clothes collar. Additionally, the RFID label antenna on wrist strap or bracelet can be controlled in correct arrangement and position by the mode of little bioadhesive patch, described little bioadhesive patch prevents bracelet from moving in wrist or rotating.

In another embodiment, distributor uses high frequency RFID reader, when for inpatient (hospital, clinic etc.), described high frequency RFID reader at the 13.56 mhz frequency band or this near band operating, the disposable bracelet or wrist strap of patient have been laid RFID tag and the antenna of coupling, if described disposable bracelet or wrist strap are so designed that namely removes bracelet or wrist strap, then another assembly of RFID tag, antenna or interlock circuit will damage or destroy so that bracelet or wrist strap are inoperative. In an example, the scope of RFID communication is very short, preferably between 0 inch and 10 inches, between 0 and 5 inch, and most preferably between 0 and 3 inch, and can be additionally directive, it is allowed to set user proper use of is comfortable, reliably, and make the unauthorized use of another individuality difficult, extremely difficult or impossible simultaneously.

Locking

Distributor provides locking, it is desirable to care-giver's communication of patient and doctor or other mandates is at fixed time period device for opening subsequently. By this way, owing to better iatrarchy and nursing are disposed, device and base provide safe drugs administration.

Distributor provides adjustment predose and the component with post dose and locking time. Depending on reaction, treatment persistent period etc., predose and locking time can adjust subsequently.

The initial timing lockup period of the distributor being claimed usually about 1 minute to about 60 minutes, 3 minutes to 40 minutes or 5 minutes to 30 minutes, under specific circumstances, arrange with the arbitrary minute interval of 1 to 60 minutes, 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.

In some cases, distributor has fixing locking between dosage, and shows closedown after the fixing period. In the other cases, locking time is programmable locking time. Locking time can also be the lockout interval determined of the lockout interval of set time, predetermined lockout interval, predetermined variable latching interval, algorithm or and far-end computer or Docking station communication after variable latching interval.

Other features

Distributor can pass through to detect and identify the machinery of cartridge case, optics (such as bar code), electronics (such as chip), magnetic, radio frequency, chemistry or other modes, it is provided that identifies the ability of concrete cartridge case. In an exemplary embodiment, the cartridge case comprising medicine comprises physics keying details (physicalkeyingdetail) about cartridge case, and it is detected for physically by the sensor in distributor or switch or a series of sensor or switch. Additionally, distributor can in the way of unidirectional or two-way with cartridge case communication, exchange information. This category information can include dose quantity or any other relevant information in medicine name, dose intensity, purposes information, lockup period, product batch number, operation instruction, side effect, drug interaction, date of manufacture, shelf-life, sequence number, cartridge case. Distributor can also write information to cartridge case except reading, as used the dose quantity etc. of date, medical personnel or other user identity, use.

Distributor can provide mechanical protection for the dosage form being contained therein, it is prevented that destruction, broken, hydration etc., allows the unbroken dosage form that distribution is contained therein accordingly. This is for little frangible and crisp dosage form particular importance.

Drugs distribution apparatus by battery, capacitor, fuel cell or other energy supply source electrode energy supplies, maybe can not need electric energy and manual actuation.

In certain embodiments, when energy supply or safety problem occur, distributor can send alarm or other notices. Alarm or other notices can trigger on distributor, base or other peripheral devices or on computer the state of alert, or by the wired or wireless network-triggered state of alert, or can report to the police to other remote equipments. Alarm or notice can be seeing of listening, tactile, visual, maybe can use other modes notifying one or more individuality.

Docking station

In certain embodiments, device includes portable or fixing Docking station, its can inquiry unit, between medication resetting apparatus, when not proper use of locking device, and control medication therapeutic scheme. Drugs distribution apparatus can via base or by wired, wireless telecommunications component and doctor, care-giver's communication.

For different types of authorized user, for instance, the medical treatment of patient, nurse, doctor, pharmacists or other mandates or health care personnel, distributor can use one or more levels interface. These different interfaces can include assembly, such as keypad, button, graphic icons (graphicalicon) and description, light, LED ' S, monochrome or color graphics or textual presentation, touch screen, LCD ' S, sound, sense of touch feedback, voice recognition interface, and other input and output device and component. The activity of user interface or pattern can by the operation mode of distributor, entered by login or entrance the activity such as password or code of user, by making distributor be connected or disconnected from base, computer or network or being determined by use key (accesskey) such as the key and/or RFID tag or similar combination of detection mandate. Once change interface model, it is possible to change the functional of device, thus activating, inactivating or changing the functional of various interface assemblies mentioned above. By allowing device to have one or more interface models, with the different functionalities relevant with each pattern, device can be optimized, for various uses.

Base station

In certain embodiments, pharmaceutical Dispensing System include in use for drugs distribution apparatus and portable docking FOB charging base station. This base station allows simultaneously for the battery in multiple distributors and/or FOBs or fuel cell charging. Except charging for drugs distribution apparatus and FOBs, base station can provide one or more following functions: wired or wireless with ancillary equipment, computer or network is connected; About just in the feedback of charger charged state; Check, increase, delete or revise the interface about drugs distribution apparatus or the data of FOB; Make the component of data syn-chronization between multiple drug delivery devices and/or FOB; And instruct the component about drugs distribution apparatus and/or the diagnostic detection of FOBs.

Single dose and multiple dose giver

The invention provides and the dosage form comprising sufentanil is sent the disposable giver being handed to patient's oral mucosa, in order to realize sending to medicine the application in the precalculated position (mouth, sublingual space etc.) passed.

In a kind of method of the present invention, utilize single dose applicator (SDA), dosage form is sent and is handed to oral mucosa. Dosage form is provided in child-resistant drugs distribution apparatus or packaging and send to be handed to such as chamber, Sublingual. Dosage form can be automedication, or alternatively, dosage form device auxiliary or without device aided case under administration.

In one embodiment, single dose applicator (singledoseapplicator, SDA) for pharmaceutical dosage form, described dosage form is to provide with solid tablet, liquid capsule, gel capsule, liquid, gel, powder, thin film, band, ribbon (ribbon), spraying, mist (mist), paster or any other suitable drug dosage form.

Single dose applicator (SDA) can comprise dosage form in inside, it is possible to makes pharmaceutical dosage form be attached to or pastes thereon, it is possible to makes dosage form dissolve wherein, and can provide the sealing member of anti-moisture, humidity and light. Pharmaceutical dosage form by patient, medical personnel or other user manual operations, can be placed in medicine and send the appropriate location passed by single dose applicator.

Implementing in process of the present invention, single dose applicator or multiple dose giver or drugs distribution apparatus may be used for sending tablet or other dosage forms be handed to hands, mouth, Sublingual or other position that demand is suitable is delivered for concrete medicine.

In one embodiment, single dose applicator or multiple dose giver or drugs distribution apparatus are handed to oral mucosa such as sublingual space for dosage form being sent.

Dosage form in distributor keeps dry before dispensing, during distribution, single dosage forms is distributed to mouth such as sublingual space from device, and wherein the saliva of patient will make tablet moisten, and allow disintegration of tablet/corrosion and medicine to send to pass.

SDA can be provided by following form: tweezers, syringe, bar or rod (stickorrod), suction pipe (straw), liner, capsule, cup (cup), spoon (spoon), band, tube (tube), giver, dropper (dropper), paster, adhesion liner, adhering film, aerosol apparatus (sprayer), nebulizer (atomizer), or be suitable for being applied to single drug dosage form any other form of the oral mucosa of the oral mucosa such as sublingual space of individuality. It will be appreciated by those skilled in the art that SDA design can change, as long as pharmaceutical dosage form such as tablet is effectively positioned over the ideal position such as sublingual space of oral mucosa by the assignment procedure in the way of keeping pharmaceutical dosage form complete. After using, dispose SDA, in order to get rid of the risk of saliva or other contaminants drugs distribution apparatus.

For sublingual administration, dosage form is generally close to the mode of little frenulum gives by being utilized SDA to be positioned over Sublingual in a small amount.

Dosage form can be provided in the packaging being made up of model plastic (moldedplastic) or laminate, described model plastic or laminate have the impression (indentations) (" bubbling (blisters) ") being referred to herein as " blister package (blisterpack) ", and dosage form is positioned in described impression. Lid, is generally material or the paillon foil of lamination, is used for sealing model part. That blister package can have or can not have preforming or model part, and may be used for packing any kind of SDA.

This kind of blister package can be provided in the drug allotter (multipledrugdispenser, MDA) of child-resistant, and the effect of described allotter is the dosage form that distribution is accommodated therein, or may be used for storing multiple SDAs.

Figure 20 A-C, Figure 21 A-F, Figure 23 A-C and Figure 24 A and B are the schematic diagrams of SDA exemplary of the present invention.

In one approach, the invention provides the disposable single dose applicator comprising blister package 151, it comprises the pharmaceutical dosage form 67 in housing and handle (handle) 131, wherein backing (backing), such as foil seal 135, cover dosage form 67 and handle 131, for instance, as shown in Figure 21 B and 21D.

In one embodiment, disposable single dose applicator, the i.e. combination of housing or tube 129 and handle 131, it is shaped as cochlear.

The housing of dosage form 67 or tube 129 are blister packages 151, and it holds the unit dose of the dosage form 67 giving individuality. Dosage form 67 is sealed in blister package 151 by paillon foil or other kinds of sealing member 135.

In certain embodiments, before giving dosage form 67, remove paillon foil or other kinds of sealing member 135, and with handle 135, dosage form 67 is positioned over the appropriate location of close individual oral mucosa, in order to dosage form 67 is attached to oral mucosa. Consult such as, Figure 21 B, 21D, 21E and 21F. In other embodiments, by before administration at the folding giver 123 in perforation 149 places, paillon foil or other kinds of sealing member 135 being punched before giving dosage form 67 and removed, with handle 135, dosage form 67 is positioned over the appropriate location of close individual oral mucosa. Consult such as Figure 24 A and B. This allows once only to process single pharmaceutical dosage form, and prevents other pharmaceutical dosage forms 67 individually sealed from contacting saliva, moisture etc.

The paillon foil of disposable giver 123 or other kinds of sealing member 135, including handle 131, usually it is made up of the protuberance (applicatortab) 147 of monolayer layers of foil plate (foillaminate), paper, plastics or other coverings and giver, it is crossed over the rear portion of housing or tube 129 or crosses over the rear portion of housing or tube 129 and handle 131, effectively seals against the dosage form 67 in blister package 151 or other containers.

Dosage form 67 can correctly be placed by handle 131 when not contacting dosage form 67.

Multiple single dose applicator can be provided, as that adhered to by backing or be contained in a series of single single dose applicator in multiple dose allotter 137.

Figure 14 A and 14B represents an embodiment of single dose applicator 123, delivers the distributor of pharmaceutical dosage form. Distributor shown in Figure 14 A illustrates the single dose applicator 123 being about to distribution pharmaceutical dosage form 67. In the one side of this embodiment, user pinches single dose applicator 125, opens this giver, and pharmaceutical dosage form 67 is just distributed as shown in Figure 14B.

Figure 15 A-C represents an embodiment of single dose applicator 123, and this single dose applicator is made up of the shape such as giver of tube 129, plug sealing member (stopperseal), handle 131 (such as hommization handle (ergonomichandle)) and one-pack type 67. Before Figure 15 A represents use, it is in and seals the single dose applicator 123 arranged. Figure 15 B represents that plug sealing member 127 removes, forms opening stand-by single dose applicator 123. Figure 15 C represents to tilt to distribute the single dose applicator 123 of dosage form 67 at oral mucosa such as sublingual space.

Figure 21 A-F represents the several optional embodiment of single dose applicator 123. In all these figure, giver sealing member 127 is destroyed, and tilts giver, in order to falls the oral mucosa of contiguous individual mouth such as at the pharmaceutical dosage form 67 in Sublingual, carries out sublingual dosage forms placement. Figure 21 A represents have handle 131, giver 129 such as tube, and handle 131 is presented axially under tube. Figure 21 B represents the giver being formed as thermoplastic shaping or blister package (blisterpackage) 151, and it has foil seal 135, is peeled off by described foil seal, in order to placing the front opening giver packaging 141 of dosage form 67. Figure 21 C is expressed as the giver 129 of tube, is destroyed so that placing breakseal part before dosage form 67. Figure 21 D represents the blister package tube 151 type dosage form packaging 141 with handle 131, in order to after sealing member 135 is peeled off backward, it is possible to hold blister package 151 and so as to tilt, in order to be positioned on oral mucosa by pharmaceutical dosage form 67. Figure 21 E and 21F represents have shape respectively as blister package 151 type of color or the handle 131 of animal is packed, for the single dose applicator used suitable in department of pediatrics. The shape of other single dose applicator includes other suitable shapes of cartoon shaped, animal, megahero or paediatric applications.

Figure 23 A represents the flat rigid giver 123 with dosage form 67, described dosage form 67 is attached to one end by the digestible adhesion material of such as rapid solution, so that when the giver end with dosage form is positioned over Sublingual, adhesion material dissolves, dosage form 67 is placed in oral mucosa such as sublingual space, and can be removed by giver. Figure 23 B represents the giver 123 being made up of the material that can permeate water, and this material is impregnated with medicine, forms material and dosage form substrate. When being placed in mouth on mucosa by the dipping end of this giver 123, the moisture in saliva dissolves medicine, and is carried out sending across mucosa passing. Figure 18 C represent dissolving thin-film dosage form 145 and wherein have multiple dissolving thin-film dosage form 143 dosage form packaging. The thin-film dosage form 143 of dissolving being removed from packaging 141, and be positioned over oral mucosa such as sublingual space, it dissolves there, and send drug delivery across mucosa.

Figure 24 A-B provides the explanation in two stages of 123 1 embodiment purposes of single dose applicator. Figure 24 A represents the setting before giver 123 use, has two giver protuberances 147, two perforation 149 and the blister package 151 comprising dosage form 67. In order to give dosage form 67, two giver protuberances are bent downwardly in perforation place, form handle 131, and by sealing member 135 strip off backward, expose blister package 151 and allow dosage form 67 in oral mucosa such as sublingual space.

In another embodiment, the drugs distribution apparatus of the present invention can contain in cartridge case or the multiple SDA ' s individually packed, and can distribute the single SDA containing the single drug dosage form for patient, medical personnel or user. Drugs distribution apparatus can distribute single SDA ' s with identical parts in an identical manner, and the distribution of single drug dosage form of the present invention is advantageous for by this.

Still in another embodiment, multiple dose giver 137 is a device, and it comprises: one or more pharmaceutical dosage forms 67 or single dose applicator 123, portable energy supply component such as battery, printed circuit board (PCB), data cube computation component and user interface. In this embodiment, drugs distribution apparatus can include the ability performing one or more following functions: record drug dose is distributed history, is verified user identity by modes such as fingerprint recognition, RFID, voice recognitions, allows dosage history transmission to another device, computer or network, and/or provides the lockup period between dose distribution.

Figure 22 is the schematic diagram sending the exemplary multiple dose giver 137 passing distribution pharmaceutical dosage form 67, and each of described dosage form is individually packaged in single dose applicator 123.

Figure 25 A-D provides the schematic diagram of other examples of single dose applicator (SDAs), including tweezers or reciprocal cross forked type SDA (25A), wherein pharmaceutical dosage form 67 is contained between the both sides 153 of SDA123, during with box lunch release bar 19, pharmaceutical dosage form 67 is no longer held by SDA, it is possible to be positioned on oral mucosa by user; Having the injector type SDA (25B) of circular channel, wherein when user promotion 155, slide block (slider) or piston (plunger) 159, pharmaceutical dosage form 67 is pushed out channel end; Having the drive-in SDA (25C) of rectangular channel, wherein when user promotion 155, slide block 159, pharmaceutical dosage form 67 is pushed out channel end; Or slider type SDA (25D), wherein when user draw 157, slide block 159 time, pharmaceutical dosage form 67 is contained in container (pocket) 161, it is possible to obtain pharmaceutical dosage form 67.

Figure 26 A-D is used for storing the schematic diagram (26A) of the container of multiple SDAs123 before providing multiple dose giver (MAD) 137 or using; Wherein in the embodiment of example, the upper cover of (MDA) 137 has the groove (slot) for removing single SDAs123; So that each single SDA123 comprises pharmaceutical dosage form 67 (26C); And SDA123 promotes to be placed in pharmaceutical dosage form 67 Sublingual (26D) of sublingual space.

IX. device is utilized to send the method and system passing sufentanil dosage form in a small amount

Provide and utilize device to send to pass the method and system in a small amount comprising sufentanil dosage form. Figure 17 provides the schematic structure connection figure that various assemblies are described, described various component is included in be sent in the distributor or system passing little pharmaceutical dosage form, including having the device of independent head 13, main body 15 and cartridge case 17, docking FOB113, patient RFID115 and base station 117.

Figure 18 A provides and the block diagram of an aspect of communication in pharmaceutical Dispensing System is described, described distribution system includes RFID tag, drugs distribution apparatus, base station/base and medical personnel personal computer system, and wherein drugs distribution apparatus can via base or by the wired or wireless means of communication and doctor or care-giver's communication.

Figure 18 B provides and the block diagram of another aspect of communication in pharmaceutical Dispensing System is described, described distribution system includes RFID tag, drugs distribution apparatus, portable docking FOB, base station and medical personnel personal computer system. Drugs distribution apparatus can via FOB or by the wired or wireless means of communication and doctor or medical personnel's communication, in order to provide use information and the information about patient respiratory state and blood at set intervals for doctor. FOB is adapted to be attached to rope, in order to allow FOB to hang on the neck of doctor or care-giver.

The example components of distributor includes what follows:

In one embodiment, head, main body and cartridge case comprise the portion of the handle of device. The assembling of this device has the door bolt making head and main body disconnect and the distribution button for patient. Device also has the lamp of display lock-out state, mistake and electric energy. In this embodiment, the cartridge case comprising pharmaceutical dosage form and main body only uses once.

System can comprise portable base, its be hand-held, independent of patient device and be intended for health care professional use. Base makes higher levels of serviceability be possibly realized, as the deeper inquiry that patient device is used, upload device data capability, open head/main body and tether, cancel locking show to patient medication, bigger reading. Base is also used for assembly or disassembly patient device.

System can also comprise RFID bracelet, and it activates via base and worn by patient with to correct patient and only to correct patient's foundation and control medication. This parts forbid that other people use this device.

System can also comprise recharging base (rechargingbase), and it is for charging to base and head, when new software can with or when being incorporated into the program when new user, be also used for updating head and base.

Pharmaceutical dosage form is commonly provided in disposable cartridge case, and described cartridge case is loaded in device before administration.

The exemplary instruction for mounting of device comprises the following steps:

At cradle (rechargingstation), device head and base are charged.

The main body of device and wrist strap are removed from the package.

The head of device and base are removed from cradle.

Shown in pressing, by by cartridge case insertion apparatus main body, cartridge case being loaded into main body, to guarantee that cartridge case sends click and suitably pins.

Apparatus main body (plus cartridge case) is assembled in head.

By the power knob on the device assembled, in order to provide electric energy for system.

Press the power knob on base, in order to provide electric energy for base.

The device of assembling is turned back to base.

In order to lock base, health care professional scans their fingerprint or inputs the password of their uniqueness.

Device reads the labelling on cartridge case and base display mount message, as medicine name, the quantity of tablet, drug level, preset locking time, use persistent period (72 hours), and the battery state of head.

After have read information from cartridge case and being shown on base, request health care professional confirms that all of information is correct and requires witness's confirmatory message.

Base requires that the wrist strap of patient is by making wrist strap approaching device mate with device.

Device is by reading wrist strap and asks to confirm wrist strap numbering; The selection of numbering and confirmation

The medical records of the identity of patient and patient is numbered input base.

Wrist strap is placed in the hands that patient is used for operating device.

Subsequently, base indicates it to be already prepared to the distribution preset tablet of plastics or " shipping tablet ".

Once confirm, device will distribute the preset tablet of plastics or " shipping tablet ". Device utilizes this step calibration distributor gear, start for cartridge case, and allow that health care professional confirmation is correct to be used and with " transport " tablet or placebo dosage form tablet training patient.

Once the preset tablet of plastics or " shipping tablet " are distributed, base would be required to health care professional and confirms that plastics tablet is assigned with.

After confirmation, display device is ready to use by display.

In some cases, it is possible to tether is connected to device via base. Permission health care professional is locked or opens tether by base on request.

If patient utilizes device, oneself gives pharmaceutical dosage form, then before use, patient is giveed training.

The device being claimed and the example of use of system are provided in embodiment 6-8.

In order to illustrate the present invention, it is provided that the following example, its any aspect being not intended to limit the present invention that claims hereinbefore or hereinafter are set forth.

Embodiment

In order to illustrate the present invention, it is provided that the following example, its any aspect being not intended to limit the present invention that claim hereinbefore or hereinafter is set forth.

Have evaluated Sublingual sufentanil preparation two kinds different, including slower erosion type, (erosion time is about 15-25 minute; Embodiment 1A and 1B) and faster erosion type (erosion time is about 6-12 minute, embodiment 2A and 2B). With [mu antagonist Naltrexone, (oral 50mg, strengthens patient twice daily).

Analyze the sufentanil plasma concentration about the time, and make form. Sum up maximum sufentanil concentration (C in the blood plasma of each dosage group_max), arrive C_maxTime and latter stage t_1/2. After the final medication of repeated doses research, measure the t of sufentanil_1/2. Relatively each single compared with IV gives the area under curve (areaunderthecurve, AUC) of Sublingual sufentanil dosage. The C of sufentanil liquid is relatively given with IV and Sublingual_max��T_maxAnd t_1/2��

Embodiment 1: Sublingual gives the bioavailability after a small amount of sufentanil dosage form and pharmacokinetic evaluation

Embodiment 1A: 10 minutes 5mcg sufentanil IV infusions of all individual acceptance. After the removing phase (1-daywashoutperiod) of 1 day, each individuality accepts single Sublingual subsequently and gives the dosage form (comprising slow erodable formulation) containing 2.5mcg sufentanil. In two research days subsequently, it is stepped up dosage and each individual dosage form (comprising slow erodable formulation) accepting to comprise 5 and 10mcg sufentanil.

Embodiment 1B: the sublingual-dosage repeated for four times of all individual dosage forms (comprising slow erodable formulation) accepting to comprise 5mcg sufentanil, every 10 minutes 1 time.

The slow corrosion Sublingual sufentanil preparation comprising 10mcg sufentanil provides as follows:

Component	Amount
		Sufentanil citrate	0.27%
Mannitol (mannitol powder 200SD)	73.77%
		PEG 8000	14.98%

Polyo��303	3.00%
		Lutrol F68	2.00%
Stearic acid	5.00%
		Magnesium stearate	1.00%
Amount to	100.00%

Single Sublingual gives 2.5,5 or 10mcg sufentanil dosage form (slow corrosion) or after being administered 5mcg sufentanil dosage form (slow corrosion) every 10 minutes 4 times, the sufentanil plasma concentration of various time points is shown in Fig. 1.

Based on dosage or route of administration, the average sufentanil t of all sufentanil dosage_1/2Similar, change between 1.56 hours (5mcg sublingual dosage forms) to 1.97 hours (10mcg sublingual dosage forms), it does not have significantly difference (table 1). Average sufentanil C_maxAnd AUC_infAlong with dosage increases, and and dose proportional. Single Sublingual gives the T after sufentanil_maxExcursion be 0.68-0.77 hour. Bioavailability after sublingual administration administration 5mcg sufentanil dosage form patient in 74.5% to administration 10mcg sufentanil dosage form patient in 95.5% between variation.

Table 1 provides and includes C_max��T_max��AUC_inf, F and t_1/2In interior pharmacokinetic parameter guide look. The repeatedly C after the medication of Sublingual_maxFor 43.36pg/mL. Average AUC_infIncrease along with the repeatedly Sublingual medication of sufentanil, and compared with single sublingual administration, usual and dose proportional. Repeatedly the bioavailability (97.2%) after the medication of Sublingual is higher than the bioavailability (74.5%) after the single-dose of same dose level.

Table 1. sufentanil pharmacokinetic parameter is had a guide look of

^*Utilize the %F that 5mcgIVAUC calculates

After to 10mcg sublingual-dosage standardization, be averaged sufentanil C_maxAnd AUC_infThe paired t-test of parameter compares. Result is shown in table 2A and 2B. It is shown that between 2.5-10mcg, C_maxAnd AUC_infWith dose proportional. C_maxAnd AUC_infThe support data of dose-proportional are shown in Fig. 2 and 3.

Watch 2A: Dose standard turns to the sufentanil pharmacokinetic parameter of 10mcg (the slow corrosion dosage form of 2.5mcg)

Relatively

N=12	2.5mcg	10mcg	Difference	Standard deviation	T value	P value
							Cmax(pg/mL)	27.24	27.45	-0.21	10.24	-0.07	0.946
AUCinf(hr*pg/mL)	71.85	71.18	-0.67	16.31	0.14	0.89

Watch 2B: be standardized as the sufentanil pharmacokinetic parameter of 10mcg (the slow corrosion dosage form of 5mcg)

N=12	5mcg	10mcg	Difference	Standard deviation	T value	P value
							Cmax(pg/mL)	21.81	27.45	-5.65	10.99	-1.78	0.10
AUCinf(hr*pg/mL)	54.85	71.18	-16.33	17.94	-3.15	0.009**

^**P value < 0.05, statistically significantly

Compared with infusion 5mcg sufentanil in 10 minutes, after repeating sublingual administration 4 �� 5mcg sufentanil dosage form (slow corrosion) to healthy human volunteer every 10 minutes, the average sufentanil plasma concentration (�� SD) of relative time is shown in Fig. 4.

Sufentanil plasma concentration after giving 4 �� 5mcg sufentanil dosage form (slow corrosion) with Simulation is assessed every 10 minutes. By giving superposed average plasma concentration in 5mcg sufentanil dosage form (slow corrosion) time spectrum (timeprofile) at single, it is simulated. Within the periods of 12 hours (Fig. 5 A) and 2.5 hours (Fig. 5 B), compare average (�� SE) sufentanil plasma concentration of the simulation and forecast compared with the time and observation. Based on simulation, it was predicted that sufentanil concentration closely follow observed sufentanil agent plasma concentration in time.

The further assessment of embodiment 2: after Sublingual gives a small amount of dosage form, sufentanil bioavailability and pharmacokinetics

Embodiment 2A: give individuality (n=2) 5mcg sufentanil agent solution via epidural route, or 10 minutes infusions (N=10) of 5mcg sufentanil agent, single sublingual administration comprise 10mcg sufentanil dosage form (faster erodable formulation) and, it was administered every 20 minutes, repeats sublingual-dosage 4 times of the dosage form (faster erodable formulation) comprising 10mcg sufentanil.

Embodiment 2B: the 50mcg sufentanil IV infusion giving all individual 20 minutes and the single sublingual administration comprising 80mcg sufentanil dosage form (faster erodable formulation).

The quick corrosion Sublingual sufentanil agent formulation comprising 10mcg sufentanil provides as follows:

Component	Amount
		Sufentanil citrate	0.26%
PEARLITOL 100SD D100	70.64%
		Dicalcium phosphate dehydrate	20.00%

HMPC K4M Premium CR	3.00%
		Stearic acid	5.00%
Magnesium stearate	1.00%
		BHT	0.10%
Amount to	100.00%

After single Sublingual gives 10mcg and 80mcg sufentanil dosage form and gives 10mcg sufentanil dosage form (faster corrosion) every 20 minutes 4 times, the sufentanil plasma concentration (meansigma methods �� SD) of each time point is shown in Fig. 6.

The average t of single sufentanil administration_1/2Similar, and change between 1.72 hours (5mcgIV) to 1.67 hours (10mcgIV). After single and the repeatedly administration of Sublingual sufentanil, average sufentanil AUC_infAlong with dosage increases. In the patient treated by 10mcg Sublingual sufentanil dosage form (quick corrosion), bioavailability is 60.9%, and repeatedly (4 �� 10mcg) Sublingual sufentanil is 87.8% after being administered.

With the administration in 20 minutes of Simulation is assessed interval, give 4 �� 10mcg Sublingual sufentanil dosage form (faster corrosion) sufentanil plasma concentration afterwards. Given the superposition of mean plasma concentration in the temporal characteristics of 10mcg sufentanil dosage form (faster corrosion) by single, be simulated. Within the period of 12 hours (Fig. 7 A) and in the period of 2.5 hours (Fig. 7 B), compare the simulation and forecast of relative time and average (�� SE) sufentanil plasma concentration of observation. Observed sufentanil plasma concentration is in time more than the sufentanil plasma concentration (based on simulation) of prediction.

Table 3. sufentanil pharmacokinetic parameter is had a guide look of

^*Utilize the %F that 5mcgIVAUC calculates

Sublingual give 80mcg sufentanil dosage form (faster corrosion) after bioavailability be 70.1%.

After 10mcg sublingual dosage forms is standardized, be averaged sufentanil C_maxAnd AUC_infThe paired t-test of parameter compares. Result shown in table 4 shows C_maxAnd AUC_infWith dose proportional between 10-80mcg. C_maxAnd AUC_infThe support data of dose ratio be shown in Fig. 8 and Fig. 9.

Table 4: 10mcg (80mcg faster corrosion dosage form) is carried out the comparison of dose normalized sufentanil pharmacokinetic parameter

N=11	10mcg	80mcg	Difference	Standard deviation	T value	P value 30-->
							Cmax(pg/mL)	16.59	16.93	-0.34	8.04	-0.14	0.89
AUCinf(hr*pg/mL)	45.02	50.88	-5.86	23.85	-0.81	0.43

It was administered every 20 minutes, multiple dosing 10 or after 15mcg sufentanil dosage form (slow corrosion), carries out sufentanil concentration of analog. The dosage form comprising slow erodable formulation produces bioavailability more than 95%, and therefore plays assessment and repeatedly give the effect on the stable state sufentanil concentration basis of the highest prediction after 10 or 15mcg Sublingual sufentanil dosage form. After repeating sublingual-dosage every 20 minutes after about 12 hours, reach stable state sufentanil concentration. Gave the stable state sufentanil concentration of the 200pg/mL simulation and forecast of 10mcg sufentanil and the stable state sufentanil concentration of the simulation and forecast to the 300pg/mL giving 15mcg sufentanil every 10 minutes every 20 minutes, be shown in Figure 10 A and 10B. Simulation shows, the minimum medication interval again of 20 minutes is safe.

Embodiment 3: by the dosage disposal to the acute pain of outpatient utilizing device administration to comprise sufentanil

Pharmacists loads the drug cartridge comprising 40 sufentanil dosage forms for distributor. Each cartridge case has two coloured preset tablets (being called " shipping tablet "), arranges this preset tablet as two tablets first distributed. Device has the component of load cartridge, and described component is safety and the non-serviceable mouth of unauthorized user (port), wicket (hatch) or door (door). Once pharmacists is by wound packages to device, he just lives entering the mouth of device, wicket or door lock. Distributor is docked by pharmacists's first time subsequently in the base being connected to personal computer or other computers, utilizes butt connector (dockingconnector), designs program for device subsequently. Programming includes uploading the numbering of dosage form used by the dose intensity of dosage form, the Formulation number being loaded in device, the assigned frequency of dosage form purposes usage, every day, current date and time, preferred language, effective thumbprint or proves for other determining patient, and the identity information of doctor when device is lost and is found.

Once devise program for device, pharmacists demonstrates correct use, and by distributing single shipping tablet detecting device. Pharmacists gives patient distributor subsequently, and observes patient and distribute tablet, to guarantee proper use of and function. In company with distributor, pharmacists provides patient's RF identification (RFID) label, and this label must be positioned in the scope of about 5 inches away from device be, to allow distributor to operate.

When patient wants to give potion medicine, he or she holds distributor, presses any button and activates device from park mode. The thumbprint of inquiry user is read or individual's identiflication number (PIN) by device. Device will search for effective FRID password in scope subsequently. Once meet these conditions, distributor will inquire about its memory internal and clock, it is ensured that the current dose treatment regimens using request not violate pharmacists's Programming Design. At this moment, device display status information, such as date and time, doses remaining is numbered, the nearest time of using dosage, patient name etc., and pharmacists is by the visual and/signalisation patient seen that listens, device is ready for distribution dosage form.

The distribution end of device is held in his or her Sublingual by patient, and presses feed rod. When dosage form is assigned with, sound will be sent, and notify that patient's dosage form is correctly sent and pass. Now, device will lock, and to prevent further distribution, until the locking time of the mistake of pre-programmed design, in this locking time, device will be ready for reusing.

Embodiment 4: by utilizing the disposal to the acute pain of inpatient of dosage form that device comprises sufentanil

Postoperative patient needs acute pain to treat at surgical site infections. Surgeon outputs the oral transmucosal sufentanil utilizing drugs distribution apparatus to be administered. Attending nurse (attendingnurse) is held prescription list and is gone for drug stock management system (such as Pyxis) of pharmacists or automatization, it is thus achieved that the drug cartridge comprising sufentanil passed is sent in Sublingual. Cartridge case posts labelling and is equipped with the RFID comprising drug labelling information. Cartridge case posts labelling and is equipped with the FRID electronic tag comprising drug labelling information.

Nurse obtains the disposable distribution portion of drugs distribution apparatus subsequently from stock, and the reusable controller part (controllerportion) of drugs distribution apparatus is obtained to base station, this controller part is complete and recharges circulation and be ready for using. Drug cartridge is inserted disposable distribution portion by nurse, is affixed to the reusable controller part of drugs distribution apparatus subsequently, and single use portion is locked the reusable part of drugs distribution apparatus. Now, device reads the RFID tag in drug cartridge, and uploads suitable drug information, including the lockup period etc. of Programming Design between drug type, dose intensity, dosage. Nurse confirms, drugs distribution apparatus have read correct drug cartridge information, and by drugs distribution apparatus to patient, in order to the distribution of Patients' rights pain medication.

When needs of patients pain medication, she is by hand held for drugs distribution apparatus, and dispensing head is placed in Sublingual in her mouth, and presses distribution button. Drugs distribution apparatus carries out internal verification subsequently, it is ensured that lockup period mistake correct after dose distribution recently. Now, drugs distribution apparatus distributes dosage form in the Sublingual of patient, and provides medication successfully to feed back. Patient removes drugs distribution apparatus from mouth, and allows sublingual dosage forms to dissolve in Sublingual. Patient can attempt distributing by its desired frequency, but drugs distribution apparatus only allows successfully medication later at suitable lockup period. Drugs distribution apparatus electronically record distribution trial and successfully distribution in its medication history.

Nurse makes regular check on patient and drugs distribution apparatus. In this checking process, nurse checks drugs distribution apparatus, watches either with or without mistake, and checks the quantity remaining dosage form in drugs distribution apparatus, and is returned patient.

As patient discharge, nurse take away distributor and can reuse part untie from single use portion, dispose the single use portion of cartridge case and drugs distribution apparatus. Reusing of device is partially attached to computer by nurse subsequently, and the patient from drugs distribution apparatus uses information be uploaded to computer, in the medical records of input patient. Reusable controller part is cleaned by nurse, and is returned to base station, recharges.

Embodiment 5: by utilizing the disposal to the acute pain of inpatient of dosage form that device and portable base comprise sufentanil

Postoperative patient needs acute pain to treat at surgical site infections. Surgeon outputs the oral transmucosal sufentanil utilizing drugs distribution apparatus to be administered. Attending nurse is held prescription list and is gone for drug stock management system (such as Pyxis) of pharmacists or automatization, it is thus achieved that the drug cartridge comprising sufentanil passed is sent in Sublingual. Cartridge case posts labelling and is equipped with the RFID comprising drug labelling information. Cartridge case posts labelling and is equipped with the FRID electronic tag comprising drug labelling information. Cartridge case includes the shipping tablet of the distribution position for dosage form lamination and preset tablet.

Nurse obtains the disposable distribution portion of drugs distribution apparatus subsequently from stock, and obtains the reusable controller part of drugs distribution apparatus to base station, and this controller part is complete and recharges circulation and be ready for using. Drug cartridge is inserted disposable distribution portion by nurse, is affixed to the reusable controller part of drugs distribution apparatus subsequently. It follows that nurse obtains portable base (or docking FOB) from base station, in described base station, it is recharged, and is docked with portable base by the drugs distribution apparatus assembled. The electronically communication of the drugs distribution apparatus of portable base and assembling, and menu is set comes across in portable base, it is used for arranging drugs distribution apparatus.

Now, reusable part and single use portion are locked together by device, read the RIFD label in drug cartridge, and upload suitable drug information, including drug type, dose intensity, the lockup period etc. between dosage. Distributor is by the RFID tag on coding write cartridge case, it is determined that it is cartridge case. Its fingerprint is inputted the finger-printer reader in portable base by nurse, it is thus achieved that secure access, and continues the drugs distribution apparatus being set using. The program of setting includes input user authentication, nurse's authentication, it was demonstrated that about the orthochronous of device, and confirm correct drug cartridge information. Nurse obtains disposable RFID bracelet subsequently and is placed near drugs distribution apparatus, and now, drugs distribution apparatus reads label, and nurse confirms that correct bracelet label is read.

By pressing primary distribution button, nurse confirms that drugs distribution apparatus is arranged correctly subsequently. Distributor starts, and is allocated in the hands of nurse by shipping tablet copy (facsimile), it was demonstrated that work well. The distribution of drugs distribution apparatus detection shipping tablet, it is allowed to the built-in system inspection of normal operation and the internal calibration of new package system. If internal distribution inspection success, then portable base inquiry nurse confirms that shipping tablet correctly distributes, and nurse confirms correct setting. Nurse takes off drugs distribution apparatus from portable base subsequently, goes to the bedside of patient, carries out last setting steps.

RFID bracelet is placed in the wrist of patient by nurse, and antitheft tether (theftresistanttether) is fixed on the bed of patient, and the other end is fixed on drugs distribution apparatus. Nurse instructs patient correctly to use sublingual medications distributor subsequently, and gives patient by drugs distribution apparatus, in order to allow the distribution of Patients' rights sufentanil.

When needs of patients pain medication, dispensing head will in hand held for drugs distribution apparatus, be placed in its mouth, Sublingual by she. And press distribution button. Drugs distribution apparatus carries out internal check subsequently, it is ensured that lockup period mistake correct after the last dose distribution, and the RFID bracelet of patient exists and can read. At this moment, drugs distribution apparatus distributes dosage form in the Sublingual of patient, and provides medication successfully to feed back. Patient removes drugs distribution apparatus from its mouth, and allows sublingual dosage forms to dissolve in its Sublingual. Patient can attempt distributing by its desired frequency, but drugs distribution apparatus only allows successfully medication later at suitable lockup period. Drugs distribution apparatus electronically records distribution behavior and successfully distribution in its medication history.

Nurse makes regular check on patient and drugs distribution apparatus. In this patient's checking process, nurse carries portable docking FOB, and is docked with FOB by device. Electronics connects can make nurse that the information from drugs distribution apparatus is downloaded to FOB. This information includes the use persistent period after using history, drug information, the quantity of residue dosage form and initial setting up. Nurse inputs its fingerprint with backward fingerprint scanner, it is thus achieved that information and drugs distribution apparatus. Because when lockup period expires, other drug dose of patient requests, nurse then makes lockup period lose efficacy, and subsequently drugs distribution apparatus is returned patient, and now, patient can take another dosage.

Nurse leaves the room of patient with portable docking FOB, and returns nurse station, recording medicine history in the record of patient. After completing, FOB is returned base station and recharges by nurse.

After patient employs all dosage forms in drugs distribution apparatus, nurse brings portable docking FOB the room of patient into, and is docked with FOB by drugs distribution apparatus. Its fingerprint is inputted the fingerprint scanner on FOB by nurse subsequently, it is thus achieved that the security clearance to drugs distribution apparatus. It follows that nurse opens safety tether, disconnect the connection of drugs distribution apparatus and bed. She then turns on drugs distribution apparatus and it is removed from FOB, splits. Nurse disconnects single use portion and can reuse linking of part, and removes cartridge case from single use portion. Nurse disposes single use portion and cartridge case, and by the sterilized reusable controller part of wet paper towel (wipe) wiping, in order to it is carried out before being returned base station. Require nurse reusable controller part is returned base station, there, it recharges, and be reuse ready before operation built in diagnostics detect.

Nurse continues to arrange new drugs distribution apparatus subsequently as described above, and provides it to patient.

Although for the purpose being aware and understand, by illustrating and aforementioned invention has been done description in considerable detail by example, but it will be apparent for a person skilled in the art that can implement some changes and modifications. Various aspects of the invention are realized by series of experiments, and some of which aspect is described by following limiting examples. Therefore, illustrate and example is not construed as the scope of the present invention that restriction is described by the explanation of the exemplary added.

Claims (6)

1., for the tablet to individual oral transmucosal administration, comprise:

The sufentanil of 5 �� g-100 �� g and bioadhesive material, wherein said bioadhesive material provides the adhesion to described individual oral mucosa, and the volume of described tablet less than 10 �� l or quality less than 10mg, and wherein give described tablet to individual single Sublingual and produce the coefficient of variation T less than 40%_max��

2. tablet as claimed in claim 1, wherein said oral transmucosal administration is Sublingual or cheek administration.

3. tablet as claimed in claim 1, the erosion time of wherein said tablet is selected from: 5 minutes, 10 minutes and 15 minutes.

4. tablet as claimed in claim 2, wherein said tablet send via epidural route passs in described tablet at least the 55% of sufentanil total amount.

5. tablet as claimed in claim 1, wherein gives described tablet to individual single Sublingual and produces the bioavailability more than 60%.

6. as claimed in claim 1 tablet, wherein repeats after Sublingual gives described tablet to individuality, and described bioavailability is more than to the bioavailability after described individual single sublingual administration.