CN106727271A - Small-volume oral transmucosal dosage forms - Google Patents

Abstract

Small-volume oral transmucosal dosage forms there is provided the pharmaceutical activity medicament comprising scheduled volume orExemplary application includes usingMedicine is given to treat Acute Pain, postoperative pain or explosive pain.

Description

Small-volume oral transmucosal dosage forms

The application is the of entitled " small-volume oral transmucosal dosage forms " submitted to on 01 08th, 2007 The divisional application of 200780007142.9 Chinese invention patent applications.

The cross reference that other are applied

This application claims the priority of the U.S. Provisional Application No. 60/756,937 submitted on January 6th, 2006, it is public Open and be incorporated herein by reference with it.

Invention field

The present invention is provided and is referred to here asThe small-volume oral transmucosal with various sizes and feature Drug-delivery devices and its application method.

Background of invention

At present, the standard regimens being administered orally for treating many morbid states are substantially by curative effect and the aspect of toxicity two Limitation.In other factorses, the control of method of administration, preparation and dosage facilitates these limitations.

Reproducible and effective Drug delivery technology is active research field, and in check drug delivery system There are many advantages compared with regular dosage form, including effect enhancing, toxicity are reduced and patient tolerability improves and more convenient.This The treatment of especially acute with pain, intermittent and explosive pain is especially relevant.

For the medicine based on various methods of administration for treating many medical conditions of such as pain and new improvement The exploitation of formulation is in progress.Still the effect water that exploitation is not seen in the medicine of current commercially available formulation is needed badly The safer pharmaceutical dosage form of flat fluctuation.Be currently available that treatment pain therapeutic scheme be typically due to work it is slow, unstable and And be difficult to regulate and control dosage without can for patient provide it is abundant or stably therapeutic effect so that medical condition can not be had The treatment of effect ground.

U.S. Patent No. 6,974,590, No. 6,764,696, No. 6,641,838, No. 6,585,997, the 6th, No. 509,036, No. 6,391,335, No. 6,350,470, No. 6,200,604 and United States Patent (USP) disclose No. 20050176790, No. 20050142197 and No. 20050142198 work for describing such as fentanyl ex hoc genus anne thing Property compound and the united drug regimen of foaming agent, the foaming agent be used as penetration enhancers with influence reactive compound it is buccal, The permeability of sublingual and gingival mucosa.

U.S. Patent No. 6,761,910 and No. 6,759,059 and United States Patent (USP) disclose No. 20040213855 and disclose logical Crossing sublingual administration has at least one medicine that carrier particle surface is adhered to by bioadhesion and/or mucoadhesion promoting agents The pharmaceutical composition of the acute disease of the substantially anhydrous ordered mixture treatment such as pain of the particulate of activating agent.United States Patent (USP) The group of No. 6,759,059 tablet sublingual administration fentanyl disclosed using size about 100mg or its drug acceptable salt Compound and method.

U.S. Patent No. No. 5,800,832 and No. 6,159,498 (Tapolsky et al.) and United States Patent (USP) disclose No. 20030194420 and No. 20050013845 disclose water miscible, biodegradable drug delivery device, such as adhere to In the bilayer film disk with adhesion layer and back sheet of mucomembranous surface, the adhesion layer and back sheet are water miscible.

U.S. Patent No. 6,682,716,6,855,310,7,070,762 and 7,070,764 and (Rabinowitz, et Al.) disclose and deliver anodyne via inhalation route, the method for being used includes：A) by analgesic drug product on solid support Thin layer heating forming steam；And the steam of the heating b) is caused air flow through to produce aerosol particle.

U.S. Patent No. 6,252,981 (Zhang et al.) discloses oral mucosa medicament delivering as systemic drug The method for delivering the alternative and oral transmucosal delivery medicine of preparation.The invention provides in helping with solid form Solid chemicals are included in the solid solution of solvent and produce the pharmaceutical preparation of solid solution.The solid solution preparation can be with root According to need with buffer and other excipient compositions to contribute to the manufacture of medicine, storage, be administered and by oral mucosa group The delivering knitted.Said preparation can be used together with various oral transmucosal delivery formulations, such as tablet, lozenge, lollipop, chewing gum And cheek or mucous membrane paster.Referring also to Zhang et al.,Clin Pharmacokinet.2002；41(9)：661-80.

Currently in clinical development, example includes oral cavity morphine spray and mouth to the transmucosal dosage forms of many treatment pain Chamber fentanyl spray (Generex Biotechnology) and the oral instant fentanyl piece for sublingual administration (Rapinyl^TM；Endo Pharmaceuticals).Current commercially available two kinds of transmucosal Sublimazes are fentanyl cheek pieces (FENTORA^TM；The oral transmucosal form of the citrate fentanyl Cephalon) and as lollipop being administered (Cephalon), both be only used for treat patient explosive cancer pain, the patient receive and to it The class opium treatment tolerance of the persistent cancer pain for undergoing.

Although it have been described that for treat various medical conditions and morbid state various oral drug delivery systems and Formulation, it is still desirable to which improved formulation, preparation and therapeutic scheme are used to treat such medical conditions and morbid state, for example, The acute and explosive pain for the treatment of.

High bioavilability for various medicines include it is opioid effectively treat most important because must business Dosage higher is encapsulated in formulation to resist generally relatively low bioavilability.For example, NumorphanBiology Availability is 10%, therefore for oral tablet, it is necessary to encapsulate nine times more than suitable IV formulations of medicine.Special problem It is the drug system for having abundant residues medicine to leave after completely using medicine.Example has poorly efficient drug delivery system (percutaneous) IonSys^TM, the system need to encapsulate in the transdermal skin patches than usually during use to the most deliverings of patient amount more than three times medicine Thing amount.These inefficient systems, either oral tablets or patch can be by being injected intravenously medicine and obtaining excess drug All biological availability and abuse easily.If provided close to complete by the given formulation that expected method of administration is administered Bioavilability, then will not provide increased bioavilability by the drug abuse being injected intravenously, and therefore this Planting formulation can mitigate drug abuse and skew.

There is still a need for mouth cavity medicine delivering improvement formulation, its provide than currently available formulation more rapidly with it is more stable Action, more stable PC and more stable bioavilability higher.The present invention is i.e. for this needs.

Summary of the invention

The present invention provide comprising small-volume oral transmucosal drug-delivery devices orComposition and Method, it is describedPharmaceutical activity amount containing predetermined unit dosage can be with the medicine of self administration, while carrying For therapeutic effect and predictable safe drugs kinetic spectrum.

Small size and its placement in sublingual chamber enable effective lipophilic molecules transmucosal Absorb and make saliva to respond and swallow minimum with medicine.This avoiding so that working more quick and steady to stomach and intestine (GI) intake Fixed, PC is more stable, bioavilability is higher.This method of administration causes that the ingestion of medicines via gastrointestinal route is minimum Change, via the ingestion of medicines of gastrointestinal route be variable and obvious drug metabolism can occur in stomach and intestines.

It is of the inventionWith bio-adhesive properties and can adhere on oral mucosa, such as sublingual film and Cheek film.It is suchCan be hydrogel formation type or corrosion type.

It is of the inventionQuality is less than 100mg and volume is less than 100 μ l.More particularly, the present invention is provided Quality be selected from less than 100mg, less than 90mg, less than 80mg, less than 70mg, less than 60mg, less than 50mg, less than 40mg, be less than 30mg, less than 20mg and less than 10mg and/or volume be selected from less than 100 μ l, less than 90 μ l, less than 80 μ l, less than 70 μ l, be less than 60 μ l, less than 50 μ l, less than 40 μ l, less than 30 μ l, less than 20 μ l and less than 10 μ l's

It is of the inventionCan be used for absorb via transmucosal route and undergoing GI and first-pass metabolism The oral transmucosal administration of any medicine therefore, it is possible to be benefited from this formulation.

On the one hand, it is of the inventionComprising 0.25 μ g to 99.9mg, 1 μ g to 50mg or 1 μ g to 10mg Medicine.

On the one hand, the present invention is providedWherein described medicine is to be selected from sufentanil, alfentanil, sweet smell too The class opium of Buddhist nun, lofentanil, Carfentanil, Remifentanil, Trefentanil and Mirfentanil.

The present invention is provided comprising class opioidThe amount of the class opium medicine is selected from about 0.25mcg extremely The sufentanil of 200 micrograms (mcg), the sufentanil of about 2.5mcg to 100mcg, the ng/kgs of about 0.02mcg to 5 (mcg/ Kg sufentanil), the sufentanil of the microgram of e.g., from about 2.5,5,10 or 15, the about alfentanil of about 10mcg to 10mg, 2mcg Fentanyl, the fentanyl of about 50mcg to 1500mcg to 1500mcg, the fentanyl of about 200mcg to 1500mcg, about The card of the Carfentanil of the lofentanil of 0.25mcg to 99.9mg, about 0.25mcg to 99.9mg, about 0.25mcg to 99.9mg is fragrant Too Buddhist nun, the Trefentanil of the Remifentanil of about 0.25mcg to 99.9mg, about 0.25mcg to 99.9mg, about 0.25mcg are extremely The Mirfentanil of 99.9mg.

It is designed to be used or without device automedication by individuality, whereinShape Selected from the disc with plane, concave surface or convex surface, oval shape is spherical and with three or more edges and plane, concave surface Or the polygonal on convex surface.

It is of the inventionCan by from 30 seconds up to 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours or longer erosion time are characterized.

Given to individual single or repeatedly oral transmucosal of the inventionThe biological utilisation of medicine afterwards Degree is more than 65%, more than 75%, more than 85%, more than 90% or more than 94%.

It is of the inventionAlso by the C after to individual single oral transmucosal administration_maxCoefficient of variation be less than The coefficient of variation of 30% or 40%, AUC is less than 30% or 40%, T_maxCoefficient of variation less than 40%, about 30 points of plasma half-life Zhong Zhiyue 4 hours and treatment time ratio are characterized more than 0.07 or for about 0.5 to about 2.0.

In the medication amount that is absorbed via oral transmucosal route be that medicine total amount is at least in the formulation 35%th, at least 40%, at least 45%, at least 50%, 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 99%.

The present invention also provides as herein described by givingEnable that medicine is effectively treated symptomatic Medical condition shows the individual method of symptomatic medical condition to treat.

In one embodiment, symptomatic medical condition is pain, such as Acute Pain, explosive pain or operation Pain afterwards, andClass opium comprising such as sufentanil or its congener.

Brief description

Fig. 1 is the sufentanil for the Human Clinical Study described in embodiment 1Preparation #46 to # The 48 dynamic (dynamical) diagram of In Vitro Dissolution.

Fig. 2 be in healthy human body volunteer (n=12) medium sized vein administration or sublingual single dose to give three kinds of differences strong The sufentanil of degreeThe diagram of sufentanil PC afterwards.

Fig. 3 be in health, clear-headed beagle model compared with intravenous sufentanil administration (n=3) it is sublingual to Give sufentanilPreparation #44 is (equivalent to human body #47 preparations；N=3) the diagram of sufentanil PC afterwards. Error bars represent the standard error (SEM) around average value.

Fig. 4 is the sufentanil that sublingual administration is slowly disintegrated in health, clear-headed beagle modelSystem The diagram of agent #58 (n=3) sufentanil PCs afterwards.

Fig. 5 be in health, clear-headed beagle model compared with intravenous administration sufentanil (n=3) it is sublingual to Give sufentanil solution (n=6) or orally ingestible sufentanil(n=6) sufentanil PC afterwards Diagram.Error bars represent the ± standard error (SEM) around average value.

Fig. 6 is the sublingual administration compared with intravenous fentanyl administration (n=3) in health, clear-headed beagle model The fentanyl of medium disintegrationPreparation #60 (n=2) and the fentanyl of slow disintegrationPreparation #62 (n =3) the diagram of fentanyl PC afterwards.Error bars represent the ± standard error (SEM) around average value.

Fig. 7 be in health, clear-headed beagle model compared with intravenous alfentanil administration (n=3) it is sublingual to Give alfentanil(n=2) diagram of alfentanil PC afterwards.Error bars represent the ± mark around average value Quasi- error (SEM).

Describe in detail

The present invention provide oral transmucosal dosage forms orIt provides high bioavilability, low T_maxFluctuation Property, low C_maxFluctuation and low AUC fluctuations.It is of the inventionIn check dissolution rate, solubility and steady are also provided It is qualitative, cause medicine with the time control release so that therapeutic window it is intraoral blood plasma level extension.

The present invention based on small solid oral transmucosal dosage forms orIts some embodiment is passed in medicine Adhered on oral mucosa during sending.Transmucosal dosage forms cause that saliva responds and minimize and hence in so that medicine is to stomach and intestine (GI) road Delivering minimize so that most of medicine is by oral transmucosal delivery.

It is of the invention that following disclosure describes compositionFormulation.The invention is not restricted to described herein Specific formulation and methodology or medical condition, because these are it is of course possible to change.It is also understood that used herein Terminology merely to description specific embodiment purpose, rather than in order to limit the scope of the present invention.

It has to be noticed that as herein with use in appending claims, singulative " a ", " an " and " the " Including plural reference, unless context has clear and definite phase antirepresentation.Thus, for example, " pharmaceutical preparation (a drug Formulation implication) " includes multiple such preparations, " drug delivery device (a drug delivery device) " Various systems including the device comprising pharmaceutical preparation and the such preparation of receiving, storage and delivering.

Unless otherwise defined, the implication of all technologies used herein and scientific terminology is common with of the art The implication that technical staff is generally understood that is identical.Although in implementation of the invention or experiment can using it is any similar to or it is equivalent In method described herein, device and material, but preferred method, device and material will now be described.

In order to describe and disclosing the composition for describing in the publication and methodology that may be employed in conjunction with, this All publications that text is referred to all are incorporated herein by reference with it.Publication discussed in this article is provided only because Its open submitting day earlier than the application.Any content of this paper is not necessarily to be construed as recognizing the present invention due to formerly invention It is not eligible for prior to such disclosure.

Definition

It is used hereinIt is related to volume to be for about that the μ l of 0 μ l (microlitre) to about 100, quality are for about 0mg (millis Gram) to the small size formulation of about 100mg.It is of the inventionCan be with or without bio-adhesive properties, being can Dissolution can have hydrogel formed or corrode piece characteristic containing pharmaceutically dosage form.

Terms " formulation " used herein or " pharmaceutical preparation " or " formulation " refer to containing at least one for delivery to individuality Therapeutic agent or medicine physical entity (physical entity).The physical entity can be lozenge, pill, tablet, glue Capsule, film, bar, liquid, paster, film, gel, spray, chewing gum or other forms.

Term " medicine (drug) ", " medicine (medication) ", " pharmacological activity medicament " etc. are commutative herein to be made With, and it is often referred to change any material of Animal physiology.It is of the inventionCan be used for delivering can pass through Any medicine of oral transmucosal route administration, by small sizeThat is 0.25 μ g to 99.9mg, 1 μ g to 50mg Or 1 μ g to 10mg, dosage can change.

Mention of the inventionMeaning can be by oral transmucosal for the term " medicine (drug) " of Shi Suoyong Approach effectively any " medicine (drug) ", " activating agent " of administration, " activity ", " medicine (medication) " or " treatment work Property agent ".

Be applied to pain therapy (analgesic art) term " medicine " include sufentanil, sufentanil congener, for example Ah Fen Tani, fentanyl, lofentanil, Carfentanil, Remifentanil, Trefentanil or Mirfentanil, and comprising a kind of or many Plant the formulation of therapeutic compounds.Use " medicine " or phrase " sufentanil or congener " to be not meant to be to be limited to use selected by these It is only a kind of in class opioid compound, or be limited to comprising the only a kind of formulation in the class opioid compound selected by these. Additionally, when individually mentioning sufentanil or individually mentioning selected sufentanil congener, such as when mentioning " fentanyl ", it should It is understood to only be suitable to the example of the medicine that the method according to the invention is delivered, and is not meant to be any limitation.It is also understood that Formulation of the invention can comprise more than a kind of therapeutic agent, wherein exemplary therapeutic combination includes two or more class opium The joint of analog, such as sufentanil plus such as alfentanil, fentanyl, lofentanil, Carfentanil, Remifentanil, The class opium of Trefentanil or Mirfentanil, or such as morphine and codeine opium alkali, the half of such as heroin and Oxycodone Synthesis class opium, or such as pethidine or methadone structure and the incoherent fully synthetic class opium of opium alkali, or can combine Any other medicine of administration.

Term " congener " used herein refer to common chemical constitution various changes or configuration in one kind.

Term " individuality " include any individuality, usually mammal (such as people, canid, cats, equine move Thing, bovid, have hoof mammal etc.), wherein expect treatment illness, such as treatment pain or anesthesia.

Term " mucous membrane " usually refers to any biomembrane wrapped up by mucus in body.Pay special attention to via oral mucosa Absorb.Therefore, the present invention especially considers that cheek, sublingual, gums and maxilla absorb.In preferred embodiments, using of the invention Penetration enhancers are promoting to be most similar in terms of its eucaryotic cell structure via these oral cavity tissue, i.e. gums and the maxilla of skin Absorb.

" transmucosal " delivering of term medicine etc. is meant comprising all delivery forms for passing over or through mucous membrane.Especially, Medicine " oral transmucosal " delivering include by mouth, pharynx, larynx, tracheae or UGI any tissue, especially including it is sublingual, The delivering of gums and palatal mucosa tissue.

Term " buccal dosage forms ", " oral transmucosal dosage forms " are interchangeably in this specification used, and are referred to for putting into practice this hair Bright formulation.

Buccal dosage forms are typically " sublingual dosage forms ", but can use other oral transmucosal routes in some cases. The present invention carrys out continuous drug delivery through oral mucosa by such formulation.

Term " oral transmucosal medicine delivery " used herein refers to such formulation, and wherein medicine delivery is basic via warp Mucosal route occurs, and is then absorbed by GI not via swallowing.Formulation of the invention is designed to provide permission via mouth Transmucosal, the drug-eluting speed for generally being delivered via the maximum that the formulation is placed in sublingual chamber.

" sublingual " used herein literally means " below tongue ", and refers to the method that material is administered via mouth, gives The mode of medicine causes that the material is absorbed rapidly via ranine blood vessel, is absorbed rather than via alimentary canal.Due to sublingual viscous The very vascular property of film and relatively low epithelial cell number of layers compared with other mucous membranes, the absorption of therapeutic substance are sent out rapidly It is raw, so as to allow to be directly entered body circulation and quick acting so as to realize effect, while avoiding oral administration All complication.

Term " hydrogel formation preparation " used herein means the not solid pharmaceutical preparation of Heshui substantially, when itself and bioresorbable When, especially with oral mucosa in bioresorbable when, the aqueous solution of such as water can be absorbed, the mode of absorption causes that its is swollen It is swollen, while holding structure matrix and being formed in situ hydrated gel.The formation of gel follows disintegration (or erosion) dynamics of uniqueness, Allow to control simultaneously medicine with the time release, this is mainly and occurs by diffusion.

Term " T used herein_max" mean the time point for observing maximal plasma concentration.

Term " C used herein_max" mean the maximal plasma concentration observed.

Term " AUC " used herein is meant in the figure of the Plasma concentrations versus time of medicine " area below curve ". Generally for AUC is given in zero to unlimited time interval, however, can not be measured for the apparent plasma drug level of patient " to unlimited ", therefore estimate AUC from a limited number of measurement of concetration using mathematical approach.In practice significance, AUC is (by zero To infinitely) the medicine total amount being absorbed by the body is represented, without considering absorption rate.This is attempting to determine two kinds of systems of same dose Agent whether to body discharge same dose medicine when be useful.By what is compared with the AUC of intravenous administration same dose The AUC of transmucosal dosage forms is used as the basis for measuring bioavilability.

Term " F " used herein mean " percentage bioavailability " and represent from measured matter absorb medicine with The fraction that identical medicine compares in intravenous administration.It is by being delivered through expecting way after measured matter AUC_∞Relative to AUC of the identical medicine after intravenous administration_∞Calculate and obtain.It is to be calculated by following equations and obtained：F (%)=AUC_∞It is (tested Material)/AUC_∞(intravenous route/material).This is an important term, is absorbed it establishes via tested approach (or material) Medicine relative to can via intravenous route obtain maximum possible amount relative fractions.

Term " treatment time ratio " or " TTR " represent the average time that medicine exists with treatment level, are defined as medicine PC remains above the C being corrected with drug eliminated half life_max50% time, and it by following formula calculate And obtain：TTR=is (more than C_max50% time)/(the final intravenous elimination half-life period of medicine).Latter term is derived from is closed Data in literature of the medicine of note in appropriate species.

Term " disintegration " used herein means the tablet physical process decomposed and the physical integrity for only relating to tablet. This can occur in a number of different manners, including be broken into smaller block and finished breaking is into thin and big particle, or Person is corroded until tablet disappears externally to interior.

Term " dissolving " as herein described means in the presence of solvent in vitro or the physiological fluid of such as saliva in vivo In the presence of the process that is dissolved from tablet of active component, without the mechanism for considering release, diffusion or corrode.

Term " expansion ratio " used herein means that formulation is fully exposed to after water compared with the dry state before it exposes Mass ratio.Expansion ratio (SR) can be defined and be represented as ratio or percentage based on the special time exposed to water, such as table It is shown as the SR=of percentage (quality-initial dry mass after water)/(initial dry mass) × 100.

Or, such " expansion ratio " can be defined as volume of the formulation of the invention after water is contacted with identical dose Type is in the ratio for contacting the volume before water.Expansion ratio (SR) can be defined and be represented as based on the special time exposed to water Ratio or percentage, be such as expressed as percentage SR=(after exposure tablet volume-exposure before tablet volume)/(before exposure The volume of tablet) × 100.When the radial dimension of such experiment is controlled well, same expansion ratio can be according to such as thick The variable-sized of degree defines, be such as expressed as the SR=(thickness of the preceding tablet of the thickness-exposure of tablet after exposure) of percentage/ (thickness of tablet before exposure) × 100.

Term " bioadhesion " used herein refers to the adhesion to biological surface, and the biological surface more generally includes viscous Film.

Term " therapeutically effective amount " means the amount of the therapeutic agent for effectively facilitating desired therapeutic effect such as pain relief, or delivering The speed (such as with the amount of time) of therapeutic agent.Accurate desired therapeutic effect (such as degree of pain relief and the pain alleviated Source of pain etc.) can be according to morbid state to be treated, individual tolerance, medicine to be administered and/or pharmaceutical preparation (such as Effect, the medicine of therapeutic agent (medicine) concentration in the formulation etc.) and those of ordinary skill in the art understand it is various its Its factor and change.

" sustained drug delivery " was related within the time period of extension, such as in 1 minute or longer time, from source Insoluble drug release or administration in (such as pharmaceutical preparation).Sustained drug delivery is actually relative with medicine injection delivering.

It is as used herein like that, when pharmaceutical preparation " adhesion " is spoken of to surface such as mucous membrane, mean said preparation and The surface contacts and keeps that on a surface external force need not be applied.Adhesion is not intended to the specific journey for implying bonding or combining Degree, nor being intended to imply that any lasting degree.

Term " activating agent " or " activity " herein can with term " medicine " be used interchangeably and herein for It is related to any therapeutically active agent.

Term " non-close " is used in its broadest sense herein, is referred to and is being retained in application site using long-time Paster apparatus on skin, fixed bank, using room, band, bandage, viscosity gypsum etc. when do not block or completely cut off skin Skin and air contact.

Be used in its broadest sense term " mucous membrane bank (mucosal-depot) " herein, refer in mucous membrane or Close to activating agent bank or deposition below mucous membrane.

Wording " mucosal adhesive " used herein refers to the adhesion to the mucous membrane such as oral mucosa covered by mucus, and at this Term " bioadhesion " used interchangeably that Wen Zhongyu is adhered to any biological surface.

Term " drug delivery device " is used interchangeably with term " dispersal device " herein, and refers to that dispersion is included herein The preparation for further describing it is such as of the inventionOral transmucosal dosage forms device.

Oral transmucosal drug-delivery devices

The present invention provide oral transmucosal dosage forms orIt can make saliva compared with other buccal dosage forms Response is reduced, so as to improve the absorption rate through the pharmaceutically active substance in the formulation of oral mucosa, and is reduced via stomach Therefore the intake of enteron aisle simultaneously provides more stable and reproducible drug delivery formats.

Buccal dosage forms orUsually " sublingual dosage forms ", other oral cavities but can be used in some cases Transmucosal route.The present invention relies on such buccal dosage forms so as to oral transmucosal continuous drug delivery.The formulation is basic Uniform composition, it includes one or more active component, it is possible to comprising the oral mucous membrane for providing to patient for one or more Adhesiveness mucomembranous adhesion agent (also referred herein as " bioadhesive polymer "), one or more in single tablet provide with assign The adhesive of the bonding of shape agent, one or more hydrogel form excipient, one or more filler, one or more lubrication Agent, one or more sorbefacient, one or more buffering excipients, and adjust and control the dissolution time of medicine and move Mechanics or prevent active ingredient degradation coating and other excipient and factor.

It is preferred that sublingual, because hypoglossis mucous membrane is easier than other mucosal areas of such as buccal mucosa for medicine Infiltration, so that more quick (Shojaei AH, the et al.Buccal mucosa as a route for of intake systemic drug delivery：A review (buccal mucosa as systemic drug delivery approach：Summary) .Journal of Pharmacy and Pharmaceutical Sciences.1：15-30,1998).

It is of the inventionMake compared with the oral transmucosal dosage forms of traditional buccal dosage forms or Clinical practice The medicine of bigger percentage (and amount) is obtained via oral transmucosal delivery, and causes accordingly to be reduced via the delivering of intestines and stomach.

The optimum position of oral transmucosal medicine delivery is sublingual area, but in certain embodiments, formulation position In in cheek or adhere to can than advantageous on oral cavity top or gums.

Formulation of the invention is suitable for (such as sublingual) delivering of oral transmucosal of medicine, and dissolution time is typically up to About 60 minutes, up to 120 minutes in some cases, in other cases up to some hours.

Generally, in formulation more than 30%, more than 50%, more than more than the 75% or 95% to 99% of medicine via oral cavity Mucous membrane is absorbed.

The application of drug-delivery devices of the invention is not limited to any specific therapeutic indication.There is provided herein this hair Bright drug-delivery devices are used to treat the application example of pain, but, it is of the inventionCan be used in treatment to be permitted Any one in many morbid states and disease, and it is not limited to any specific medicine or patients.So, the present invention For being administeredCan be used in children and Adult Groups being administered and treating the mankind and non-human mammal.

When using of the inventionTo treat during pain, the present invention can be used in children and Adult Groups to Medicine is simultaneously treated the mankind and non-human mammal and the tolerance of class opium and receives opioid patients first.

The feature of formulation

In one embodiment, formulation of the invention orIt is generally suitable for being adhered to during medicine delivery On to oral mucosa (i.e. bioadhesion), until most or all medicines are delivered on oral mucosa from formulation. In other embodiments, formulation of the invention orWithout bioadhesive.

The present inventionVolume is about the 0 μ l of μ l (milliliter) to about 100, and quality is for about 0mg (milligram) to about 100mg, thickness is for about 0.1mm to about 10.0mm, e.g., from about 0.5mm to about 3.0mm；And diameter is for about 1.0mm to about 30.0mm, about 1.0mm are to about 10.0mm, e.g., from about 3.0mm.

More particularly, it is of the inventionQuality be selected from less than 100mg, less than 90mg, less than 80mg, be less than 70mg, less than 60mg, less than 50mg, less than 40mg, less than 30mg, less than 20mg and less than 10mg.

It is of the inventionVolume be also selected from less than 100 μ l, less than 90 μ l, less than 80 μ l, less than 70 μ L, less than 60 μ l, less than 50 μ l, less than 40 μ l, less than 30 μ l, less than 20 μ l and less than 10 μ l.

Shape：It is of the inventionFormulation substantially can have matching it is described herein on Any shape of the parameter of size.Exemplary shape is selected from the disc with plane, concave surface or convex surface, and oval shape is spherical, And the polygonal with three or more edges and plane, concave surface or convex surface.Shape can symmetrically or not Symmetrically, and with can make storage, process, pack or take controlled, convenient or readily feature or geometry.

Absorbed with GI in oral cavity：Generally, it is of the inventionIn higher than 30%, higher than 50%, higher than 75% or Medicine higher than 95% to 99% is absorbed via oral mucosa.

In certain embodiments of the invention,It is suitable for via oral mucosa to the individuality single medicine of delivering The medicine of 30% or more of agent type contained drug total amount.The single pharmaceutical dosage form of transmucosal delivery in other embodiments The percentage of contained drug total amount can be more than 30% to 40%, 40% to 50%, 60% to 70%, 70% to 80%, 80% To 90% and preferably greater than 95%.In exemplary embodiment, single pharmaceutical dosage form contained drug total amount is at least 35%th, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% warp By oral transmucosal delivery.

The corresponding shortage that the medicine of bigger percentage (and amount) is delivered via the delivering of oral mucosa and via GI roads is provided Existing method than medicine delivery is significantly improved.

Saliva response is reduced：It is of the inventionPharmaceutical dosage form is designed to and is suitable for reducing saliva sound Should, the medication amount that reduction is swallowed, so as to deliver high amount of drug to individuality via oral mucosa.It is of the invention The stripping curve of the improvement compared with foregoing oral cavity or oral transmucosal dosage forms is provided for oral transmucosal dosage forms, it is viscous via oral cavity The high potency drugs delivering of film, and the intraoral stable PC of therapeutic window.

Erosion time：Formulation of the invention is designed to provide for be placed in typically via by the formulation by oral cavity Sublingual position, maximum delivering erosion rate.It is of the inventionThe erosion time of sublingual administration be typically about 30 seconds up to 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, it is 4 small When and 8 hours.

Dissolution time：Oral transmucosal preparation of the invention is commonly designed for reaching 30 seconds up to 1 minute, 2 points Clock, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours or longer medicine Dissolution time, this depends on patient and administration situation and the intrinsic pharmacokinetics of medicine.It should be appreciated that this hair can be adjusted The composition of bright oral transmucosal preparation meets specific clinic shape to provide a series of dosage and a series of dissolution times Condition.

Preparation：Pharmaceutical dosage form of the invention for oral transmucosal delivery can be solid-state or non-solid.It is preferred one Embodiment in, the formulation is the solid-state for being transformed into hydrogel after with saliva contacts.In another preferred embodiment of the present, should Formulation is the solid-state corroded after with saliva contacts without forming hydrogel.

Formulation of the invention is substantially homogeneous preparation, active component that it includes 0.01% to 99%w/w (medicament, Medicine etc.) and also contain one or more：The mucoadhesive of offer and the adhesion of patient's oral mucosa is (also referred herein as " bioadhesive ")；The bonding agent that excipient is combined is provided in single tablet one or more；One or more formation water-setting The excipient of glue；One or more filler；One or more lubricant；One or more sorbefacient；One or more Buffering excipients；One or more coating；One or more controlled release conditioning agent；And one or more regulation and control medicine Dissolution or disintegration time and dynamics or prevent active medicine degrade other excipient and factor.

Excipient is not limited to above-mentioned substance.Many can be sent out for the appropriate nontoxic drug acceptable carrier of buccal dosage forms Now in Remington ' s Pharmaceutical Sciences (Remington pharmaceutics), 17th Edition, 1985.

Formulation of the invention for oral transmucosal medicine delivery can include that (mucous membrane glues at least one bioadhesive polymer Attached dose) or various bioadhesive polymers mixture to promote the adhesion to oral mucosa during medicine delivery.Additionally, working as institute When stating formulation and being wetted with saliva, bioadhesive polymer or mucomembranous adhesion agent can also efficiently control the erosion time of the formulation And/or medicine is with the Dissolution parameters of time.Additionally, some mucomembranous adhesion agents that the present invention is enumerated also act as it is viscous in preparation Mixture, to provide the necessary combination to the formulation.

Exemplary Mucoadhesive materials or bioadhesive material are selected from natural, synthesis or biopolymer, lipid, phosphatide Etc..The example of natural and/or synthetic polymer includes cellulose derivative (such as methylcellulose, carboxymethylcellulose calcium, hydroxyl second Base cellulose, HEMC etc.), natural gum (for example guar gum, xanthans, locust bean gum, karaya, Veegum etc.), polyacrylate (such as carbopol, Polycarbophil etc.), alginates, polyoxyethylene, the poly- second of all molecular weight Glycol (PEG) (preferably 1000Da to 40,000Da can be any chemical constitution of straight or branched), the Portugal of all molecular weight Glycan (preferably 1000Da, to 40,000Da, can be any source), block copolymer, for example those are by lactic acid and glycolic Combination and prepare block copolymer (PLA, PGA, the PLGA of various viscosity, molecular weight and lactic acid to glycolic ratio), tool There are the arbitrary number of repeat unit and PLURONIC F-127 (such as Pluronics, Tektronix of combination Or Genapol copolymers), combination (such as PEG-PLA or PEG-PLGA copolymerization of above-mentioned copolymer physically or chemically connection unit Thing) mixture.Preferably, the bioadhesion excipient is selected from polyethylene glycol, such as polyoxyethylene, carbopol (such as card ripple General 71G, 934P, 971P, 974P) and Polycarbophil (such as Noveon AA-1, Noveon CA-1, Noveon CA-2) is poly- Acrylate copolymer, cellulose and its derivates, and it is most preferably polyethylene glycol, carbopol and/or cellulose derivative Or their any combination.

The amount of mucomembranous adhesion agent/bioadhesive polymer is usually 1% to 50%w/w, preferably 1% to 40%w/w or most Preferably 5% to 30%w/w.Preparation of the invention can contain one or more different bioadhesive polymer of any combination.

The present invention also includes the mixed of adhesive or two or more adhesives for the formulation of oral transmucosal medicine delivery Compound, it helps for excipient to be incorporated into single formulation.Exemplary adhesive is selected from cellulose derivative (such as Methyl cellulose Element, carboxymethylcellulose calcium, hydroxyethyl cellulose, HEMC etc.), polyacrylate (such as carbopol, poly- card ripple Phenanthrene etc.), PVP (all grades), irradiation or non-irradiated any molecular weight or grade Polyox, starch, polyvinyl pyrrole Alkanone (PVP), Avicel etc..

The amount of adhesive is usually 0.5% to 60%w/w, preferably 1% to 30%w/w and most preferably 1.5% to 15%w/w.

The present invention can also be formed for the formulation of oral transmucosal medicine delivery including at least one or more of hydrogel Excipient.Exemplary hydrogel forms excipient has the polymer of ethylene glycol skeleton selected from polyethylene glycol with other, no matter It is the homopolymers of ethylene glycol unit or heteropolymer, the block copolymer of crosslinking, such as polyoxyethylene homopolymer (such as Polyox N10/MW=100,000；Polyox-80/MW=200,000；Polyox 1105/MW=900,000；Polyox-301/MW= 4,000,000；Polyox-303/MW=7,000,000；Polyox WSR-N-60K；It is all these to be Union Carbide Trade name), the hydroxypropyl methyl cellulose (HPMC) of all molecular weight and grade (such as Metolose 90SH50000, Metolose 90SH30000, are the trade name of Shin-Etsu chemical companies), poloxamer (Poloxamer) (for example Lutrol F-68, Lutrol F-127, F-105 etc., are the trade name of BASF chemical companies), Genapol, polyethylene glycol (PEG, such as PEG-1500, PEG-3500, PEG-4000, PEG-6000, PEG-8000, PEG-12000, PEG-20,000 Deng), natural gum (xanthans, locust bean gum etc.) and cellulose derivative (HC, HMC, HMPC, HPC, CP, CMC), it is free or Polymer based on polyacrylic acid and combinations thereof of crosslinking, such as PLA, polyglycolic acid and its by physical mixed or crosslinking Any combination biodegradable polymer.In embodiments, the hydrogel component can be crosslinking.The water The amount of gel-forming excipient is usually 0.1% to 70%w/w, preferably 1% to 50%w/w or most preferably 1% to 30% w/w。

The present invention can also include at least one controlled release conditioning agent for the formulation of oral transmucosal medicine delivery, and it is this The material of sample：When the formulation occur aquation when, the material can be adhered preferentially on drug molecule so as to reduce medicine from The diffusion rate of buccal dosage forms.Such excipient can also reduce the speed of the preparation intake water and thereby can realize more The drug-eluting of extension and the release from tablet.In one embodiment, such controlled release conditioning agent can via physics (and Therefore it is reversible) interaction and activating agent generation molecule combined, so as to increase the effective molecular weight and therefore of activating agent Further adjust infiltration (diffusion) feature of epithelium that it passes through hypoglossis mucous membrane and basilar memebrane.Such combination is actually reversible And any chemical modification for not being related to activating agent, therefore its pharmacological action is had no effect.In another preferred reality Apply in scheme, such controlled release conditioning agent can form discontinuous structure when there is aquation, and it can spontaneously capture work Property agent and therefore further extend its effect.Exemplary controlled release conditioning agent is selected from lipid, phosphatide, sterol, surfactant, poly- Compound and salt.Generally selected excipient is lipophilic and can be with hydrophobicity or lipophilic drugs self-assembling formation complex. The associating intensity of release regulator and medicine can be changed to the ratio of medicine by changing conditioning agent in preparation.Additionally, can Suitably strengthen such interaction by the fabrication process that release regulator and active medicine is appropriately combined.Or, The controlled release conditioning agent can be synthesis or biopolymerization the electropolymer with positive or negative net charge, and its energy Enough combined with activating agent so as to adjust diffusion that it passes through tablet and/or it passes through oozing for mucomembranous surface by electrostatic interaction Saturating dynamics.With above-mentioned other compounds seemingly, such interaction is reversible and is not related to permanent with activating agent Chemical bond.

The amount of controlled release conditioning agent typically 0 to 80%w/w, preferably 1% to 20%w/w, most preferably 1% to 10%w/w.

The present invention also generally includes at least one filler for the formulation of oral transmucosal medicine delivery.Exemplary fills out Fill agent and be selected from lactose USP, starch 1500, mannitol, sorbierite, maltitol or other nonreducing sugars；Microcrystalline cellulose is (such as Avicel), dehydration calcium monohydrogen phosphate, sucrose or its mixture.The amount of filler is usually 20% to 99%w/w, preferably 40% To 80%w/w.

The present invention can also include at least one lubricant for the formulation of oral transmucosal medicine delivery.Exemplary lubrication Agent is selected from magnesium stearate, stearic acid, calcium stearate, talcum, stearowet and terotex etc..The amount of lubricant is usually 0.01% to 8%, preferably 0.1% to 3%.

The preparation can also containing flavor enhancement or sweetener and colouring agent for example aspartame, mannitol, lactose, sucrose, Other artificial sweeteners；Ferriferous oxide and FD＆C color lakes.

The preparation can also not occur chemically or physically to degrade containing additive to help to stablize drug substance.So Degradation reaction can be including oxidation, hydrolysis, aggregation, deamidation etc..The suitable vehicle of drug substance stable can be allow to be included Antioxidant, hydrolysis-resisting agent, aggregation retarding agent etc..Antioxidant can be including BHT, BHA, vitamin, citric acid, EDTA etc.. Aggregation retarding agent can be including surfactant, amino acid etc..

The preparation can also especially need to discharge power faster containing surfactant to increase the moisture of tablet In class hour, this can cause film adhesion quickly to start.Such surfactant should account for the 0.01% to 3% of composition weight. Exemplary surfactants are selected from ionic (sldium lauryl sulfate etc.), such as polysorbate (tween and sapn surface-active Agent series) nonionic, bile salt (such as natrium taurocholicum, sodium taurodeoxycholate, glycocholeic acid sodium, sodium glycocholate Deng), various APGs and their mixture.

Formulation of the invention can also be comprising can influence tablet breakdown kinetics and medicine one or more from tablet Release so as to influence the excipient of pharmacokinetics.Such additive is disintegrant, as is known to persons skilled in the art Those, it is possible to selected from starch, carboxymethylcellulose calcium type or PVPP (such as PVPP, PVP-XL), Alginates, the disintegrant based on cellulose are (such as cellulose, methylcellulose, the Ac-Di-Sol (Ac-Di- of purifying Sol) and carboxymethylcellulose calcium), microcrystalline cellulose such as (Avicel), ion exchange resin (such as Ambrelite IPR 88), tree Glue (such as agar, locust bean, thorn Chinese parasol tree, pectin and tragacanth), guar gum, karaya, chitin and shitosan, dioctahedral smectite, Gellan gum, plantago ovata shell, polacrilin potassium (Tulsion³³⁹), release disintegrant (such as citric acid and tartaric acid of gas With sodium acid carbonate, sodium carbonate, saleratus or calcium carbonate), sodium starch glycollate (such as Explotab and Primogel).With not Close disintegrant to compare, add such additive to contribute to formulation rapid disruption or disintegration, it is faster more as dissolution rate Little particle.Another benefit of such additive containing bioadhesion material described herein is added in formulation of the invention It is that the smaller medicine-containing particle formed during disintegration is more preferable because the surface area contacted with oral mucosa for greatly increasing has Bio-adhesive property.In addition, surface area increase can also promote the quick release of active material to be inhaled so as to further speed up medicine Treatment level needed for receiving and reaching whole body.However, as described above, such disintegrant is made in solid dosage forms with low-level With usually 1% to the 20%w/w of dosage unit gross weight.

In one aspect of the invention, the formulation is used for comprising at least one any kind of Biodegradable polymeric Increase insoluble drug release.Exemplary polymer composition include lactic acid and glycolic condensing model and copolymer, it is poly- (dl- lactides- Co- glycolide) (PLGA), poly- (lactic acid) (PLA), poly- (glycolic) (PGA), poe, albumen and polysaccharide.

The present invention can also include one or more sorbefacient, Yi Zhonghuo for the formulation of oral mucosa medicament delivering Various buffering excipients and/or one or more are coated to improve such as hardness and fragility.

In another aspect of this invention, active component can be chemically modified to significantly improve its medicine in blood plasma Thing dynamics.This for example can be realized by being combined with polyethylene glycol (PEG), including locus specificity PEGylation.Can pass through Optimization pharmacokinetics reduces immunogenicity and administration frequency improving the PEGylation of pharmaceutical properties.

It is of the inventionThere is provided with various formulations, the formulation is keeping the present invention in the oral cavity controllably DissolutionFeature while, depending on the property quality and quantity according to active component.Therefore, greater percentage of medicine Absorption carried out via Oral Mucosal Route rather than GI approach, cause medicine with the time control release so that extended treatment window Interior blood plasma level.It is of the inventionAlso have that bioavilability is high, T_maxFluctuation is low, C_maxFluctuation The low advantage of low, AUC fluctuation.

In one aspect of the invention, it is placed in sublingual chamber by the equal one dosage type low temperature comprising preparation of the invention, preferably In the sublingual side of any side of the small frenulum of tongue, a contact is adhered to.Because the formulation is in the moisture in sublingual space, should Formulation absorbs water, so as to form the hydrogel network comprising fine pore and macrovoid (or passage).The aquation of medicine passes through the formulation Porous web influence dissolution and subsequent diffusion.Hydrogel formulation of the invention by being contacted with the aqueous solution after be expanded to just initial body Long-pending at least 110% is characterized.

Hydrogel in formulation of the present invention occurs in the presence of being formed in the excipient that some can form hydrogel, described Excipient can absorb water and form gel.Such excipient includes the gradational Polyox of institute, poly- second as detailed above The copolymer (such as poloxamer etc.) based on PEG of glycol (all grades), whether homopolymers or heteropolymer, glucan, HPMC, starch etc..Additionally, any combinations of such excipient can help to hydrogel when with bioresorbable being formed.In addition, Such hydrogel forms excipient and is not formed (i.e. without this with the gel that contributes to of carbopol, some celluloses etc. The swelliong power of sample) the combination of excipient can result in hydrogel structure, although the property with modification.

Another aspect provides the formulation for being referred to herein as " corrosion type " formulation." the erosion of even now Type " formulation can absorb substantial amounts of water (depend on their composition), but they are without identical swelliong power and therefore not Form the gel of aquogel type preparation defined above.These " corrosion type " preparations adhere to sublingual chamber once contact, with Aqueogel is similar.However, with hydrogel conversely, they follow surface erosion mechanism without being initially formed hydrogel.Due to " invading In the moisture in sublingual chamber, coat tablets merge and are etched erosion type " formulation with aquation；Subsequent each layer becomes hydration and quilt Corrode, so as to cause the lasting reduction of tablet size.

Such corrosion type formulation is generally characterized with forming excipient not comprising hydrogel.It will be appreciated, however, that the agent The weight of various composition can influence erosion mechanism with percentage (w/w) composition of weight in type.For example, a small amount of particularly can shape Excipient into hydrogel will not cause the formation of hydrogel, so, can include some excipient that can form hydrogel Without changing the differential swelling that they are based on corroding in aggressive agents.The exactly combination of excipient and its percentage by weight is constituted Hydrogel is expanded and structural matrix is maintained after being contacted with the aqueous solution.In other words, generally, institute includes energy to preparation The excipient for forming hydrogel can not necessarily cause the formulation " expansion ", as aqueogel is usual.Become water-setting The formulation of glue is expanded at least the 110% of its initial volume after being contacted with aqueous fluid.

Pharmacokinetics (PK)

Compared with the oral transmucosal dosage forms that currently available most of medicine is absorbed via GI approach, viaThe intake of transmucosal drug cause that medicine delivery between each formulation and each patient is more consistent.

Formulation of the invention is designed to effectively be worked in the unique environments in oral cavity so that limited amount fluid, Relative short time and intraoral pH levels for drug-eluting do not produce opposite influence to the absorption of medicine.The system Agent is also designed to improve dissolution rate, dissolubility and the stability of pharmaceutical dosage form.Advantage of the invention includes that warp can be provided By the higher level drug absorption and the ability of constant dosage effect time of oral transmucosal route so that this preparation is notable Improve the treatment of acute or explosive pain.

Oral transmucosal preparation of the invention is designed to be collapsed by using hypoglossis mucous membrane and by independent control tablet Solution (or corrode) and drug-eluting and from tablet with the release of time with provide avoided safer delivering is composed it is intravenous The high peak plasma level of formulation.Oral transmucosal dosage forms of the invention provide the individual of the activating agent containing specified rate and repeat agent Amount, so as to allow patient accurately to titrate the amount of delivered medicine and suitably adjust the amount in safely and effectively mode.

The advantage of controlled release oral transmucosal dosage forms of the present invention is that it has more constant bioavilability, and energy Enough make the time that plasma drug level is maintained in targeted therapy window with significantly lower fluctuation than currently available dose Type is longer, whether solid dosage forms or IV formulations.Can given for the high peak plasma level that IV formulations are generally observed It is of the inventionAfter be weakened, this can by medicine at 1 to 60 minute or longer time in control release come Characterize.Further, since medicine can continue direct oral cavity and enter blood flow during the time period of tablet dissolution or longer time section, therefore The rapid decline of blood plasma level is avoided, so that the drug plasma for providing the plateau compared with IV methods of administration with extension is moved Mechanics.Additionally, formulation of the present invention can improve Therapeutic safety by minimizing potentially harmful side effect, should Side effect is that, due to the relative reduction of peak and valley in plasma pharmacokinetics, it jeopardizes Therapeutic safety and currently available It is very typical in formulation.

Solid sublingual dosage forms are relative to the advantage bag for opioid sublingual or intranasal administration various liquid dosage forms Include the local controlled release system of solid dosage forms and avoid swallowing liquid medicine via nasal cavity or oral cavity.Sufentanil liquid in human nasal The disclosed pharmacokinetic data of body administration (15mcg) shows that bioavilability is 78% (Helmers et al.Comparison of intravenous and intranasal sufentanil absorption and Sedation (intravenous and intranasal sufentanil absorbs and calm contrast) .Canadian Journal of Anaesthesia 36：494-497,1989).Sublingual sufentanil fluid administration (5mcg) is (referring to following reality in beagle Apply example 4) bioavilability be 40%.Aforementioned biological is less than in human volunteer with sufentanil with this hair using degrees of data BrightForm sublingual administration obtained 91% mean bioavailability (referring to the following examples 1).

Because size is small, can repeatedly byA period of time is persistently placed in sublingual chamber.Small size is caused Saliva produces and is minimized with uncomfortable, and this allows to repeat to titrate within a few days to several weeks to several months.Due to the parent in sublingual chamber Lipid, for some drugses, this approach also allows more slowly to be released into blood plasma, and this is probably to be passed with cheek because make use of Send " bank " effect compared to further stabilization blood plasma level.

Oral transmucosal dosage forms of the invention it is to be designed to be placed in comfortably sublingual so that the pharmaceutical dosage form is abundant And the peak of plasma levels for producing immediately and being then remarkably decreased to avoid being seen in prior art preparation is slowly disintegrated, As described in U.S. Patent No. 6,759,059 (Rapinyl), wherein fentanyl is via containing 400mcg fentanyls Tablet for administration, which results in the peak of plasma levels of 2.5ng/ml, subsequent blood plasma level is reduced immediately.Fentora (fentanyl cheeks Piece) there is also without plateau but have precipitous slope until C_max, subsequent blood plasma level reduces rapidly (Fentora packing instruction Book) problem.

Evaluate Experiment

In order to support the present invention and carry out and be described in description below and the human body of embodiment 1 to 6 and animal It is sublingualHuman body and zooscopy before, the present inventor is not known in animal or human body from using any formulation Any disclosed pharmacokinetic data obtained in the alfentanil of sublingual sufentanil or any formulation.

Interior evaluating

Human research

Human Clinical Study is carried out with healthy volunteer.The research described in detail in following embodiment 1 is with 12 individualities (6 Male 6 female), (correspond respectively to the citric acid of 3.7 μ g, 7.5 μ g or 15 μ g using containing 2.5 μ g, 5 μ g or 10 μ g sufentanils alkali Sufentanil) sublingual sufentanilCarry out.All of excipient is all inactive and (" usual with GRAS Be known as safety ") state.

The sufentanil of sublingual purposes will be designed forGiven by IV pipe continuous infusions with 10 minutes The IV sufentanils of medicine compare.From different IV pipes plasma sample is extracted in remote location.Analysis is confirmed in high, neutralization Good day to day precision and the degree of accuracy under low quality control sample concentration.

In all individualities, the researchEaten away within the time period of 10 to 30 minutes.It is strong at 12 Sufentanil is placed in each sublingual chamber of health volunteer sublingualAfterwards, very consistent pharmacokinetics have been obtained Spectrum is learned (referring to accompanying drawing 2 and table 2).Compared with IV is administered, the average value of the bioavilability of the single-dose of all three dosage Be 91%, this be far superior to percentage measured by commercially available fentanyl transmucosal formulations Actiq and Fentora (respectively 47% and 65%-Fentora package inserts).Although this high bioavilability may be caused by many factors, very may be used Can be due toAsialia significantly limit swallowing for medicine caused by size is small, and avoid via GI on the way The common low bioavilability of the drug absorption in footpath.The package insert of Fentora and Actiq claims respectively, at least 50% He 75% drug dose is swallowed via saliva, and bioavilability is all than of the inventionIt is low.For clinic ExperimentAbout 5 microlitres of volume (quality 5.5mg), only accounts for the fraction of Actiq and Fentora lozenge sizes. Dog research and those discussed above described in embodiment 4 show that the GI bioavilabilities of sufentanil are very low (12%), therefore, if sufentanilBioavilability it is high, wherein medicine is given by oral transmucosal route Give, then the data support the conclusion that the medicine more than 75% absorbs for transmucosal.Therefore, the medicine swallowed is less than 25%, this Far below the ratio that Fentora and Actiq are swallowed.

Importantly, high consistency of this high bioavilability also with the total medicine for being delivered to patient is relevant.For example, 10mcg sufentanilsCurve under total drug plasma area (AUC 0- infinitely great) be 0.0705 ± 0.0194hr*ng/ml (average value ± standard deviation (SD)).The SD is only the 27.5% of total AUC.Coefficient of variation (CV) is description The term of the SD percentages of average value.The coefficient of variation of Fentora AUC is that 45%, Actiq AUC are 41% (Fentora bags Dress specification).Therefore, the accumulated dose of patient/individuality is delivered to not only for sufentanilIt is more biological to obtain Obtain and more consistent between each patient.

Upon administration in the uniformity of the drug blood plasma level at initial stage, sufentanil is sublingualAlso have superior Property.Use 10mcg sufentanilsThe C of acquisition_maxIt is 27.5 ± 7.7pg/ml.Therefore, C_maxCoefficient of variation be only 28%.The C of Fentora and Actiq_maxThere is a problem of the fluctuation of GI ingestion of medicines.The C of Fentora_maxFor 1.02 ± 0.42ng/ml, therefore C_maxCoefficient of variation be 41%.The scope of the coefficient of variation of the Fentora of various dosage be 41% to 56% (package insert).The C of Actiq_maxCoefficient of variation report value is 33% (Fentora package insert).

Except the uniformity of more excellent bioavilability and PC, C is reached_maxTime (also referred to as T_max) very It is important, because the rapid and consistent action of pain relief effect is critically important in the treatment of Acute Pain.SufentanilThe T of 10mcg_maxIt is 40.8 ± 13.2 minutes (scope is 19.8 to 60 minutes).The average T of Fentora_maxReport It is 46.8 to be worth, and scope is 20 to 240 minutes.The T of Actiq_maxIt it is 90.8 minutes, scope is that (Fentora was packed in 35 to 240 minutes Specification).Therefore sufentanilThe uniformity that works of analgesic effect have compared with Fentora and Actiq and significantly change Kind, most slow initial T_maxReduce 400%.

In the Acute Pain especially treatment of acute explosive pain, the half-life period of medicine is consistent and shorter very heavy Will.10mcg sufentanilsPlasma elimination half life be 1.71 ± 0.4 hours, this causes the medicine for each It is titratable to plant levels of pain.If explosive pain events are continued above 1.5 hours, patient can take anotherFor lowest dose level, the plasma elimination half life of Actiq and Fentora is respectively 3.2 hours and 2.63 small When.For higher doses, the half-life period of these medicines is substantially all increase, so as to limit the titratable of these medicines.

Although still under development, published data allow we by provided herein is sufentanilThe data of pharmacokinetic data instant lozenge Rapinyl sublingual with fentanyl are compared.As previously mentioned As, sufentanil of the inventionObserved bioavilability average out to 91%, and it is published The bioavilability of Rapinyl is about 70% (Bredenberg, New Concepts in Administration of Drugs in Tablet Form (new ideas in administered in tablet form), Acta Universitatis Upsaliensis, Uppsala, 2003).The coefficient of variation scope of the AUC (0- is infinitely great) of Rapinyl is 25% to 42%, depending on dosage, and For 10mcg sufentanilsOur value is 27.5%.Our high bioavilability can be shown that, no matter Dosage is how many, sufentanilBy with the consistent low fluctuations of AUC, but it is not for Rapinyl So.In fact, for the sufentanil of all three dosageThe AUC coefficient of variation that we measure it is average It is 28.6% to be worth, and shows that this low fluctuation is unrelated with dosage.

The C of Rapinyl_maxCoefficient of variation is 34% to 58%, depending on dosage.As shown in data given herein, 10mcg sufentanilsThe C of dosage_maxVariation is only 28%, all three dose intensity (2,5 and 10mcg)Average C_maxCoefficient of variation is 29.4%, shows the minimal ripple relevant with dosage.Similarly, Rapinyl T_maxCoefficient of variation is 43% to 54%, depending on dosage, and for our sufentanilAll three Plant this T of dose intensity_maxCoefficient of variation average value is only 29%.Compared with any one in three kinds of drugs compareds, with relax FentanylThis consistent action realized allows safer administration window again, because elevated blood plasma level It is contained in the shorter time period.

In addition, comparing sufentanil for Fentora and Actiq, RapinylEliminated with longer blood plasma Half-life period (5.4 to 6.3 hours, depending on dosage).After single oral transmucosal administration in human body, sufentanilPlasma elimination half life be 1.5 to 2 hours (table 2), this allows more titratables simultaneously to be avoided dosage mistake Greatly.It will be appreciated by those skilled in the art that described herein exemplaryHalf-life period can by change be used for Prepare givenPreparation in excipient composition and relative quantity adjust.In this human research, also survey Try by sublingual sufentanilRepeat administration be titrated to the ability of more high plasma levels.Repetition in every 10 minutes Give 5mcgUntil four dosage, the bioavilability for obtaining is 96%, shows to be realized by repeat administration Blood plasma level higher and still maintain high bioavilability.Postoperative pain or cancer burst pain are either treated, Individual itself level that pain relief can be effectively titrated to is particularly significant.

Platform blood plasma level

Sublingual sufentanilThe another aspect of the PK curves of generation is plateau, and the plateau takes into account blood Pulp-water puts down the consistent time period, all critically important to security and efficiency.Either with IV inject administrations (referring to embodiment 2 to 6 Zooscopy) or compared with IV in our human research infuses 10 minutes (embodiment 1 and accompanying drawing 2), sufentanilPK spectrum substantially it is safer.Fast and high C_maxBlood plasma level is avoided.As fruit opium can produce breathing Suppress, then the peak value for avoiding these high in PK spectrums is favourable.

Confirm administrationThe important mathematics that the plateau of the blood plasma level of measured sufentanil extends afterwards Than being the C more than 50%_maxTime used, end eliminated half-life period eventually divided by IV known to medicine：

Eliminating half-life period is the build-in attribute of molecule, and can carry out most reliable measurement using IV approach, it is to avoid tongue The pollution for causing of lower approach continuous ingestion medicine.Due to the test limit analyzed under these low dosages, ground in our human body The IV for studying carefully middle 5mcg sufentanils eliminated half-life period for 71.4 minutes.Due to detecting via the redistribution of metabolism and secretion The β of fast alpha-elimination mechanism and long period-elimination phase, the published IV of sufentanil is eliminated and partly declined under much higher dosage Phase is 148 minutes.This published elimination half-life period is more accurate and more suitable for being used in aforesaid equation.12 aspirations C of the person under 2.5,5 and 10mcg dose intensities more than 50%_maxThe time of average cost is respectively 110,111 and 106 minutes. Therefore, these specific sufentanilsTreatment time ratio be 0.72 to 0.75.Due to's Preparation can change,Erosion time can reduce or increase, the treatment time ratio of sufentanil may be about for 0.2 to 2.0.In fact, for sufentanil, the treatment time ratio of any oral transmucosal dosage forms of the invention can be In the range of this, therefore will not be defined to this scope for seeking protection specifically by weAttribute.

This treatment time ratio is the medicine worked in the short time by avoiding high peak plasma C_maxHow concentration succeeds Be formulated so that treatment time increases and security is increased measures.For example, as a comparison, the sufentanil IV of human research Arm shows that treatment time ratio is 10min/148min=0.067.Therefore, the low ratio of this IV arms is by sufentanil The peak value that IV transfusions are produced is measured, and shows that this preparation does not produce significant plateau.(the institute in human research of table 1 Dosage) listed by sufentanil preparation treatment time ratio it is higher than IV sufentanil 10 times, show theseThe treatment platform curve of preparation has extended.

Zooscopy

A series of researchs have been carried out in the clear-headed, beagle (Beagle dog) of vigilance more fully to use various medicines Thing andPreparation is illustratedPerformance.Will be using of the inventionOral transmucosal Medicine delivery and liquid sublingual administration and swallowIt is compared to evaluateEach attribute. Result supports our opinion, i.e., small bioadhesive of the inventionInclude with other oral transmucosal dosage forms The liquid phase ratio of instillation, it is fine (as the use in clear-headed dog is confirmed) in sublingual tolerance, and can obtain To bioavilability and more consistent pharmacokinetic data higher.

As being more fully described in following embodiment 2, the first beagle research is carried out so as to relatively more sublingual 5mcg sufentanilsWith IV sufentanils.3 beagles are have studied altogether, as a result as shown in figure 3, being listed in table In 3.Compared with IV, sublingual sufentanilBioavilability be 75%.Therefore, it is similar to somatic data, dog This bioavailability data confirmThan the superior properties of bigger formulation.Additionally, it is similar to somatic data, The coefficient of variation of AUC is lower than the fluctuation of other business transmucosal dosage forms, is 14%.Sublingual sufentanilTreatment Time ratio is 0.28, and the treatment time ratio of IV sufentanils (uses 139 points of the published dog of sufentanil for 0.05 The IV of clock eliminates half-life period).Therefore, it is similar to human body, the 5mcg in table 1With the IV sufentanils in dog Compare, the treatment time ratio for obtaining is much higher (5.6 times).

Other has determined changeThe influence that preparation is composed to pharmacokinetics.Following embodiment 3 This research is explained in more detail.By extensionErosion time, plasma half-life collapses from medium Solution33 minutes (in embodiments 2) be extended to 205 minutes.Slow disintegrationTreatment when Between ratio extended to 1.13 from 0.28.This research illustrates the selection based on excipient and changes medicine PK's Flexibility.Due toSize it is small so that its can shorten with the time of contact of hypoglossis mucous membrane or extend without The excessive saliva that medicine can be washed constantly GI roads is removed or produces, this flexibility is possible.

Another research is carried out in beagle sublingual to evaluateFormulation is administered relative to sublingual liquid Advantage.Following embodiment 4 is described in more detail to this research.Although result shows in the liquid dosage form for instiling Sufentanil (5mcg) cause T to the delivering in sublingual chamber_maxQuickly, but with sublingual sufentanil(75%) Cause that bioavilability is very low (40%) compared to this medication.Due to swallowing for liquid medicine, this is possible.Additionally, AUC is extremely variable, (82%) as shown in coefficient of variation high.With the C of this medication_maxFluctuation it is also high, ripple Dynamic coefficient is 72%.It is computed, the treatment time ratio of the liquid sufentanil of sublingual instillation is 0.06, and the IV studied with this relaxes The ratio of the 0.03 of fentanyl arm is closely similar.Therefore, the sublingual liquid curve of this instillation does not have with sublingualObserved favourable treatment platform.These results are supported from the applicationIt is claimed Biologic adhesion preparation in the sublingual high bioavilability observed be not molecule intrinsic, but the formulation and its preparation The direct result of unique design.Strongly adherent in sublingual chamber causes to can be used for the fluctuation of the surface area for absorbing Property minimize, such as the situation of liquid solution, so as to improve delivering of the molecule to systemic circulation.Further, since its uniqueness sets Meter and small size,Obvious saliva is not induced to produce, so as to reduce the possibility that discharged medicine is ingested.Two The drug absorption that the factor of kind is both contributed to from sublingual chamber is higher more homogeneous.

The other part of this research in embodiment 4 is the sufentanil swallowedBioavilability survey It is fixed.Because the GI bioavailability datas on sufentanil arrive do not have less in document, it is important that further evaluate it is this to The low bioavilability of medicine approach is so as to further supportThe sublingual medicine for using will not be swallowed and can be tieed up Hold the conclusion of high bioavilability.As shown in the PK analyze datas in table 7, from what is swallowedSufentanil Oral bioavailability it is very low, about 12%.Additionally, irregular GI intakes are predicted as known to from fentanyl homologue Like that, these are swallowedIn the medication amount (AUC) and the dynamics (C that absorbs the drug that are absorbed_max、T_max) on all With high fluctuation, as shown in table 7.The conclusion that these data are supported is the sublingual of bioadhesion of the present invention In its irremovable mode is tightly sticked to sublingual chamber, so as to avoid oral ingestion and avoid in medicine via GI approach The height fluctuation of common blood plasma level during absorption.

Evaluation other medicines have been carried out also in beagle to be such as formulated intoFentanyl and alfentanil Other research, and be described in more detail in following embodiment 5 and 6.These researchs are supportedCan be effectively Sublingual has the conclusion of the various medicines of high bioavilability.By fentanylIt is prepared into moderate and slowly collapses SolutionPreparation (referring to table 8 and table 9).Two kinds of preparations are obtained for high bioavilability (respectively 95% He 90%), far above any other fentanyl oral transmucosal preparation of current granted patent.The coefficient of variation of AUC is extremely low (respectively For 10.5% and 4.5%).These data are supportedAttribute, and show that these attributes are not limited to specific medicine. Compared with the form of moderate disintegration, the fentanyl of relatively slow disintegrationWith slower T_max(50 minutes to 22 minutes) Half-life period more long (154 minutes to 121 minutes).These data are further demonstrated thatSelection based on excipient Adjust the ability of PK.

Compared with IV alfentanils, alfentanilThe bioavilability for obtaining is the fluctuation system of 94%, AUC Number is 5%, C_maxCoefficient of variation be 7%, T_maxCoefficient of variation be 28%.It is computed, treatment time ratio is 0.33, and this The treatment time ratio of the IV alfentanil arms of one research (was eliminated for 0.04 with the IV of 104 minutes of dog disclosed in alfentanil Half-life period calculates).Therefore, alfentanilPreparation (as described in Example 6) 8 times of IV alfentanil arms of generation The treatment time ratio of improvement.The high bioavilability of this preparation is supported againUse so that medicine is gulped down What pharynx was minimized asserts.

In vitro Experiment

Bioadhesive

Mucoadhesive strength is by tablet to be adhered to the bottom of suspension platform and is measured said preparation from pig buccal mucosa matrix Power needed for upper separation is determined.Mucosal adhesive test system is by accurate loading unit (GS-500Tranducer Techniques, Temecula, CA) and hook-shaped annex composition.Loading unit produces analog signal, and the signal is by equipped with A/ The data-acquisition system quilt of D converters (Model 500A, Keithley Metrabyte, Taunton, MA) and ibm computer It is converted into data signal.With ELasyLx softwares (Keithley Metrabyte) analyze data.Plastic piston will be stained with by top The sheet glass of (8cm) and bottom have flat surface circular steel ridge (0.5cm) constitute suspension platform adhere to plus On carrier unit.The tablet mould of platform surface is used as relatively low fixed platform.Mucosal tissue is arranged on compared with low platform using screw-pincers On.In order to determine adhesion, the optimal level of the variable is set to keep constant in ensuing evaluation.In each measurement Between, clean mucomembranous surface with 4mL purified waters.The soft cotton paper of excessive water is wiped and by the pH of mucous membrane known volume is 6.8 phosphate buffer wetting.Suspension platform with film is reduced and uses known applying power to be placed on mucomembranous surface The time that Fang Jingli needs.Measurement separating force is simultaneously converted into N/cm².(23 DEG C to 25 DEG C) are carried out three times at room temperature for the research. Adhesion and peak separation power can be used in evaluating the bioadhesive intensity of the formulation comprising various preparations of the invention.

Drug-eluting dynamics

Drug-eluting dynamics is determined by the USP digestion instruments of standard, such as I types, II types and/or IV types, for giving agent Type carries out appropriate change such as the formulation containing very small amount of active medicine.Standard can be used from the insoluble drug release in formulation Analysis method such as one of UV spectrophotometers, HPLC or LC/MS are carried out.Dissolution medium is defined into physiological buffer such as pH is 6.5 to 7.8 phosphate, Tris or other.Can prepare formulation of the invention make it have from 30 seconds to 1 minute, 2 minutes, 3 When minute, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours or longer dissolution Between.

Formulation erosion dynamic

Formulation corrodes can be sublingual by visual observationsMonitored with the disappearance of time.Complete formulation is invaded Erosion by range estimation can with it will be evident that about 30 seconds to 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, In 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours or longer time, depending on the patient of medication and environment and intrinsic Tablet excipient.It should be appreciated that the composition of oral transmucosal preparation of the invention can be adjusted to provide a series of dosage and one The series of erosion time is adapting to specific clinical condition.

Active constituents of medicine

The invention provides small size formulation orSo that oral transmucosal delivery is comprising can be by oral cavity Transmucosal route is delivered and its amount is suitable for small sizeAny medicine preparation.The present invention One of the example of purposes be lenitive application.When of the inventionWhen being used for treatment pain, their meetings Comprising medicine such as class opium or class opiate antagonists, for treating acute or explosive pain.Class opium be special efficacy anodyne simultaneously Be used to treat the acute and chronic pain of medium to violent intensity in the whole world.If however, improper use they also can Acted on serious respiration inhibition, and they also there is a problem of highly being abused., a total of 36,848 in 1998 Example class opium contamination (pure and mix preparation) reports to drugs control centre of the U.S., wherein 1227 (3.3%) cause seriously Poisoning, 161 cause (0.4%) dead.Main cause from the excessive morbidity and mortality of pure class opium is comprehensive by breathing Close disease.

Class opium is still widely used in treatment pain, and generally via intravenous, oral cavity, exterior dura, percutaneous, rectum Delivered with intramuscular.Morphine and the like is usually intravenous delivery and effective for serious, chronic and Acute Pain.

Class opium plays their effect by μ opioid receptors, and the μ opioid receptors are located at and consciousness and sore place Presynaptic and postsynaptic, brain stem, midbrain and cortex region in reason relevant peripheral nerve end, spinal cord.

These activating agents in such preparation can include sufentanil, or sufentanil homologue such as alfentanil, Fentanyl, lofentanil, Carfentanil, Remifentanil, Trefentanil or Mirfentanil.One preferred embodiment uses Shu Fen Too Buddhist nun is used as activating agent.Another preferred embodiment uses sufentanil homologue as activating agent.Another preferred embodiment At least one other medicament of sufentanil and treatment pain is applied in combination as activating agent.Activating agent can also include any class crow Piece or class opioid agonist such as morphine or derivatives thereof.

Formulation of the invention can also be comprising at least active constituents of medicine of 0.001 weight %.The pharmaceutical activity medicine Generally exist with the therapeutically effective amount of about 0.25 μ g to 99.9mg, about 1 μ g to 50mg or about 1 μ g to 10mg.

Preferably, the formulation comprising about at least 0.005 weight % up to 99.9 weight %, e.g., from about 0.25 μ g extremely The sufentanil of 99.9mg, about 1 μ g to 50mg or about 1 μ g to 10mg；Sufentanil homologue such as alfentanil, fentanyl, Lip river Fentanyl, Carfentanil, Remifentanil, Trefentanil or Mirfentanil.

In alternative embodiments, preparation of the invention includes the combination of two or more class opium analogs, such as relaxes Fentanyl adds such as sufentanil, alfentanil, fentanyl, lofentanil, Carfentanil, Remifentanil, Trefentanil or rice The class opium of fentanyl.There are various types of opioid different pharmacokinetics to compose and engage variable with μ opioid receptors Difference interacts, therefore can be applied in combination to strengthen therapeutic effect.

In alternative embodiments, pharmaceutical dosage form of the invention can include an at least class opioid and one kind or many Other medicines are planted, wherein the other medicines can be class opium or non-class opioid.Non- class opioid can be added Prevent to abuse or avoid the side effect that class opium is induced to increase analgesic effect or help.

In certain embodiments, oral administration preparation of the invention includes class opiate antagonists such as naloxone.So Embodiment in, naloxone is provided so as to the activity of the class opium composition of inhibitory preparation in injection with appropriate concentration.

The present invention can be used for treatment and receive opioid patient and class opium intolerant patient first.

Term " receiving opioid patient first " used herein refers to and does not receive class within the time period of several weeks to several months The patient of opioid repeat administration.

Term " class opium intolerant patient " used herein means such physiological status, it is characterized by class after being administered continuously The reduction (such as pain missing, nausea or calm) of opioid effect.Opioid be medicine, hormone or other have it is similar Pain missing, calm and/or nausea effect chemical substance in the material containing opium or derivatives thereof.If generation pain lacks Tolerance is lost, then dosage to the pain for reaching phase same level for increasing opioid is lacked.The tolerance may be not extend to pair Act on, and side effect may not increase with dosage and tolerate well.

In certain embodiments, dosage of the invention can for example relax comprising at least active component of 0.001 weight % Fentanyl, alfentanil, fentanyl, lofentanil, Carfentanil, Remifentanil, Trefentanil or Mirfentanil.Preferably, The formulation includes sufentanil, alfentanil, fentanyl, lofentanil, the card sweet smell of 0.005 weight % up to 99.9 weight % Too Buddhist nun, Remifentanil, Trefentanil or Mirfentanil.The percentage of active component can be with the size of formulation and active component Property and change, it is optimized with obtain via Oral Mucosal Route maximum delivering.In certain aspects of the invention, More than one active component can be included in single formulation.

In various embodiments, preparation of the invention generally all types of patients include class opium tolerate or first All there is appropriate pain relief to act in the children of institute's has age of receiving, adult and non-human mammal.The present invention can For inpatient and out-patient.

The Clinical practice of sufentanil is limited primarily to the IV administrations in operating room or intensive care unit.Some are on inciting somebody to action Liquid sufentanil preparation is used for research (the Helmers et al., 1989 of low dosage intranasal administration；Jackson K, et Al., J Pain Symptom Management 2002：23(6)：450-452) with sublingual liquid sufentanil preparation Case report (Gardner-Nix J., J Pain Symptom Management.2001Aug；22(2)：627-30；Kunz KM, Theisen JA, Schroeder ME, Journal of Pain and Symptom Management, 8：189-190, 1993).In most of these researchs, the minimum dose of sufentanil is in class opium patient is received first in adult 5mcg.There is a problem of that bioavilability is low and acting duration may be very short to the liquid in oral cavity or nasal administration, As we zooscopy (sublingual liquid) and ((nasal cavity liquid drips nasal liquid drops as document is confirmed Agent)-Helmers et al., 1989).Gardner-Nix only describes the analgesic data (nothing that the sublingual sufentanil of liquid is produced Pharmacokinetic data) and describe within 6 minutes occur the sublingual sufentanil of liquid analgesic work, but pain relief Duration only maintain about 30 minutes.Before this patent application, without open sublingual on being used with any formulation The pharmacokinetic data of sufentanil.

Long-term use class opium produces physical dependence, is known there may be habituation sexual behaviour and tolerance.With class The cell of opium contact can show μ opioid receptors internalization (quick endocytosis).A series of Clinical practices it is opioid External μ-opioid receptor endocytosis is individually evaluated or combined with morphine and evaluated in the cell of human embryo kidney (HEK) (HEK) 293 (Koch et al., MoI Pharmacol.67 (1)：12-4,2005).Result shows the endocytosis potential of class opioid and draws The ability for playing desensitization and class opioid tolerance of the acceptor in the cells of HEK 293 is negatively correlated, and with endocytosis high effect The class opium of energy may cause the reduction of class opioid tolerance.In Koch et al., the result shown in 2005 shows that sufentanil is Class opium with endocytosis efficiency high, therefore cause the possibility of class opioid tolerance compared with the associated class opium analog of experiment Property is small.

Sufentanil (N- [(4- (methoxy -1- (2- (2- thienyls) ethyl) -4- piperidyls)]-N- phenylpropionyls Amine), as main anesthetic so that the epidural administration in openheart surgery, during giving a birth and delivering produce stable whole body Anesthetic effect, and be tentatively administered with intranasal and liquid oral medicine.For the business shape of the sufentanil of IV deliverings Formula is SUFENTAPreparation.This liquid preparation sufentanil citrate (phase containing 0.075mg/ml in water When in the sufentanil alkali of 0.05mg) and 9.0mg/ml sodium chloride.Its plasma half-life is 148 minutes, 80% to medicament Amount was drained in 24 hours.

Fentanyl (N- (1- phenethyl -4- piperidyls)-N- phenylpropionamides) in late period the 1950's first than Synthesize when sharp, and with about 80 times of analgesic effects of morphine.Fentanyl and its homologue are the μ initially as anodyne exploitation Opium agonist, and because what it was relieved pain quickly starts and frequent intravenous administration.After intravenous administration, the analgesic of fentanyl is made With faster, Duration Ratio morphine and meperidine are short.By lozenge (for example) after buccal administration, the consumption of lozenge is led to Often completed in 30 minutes, bioavilability is 50%, although the T of 200mg Actiq formulations_maxIt is 20 to 120 minutes, display Due to 75% medicine swallow the unstable GI intakes for causing (Package insert).T on Actiq_max's Closer to publication show to tend to faster to work these initial times that (Fentora package inserts show Actiq's T_maxScope is extended to 240 minutes).The PK spectrums of Fentora slightly improve due to 50% swallowing for medicine, biological utilisation Spend is 65%.Therefore, a kind of major defect of this therapy is that the fentanyl being largely administered with lozenge form is swallowed by patient.It is fragrant Too Buddhist nun and other opioid agonists has potential harmful side effect, including respiration inhibition, Nausea and vomiting and constipation.Due to sweet smell Too Buddhist nun is 30% via the bioavilability of GI approach, and this medicine swallowed can dramatically increase C_maxBlood plasma level so that With the C observed by these products_maxAnd T_maxIt is unstable.

Although sufentanil and fentanyl there are many similarities with potential μ opioid receptors activator, permitted Difference has been shown on many key ways.Existing multiple research show the efficiency ratio fentanyl of sufentanil it is strong 7 to 24 times (Package insert；Paix A, et al.Pain, 63：263-69,1995；Reynolds L, et al., Pain, 110：182-188,2004).Therefore, it can give sufentanil with less formulation, it is to avoid the saliva that larger formulation causes Liquid response increases, so that swallowing for the medicine related to larger formulation absorbs minimum with minimum, variable GI.

In addition, fat-soluble (octanol-water partition coefficient) of sufentanil (1778: 1) is more than fentanyl (816: 1).Shu Fen The protein binding (91% to 93%) of too Buddhist nun (is shown in respectively also greater than fentanyl (80% to 85%)With Package insert).The pKa of sufentanil be 8.01, and the pKa of fentanyl be 8.43 (Paradis et al., Therapeutic Drug Monitoring (Therapeutic Drug Monitoring), 24：768-74,2002).These differences can influence many Pharmacokinetic parameter is planted, for example, sufentanil is had shown that when faster worked than fentanyl and faster recovering Between (Sanford et al., Anesthesia and Analgesia (are anaesthetized and analgesic), and 65：259-66,1986).This for During repeatable administration treatment Acute Pain be it is favourable, for example in the present invention.The use of sufentanil can be imitated due to titration The ability of fruit makes pain quickly alleviate, and avoids polypharmacy.

It is important that, it has been suggested that sufentanil producing ratio fentanyl is strong by 80,000 times of μ-opioid receptor endocytosis (Koch et al., Molecular Pharmacology (molecular pharmacology), 67：280-87,2005).This receptor internalisation Result be that neuron more strongly proceeds to respond to sufentanil than fentanyl as time goes by, show clinically to repeat to The tolerance that sufentanil is produced during medicine can be fewer than fentanyl.

As described above, sufentanil is with oral liquid (Gardner-Nix J., 2001；Kunz et al., 1993) Form and as nasal drop (Helmers et al., 1989) and nasal spray (Jackson et al., 2002) in adult Tentatively use.Not yet announce the pharmacokinetic data of the sublingual sufentanil of any formulation.

The homologue of sufentanil and fentanyl can be used for the compositions and methods of the invention, the example of the homologue Including Remifentanil and alfentanil.

Remifentanil is many effective fentanyl homologues faster than the metabolism of fentanyl and sufentanil, but in warp May be suitable for treating Acute Pain when being delivered by sustained release preparation.It is of the inventionGenerally comprise about 0.25mcg extremely The Remifentanil of 99.9mg.The dosage range of Remifentanil preparation can be included in the time period of 20 minutes in 0.1mcg/kg extremely 50mcg/kg, such as adult and pediatric patients.These dosage can be repeated at desired intervals, the time interval Fentanyl or sufentanil can be shorter than.

Alfentanil is also the effective fentanyl homologue of tachymetabolism, but may be suitable for making in sustained release preparation With.It is of the inventionGenerally comprise the alfentanil of about 10mcg to about 10mg.The suitable dosage of alfentanil can be with It is 1mcg/kg to 2000mcg/kg in 20 minutes, such as adult and pediatric patients.These dosage can be with reasonable time Interval repeats, and the time interval can be shorter than fentanyl or sufentanil.

Patient with chronic pain disorders state, its pain is also possible to have intermittent exacerbation, delays except they use The slow time controlled released class opium for working is treating outside its baseline chronic ache, it is necessary to promptly use the explosive class of rapid-onset Opium.

Explosive pain or surgical pain can aggravate in short time, be as short as 1 or 2 minute or long to 30 minutes or longer, because This has being to provide such as lower class opiate of significant advantage：It produces clinical effective, action time more constant more quickly With predictable blood plasma level, but there is limited half-life period to avoid the class opium for short time pain events simultaneously To drug overdose.

Class opium is still maximally effective anodyne form, however, people need side effect minimum and can be with doctor's energy The improved form that the mode that tracking patient uses enough easily is provided.

Using current treatment method, trial is generally included with various interference technique control pains, the interference technique：It is quiet The analgesia (PCA) of patient's control, continuous epidural (CEI), the control of other types of Acute Pain, mitigation shield in arteries and veins Reason Pain management and family health care patient pain control.These methods are in control duration, the convenience and safety for the treatment of Property aspect achieve different degrees of success relative to side effect.

Fast treating Acute Pain is needed under many different clinical settings, these clinical settings include that Post operation is extensive Multiple, rheumatoid arthritis, the impaired, TCA in back etc..For example, receiving severe pain in patient's initial a couple of days after surgery Torment, tormented by the slight pain to medium level in subsequent a couple of days.

It is IV morphines for treating the medium most common anodyne to pain after major surgeries.This or by nurse's base Patient is given by IV injected deliveries or generally injection of morphia device is placed in PCA pumps and patient is by pressing tool in " needs " There is the button of lock-in feature and carry out opioid self administration.Other class opium of such as hydromorphone and fentanyl also may be used Use by this way.

Patient during the treatment of Acute Pain is disposed for outpatient is also necessary.For example, many patients are by chronic Pain is tormented, it is necessary to press week or their pain is daily treated using class opium.Although they can using long-acting oral or Percutaneous class opiate to treat the chronic pain level that they are being subjected to, but they be frequently necessary to short-acting potent class opium with Treat its serious burst pain.

Under conditions of extremely good enough, " scene " treatment Acute Pain is also necessary.Nursing staff and military doctor are led to Often it is required to treat serious Acute Pain in the case where not sterilizing, wherein can cause undesirable for the pin that IV or IM is administered Pricking wound, infection risk etc..Oral class dream-stick generally needs 60 minutes to provide mitigation, and this is for severe pain Some people for it is oversize.

In a number of clinical situations, clearly need by it is titratable, can safely and conveniently use in the way of effectively delay Solve pain and alleviate the preparation of serious explosive pain and intermittent pain within the appropriate time long.

Drug-delivery devices of the invention or preparation, each oral transmucosal delivery formulation contain about 0.25 to about 200mcg Sufentanil.In an exemplary of the invention, about 0.25 to about 200mcg sufentanil is contained per one dosage type low temperature, it is single Solely or with one or more other therapeutic agent or drug regimen.

It will be appreciated by those skilled in the art that low side of the dosage of children in scope, the dosage of adult in the high-end of scope, Depending on body weight, when particularly to adult's long term administration of class opium tolerance.The small-volume oral transmucosal medicine of sufentanil Delivering formulation is not yet disclosed.

The present invention contains about 0.25mcg to about for the exemplary formulation of children's (pediatric patients) administration per one dosage type low temperature 120mcg sufentanils.For example, the present invention for children's administration preparation can containing about 0.25,0.5,1,2.5,4,5,6,8, 10th, the sufentanil of 15,20,40,60 or 120mcg is used for oral transmucosal delivery.Pediatric patients are also in this way, exemplary dose Amount scope be at least about 0.02mcg/kg to about 0.5mcg/kg, preferred scope is for about 0.05mcg/kg to about 0.3mcg/kg.

The present invention contains about 2.5mcg/kg to about 200mcg/kg for the exemplary formulation of administration of being grown up per formulation.Example Such as, the present invention for administration of being grown up preparation per formulation can containing about 2.5,3,5,7.5,10,15,20,40,60,80,100, 120th, the sufentanil of 140,180 or 200mcg or more is used for oral transmucosal delivery.

Also in further embodiment of the present invention, the fentanyl of about 2mcg to about 1500mcg is contained per one dosage type low temperature, individually or With one or more other therapeutic agent or drug regimen.It will be appreciated by those skilled in the art that the dosage of children is in scope Low side, the dosage of adult in the high-end of scope, depending on body weight, particularly to class opium tolerance adult's long term administration when.

The present invention contains about 2mcg to about 900mcg for the exemplary formulation of children's (pediatric patients) administration per one dosage type low temperature Fentanyl.For example, the present invention for children's administration formulation can containing about 2,3.75,7.5,18.75,30,37.5,45, 60th, the fentanyl of 75,112.5,150,300,450 or 900mcg is used for oral transmucosal delivery.

The sweet smell that the present invention contains about 18.75mcg/kg to about 1500mcg for the exemplary dosage forms of administration of being grown up per formulation Too Buddhist nun.For example, the present invention for administration of being grown up formulation can containing about 18.75,22.5,37.5,56,75,112.5,150, 300th, the fentanyl of 450,600,750,900,1050,1350 or 1500mcg or more is used for oral transmucosal delivery.

In an exemplary, the formulation for treating pain can be containing about 0.25mcg to about 200mcg's Sufentanil, about 0.5mcg to about 120mcg sufentanil, the sufentanil of about 2.5mcg to about 40mcg, about 2.5mcg is extremely The sufentanil of about 15.0mcg, about 2.0mcg to about 1500mcg fentanyl, the fentanyl of about 20mcg to about 1200mcg, or The fentanyl of about 100mcg to about 900mcg.

Formulation of the invention contains about 10mcg per formulation passs to the alfentanil of about 10000mcg for oral transmucosal Send.It will be appreciated by those skilled in the art that low side of the dosage of children in scope, the dosage of adult in the high-end of scope, according to body Depending on weight, when particularly to adult's long term administration of class opium tolerance.

The present invention contains about 10mcg to about for the exemplary dosage forms of children's (pediatric patients) administration per one dosage type low temperature The alfentanil of 6300mcg.For example, the present invention for children's administration formulation can containing about 10,25,50,130,210, 280th, the alfentanil of 310,420,600,780,1050,2100,3000 or 6300mcg is used for oral transmucosal delivery.

The A Fenta that the present invention contains about 70mcg to about 10000mcg for the exemplary dosage forms of administration of being grown up per formulation Buddhist nun.For example, the present invention for administration of being grown up formulation can containing about 70,140,160,210,280,310,420,600,780, 1050th, the alfentanil of 2100,3000,6300 or 10000mcg or more is used for oral transmucosal delivery.

In different exemplaries, the formulation for treating pain can be comprising about 0.25mcg to about The sufentanil of 200mcg and about 2mcg to the fentanyl of about 1500mcg combination, or about 0.25mcg to the Shu Fen of about 200mcg The too fentanyl and one or more combination of other medicines of Buddhist nun or about 2mcg to about 1500mcg.

To human individual delivering it is of the invention containing sufentanil, alfentanil or fentanyl dosage form after, Shu Fentai The blood plasma level of Buddhist nun, alfentanil or fentanyl reaches maximum in 0 to 60 minute upon administration, 5 to 50 minutes or 10 to 40 minutes Value.

The delivering method of oral transmucosal dosage forms

The device of delivering can be incited somebody to action using various mechanically or electrically chemical methodesDrive in mouth Chamber or sublingual space.For example, once trigger,Can be strong by spring, compressed air or other machinery device System is released.

The preparation method of oral transmucosal dosage forms

Present invention also offers pastille oral transmucosal delivery formulation such asPreparation method.For example, should Method comprises the following steps：Weigh medicine and one or more bioadhesive polymer, adhesive, gel-forming excipient, filler, The factor of lubricant or glidant and influence dissolution time, possible powder mull, directly dry powder mixing and the pressure of compression Piece.

It is alternatively possible to use wet granulation method.Such method (such as high shear method of granulating) is included in blender Middle mixed active composition and possible some excipient.Adhesive can be one of excipient of addition under dry mixed state Or be dissolved in the fluid for pelletizing.Granulation solution or suspension are added in dry powder and mixed to reaching in a mixer Desired characteristic.So the particle of generation would generally have and be suitable for producing with enough hardness, dissolution rate, uniform content The characteristic of the formulation of property and other physical features.After wet granulation step, most commonly by product drying and/or after the drying Grinding is so that most products are in the range of desired size.Sometimes, sieved in use device such as oscillating granulator or grinder wet method / after by product drying.Then dry granulation can be carried out to obtain acceptable size range, is sieved with sieving equipment first Divide, then the excessive particle of grinding size.In some cases, appropriate glidant is added to improve the mobile performance of particle； Suitable glidant include silicate (such as trade mark of SILOID and SILOX silicas-Grace Davison Products, The trade mark of Aerosil-Degussa Pharma).

In addition, said preparation can be by all optional method of granulating productions well known by persons skilled in the art, such as spray flow Change bed granulation, extrusion and round as a ball or fluid bed rotogranulation.

It should be appreciated that said preparation can be converted to the operation commonly used with those skilled in the art to the individual formulation for delivering. The preparation method of the formulation is optimised to realize high dose content uniformity, and this is for generally with 0.01% to 10%w/w's It is especially important for the potent compound that mass ratio is present.

The practice present invention is well known in the art and can be used for for many preparation methods of formulation of the invention, Such as direct tablet compressing, wet granulation.

It is of the inventionFormulation can be with or without coating membrane in formulation outer surface.

The effectiveness of small-volume oral transmucosal dosage forms of the invention

Formulation of the invention is used to deliver any medicine that can be administered by oral transmucosal route.Oral cavity of the invention Transmucosal dosage forms orSmall size high bioavilability, T can be provided_maxLow fluctuation, C_maxLow fluctuation The low fluctuation of property and AUC.It is of the inventionAlso provide in check dissolution, solubility and stability so that medicine Thing controllably discharges with the time, so that the blood plasma level in extended treatment window.

In the exemplary described in detail herein, formulation of the invention can be used to treat individual with pain Body, the pain can differentiate or not identifiable etiologic etiological any one is related to various.In such an implementation, Formulation of the invention can be used to suppress or pain of alleviation.Term " treatment (treatment) " or " treatment on pain (management) " be generally used herein to describe the recovery of pain, suppress or alleviate so that individual more comfortable, such as example, by Determined by pain scores like that.

Term " Acute Pain " used herein refers to the pain generally existed less than 1 month, but in some cases, deposits Pain at long to 3 months be also contemplated as " it is acute,.

Term " chronic ache " used herein refers to the pain generally existed more than 1 month.

Formulation of the invention is used especially for treating the Other diseases state at Acute Pain or " scene ", i.e., extremely not good enough Under conditions of.Nursing staff and military doctor be usually required to be treated in the case where not sterilizing serious Acute Pain or other Wound or morbid state, wherein undesirable pricking wound, infection risk etc. can be caused for the pin that IV or IM is administered.Oral class crow Tablet generally needs 60 minutes to provide mitigation, and this is oversize for some people of severe pain.Of the invention dose Type can be used for for this needs.

Formulation of the invention can be additionally used in paediatric applications, because the comfortable and safe property of the formulation can allow young children It is easy to receive the therapy of this pattern, and can reliably transmucosal delivery medicine.Instantiation is included but is not limited to, in IV methods Can not carry out or treat Pediatric Acute pain when inconvenient, paediatrics be treated when children effectively can not be administered by inhalation route and is roared Breathe heavily, when children or can not be unwilling to swallow pill treat nausea, children be NPO (being unable to oral ingestion) or need more rapidly Preoperative calmness when ground works.

Formulation of the invention can be additionally used in veterinary application.Instantiation is included but is not limited to, and IV administrations are difficult to carry out or not Any acute disease state, such as pain relief, anxiety/anxiety alleviation, preoperative calmness are treated at one's leisure.

Oral transmucosal delivery is simple, non-intruding, and can be by nursing staff or patient to minimize sense of discomfort Administration.Generally, the oral transmucosal delivery of medicine solid dosage forms such as lozenge or tablet are completed, but can also using liquid, Spray, gel, chewing gum, powder, film etc..

For some drugses, as via GI roads bioavilability it is low, such as many lipophilicity class opium, oral cavity is through viscous Film delivering can be provided and deliver more preferable route of delivery than GI.For the opioid medicine of such as lipophilicity, oral transmucosal is passed Send with the onset time (i.e. from the time that is administered into therapeutic action) more shorter than oral cavity GI deliverings, and bioavilability has bright Aobvious improvement.

Following examples are used for the sheet explained the present invention rather than be intended to described in limitation claim as described above or following Any aspect of invention.

Embodiment

Interior medicine dynamics

It is above-mentionedFormulation can be after sublingual administration in test body in the mankind and suitable animal model Pharmacokinetics.Following embodiment is confirmedFormulation is in human volunteer and the beagle mould of clear-headed, vigilance The ability of consistent sufentanil citrate absorption spectra is obtained in type after sublingual administration.

Embodiment 1.The sublingual sufentanil of sublingual administration in adult human volunteer

The sufentanil used in the Human Clinical Study of table 1.Preparation

Human Clinical Study is carried out with healthy volunteer.The research carries out (6 male 6 female) with 12 individualities, using being made body 5 μ l of product, quality about 5.5mg and through measure all formulation intensity all with diameter about 3mm, thickness about 0.8mm it is equal The sufentanil of one size(the preparation #46 to #48 shown in table 1).SufentanilContain 2.5 μ G, 5 μ g or 10 μ g sufentanil alkali, correspond respectively to the sufentanil citrate of 3.7 μ g, 7.5 μ g or 15 μ g.All excipient State all without activity and with GRAS (" being known as safety ").SufentanilIt is tested for sublingual making With.Researcher will be single by the way that they directly are placed on into small frenulum bottom with the very blunt tweezers in tipGive individual Body.

Attribute

Bioadhesive

Bioadhesive is as previously described with sufentanil clinical test preparation (#46 to #48) without sufentanil composition Measure.Through measurement, removeRequired bioadhesion power is 0.046 ± 0.01N/cm²。

Dissolution in vitro is evaluated

Sufentanil citrate is certainlyThe dissolution rate of preparation #46, #47 and #48 is external in II types as previously described Evaluated in digestion series, and as shown in following Fig. 1.

Calculated for bioavilability, the 5 intravenous sufentanils of μ g are diluted to 20mL's in 0.9% physiological saline Cumulative volume, and be administered in 10 minutes in the form of continuous infusion by IV pipes.With different IV pipes blood is extracted in remote location Slurry samples.This human trial is cross-over design, there is the cleaning phase between the transformation from more up to relatively low-dose.Individual clothes daily The side effect to avoid class opium from inducing is blocked with class opiate antagonists naltrexone.

● the 0th day：IV sufentanils are infused

Zero collects 17 parts of samples：

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

● the 2nd day：Sublingual 2.5 μ g sufentanils

0 17 parts of samples：

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

● the 3rd day：Sublingual 5.0 μ g sufentanils

0 17 parts of samples：

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

● the 4th day：Sublingual 10.0 μ g sufentanils

0 17 parts of samples：

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

● the 7th day：Sublingual 5.0 μ g sufentanilsWith 10 minutes for interval is repeated 4 times

0 23 parts of samples：

- 5.0 (give for the first timeBefore), 5,7.5 minutes

10 (give for the second timePreceding moment), 15,17.5 minutes

20 (give for the third timePreceding moment), 25,27.5 minutes

30 (give for the 4th timePreceding moment), 35,40,45,50,55,60,90,120,150,190,350, 510 and 670 minutes.

Total blood volume needed for pharmacokinetics sampling is about 455mL.

Sufentanil concentration in plasma sample is analyzed with effective LC-MS/MS sufentanils human plasma and determined.This point Analysis is confirmed in high, day to day precision and the degree of accuracy neutralized under low quality control sample concentration.

Erosion time

In all individualities, this researchCorroded within the time of 10 minutes to 30 minutes.Relaxed by each Fentanyl is sublingualAfter being positioned in 12 sublingual chambers of healthy volunteer, the obvious consistent of Three doses is obtained Pharmacokinetics spectrum (Fig. 2).

With the sublingual sufentanil of Three doses intensity in table 2.IV (5mcg) and Human Clinical StudyAgent The PK analyses of amount arm (2.5mcg=#46,5mcg=#47,10mcg=#48)

¹Represent medicine and reach treatment level (more than C_maxRelative time 50%), and by following formula calculate：TTR=is (super Cross C_max50% cost time)/(IV eventually end eliminate half-life period).Denominator is obtained from document, for sufentanil in human body For be 148 minutes.

Embodiment 2.Sublingual sufentanil in canine modelInterior evaluating

Examples below 2 to 5 uses beagle model, andPreparation be all using gross mass 5.5mg'sThe above-mentioned 5mcg of sublingual administrationAfter (the preparation #44 of dog, identical with people's body preparation #47) The interior medicine dynamics (PK) of sufentanil are evaluated in the beagle of health.In brief, by direct in sublingual chamber Place single above-mentioned 5mcgThe sublingual administration in wide-awake Healthy Dogs.Three dogs are evaluated altogether.Give After medicine, visually observed every 5 to 15 minutesPosition in sublingual chamber.Compare tongue under identical dosage level Lower sufentanil PK and IV is administered the PK of sufentanil.

All of dog is up to the blood collection of 2 hours after being used to be administered via cephalic vein insertion conduit.2 is small after whole administration When blood collection during, all of dog all loads onto Elizabeth's necklace to prevent conduit from coming off.The blood collection of 2 hours terminates After remove conduit.From the beginning or other suitable venous collections the blood collection of 4,8 and 24 hours after administration.Will at following time point About 2ml blood collections are in the precooling pipe containing EDTA potassium：Administration before and administration after about 1,3,5,10,15,30 minutes, 1, 2nd, 4,8 and 24 hours.Analyze sample to determine the citric acid Shu Fen in dog plasma with appropriate attested LC/MS/MS methods Too Buddhist nun.Sufentanil PC and pharmacokinetics results are as shown in Fig. 3 and Biao 3.

Table 3.Sufentanil in beagle compared with intravenous sufentanil is sublingual PK analysis

¹Represent medicine and reach treatment level (more than C_maxRelative time 50%), and by following formula calculate：TTR=is (super Cross C_max50% cost time)/(IV eventually end eliminate half-life period).Denominator is obtained from document, for Shu Fentai in beagle It is 139 minutes for Buddhist nun.

Embodiment 3：The exemplary sufentanil formulation of Drug controlled release and interior medicine dynamics

For purposes of explanation, it is longer with the sufentanil citrate preparation durationFormulation (preparation # 58) dosage form release rate and interior medicine dynamics slower to evaluate long-acting dosage form.This disintegration as shown in table 4 is slower SufentanilPrepared with direct compression and tested as described above.Erosion time scope in dog for 35 to 120 minutes, the bioadhesive of placebo preparation was tested and is measured as 0.18 ± 0.08N/cm as described above²。

Carry out sample analysis to analyze the sufentanil in dog plasma with attested LC/MS/MS methods.Use what is absorbed Non- compartment model carries out pharmacokinetic analysis.Sufentanil PC is as shown in Figure 4.The result such as table of limited PK analyses Shown in 5.

The sufentanil that table 4. is slowly disintegratedDosage formulation

The sublingual sufentanil of slow disintegration in the beagle of table 5.PK analysis

¹Represent medicine and reach treatment level (more than C_maxRelative time 50%), and by following formula calculate：TTR=is (super Cross C_max50% cost time)/(IV eventually end eliminate half-life period).Denominator is obtained from document, for Shu Fentai in beagle It is 139 minutes for Buddhist nun.

Embodiment 4.Sublingual sufentanil solution and sufentanil in canine modelThe In vivo study swallowed

A.The bioavilability of sufentanil after evaluation sublingual administration solution dosage

Evaluated in health, clear-headed beagle animal model from after solution sublingual administration with intravenous administration after Shu Fentai The bioavilability of Buddhist nun, as shown in table 6.Research two-arm in all using sufentanil citrate commercially available preparation (50 μ g/mL) and be administered with the identical accumulated dose of 5 μ g sufentanil alkali.Intravenous administration (group 1) is by via suitable When the sterile needle and syringe of size are to cephalic vein bolus infusion single-dose (n=3)50 μ g/mL are carried out.For Sublingual administration (group 2), suitably dilutes by with 0.9%w/wThe 50 μ g sufentanil alkali of μ g/mL to 5 it is identical most Whole dosimetric system is for test sample, and sublingual administration is twice (n=6 altogether), and administration every time was separated by the cleaning phase of at least 2 days. Sublingual near small frenulum is slowly administered via asepsis injector.Blood sample exists via jugular vein or other suitable veins Collected within about 1,3,5,10,15,30 minutes, 1,2,4,8 and 24 hours before administration and after being administered.Will about at each time point 2mL blood collections enter in the precooling pipe containing K2EDTA.Sample is centrifuged about 10 points under 3,000xg in refrigerated centrifuge Clock.Blood plasma is collected in 20 minutes after centrifugation and is freezed at about -70 DEG C, identical temperature was maintained before analysis Degree.Carry out sample analysis to analyze the sufentanil in dog plasma with attested LC/MS/MS methods.

Pharmacokinetic analysis are carried out with the non-compartment model for absorbing.Sufentanil PC is as shown in Figure 5.PK is analyzed Result it is as shown in table 7.

B.Orally ingestible The Evaluation On The Bioavailability of sufentanil afterwards

Intake 5mcg sufentanils(preparation #47 phases used in preparation #44, with human research above After together), the sufentanil bioavilability compared with intravenous sufentanil is administered is in health, clear-headed beagle animal model In evaluated, as in the foregoing embodiment.Single 5mcgIt is administered orally twice, per dose with minimum 2 It cleaning phase separates, n=6 (table 6) altogether.WillIt is artificial to be rushed toward placement in throat and with water as far as possible Wash to promote to swallow reaction in animal.Pharmacokinetic analysis are carried out with the non-compartment model for absorbing.Sufentanil blood plasma is dense Degree is as shown in Figure 5.The result of PK analyses is as shown in table 7.

The tissue of the test group of table 6.

A=is expressed as free alkali

B=groups 1 to 3 can use identical animal, there is the cleaning phase of minimum 2 days between administration.

The animal of c=groups 2 and group 3 is administered twice, the cleaning phase of a minimum of 2 days, altogether n=6.

D=with physiology (0.9%w/w) salt solution dilute test sample (50 μ g/mL) to expectation concentration.

Table 7. in beagle with the sufentanil solution of sublingual instillation and the sufentanil of intakeCompare Intravenous administration sufentanil PK analysis

¹Represent medicine and reach treatment level (more than C_maxRelative time 50%), and by following formula calculate：TTR=is (super Cross C_max50% cost time)/(IV eventually end eliminate half-life period).Denominator is obtained from document, for Shu Fentai in beagle It is 139 minutes for Buddhist nun.

Embodiment 5Sublingual fentanyl in canine modelInterior evaluating

It is described in order to confirmAnd its performance is excellent compared to other business fentanyl oral transmucosal preparations More the purpose of property, fentanyl is prepared with citrate fentanylFormulation is to evaluate the insoluble drug release of various formulations Speed and interior medicine dynamics.The fentanyl of medium (preparation #60) and slow (preparation #62) disintegrationSuch as table 8 It is described, all with the formulation evaluation prepared by direct tablet compressing.Erosion times of the preparation #60 in dog is 5 to 20 minutes, placebo The bioadhesive of preparation is measured as 0.056 ± 0.01N/cm².Erosion times of the preparation #62 in dog is 35 to 65 minutes, The bioadhesive of placebo preparation is measured as 0.18 ± 0.08N/cm²。

The fentanyl of 70 μ g is administered using the commercially available preparation (the μ g/mL of Sublimaze 50) and IV of citrate fentanyl Alkali.Intravenous administration by via appropriately sized sterile needle and syringe to cephalic vein bolus infusion single-dose (n=3)50 μ g/mL are carried out.For sublingual administration, it is positioned near sublingual small frenulum by with tweezers, willSublingual administration (n=3 in every group).These parameters are as shown in table 9.Fentanyl PC is illustrated in Fig. 6.With non- Chamber absorbing model carries out PK analyses.The result of PK analyses is as shown in table 10.The bar of blood sampling and the storage description with reference to before Part；Sample analysis is carried out analyzing the fentanyl in dog plasma with attested LC/MS/MS methods.

The exemplary fentanyl of table 8.Formulation

Fentanyl in the beagle of table 9.Medication administration parameters

^aIt is expressed as free alkali.

Medium disintegration (preparation #60) and slow disintegration (preparation #62) of the table 10. compared with intravenous fentanyl is administered are fragrant too Buddhist nunPK analysis

¹Represent medicine and reach treatment level (more than C_maxRelative time 50%), and by following formula calculate：TTR=is (super Cross C_max50% cost time)/(IV eventually end eliminate half-life period).Denominator is obtained from document, for fentanyl in beagle For be 244 minutes.

Embodiment 6：Sublingual alfentanil hydrochloride in canine modelInterior evaluating

In order to explain that other medicines are used forPurpose, prepared with alfentanil hydrochloride another Formulation is to confirm the ability that formulation described in this application effectively improves the PK of alfentanil compared with IV methods of administration.In Deng disintegrationPreparation composition it is as described in Table 11.Erosion times of the preparation #63 in dog is 20 minutes, placebo system The bioadhesive of agent is measured as 0.056 ± 0.01N/cm²。

The dosimetry parameter of this research is as shown in table 12.Alfentanil PC is as shown in Figure 7.Mould is absorbed with non-chamber Type carries out PK analyses.The result of PK analyses is as shown in table 13.The condition that blood plasma is sampled and storage was described with reference to before；Sample analysis Carried out analyzing the alfentanil in dog plasma with attested LC/MS/MS methods.

The exemplary alfentanil of table 11.Formulation

Sublingual alfentanil in the beagle of table 12.With the medication administration parameters of intravenous solution

A=is expressed as free alkali.

B=groups 1 and group 2 use identical animal, there is the cleaning phase of minimum 2 days between administration.It is sublingual in the beagle of table 13. AlfentanilPK relative to intravenous alfentanil is analyzed

¹Represent medicine and reach treatment level (more than C_maxRelative time 50%), and by following formula calculate：TTR=is (super Cross C_max50% cost time)/(IV eventually end eliminate half-life period).Denominator is obtained from document, is 104 minutes in beagle.

Claims (9)

1. the small size formulation to individual oral transmucosal administration is used for, and it includes sufentanil and bioadhesive material, wherein The formulation has the quality less than 30mg and the volume less than 30ml.

2. formulation as claimed in claim 1, wherein the sufentanil is for about 2.5 micrograms (mcg) to 100 micrograms (mcg).

3. formulation as claimed in claim 2, wherein providing the sufentanil in the form of sufentanil citrate.

4. formulation as claimed in claim 1, wherein giving the formulation to the individual single oral transmucosal causes T_max's Coefficient of variation is less than 40%.

5. formulation as claimed in claim 1, wherein to the individual single oral transmucosal give the formulation cause it is described The medication amount of at least the 55% of medicine total amount absorbs via oral transmucosal route in formulation.

6. formulation as claimed in claim 1, wherein give the formulation to the individual single oral transmucosal to cause to corrode Time is from 30 seconds to 30 minutes.

7. formulation as claimed in claim 1, wherein after the formulation is given to the individuality, the agent that the formulation is provided Amount-normalized C_maxIt is the every mcg of 2.72+/- 0.84pg/mL.

8. formulation as claimed in claim 1, wherein to the individual single oral transmucosal give the formulation cause it is described The medication amount of at least the 55% of medicine total amount absorbs via oral transmucosal route in formulation, T_maxCoefficient of variation be less than 40%, And dosage-normalized C_maxIt is the every mcg of 2.72+/- 0.84pg/mL.

9. the formulation in claim 1-8 described in any claim is in preparing for treating the individual medicine with pain Purposes.