CN101378732A

CN101378732A - Bioadhesive drug formulations for oral transmucosal delivery

Info

Publication number: CN101378732A
Application number: CNA2007800046111A
Authority: CN
Inventors: 斯泰里奥斯·查尼斯; 帕米拉·帕尔梅; 托马斯·斯科瑞克; 拉利·海梅尔; 安德鲁·I·普替亚延
Original assignee: AcelRx Pharmaceuticals Inc
Current assignee: Talphera Inc
Priority date: 2006-01-06
Filing date: 2007-01-08
Publication date: 2009-03-04
Also published as: CN101394863B; CN101495080B; CN106727271B; CN101495080A; CN106727271A; CN101394863A

Abstract

The present invention provides a preparation which is used for controllable medicine used for oral cavity and is delivered through tunica mucosa. The preparing is characterized in that the preparation forms a hydrogel or is a corrosion-type product. The preparation is bioadhesive and provides medically controllable and continuous releasing thereby providing increased bioavailability and efficacy.

Description

The bioadhesive drug formulations that is used for oral transmucosal delivery

Cross reference to other application

The application requires in the U.S. Provisional Application the 60/860th of submission on November 22nd, 2006, No. 569 priority, described U.S. Provisional Application the 60/860th, require for No. 569 in the U.S. Provisional Application the 60/818th of submission on July 6th, 2006, No. 730 priority, described U.S. Provisional Application require for the 60/818th, No. 730 in the U.S. Provisional Application the 60/756th of submission on January 6th, 2006, No. 937 priority, it openly incorporates this paper into by reference with its integral body.

Invention field

The present invention relates to be used for the method for the pharmaceutical dosage form delivering drugs oral transmucosal that preparation that the oral transmucosal medicine sends and use comprise such preparation.Exemplary hydrogel and aggressivity preparation is provided.

Technical background

Peroral dosage form accounts for 80 percent of all pharmaceutical dosage forms on the market.Peroral dosage form is a non-intrusion type, and easy administration also has higher patient's compliance.

The therapeutic agent of oral administration is transported to the harmonization of the stomach small intestinal rapidly, enters blood through gastrointestinal (GI) mucosa absorption.Because metabolism in the GI road and the first pass metabolism in the liver, the efficient of drug absorption can be very low behind the oral administration, and this causes long onset time or irregular absorption feature, and this is unsuitable for controlling acute disease.Most peroral dosage form is designed to GI and sends on the market.Less peroral dosage form is designed to oral transmucosal and sends.

Yet oral transmucosal delivery provides multiple advantage, and it can provide than shorter onset time of oral delivery and reach maximal plasma concentration (C _Max) the time (T of more stable and consistent _Max), especially for lipophilic drugs.This be since medicine directly effectively rapidly the infiltrative epithelium that has relatively of the mucosal tissue by the height vascularization enter blood plasma, thereby arrive blood circulation rapidly, and avoided slower, poor efficiency and variable GI picked-up usually.In addition, owing to avoided first pass metabolism and avoided medicine to absorb by gastral poor efficiency, the Sublingual ingestion of medicines has also improved drug bioavailability.Therefore the T that works as quick acting, unanimity _MaxAnd C _MaxWhen more favourable, this for want the through port transmucosal (as, by the Sublingual approach) medicine sent is favourable.

Carrying out the oral transmucosal medicine when sending, medicine is by the absorption across epithelial membranes in oral cavity.Yet the key risk relevant with oral transmucosal delivery is normally owing to continuing generation, reverse flow and swallowing the probability increase of swallowing medicine that saliva causes.When used dosage form bigger, thereby the saliva that produce to increase response, it causes again increasing swallows and when oral mucosa was removed dosage form, this became special risk.Advantage provided by the invention is: described preparation has bioadhesion character, and this helps to adhere to oral mucosa in the administration process, thereby makes risk and the inefficient minimizing possibility of swallowing of sending.

Various solid dosage formss, for example sublingual tablet, lozenge, lozenge, lollipop, chewing gum and mouth paster have been used to the delivering drugs via oral mucosas tissue.Be generally used for the oral transmucosal delivery of medicine such as the solid dosage forms of lozenge and tablet, as the nitroglycerine sublingual tablet.

Be used for the related preparations of the oral or oral administration of analgesic and delivery system and for example before be disclosed in United States Patent (USP) the 2nd, 698, No. 822; The 3rd, 972, No. 995; The 3rd, 870, No. 790; The 3rd, 444, No. 858; The 3rd, 632, No. 743; The 4th, 020, No. 558; The 4th, 229, No. 447; The 4th, 671, No. 953; The 4th, 836, No. 737; With the 5th, 785, in No. 989.

The cheek of medicine and the relevant non-patent publications of sublingual administration are discussed to be comprised: Culling et al., and Br.J.Clin.Pharm.17,125-131,1984, it discloses the sublingual administration of glyceryl trinitrate; Osborne et al., Clin.Pharmac.Ther.47,12-19,1990, be cheek administration about morphine; Rosen et al., Am.J.Drug Alcohol Abuse, 19,451-464,1993, be sublingual administration about buprenorphine.

U.S. Patent Publication discloses for No. 20020160043 and has been used for the mucosal tissue of medicine by patient's oral cavity, pharynx and esophagus carried out the solubility of non-intrusion type administration and the compositions and the preparation method of insoluble pastille agent type

United States Patent (USP) the 4th, 671, No. 953 and the 5th, 785, No. 989 (people such as Stanley) discloses and has been used for the lollipop dosage form that transmucosal drug is sent.In case send after the medicine of appropriate amount, patient or caretaker can remove lozenge, thus stop medicine sending to prevent administration excessive.

United States Patent (USP) the 5th, 296, No. 234 (people such as Hadaway) disclose the citrate fentanyl that is used to contain doses and flange hardened, based on the bar-shaped holder of the substrate of sucrose with comprise the packing of tamper paper tinsel bag, described citrate fentanyl is fixed in an end of described holder, and when placing patient's mouth to patient's medication or premedicate, described flange prevents the holder of swallowing.

United States Patent (USP) the 6th, 974, No. 590, the 6th, 764, No. 696, the 6th, 641, No. 838, the 6th, 585, No. 997, the 6th, 509, No. 036, the 6th, 391, No. 335, the 6th, 350, No. 470, the 6th, 200, No. 604 and U.S. Patent Publication have been described for No. 20050176790, No. 20050142197 and No. 20050142198 such as the reactive compound of fentanyl ex hoc genus anne thing and the drug regimen of foaming agent associating, and described foaming agent is used as penetration enhancers to influence the permeability of reactive compound through cheek, Sublingual and gums mucosa.

United States Patent (USP) the 6th, 761, No. 910 and U.S. Patent Publication disclose for No. 20040213855 and have been used for by the substantially anhydrous ordered mixture of microgranule and at least a pharmaceutically active medicament sublingual administration that adheres to carrier particle surface by bioadhesion and/or mucosal adhesive promoter being treated the pharmaceutical composition of acute disease.

United States Patent (USP) the 6th, 759, disclose for No. 059 and be used for containing compositions and the method that 0.05mg to 20mg fentanyl or its medicine can receive the combination treatment acute pain of salt by the Sublingual, described fentanyl or its medicine can receive the form of salt for adhere to the microgranule of carrier particle surface by bioadhesion and/or mucosal adhesive promoter, and wherein the size of each tablet is about 100mg.

United States Patent (USP) the 5th, 800, No. 832 and the 6th, 159, No. 498 (people such as Tapolsky) and U.S. Patent Publication disclose water miscible, biodegradable drug delivery device for No. 20030194420 and No. 20050013845, as adhering to the bilayer film dish with adhesion layer and backing layer of mucomembranous surface, described adhesion layer and backing layer are water miscible.

United States Patent (USP) the 6th, 682, No. 716; The 6th, 855, No. 310; The 7th, 070, No. 762 and the 7th, 070, No. 764 people such as () Rabinowitz disclose via inhalation route and have sent analgesic, and employed method comprises: a) with the thin layer heating of analgesic drug product on solid support to form steam; And b) make air flow through the steam of described heating to produce aerosol particles.

United States Patent (USP) the 6th, 252, No. 981 (people such as Zhang) discloses oral mucosa medicament and sent method as the optional method and the oral transmucosal delivery medicine of system's drug delivery formulation.The invention provides the pharmaceutical preparation that comprises solid chemicals, described solid chemicals is present in the solid solution of the lytic agent with solid form that produces solid solution.Described solid solution preparation as required can be further united with the manufacturing that helps medicine, storage, administration with by oral mucosas tissue with buffer agent and other excipient and is sent.Described preparation can use with multiple oral transmucosal delivery dosage form, for example tablet, lozenge, lollipop, chewing gum and cheek or mucosa paster.Also can be referring to Zhang et al, Clin Pharmacokinet.2002,41 (9): 661-80.

Although described various oral mucosa medicament delivery systems, thus the improved preparation that still needs to be used for oral transmucosal dosage forms with the controlled medicine that allows described dosage form send, the ability of control and regulating medicine dissolution kinetics can realize multiple pharmacokinetics spectrum.The present invention is in order to address this problem.

Summary of the invention

The invention provides compositions and method, it comprises the soluble agents dosage form that comprises preparation of the present invention as hereinafter being described in detail.

Soluble agents dosage form of the present invention has the bioadhesion feature and can adhere to oral mucosa, as Sublingual or cheek film.Preparation of the present invention can be that hydrogel forms or the aggressivity type.

Preparation of the present invention can be used for the administration of any medicine, and especially can be used for can be by the medicine that absorbs through the film approach.

On the one hand, use the soluble agents dosage form of formulation preparation of the present invention to comprise about 0.25 μ g to 99.9mg medicine, about 1 μ g to 50mg medicine or about 1 μ g to 10mg medicine.

On the other hand, the invention provides such preparation, its Chinese medicine is the class Opium that is selected from sufentanil, alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil or mirfentanil.

More specifically, the invention provides such preparation, its amount that comprises class Opium medicine is selected from about 0.25 microgram (μ g) to 200 μ g, the sufentanil of about 2.5 μ g to 100 μ g, the sufentanil of about 0.02 μ g to 5 microgram every kilogram (μ g/kg) (sufentanil of 10 micrograms according to appointment), the alfentanil of about 10 μ g to 10mg, the fentanyl of about 2 μ g to 1500 μ g, the fentanyl of about 50 μ g to 1500 μ g, the fentanyl of 200 μ g to 1500 μ g, the lofentanil of about 0.25 μ g to 99.9mg, the carfentanil of about 0.25 μ g to 99.9mg, the carfentanil of about 0.25 μ g to 99.9mg, the remifentanil of about 0.25 μ g to 99.9mg, the trefentanil of about 0.25 μ g to 99.9mg, the mirfentanil of about 0.25 μ g to 99.9mg.

The feature that comprises the soluble agents dosage form of preparation of the present invention can be high 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 from 30 seconds.

To individual single or repeat after the soluble agents dosage form that oral transmucosal comprises preparation of the present invention bioavailability of medicament for surpassing 70%, surpass 75%, surpass 85%, surpass 90% or surpass 94%, and have and be lower than 30% or be lower than 40% variation coefficient.

The another feature that comprises the soluble agents dosage form of preparation of the present invention is that variation coefficient is lower than 30% or 40% C _MaxTo about 4 hours T _MaxAnd to surpassing 0.05 or about 0.05 to about 2.0 treatment time ratio after the administration of individual single oral transmucosal.

The amount that comprises the soluble agents dosage form Chinese medicine of the preparation of the present invention that absorbs by the oral transmucosal approach is total medication amount of at least 35%, 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% in the described dosage form.

The present invention also provides the soluble agents that comprises preparation of the present invention dosage form, and its disintegration time is about 30 seconds to about 30 minutes.

The oral transmucosal administration of such pharmaceutical dosage form causes from about 3 minutes to about 23 minutes, 30 minutes, 45 minutes or 60 minutes onset time (T _Onset).The oral transmucosal administration that wherein said preparation comprises such pharmaceutical dosage form of sufentanil causes from about 3 minutes to about 15 minutes, 20 minutes, 25 minutes or 30 minutes onset time (T _Onset).The oral transmucosal administration that wherein said preparation comprises such pharmaceutical dosage form of alfentanil causes from about 10 minutes to about 15 minutes, 20 minutes, 25 minutes or 30 minutes onset time (T _Onset).

The oral transmucosal administration of such pharmaceutical dosage form causes from about 20 minutes to about 180 minutes or 240 minutes plasma half-life.The oral transmucosal administration that wherein said preparation comprises such pharmaceutical dosage form of sufentanil causes from about 25 minutes to about 70 minutes or from about 20 minutes to about 80 minutes, 90 minutes or 120 minutes plasma half-life.

The oral transmucosal administration that wherein said preparation comprises such pharmaceutical dosage form of alfentanil causes from about 30 minutes to about 50 minutes or from about 25 minutes to about 100 minutes, 120 minutes or 180 minutes plasma half-life.

The oral transmucosal administration of such pharmaceutical dosage form causes from about 0.08 to about 0.48 or from about 0.05 to about 2.0 treatment time ratio.The oral transmucosal administration that wherein said preparation comprises such pharmaceutical dosage form of sufentanil causes from about 0.08 to about 0.45 or from about 0.05 to about 0.5,0.8 or 1.0 treatment time ratio.The oral transmucosal administration that wherein said preparation comprises such pharmaceutical dosage form of alfentanil causes from about 0.25 to about 0.4 or from about 0.1 to about 0.5,0.8 or 1.0 treatment time ratio.

The present invention also provides the soluble agents that comprises preparation of the present invention dosage form, and its disintegration time is from about 15 minutes to about 8 hours or longer.

The oral transmucosal administration of such pharmaceutical dosage form causes from about 14 minutes to about 82 minutes or from about 10 minutes to about 100 minutes or 120 minutes onset time (T _Onset).The oral transmucosal administration that wherein said preparation comprises such pharmaceutical dosage form of sufentanil causes from about 14 minutes to about 82 minutes or from about 10 minutes to about 100 minutes or 120 minutes onset time (T _Onset).

The oral transmucosal administration of such pharmaceutical dosage form causes from about 100 minutes to about 300 minutes, 360 minutes or 420 minutes plasma half-life.The oral transmucosal administration that wherein said preparation comprises such pharmaceutical dosage form of sufentanil causes from about 112 minutes and about 298 minutes or from about 100 minutes to about 300 minutes, 360 minutes or 420 minutes plasma half-life.

The oral transmucosal administration of such pharmaceutical dosage form causes from about 0.42 to about 1.82 or from about 0.4 to about 2.0,2.5 or 4.0 treatment time ratio.The oral transmucosal administration that wherein said preparation comprises such pharmaceutical dosage form of sufentanil causes from about 0.42 to about 1.82 or from about 0.4 to about 2.0,2.5 or 4.0 treatment time ratio.

The present invention also provides treatment to show the method for the individuality of symptomatic medical condition, and described method is by giving the soluble agents dosage form that comprises preparation of the present invention as herein described, making medicine can treat described symptomatic medical condition effectively.

Brief description of the drawings

Fig. 1 is that the diagram of design of the hydrogel bioadhesion tablet of thin film bag quilt is described.

Fig. 2 contains The dynamic (dynamical) diagram of the dissolution in vitro of preparation #46-#48 describe.

Fig. 3 will contain in healthy, clear-headed beagle model

The diagram description of pharmacokinetics of preparation #44 sublingual administration (n=3) the back sufentanil of comparing with intravenous administration (n=3).Error bars is represented the standard error (SEM) with respect to meansigma methods.

Fig. 4 is (n=6) back and will containing of in healthy, clear-headed beagle model sufentanil solution Sublingual being instiled

The diagram description of preparation #44 orally ingestible (n=6) back and the pharmacokinetics of the sufentanil that sufentanil intravenous administration (n=3) is compared.Error bars is represented the standard error with respect to meansigma methods.

Fig. 5 is with quick disintegrate in healthy, clear-headed beagle model

Preparation #55 (n=3) and medium disintegrate

The diagram of the pharmacokinetics of the sufentanil of comparing with intravenous administration (n=3) behind preparation #54 (n=3) sublingual administration is described.Error bars is represented the standard error with respect to meansigma methods.

Fig. 6 is with slow disintegrate in healthy, clear-headed beagle model

Preparation #58 sublingual administration (n=3) back is described with the diagram of the pharmacokinetics of the sufentanil that sufentanil intravenous administration (n=3) is compared.Error bars is represented the standard error with respect to meansigma methods.

Fig. 7 is with medium disintegrate in healthy, clear-headed beagle model

Describe with the diagram of the pharmacokinetics of the fentanyl that fentanyl intravenous administration (n=3) is compared behind preparation #59 (n=2) and preparation #60 (n=3) sublingual administration.Error bars is represented the standard error with respect to meansigma methods.

Fig. 8 is with slow disintegrate in healthy, clear-headed beagle model

(n=3) describes with the diagram of the pharmacokinetics of the fentanyl that intravenous fentanyl administration (n=3) is compared behind the preparation #62 sublingual administration.Error bars is represented the standard error with respect to meansigma methods.

Fig. 9 is will in healthy, clear-headed beagle model (n=2) and the standard error of intravenous alfentanil administration (n=3) error bars being represented with respect to meansigma methods behind the preparation #63 sublingual administration.

Figure 10 is will in healthy human volunteer

The diagram of the pharmacokinetics of the sufentanil of comparing with intravenous administration (n=12) in the single sublingual administration of preparation #46-48 (n=12) back is described.

Describe in detail

The present invention is based on the preparation for the oral transmucosal drug delivery, and described preparation can adhere to oral mucosa in delivery process, so that most of medicine oral transmucosal is sent.

The invention provides novel preparation, comprise the formulation that can be used for preparing self administration, result for the treatment of and pharmaceutical preparation predictable and the safe drugs kinetic spectrum are provided.

Example comprise contain be used for the treatment of acute, intermittently or the preparation of the medicine of explosive pain.

In an exemplary application, the present invention can be used on hospital and be used for to replace intravenous (IV) class opium with management of acute pain in arranging, and also can be used on the outpatient and is used for the treatment of acute and explosive pain in arranging.

Following openly the description consists of preparation of the present invention. The invention is not restricted to concrete preparation as herein described and methodology or medical condition, this is because described preparation and methodology or medical condition can change certainly. It is also understood that terminology used herein only in order to describe the purpose of particular embodiments, rather than will limit the scope of the invention.

Have to be noted that singulative " a ", " and " and " the " comprise plural implication, unless context has clear and definite phase antirepresentation in this paper and appended claim. Therefore, for example, mentioning " a drug formulation (pharmaceutical preparation) " comprises a plurality of such preparations and mentions " a drug delivery device (drug delivery device) " and comprise and comprise pharmaceutical preparation and be used for the system that holds, store and send the device of such preparation.

Unless otherwise defined, all technology used herein have the identical implication of usually understanding with those skilled in the art with scientific terminology. Although in enforcement of the present invention or test, can use anyly to be similar to or to be equal to method as herein described, device and material, now will describe preferred method, device and material.

Provide publication discussed in this article only to be because its open submission day early than the application. Any content of this paper should not be interpreted as all admitting that the present invention does not have qualification prior to such disclosing owing to formerly invent.

Definition

Terms " formulation " used herein or " pharmaceutical preparation " or " formulation " refer to contain at least a for delivery to the therapeutic agent of individuality or the composition of medicine. Described formulation comprises given " preparation " or " pharmaceutical preparation " also can be with lozenge, pill, tablet, capsule, film, bar, liquid, paster, film, gel, spray or other form to patient's administration.

The in this article commutative uses such as term " medicine (drug) ", " medicine (medication) ", " pharmacologically active medicament ", and be often referred to the zoodynamic any material of change. The formulation that comprises preparation of the present invention can be used for sending can be by any medicine of oral transmucosal administration. Used term " medicine (drug) " means any " medicine (drug) ", " activating agent ", " activity ", " medicine (medication) " or " therapeutic activity agent " that can pass through the effective administration of oral transmucosal approach when mentioning preparation of the present invention.

The term " medicine " that is applied to the pain relieving art comprises sufentanil or sufentanil congener, for example alfentanil, fentanyl, lofentanil, Carfentanil, Remifentanil, Trefentanil or Mirfentanil, and the preparation that comprises one or more treatment compounds. Use " medicine " or phrase " sufentanil or congener " not to mean the preparation that only limits to use these selected class opium compounds or only comprise these selected class opium compounds. In addition, when mentioning separately sufentanil or mentioning separately selected sufentanil congener, as when mentioning " fentanyl ", it only should be understood to as being suitable for the example of the medicine that the method according to this invention sends, and does not mean any restriction.

Term " medicine (drug) " in this article can with term " therapeutic agent " or " medicine (medication) " Alternate. Be to be understood that, " medicine " of the present invention preparation can comprise above a kind of therapeutic agent, wherein exemplary therapeutic combination comprises the associating of two or more class opium analogs, and for example sufentanil adds such as the class opium of fentanyl, alfentanil, lofentanil, Carfentanil, Remifentanil, Trefentanil or Mirfentanil or any other medicines that can administering drug combinations.

Term used herein " congener " refers to a kind of in the multiple variation of common chemical constitution or the configuration.

Term " individuality " comprises any individuality, is generally mammal (such as people, canid, cats, equine species, bovid, hoof mammal etc. is arranged), and expectation treatment illness wherein is as processing pain or anesthesia.

Term " mucous membrane " usually refers to the coated biomembrane of any mucus in the health. Special concern is via the absorption of oral mucosa. Therefore, the present invention considers that especially cheek, hypogloeeis, gums and maxilla absorb. In preferred embodiments, use penetration enhancers of the present invention with promote via these at the oral cavity tissue that is similar to most skin aspect its eucaryotic cell structure, be the absorption of gums and maxilla.

" through the mucous membrane " of term medicine send etc. mean comprise through or all delivery form by mucous membrane. Especially, " oral transmucosal " of medicine sent and comprised through mouth, pharynx, larynx, tracheae or upper gastrointestinal any tissue, especially comprises sending of hypogloeeis, gums and maxilla mucosal tissue.

Term " peroral dosage form ", " oral transmucosal dosage forms " and " dissolvable dosage forms " are used interchangeably in this article and refer to that it comprises pharmaceutical preparation as herein described be used to implementing formulation of the present invention. Described peroral dosage form is " sublingual dosage forms " normally, but can use in some cases other oral transmucosal approach. The present invention depends on such peroral dosage form so that the controllable delivery of medicine through oral mucosa to be provided; By the design of control preparation, can realize the at once, moderate of medicine and the release that continues, as mentioned below. Described formulation is basic uniformly composition, it comprises active component and one or more provide the adhering mucomembranous adhesion agent to patient's oral mucosa (being also referred to as " bioadhesive polymer " herein), be used for the adhesive bonding with the excipient of single tablet, one or more hydrogels form excipient, one or more fillers, one or more lubricants, and other affects excipient and the factor of dissolution time or medicine stability. Soluble agents preparation of the present invention is bubble-tight, and they do not comprise the substantially anhydrous ordered mixture of the drug microparticles that adheres to carrier particle surface yet, and wherein said carrier granular is significantly greater than drug microparticles. On the one hand, the invention provides small-volume oral transmucosal drug delivery formulation.

Term used herein " oral transmucosal drug delivery " refers to such formulation, and wherein drug delivery is substantially via occuring through mucosal route, and do not absorb by GI via swallowing then. Preparation of the present invention is designed to provide and allows the medicine dissolution rate sent via the oral mucosa maximum, and the controllable delivery speed through oral mucosa is provided via described formulation is placed the chamber, hypogloeeis usually.

" hypogloeeis " used herein literally means " tongue following ", and refers to the method for material via the mouth administration, and the mode of administration rather than is absorbed via alimentary canal so that this material absorbs via ranine blood vessel rapidly. Various in the mucous membrane site, the mucous membrane of finding the chamber, hypogloeeis is to send for local delivery and as the most convenient of the therapeutic agent of controlled release form systemic delivery with hold accessible site most, and this is because its vascularization of enriching and substantially do not have youth's lattice Chinese cell. Directly enter the first-pass metabolism that the body circulation has got around liver via interior jugular vein, cause high bioavilability. In addition, because the height vascularization character of hypoglossis mucous membrane and the epithelial cell number of layers of comparing low with other mucous membrane, the absorption of therapeutant can occur rapidly, thereby thereby allow directly to enter body circulation and quick acting that can the realization effect, avoided simultaneously the complication of oral administration.

Term used herein " hydrogel formation preparation " means water-free substantially solid preparation, when it contacts with body fluid, especially when body fluid in the oral mucosa contacts, can absorb water by this way, make it be expanded at least 110% of initial mass or volume, keep structural matrix and original position to form hydrated gel simultaneously.Unique disintegrate (or erosion) kinetics is followed in the formation of gel, allows the control medicine to discharge in time simultaneously, and this mainly is to take place by diffusion.

Term used herein " disintegrate " means the physical process of tablet decomposition and only relates to the physical integrity of tablet.This can take place with different ways, comprises that being broken into littler piece and finished breaking becomes thin and big microgranule, perhaps inwardly corrodes from the outside to disappear until tablet.

Term as herein described " dissolving " means in the presence of external solvent or in vivo such as active component dissolved process from tablet in the presence of the physiological fluid of saliva, and does not consider to discharge, spread, corrode or corrode and spread the mechanism of associating.

Term used herein " expansion ratio " or SR mean dosage form fully be exposed to behind the water quality with expose before the mass ratio compared of the quality of its dried state.Expansion ratio (SR) can be defined as based on the special time that is exposed to water and be represented as ratio or percent, as is expressed as SR=(being exposed to the quality-initial dry mass behind the water)/(initial dry mass) * 100 of percent.

Perhaps, such " expansion ratio " can be defined as volume after the dosage form contact water of the present invention and contact the water volume ratio compared of the volume of same dosage form before.Expansion ratio (SR) can be defined as based on the special time that is exposed to water and be represented as ratio or percent, as is expressed as SR=(exposing the volume of the preceding tablet of volume-exposure of back tablet)/(volume of tablet before exposing) * 100 of percent.When controlling the radius size of such experiment well, same expansion ratio can be according to such as variable-sized definition such as thickness, as is expressed as SR=(exposing the thickness of tablet before thickness-exposures of back tablet)/(exposing the thickness of preceding tablet) * 100 of percent.

Term used herein " bioadhesion " refers to the adhesion process of described dosage form to biological surface, and described biological surface more generally comprises mucosa.

Wording used herein " mucosal adhesive " refers to the adhesion to the mucosa that is covered by mucus such as mucosa in the oral cavity etc., and uses with the adherent term of any biological surface " bioadhesion " is exchanged in this article.

Term " treatment effective dose " means effective promotion desired therapeutic effect, as the amount of lenitive therapeutic agent, or the speed of delivering therapeutic agents (as amount in time).Accurate expectation therapeutic effect (as source of lenitive degree and the pain alleviated or the like) can change according to the multiple other factors that morbid state to be treated, individual toleration, the medicine for the treatment of administration and/or pharmaceutical preparation (as the effectiveness of therapeutic agent (medicine), medicine concentration in preparation or the like) and those of ordinary skills understand.

" controlled medicine is sent " refers to that medicine discharges from given dosage form with controllable mode or administration is composed with the pharmacokinetics that realizes expectation in vivo.The one side that " controlled " medicine is sent is to handle preparation and/or the dosage form ability with the drug release kinetics of setting up expectation.

" continue medicine send " refer to medicine delay but mode release or the administration from source (as pharmaceutical preparation) to continue in clear and definite time period, the described time period can extend to a few hours, a couple of days, several weeks or several months from several minutes.Especially in this application, can use term " to continue " to refer to send the medicine of constant level in several minutes to the time period of a couple of days, the feature of sending spectrum is not have the release phase at once that obtains such as from intravenous administration the time.

Term " T used herein _Max" mean the time point of observing maximal plasma concentration.

Term " C used herein _Max" mean observed maximal plasma concentration.

Term used herein " AUC " means in the figure of plasma concentration to the time of medicine " area of curve below ".Usually to unlimited interval, provide AUC for zero, yet clearly plasma drug level can not measured " to unlimited " for the patient, therefore uses mathematical approach to estimate AUC from a limited number of measurement of concetration.On practice significance, the medicine total amount that AUC (extremely unlimited by zero) expression is absorbed by health, and do not consider absorption rate.This is attempting to determine whether the preparation of two kinds of same doses is useful when health discharges the medicine of same dose.The AUC of transmucosal dosage forms compares with the AUC of the same dose of intravenous administration, as the basis of measuring bioavailability.

Term used herein " F " means " percentage ratio bioavailability " and representative is compared with the same medicine of intravenous administration from the medicine mark that measured matter absorbs.It is the AUC by measured matter after sending through expecting way _∞AUC with respect to same medicine behind the intravenous administration _∞Calculate and get.It is to be got by following Equation for Calculating: F (%)=AUC _∞(measured matter)/AUC _∞(intravenous route/material).This is an important term, and it has set up the medicine that absorbs via tested approach (or material) the relative mark with respect to the maximum that may absorb via intravenous route.

Term used herein " blood plasma t _1/2" mean observed " plasma half-life " and represent that drug plasma concentration reaches its maximum (C _Max) 50% required time.This is a very useful term, and it allows to determine the average duration of pharmacotoxicological effect.In addition, it allows directly and persistent period after more different measured matters are sent via identical or different approach targetedly.

Term " T used herein _Onset" mean observed " onset time " and represent that plasma drug level reaches observed maximal plasma concentration C _Max50% required time.

Term " treatment time ratio " or " TTR " expression medicine were defined as drug plasma concentration and keep carrying out gauged C above removing the half-life with medicine with the average time that treatment level exists _MaxTime of 50%, and it calculates by following formula and get TTR=(above C _MaxTime of 50%)/(the final intravenous of medicine is removed the half-life).Back one term derives from the data in literature of medicine in suitable species of being paid close attention to.

In this article, when pharmaceutical preparation is called as " adhesion " in the surface such as mucosa, it means described preparation and contacts with described surface and need not apply external force and be retained on the described surface.Adhere to the adhesion or the combination that do not mean any specific degrees of hint, also do not mean the persistency of any degree of hint.

In this article, term " activating agent " or " activity " can be exchanged with term " medicine " and be used, and are used in reference to any therapeutic activity agent in this article.

This paper uses term " nonocclusive " with its wide significance, refers to by the paster apparatus on the skin that is retained in application site for a long time, fixedly the mode of bank, application chamber, band, binder, viscosity Gypsum Fibrosum or the like will be blocked or be close to skin it is not contacted with air.

II. the oral transmucosal medicine is sent dosage form

The invention provides the oral transmucosal medicine and send dosage form, it produces the saliva response of comparing reduction with other peroral dosage form, thereby provides the height of pharmaceutically active substance oral transmucosal to absorb and controlled absorbed speed, send and provide the mode of more repeatably sending to the gastrointestinal tract minimizing.

Described peroral dosage form is generally " sublingual dosage forms ", but can use the oral transmucosal approach in some cases.The present invention relies on such peroral dosage form to continue the delivering drugs oral transmucosal.Described dosage form is basic compositions uniformly; it comprises active component and one or more provide the oral mucosal adhering mucomembranous adhesion agent to the patient (being also referred to as " bioadhesive polymer " herein); one or more provide in single tablet and the adherent binding agent of excipient; the excipient that one or more hydrogels form; one or more filleies; one or more lubricants, and regulate and other excipient and factor that the dissolution time of control medicine and kinetics or protection active component are not degraded.

Dosage form of the present invention be applicable to that the oral transmucosal (for example Sublingual) of medicine is sent and the erosion time that has usually for high to being selected from the following time from 30 seconds: 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours or 8 hours or longer.

Usually, comprising in the dosage form of preparation of the present invention at least 35%, 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% medicine absorbs via oral mucosa.

III. Preparation of the present invention

Preparation of the present invention is basic compositions uniformly, it comprises 0.01% to 99% w/w (w/w), 0.05% to 99%w/w, 0.01% to 50%w/w and 0.1% to 10%w/w active component (medicine, medicament or the like) and one or more provide the oral mucosal adhering mucomembranous adhesion agent to the patient (being also referred to as " bioadhesive polymer " herein), and can also comprise or not comprise one or more following ingredients: one or more provide in single tablet and the adherent binding agent of excipient; The excipient that one or more hydrogels form; One or more filleies; One or more lubricants; One or more fluidizer; One or more solubilizing agents; One or more surfactants; One or more flavoring agents; One or more disintegrating agents; One or more cushion excipient; One or more coatings; One or more controlled release regulators; And one or more adjustings and the control dissolving of medicine or disintegration time and kinetics or protection active medicine other excipient and the factor of not degrading.

The pharmaceutical dosage form that the present invention is used for oral transmucosal delivery can be a solid or non-solid.In a preferred embodiment, described dosage form be with the solid that changes into hydrogel after saliva contacts.

Excipient comprises the material that joins in the preparation of the present invention, require this material to produce qualified products, described excipient includes but not limited to: the additive or the factor of filler, binding agent, surfactant, bioadhesive polymer, lubricant, disintegrating agent, stabilizing agent, solubilizing agent, fluidizer and influence dissolving or disintegration time.

Excipient is not limited to above-mentioned substance.Other suitable nontoxic drug acceptable carrier that is used for oral formulations can be found in Remington ' s Pharmaceutical Sciences (Lei Mingdun pharmacopedics), 17th Edition, 1985.

Be used for preparation of the present invention that the oral transmucosal medicine sends and comprise that the mixture of at least a bioadhesive polymer (mucomembranous adhesion agent) or bioadhesive polymer is so that promote adhesion to oral mucosa in delivery process.In addition, when described dosage form during by the saliva moistening, bioadhesive polymer can also be controlled the erosion time and/or the medicine dissolution kinetics in time of described dosage form effectively.In addition, some mucomembranous adhesion agent that the present invention enumerates also can be used as the binding agent in the preparation, so that the combination to necessity of described dosage form to be provided.Such mucosal adhesive drug delivery system is very useful, this be since they can prolong drug in the time of staying that absorbs the site and increase bioavailability of medicament.It is hydrophilic and expandable that the hydrogel of mucosal adhesive forms polymer, contains a plurality of hydrogen bonds and forms group, and as hydroxyl, sulfydryl, carboxyl or amino, it helps to adhere to.When contacting with mucomembranous surface, they can interact with part on the bioelectric interface, interact and cause polymer/mucus interact (adhesion) via hydrogen bond, electrostatic interaction, hydrophobic interaction or Van der Waals.In addition, when using with dried forms, they can absorb water and expansion from mucomembranous surface.

That exemplary mucosal adhesive material or bioadhesive material are selected from is natural, synthetic or biopolymer, lipid, phospholipid or the like.Example natural and/or synthetic polymer comprises cellulose derivative (methylcellulose for example, carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose etc.), natural gum (guar gum for example, xanthan gum, locust bean gum, karaya, veegum etc.), polyacrylic acid (Carbopol for example, Polycarbophil etc.), alginate, contain the sulfydryl polymer, polyoxyethylene, all molecular weight polyethylene glycol (PEG) (preferred 1000Da to 40,000Da, can be any chemical constitution of straight or branched), the glucosan of all molecular weight (preferred 1000Da to 40,000Da, can be any source), block copolymer, those block copolymer for preparing by the combination of lactic acid and glycolic (various viscosity for example, molecular weight and lactic acid are to the PLA of glycolic ratio, PGA, PLGA), has the arbitrary number of repetitive and the polyethylene glycol-propylene glycol block copolymer of combination (Pluronics for example, Tektronix or Genapol block copolymer), the combination of above-mentioned copolymer physics or chemical linkage unit (for example PEG-PLA or PEG-PLGA copolymer) mixture.Preferably, described bioadhesive material is selected from Polyethylene Glycol, polyoxyethylene, such as acrylic acid polymer, cellulose and the derivant thereof of Carbopols (for example Carbopol71G, 934P, 971P, 974P) and Polycarbophil (for example Noveon AA-1, Noveon CA-1, Noveon CA-2), and most preferably it is Polyethylene Glycol, Carbopol and/or cellulose derivative or its combination in any.

Mucosal adhesive/amount that the excipient of bioadhesion exists usually is 1% to 50%w/w, is preferably 1% to 40%w/w or most preferably be 5-30%w/w.Preparation of the present invention can contain one or more different bioadhesive polymers of combination in any.

The present invention is used for the mixture that preparation that the oral transmucosal medicine sends also comprises binding agent or two or more binding agents, and it helps excipient is incorporated into single dosage form.Exemplary adhesive is selected from Polyox, starch, polyvinylpyrrolidone (PVP), Avicel of cellulose derivative (for example methylcellulose, carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose etc.), polyacrylate (for example Carbopol, Polycarbophil etc.), polyvidone (all grades), irradiation or non-irradiated any molecular weight or grade or the like.

The amount of binding agent is generally 0.5% to 60%w/w, is preferably 1% to 30%w/w and most preferably be 1.5% to 15%w/w.

In one embodiment, the present invention is used for the preparation that the oral transmucosal medicine sends and comprises that also at least a hydrogel forms excipient.Exemplary hydrogel formation excipient is selected from Polyethylene Glycol and other has the polymer of ethylene glycol skeleton, no matter it is the homopolymer of ethylene glycol unit or crosslinked heteropolymer, block copolymer, polyoxyethylene homopolymer (PolyoxN10/MW=100 for example, 000 for example; 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; All these are the trade name of Union Carbide), the hydroxypropyl emthylcellulose of all molecular weight and grade (HPMC), Poloxamers (LutrolF-68 for example, Lutrol F-127, F-105 etc., be the trade name of BASF chemical company), Genapol, Polyethylene Glycol (PEG, PEG-1500 for example, PEG-3500, PEG-4000, PEG-6000, PEG-8000, PEG-12000, PEG-20,000 etc.), natural gum (xanthan gum, locust bean gum etc.) and cellulose derivative (HC, HMC, HMPC, HPC, CP, CMC), free or crosslinked based on polyacrylic polymer and combination thereof, such as polylactic acid, polyglycolic acid and the biodegradable polymer by physical mixed or crosslinked combination in any thereof.In one embodiment, described hydrogel component can be crosslinked.Described hydrogel forms the amount that excipient exists and is generally 0.1% to 70%w/w, is preferably 1% to 50%w/w or most preferably be 1% to 30%w/w.

The present invention is used for the preparation that the oral transmucosal medicine sends can also comprise at least a controlled release regulator, it is such material: when described dosage form generation hydration, thereby this material can be preferential with medicine physics or molecular level take place to interact and the reduction medicine from the diffusion rate of transmucosal dosage forms.Thereby excipient can also reduce the speed of described preparation picked-up water and the medicine dissolution that can realize more prolonging and from the release of tablet like this.In one embodiment, such controlled release regulator can interacting combines with activating agent generation molecule via physics (and being reversible therefore), thereby increases the effective molecular weight of activating agent and therefore further regulate it by the epithelium of hypoglossis mucous membrane and infiltration (diffusion) feature of basement membrane.Such combination is actually reversible and does not relate to any chemical modification of activating agent, therefore its pharmacological action is not produced any influence.In another preferred embodiment, such controlled release regulator can form discontinuous construction when hydration takes place, and it can spontaneously be caught medicine and therefore further prolong its effect.Exemplary controlled release regulator is selected from lipid, phospholipid, sterin, surfactant, polymer and salt.Common selected excipient is lipophilic and can forms coordination compound naturally with hydrophobicity or lipophilic drugs.Can change the associating intensity of release regulator and medicine by regulator in the change preparation to the ratio of medicine.In addition, can by in manufacture process with release regulator and active medicine appropriate combination and suitably strengthen such interaction.Perhaps, described controlled release regulator can be the electropolymer of synthetic or biopolymerization that has the net charge of plus or minus, thereby and its can combine with activating agent by electrostatic interaction and regulate its diffusion and/or its penetration kinetics by mucomembranous surface by tablet.With above-mentioned other compounds seemingly, such interaction is reversible and does not relate to permanent chemical bond with activating agent.

The amount that the controlled release regulator exists is generally 0 to 80%w/w, is preferably 1% to 20%w/w, most preferably is 1% to 10%w/w.

Such controlled release regulator also can produce capsule or micro structure territory in spreading all over the expansion network of hydrogel.These capsules can be as the bank of medical compounds, and this is because they tend to reduce by the concentration that reduces the whole Chinese medicine solute of hydrogel the motive force of diffusion.Can select and design the hydrogel matrix that has the controlled release regulator, make medicine enough slow, to realize the lasting dissolving of medicine from described dosage form from the release in micro structure territory.

The present invention is used for the preparation that the oral transmucosal medicine sends and also comprises at least a filler.Exemplary filler is selected from lactose USP, starch 1500, mannitol, sorbitol, maltose alcohol or other nonreducing sugar; Microcrystalline Cellulose (as Avicel), dehydration calcium hydrogen phosphate, sucrose or its mixture.The amount that filler exists is generally 20% to 95%w/w, is preferably 40% to 80%w/w.

The present invention is used for the preparation that the oral transmucosal medicine sends also can comprise at least a cosolvent.Such reagent helps improving the dissolubility of active medicine and strengthens its absorption feature, and helps handling and making.Suitable cosolvent can comprise the slaine of cyclodextrin, pH regulator agent, salt and buffer agent, surfactant, fatty acid, phospholipid, fatty acid etc.Exemplary surfactant is selected from lipid or its mixture of ion-type (sodium laurylsulfate etc.), the nonionic such as polysorbate (Tween and Span surfactants, Poloxamers etc.), bile salts (for example sodium taurocholate, deoxidation sodium taurocholate, glycocholeic acid sodium, sodium glycocholate etc.), various alkyl glucoside, fatty acid, phosphatidylcholine, triglyceride, sphingolipid, glycosylated lipid, PEGization, and the amount that exists of surfactant can be 0.01% to 5%w/w.Exemplary slaine and buffer agent can comprise at least organic salt (acetate, citrate, tartrate etc.) or the inorganic salt (phosphate, carbonate, bicarbonate, borate, sulfate, sulphite, bisulfites, metabisulfite, chloride etc.) such as metals such as sodium, potassium, calcium, magnesium.In addition, can use the combination of one or more such salt to guarantee that medicine enough stability and amount of existing in dosage form can be 0.1% to 20%w/w, are preferably 1% to 10%w/w in preparation.Exemplary pH regulator agent comprises hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, ammonium hydroxide or the like, and the amount that exists in preparation can be 0.1% to 5%w/w.

The present invention is used for the preparation that the oral transmucosal medicine sends and also comprises at least a lubricant.Lubricant has some functions, comprise prevent tablet adhere to compression device and improve compression in some cases or encapsulation before the flowing of pelletize.In most of the cases lubricant is a lyophobic dust.Exemplary lubricant is selected from stearic acid and such as the bivalent cation of magnesium stearate, calcium stearate etc., Talcum, glyceryl monostearate or the like.The amount that lubricant exists is generally 0.01% to 10%w/w, is preferably 0.1% to 3%w/w.

The present invention is used for the preparation that the oral transmucosal medicine sends also can comprise at least a fluidizer.Fluidizer is such material, its improve blended or granular material from distributing device to feed arrangement and finally to the flow performance of tablet mould.Exemplary fluidizer is selected from silica sol, precipitated silica, pyrogenic silica (CAB-O-SIL M-5P, the trade mark of Cabot company), stearowet and sterotex, Silicon stone (for example the trade mark of SILOID and SILOX Silicon stone-Grace Davison Products, the trade mark of Aerosil-Degussa Pharma), higher fatty acids, its slaine, hydrogenated vegetable oil or the like.The amount that fluidizer exists is generally 0.01% to 20%w/w, is preferably 0.1% to 5%w/w.

Described preparation also can contain flavoring agent or sweeting agent and coloring agent, for example aspartyl-phenylalanine methyl ester, mannitol, lactose, sucrose, other artificial flavoring; Ferrum oxide and FD﹠amp; The C color lake.

Described preparation also can contain additive and to help stablizing drug substance chemistry or mechanical degradation not take place.Such degradation reaction can comprise oxidation, hydrolysis, gathering, deacylated tRNA amine etc.Can make the stable suitable vehicle of medicine can comprise antioxidant, hydrolysis-resisting agent, gathering blocker etc.Antioxidant can comprise BHT, BHA, vitamin, citric acid, EDTA, sodium bisulfate, sodium metabisulfite, thiourea, methionine etc.Assemble blocker and can comprise surfactant, aminoacid, for example arginine, glycine, histidine, methionine etc.The other excipient that can protect active agents not degrade is salt, pH regulator agent, chelating agen and the buffer agent of drying or solution form.Multiple salt can comprise all salt known in the art and be found in Remington ' s Pharmaceutical Sciences, 17th Edition, 1985.Exemplary pH regulator agent comprises hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, ammonium hydroxide or the like.The example of such chelating agen comprises polylysine, disodium edetate, sodium citrate, condensed phosphoric acid sodium of different molecular weight or the like.The example of salt and buffer agent can comprise at least organic salt (acetate, citrate, tartrate etc.) or the inorganic salt (phosphate, carbonate, bicarbonate, borate, sulfate, sulphite, bisulfites, metabisulfite, chloride etc.) such as metals such as sodium, potassium, calcium, magnesium.In addition, can use the combination of one or more such salt to guarantee medicine enough stability in dosage form.The amount that stabilising carriers exists in preparation can be 0.01% to 15%w/w, is preferably 0.1% to 5%w/w.

Described preparation also can contain surfactant to increase the wettability of tablet, and especially when expecting faster release dynamics, it can cause beginning quickly mucosal adhesive.The amount that such surfactant exists is generally 0.01% to 3% percetage by weight of compositions.Exemplary surfactant is selected from lipid or its mixture of ion-type (sodium laurylsulfate etc.), the nonionic such as polysorbate (Tween and Span surfactants, Poloxamers etc.), bile salts (for example sodium taurocholate, deoxidation sodium taurocholate, glycocholeic acid sodium, sodium glycocholate etc.), various alkyl glucoside, fatty acid, phosphatidylcholine, triglyceride, sphingolipid, glycosylated lipid, PEGization.

Thereby also can comprising one or more, dosage form of the present invention can influence disintegration of tablet kinetics and medicine discharge and influence pharmacokinetics from tablet excipient.Such disintegrating agent is well known by persons skilled in the art and can be selected from starch, carboxymethyl cellulose type or crosslinked polyvinylpyrrolidone (polyvinylpolypyrrolidone for example, PVP-XL), alginate, based on cellulosic disintegrating agent (purifying cellulose for example, methylcellulose, crosslinked sodium carboxymethyl cellulose (Ac-Di-Sol) and carboxymethyl cellulose), the low cellulosic hydroxypropyl ether that replaces, microcrystalline Cellulose (for example Avicel), ion exchange resin (for example Ambrelite IPR 88), natural gum (agar for example, Semen sophorae, the thorn Firmiana platanifolia (Linn. f.) Marsili, pectin and tragacanth), guar gum, karaya, chitin and chitosan, dioctahedral smectite, gellan gum, the plantago ovata shell, polacrilin potassium (Tulsion ³³⁹), emit disintegrating agent (for example citric acid and tartaric acid and sodium bicarbonate, sodium carbonate, potassium bicarbonate or calcium carbonate), Explotab (for example Explotab and Primogel), starch DC of gas or the like.Adding such additive helps to make quick fragmentation of tablet or disintegrate to become faster erosive more fractionlet.The littler drug particles that contains that the other benefit that comprises such disintegrating agent in preparation of the present invention forms when being disintegrate has bioadhesion character preferably owing to the surface area height that contacts with oral mucosa increases.In addition, thus the surface area of increase can further help active substance rapid release and further quicken drug absorption and systematically meet the requirements of treatment level.Yet, as indicated above, in solid dosage forms, use such disintegrating agent of low percentage ratio w/w level, be generally with respect to the dosage unit gross weight 1% to 30%w/w, be preferably 5% to 25%w/w.

In an aspect of of the present present invention, described dosage form can comprise one or more biodegradable polymers that is used for any kind of prolong drug release.Exemplary polymer composition comprises the poly-anhydride and the copolymer of lactic acid and glycolic, poly-(dl-lactide-co-glycolide) (PLGA), poly-(lactic acid) (PLA), poly-(glycolic) (PGA), poe, albumen and polysaccharide.

The present invention also provides the preparation method of the preparation that is used for oral transmucosal delivery.One method comprises the following steps: to take by weighing the factor that medicine and one or more bioadhesive polymers, binding agent, hydrogel form excipient, filler, lubricant or fluidizer and influence dissolution time; Possible powder grinds; Dry powder is mixed; And tabletting by directly compressing.Perhaps, can use wet prilling process.Such method (for example high shear prilling process) relates in blender active medicine and some possible mixed with excipients.Can add in mixture with dry state binding agent or be dissolved in the fluid that is used for pelletize.Join granulation solution or suspension in the dry powder in the blender and be mixed to the character that reaches expectation.This produces the granule with suitable character usually and has all dosage forms of even other physical property of enough dissolution times, content to be used to produce.After the wet granulation step, usually that product is dry and/or pulverizing after the drying to obtain most product in the magnitude range of expectation then.Sometimes, using appropriate device that product is carried out wet method sizing after drying such as vibration comminutor or grinder.Can handle dried granulate mixture to obtain acceptable magnitude range by at first then grinding oversized particles then with the screening plant screening.In some cases, add suitable fluidizer to improve particulate flowability; Suitable fluidizer is as indicated above.

In addition, can make described preparation by selectable prilling process well known by persons skilled in the art, for example the fluidized bed spray granulation method, extrude spheronization or fluid bed rotating granulation method.

In addition, can be by being prepared bioadhesion tablet of the present invention by the elementary tablet of manufacturing as indicated above with suitable coating bag known in the art.Such coating purpose is that the protection active nucleus is without prejudice (wearing and tearing, damaged, formation dust), is not examined the influence (air humidity, temperature fluctuation) that is faced in transportation and storage process, and also can make these film coatings painted naturally.Film coating is expressed as water vapor permeability to the sealing function of water vapour.Can carry out coating by one of known method, for example W ü rster coating, dry-method coating, film coating, fluidized bed coating, pan coating etc.Typical capsule material comprises polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate copolymer (PVPVA), polyvinyl alcohol (PVA), polyvinyl alcohol/ethylene glycol copolymer (PVA/PEG), cellulose ethanoate phthalic acid ester, ethyl cellulose, gellan gum, maltodextrin, methacrylate, methylcellulose, hydroxypropyl emthylcellulose (HPMC of all grades and molecular weight), carrageenan or the like.

In specific embodiment, available all defined as mentioned bioadhesive material bags by tablet core of the present invention to improve the bioadhesion of tablet in the chamber, Sublingual.In such design, that design can be lost or hydrogel nucleus and with it with suitable bioadhesive material bag quilt, thereby produce as shown in Figure 1 design.Preferred hydrogel type nuclear in the quickly disintegrated application of needs tablet.When contacting with saliva, the thin biological slime membrane of penetration by water coating causes the hydrogel nucleus of tablet to expand.Along with hydrogel continue to expand, it applies bigger power to thin coating membrane, causes it to break and the quick erosion of tablet.In order further to promote this process, can be in nuclear as indicated abovely comprise suitable disintegrating agent.The thickness of shell is generally 0.05mg/cm ²To 1mg/cm ²

In another particular; thereby barrier and the further medicine of protecting moisture-sensitive that available moisture proof coating bag is entered to produce dampness in tablet by tablet core of the present invention; described moisture proof coating is hydrophobic polymer for example, comprises cellulose etc.In addition, such waterproof coating can improve its behavior in manufacture process by reducing the isochronous increase of environment that is exposed to high percentage ratio RH (relative humidity) when tablet.Can use multiple capsule material to improve the moisture proof performance of tablet, for example

E PO,

AMB, starch acetate or the like.Special concern is to have that very limited water absorbs and at the capsule material of＞85%RH fast Absorption water at＜85%RH among the application.Such function can help described dosage form in the environment of Sublingual moistening and under common storage and middle equal percentage RH condition the protection described dosage form.

Should be appreciated that can use the conventional operation of using of those skilled in the art that described preparation is converted into is used for the dosage form of sending to individuality.The preparation method of optimizing described dosage form to be reaching the high dose content uniformity, and this is to the compounds effective particular importance, and this chemical compound exists with 0.01% to 10%w/w mass ratio usually.The content uniformity of preparation of the present invention is to be lower than 10% percentage ratio relative standard deviation (%RSD).

Many methods that preparation is used for dosage form of the present invention are known in the art and can be used for implementing the present invention, for example directly compression, wet granulation etc.The preparation such as

Tabloid the time, shown that erosion time and adhesiveness do not rely on the compression force of 2K psi to 500K psi.

Dosage form of the present invention is applicable in delivery process and until most of or all medicines and adheres to oral mucosa from the process that described dosage form is sent via oral mucosa.

Further design dosage form of the present invention is to realize preparation that continue and controlled disintegrate in the time period that prolongs after being applied in the oral mucosa chamber in vivo.Can be after administration, to corrode in 30 seconds to 8 hours dosage form design of the present invention.In addition, it is designed to be provided at the scope of the different disintegration rate from linearity to two-phase during this process whole.

In addition, oral transmucosal dosage forms of the present invention is designed in vivo or external be applied in the oral mucosa after keep and control the release (dissolving) of medicine from described dosage form.One-level or secondary dissolution kinetics are followed in the dissolving of medicine from these transmucosal dosage forms that postpone to discharge, and can control it and reach best interior medicine dynamics spectrum and pharmacological action.

In certain embodiments of the invention, described pharmaceutical dosage form be applicable to medicine total amount contained in the single medicine dosage form 30% or manyly be delivered to individuality via oral mucosa.In another embodiment, the percent that contains the total amount transmucosal delivery of medicine in the single medicine dosage can surpass 30% to 40%, 40% to 50%, 60% to 70%, 70% to 80%, 80% to 90% and preferably surpass 95%.In exemplary embodiment, at least 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the medicine total amount that contains in the single medicine dosage form is sent via oral mucosa.

In certain embodiments of the invention, described pharmaceutical dosage form is applicable to that being no more than of the medicine total amount that will contain in the single medicine dosage form 60% is delivered to individuality via the GI road.In other embodiments, the percent of sending via the GI road can be lower, makes being no more than of the medicine total amount that will contain in the single medicine dosage form 50%, 40%, 30%, 20%, 10%, 5% or 1% be delivered to individuality via the GI road.

To send via oral mucosa and seldom send the remarkable improvement that provides with respect to prior art Chinese medicine delivering method accordingly than the medicine of big percent (and amount) via the GI road.

It is the zone, Sublingual that preferred medicine is sent the site, although in certain embodiments described dosage form is placed cheek inner or adhere to the top, oral cavity or gums may be favourable.

Saliva response being minimized produce consistent and the predictable spectrum of sending between the different patients, then is not like this for the oral lozenge that produces remarkable saliva response.Reducing the medicine that the saliva response has relatively poor bioavailability for by the GI road time is even more important.

Because hypoglossis mucous membrane sees through than such as the easier permission medicine of other mucosal areas of buccal mucosa, this causes taking in faster, (Shojaei AH is sent in therefore preferred Sublingual, et al..Buccalmucosa as a route for systemic drug delivery:a review (approach that buccal mucosa is sent as systemic drug: summary) .Journal of Pharmacy and PharmaceuticalSciences.1:15-30,1998).

Preparation of the present invention also provide with respect to previous oral or oral transmucosal preparation have the dissolving spectrum of improvement, via oral mucosa delivering drugs and in the treatment window, have the oral transmucosal dosage particles of constant blood plasma level effectively.

Compare with using commercially available preparation, the more constant absorption of minimizing that the medicine that uses preparation of the present invention to reach is swallowed and oral transmucosal medicine causes more constant peak plasma level between the individual dose.

Dosage form of the present invention is designed to effectively work in the unique environments in oral cavity, make limited amount fluid, be used for relative short time and intraoral pH level that medicine sends and the absorption of medicine do not produced opposite influence.Described preparation also is designed to improve dissolving, dissolubility and the stability of pharmaceutical dosage form.Advantage of the present invention has promoted pharmaceutical preparation that higher level drug absorption and the ability of constant dosage effect time via the oral transmucosal approach is provided, and makes this preparation significantly improve acute or explosive treatment of pain.

Oral transmucosal preparation of the present invention is designed to realize the more constant peak value blood plasma level of avoiding discharging at once liquid preparation of sending by independent control disintegration of tablet (or erosion) and medicine dissolution with from the release of tablet.Oral transmucosal preparation of the present invention provides the individual repeated doses of the activating agent that contains specified rate, thereby allows the amount of the medicine that the accurate titration of patient sent and suitably regulate this amount in mode safely and effectively.

The advantage of controlled release oral transmucosal preparation of the present invention is, it can make plasma drug level keep than longer time of delivery formulations at once in the treatment window of targeting, no matter and be solid dosage forms or based on the dosage form of liquid.For such routine at once the common observed peak value blood plasma level of delivery formulations can be weakened by the controlled release of medicine.In addition,, therefore can avoid the rapid decline of blood plasma level, have the more drug plasma kinetics of stabilized platform thereby provide owing to can continue to enter systemic circulation through the oral cavity at the whole process Chinese medicine of tablet dissolved.In addition, dosage form of the present invention can be improved the treatment safety by potential deleterious side effect is minimized, and this side effect is that it jeopardizes the treatment safety owing to the reduction of drug plasma kinetics Zhong Feng and paddy.

Oral transmucosal biologic adhesion preparation of the present invention be usually designed to disintegrate (or all corrode) time be 30 seconds high 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, this depends on the situation and the inherent pharmacokinetics of patient and drug administration.Should be appreciated that the composition of scalable oral transmucosal preparation of the present invention, provide different dosage and different dissolution time to adapt to concrete clinical setting.

The dissolution time of preparation sublingual administration of the present invention be 30 seconds high 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.

Oral transmucosal dosage forms of the present invention is designed to cosily be positioned over the Sublingual, make medicine fully form the disintegrate thing slowly to avoid visible peak plasma level at once and remarkable decline afterwards in the prior art formulations, described prior art is United States Patent (USP) the 6th for example, 759, No. 059, wherein with fentanyl via the tablet administration that contains 400 μ g fentanyls, after administration, caused the peak plasma level of 2.5ng/ml in 5 minutes, blood plasma level descends at once subsequently.

To provide preparation of the present invention with multiple dosage form, described dosage form changes according to the property quality and quantity of active component, keep preparation of the present invention dissolved feature in the oral cavity simultaneously, make the drug absorption of higher percentage ratio take place via oral mucosa approach rather than GI approach.

In one aspect of the invention, when the homogeneous dosage form that will comprise preparation of the present invention place the chamber, Sublingual, when preferably placing the Sublingual of lingual frenum either side, its once the contact promptly adhere to.Though wish not bound by theory, it seems that when the dosage form that comprises preparation of the present invention is exposed to the spatial moisture content in Sublingual described dosage form absorbs water, causes forming hydrogel network, it comprises micropore and macropore (or passage).The hydration influence dissolving and the diffusion of passing through the porous network of described dosage form subsequently of medicine.Yet, because as if the process of dosage form hydration and gel formation relatively slow, still believe discharge at this starting stage (Phase I) Chinese medicine relatively slow, thereby avoid at once " outburst " of medicine from tablet.Believe when reaching critical hydration level, restart to expand (stage 2) and the drug release process acceleration.By the appropriate combination of tablet excipient, the kinetics that can regulate these two stages is to reach the suitable release spectrum of concrete drug candidate.Being characterized as of hydrogel dosage form of the present invention is expanded at least 110% of initial volume when contacting with aqueous solution.

The existence that hydrogel in the dosage form of the present invention is formed on some excipient that can form hydrogel takes place down, and described excipient can absorb water and form gel.Such excipient comprises as mentioned the Polyox, Polyethylene Glycol (all grades) of all grades that describe in detail no matter be the copolymer based on PEG (for example Poloxamer etc.), glucosan, HPMC, starch etc. of homopolymer or heteropolymer.Can help hydrogel to form when in addition, such excipient any is combined in and contacts with body fluid.In addition, such hydrogel forms excipient can cause forming hydrogel structure with combination such as the excipient that is unfavorable for gel formation (promptly not having such swelliong power) of some cellulose or the like, though have the character of modification.

In another aspect of this invention, provide this paper to be called the dosage form of " corrosion type " dosage form.Therefore " corrosion type " so do not have identical swelliong power although dosage form can absorb big water gaging (depending on its composition), and forms gel unlike defined aquogel type preparation above.These " corrosion type " preparations and aqueogel are similar, promptly adhere to the chamber, Sublingual once contact.Yet opposite with hydrogel, they follow surface erosion mechanism, and do not form hydrated gel earlier.When " corrosion type " preparation was exposed to the spatial dampness in Sublingual, the tablet surface hydrate water merged erosion, thus the layer below exposing; When hydration took place the layer when subsequently, it corroded subsequently, by that analogy, thereby cause the tablet size continue reduce.

So common feature of corrosion type dosage form is not contain hydrogel to form excipient, particularly Polyox (all grades) no matter be the copolymer based on PEG (for example Poloxamer etc.), HPMC etc. of homopolymer or heteropolymer.Yet, should be appreciated that the percentage ratio w/w composition of the heterogeneity of described dosage form can influence erosion mechanism.For example, a small amount of special excipient that can form hydrogel may not cause the formation of hydrogel, and corrodes thus and can comprise in the preparation that some can form the excipient of hydrogel and not change it based on erosive disintegrate mechanism.The combination of excipient with and percent by weight form the ability of expansion and maintenance structural matrix when hydrogel is given it and contact with aqueous solution.Therefore, in giving customization agent, comprise hydrogel formation excipient and not necessarily as typical aqueogel, cause " expansion ".Hydrogel of the present invention forms and the corrosion type preparation provides control to absorption dynamics in medicine dissolution and/or the body can realize the effect of enhanced bioavailability and improvement.

Preparation of the present invention is particularly useful for paediatric use, and this is because the comfortable security property of described dosage form can make the acceptant this therapeutic modality of child and can be with medicine transmucosal delivery reliably.Instantiation includes but not limited to: treatment department of pediatrics acute pain when IV method non-availability or inconvenience, treatment pediatric asthma when the child can not effectively use the route of administration of suction, treatment is felt sick when the child can not or be unwilling ingestion of pills, and is calm before the child is NPO (not allowing oral absorption) or the art when needing quick acting more.

Preparation of the present invention also can be used for veterinary purpose.Instantiation includes but not limited to that the IV administration is not easy to obtain or any treatment of the acute illness state of inconvenience, for example pain relief, anxiety/stress reduction, the preceding calmness of art etc.

IV. Preparation of the present invention is used for suppressing or alleviating pain

In an exemplary type purposes, preparation of the present invention can be used for suffering from the individuality of pain, and described pain can be relevant with the various certifiable etiology that maybe can not confirm.Preparation of the present invention can be used for suppressing or alleviating pain.Use " treatment (treatment) " of term pain or " treatment (management) ",, for example to determine at this by pain scores so that make individuality more comfortable usually to describe disappearing, suppress or alleviating of pain.

Term used herein " acute pain " refers to exist usually be less than 1 month pain, yet in some cases, exists the pain of growing to 3 months also can be considered to " acute ".

Term used herein " chronic pain " refers to exist usually the pain above 1 month.

In an illustrative aspects, what the present invention relates to that oral transmucosal delivery is used for pain relief comprises preparation such as the medicine of class Opium or class opioid agonist to treat acute or explosive pain.

Activating agent in such preparation can comprise sufentanil or sufentanil congener, for example alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil or mirfentanil.One preferred embodiment uses sufentanil as activating agent.Another preferred embodiment uses fentanyl as activating agent.Other preferred embodiment uses alfentanil, lofentanil, carfentanil, remifentanil, trefentanil or mirfentanil as activating agent.Another preferred embodiment uses the combination of sufentanil and at least a other medicament to be used for the treatment of analgesia as activating agent.

In optional embodiment, preparation of the present invention comprises the combination of two or more class Opium analog, and for example sufentanil adds the class Opium such as fentanyl, alfentanil, trefentanil, mirfentanil or remifentanil.Various types of Opium medicine have different pharmacokinetics spectrum and with the different interactions of μ opioid receptor splice variant, and therefore can make up and be used to strengthen therapeutic effect.For example, sufentanil and fentanyl combination can have onset fast, and this is because the loss that the sufentanil pain slower because of fentanyl has lacks.

In optional embodiment, pharmaceutical dosage form of the present invention can comprise at least one kind Opium medicine and one or more other medicines, and wherein said other medicines can be class Opium or non-class Opium medicine.Described oral transmucosal drug delivery formulation can be used for the treatment with any situation of sending of any active pharmaceutical compounds, and active pharmaceutical compounds can be sent via the oral mucosa approach in described any situation.

Preparation of the present invention can contain efficient class Opium, for example sufentanil, fentanyl or sufentanil congener.

In the present invention's one exemplary, each dosage form contains the sufentanil to about 200 μ g with about 0.25 μ g of one or more other therapeutic agents or drug regimen.

In another example of the present invention, each dosage form contains the fentanyl to about 1500 μ g with about 2 μ g of one or more other therapeutic agents or drug regimen.

In certain embodiments, oral dose preparation of the present invention comprises class Opium antagonist, for example naloxone.The activity of class Opium component in the inhibitory preparation when in such embodiments, providing naloxone to inject with box lunch with suitable concentration.

The present invention can be used for treatment and accepts opioid patient and class Opium tolerance patient first.

The patient of opioid repeat administration " accepted opioid patient " and refer to not accept first in term used herein in the time period of several weeks to several months.

Term used herein " class Opium tolerance patient " means such physiological status, it is characterized by the reduction (as pain disappearance, nauseating or calm) of the back opioid effect that continues medication.Opioid is the chemical substance that medicine, hormone or other have the pain disappearance that is similar to the material that contains the Opium or derivatives thereof, the calm and/or effect of feeling sick.If the tolerance of pain disappearance takes place, the dosage that then increases opioid is to the pain disappearance that reaches par.This toleration may not extend to side effect, and side effect may not increase and tolerance well with dosage.

In certain embodiments, the dosage form that comprises preparation of the present invention contains the active component of at least 0.001% percentage by weight.Preferably, described dosage form comprises about at least 0.005% height to 99.9% weight ratio, 0.05% to 99%, 0.01% to 50%, 0.1% to 10% active component.In some other embodiment, the dosage form that comprises preparation of the present invention contains nearly active component or the medicine of 10 μ g, 15 μ g, 25 μ g, 50 μ g, 100 μ g, 500 μ g, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg or 10mg.

The percent of active component can change according to the size of dosage form and the character of active component, it is optimized with acquisition sends via the maximum of oral mucosa approach., can in single dosage form, comprise surpassing a kind of active component aspect some of the present invention.

In an exemplary, the dosage form that is used for the treatment of pain can comprise the sufentanil of about 0.25 μ g to about 200 μ g, about 2.5 μ g are to the sufentanil of about 100 μ g, about 2.5 μ g are to the sufentanil of about 40 μ g, about 2.5 μ g are to the sufentanil of about 15.0 μ g, about 2.0 μ g are to the fentanyl of about 1500 μ g, the fentanyl of about 50 μ g to the fentanyl of about 1500 μ g or about 200 μ g to about 1500 μ g.

In various embodiments, preparation of the present invention is generally all types of patients suitable pain relief is provided, and described patient comprises class Opium adult tolerance or that accept opioid child and institute's has age first.The present invention can be used for the inpatient and the outpatient is provided with.

The clinical use of sufentanil mainly is limited to the IV administration in operating room or the reinforcement nursing unit.As further described herein, existing about some researchs that liquid sufentanil preparation are used for the low dosage intranasal administration and the case report of Sublingual delivering liquid sufentanil preparation.In these researchs of great majority, adult's minimum dose of sufentanil is 5 μ g in accepting opioid patient first.The intranasal bioavailability is the about 75% of the bioavailability that obtains by IV, however the unexposed pharmacokinetic data that uses about the sufentanil Sublingual.

Bioadhesion through mucous membrane preparation of the present invention contains the sufentanil of 0.25 μ g to about 200 μ g of having an appointment in the dosage form that each is used for oral transmucosal delivery.Skilled person in the art will appreciate that this dosage for the low side of child, and, depend on body quality, especially when long term administration is grown up in tolerance to class Opium for adult high-end in this scope in this scope.Do not describe a small amount of oral transmucosal medicine of sufentanil and send dosage form.

Be used for containing the sufentanil of 0.25 μ g of having an appointment in each dosage form to about 120 μ g to the exemplary formulation of the present invention of child's (pediatric patients) administration.For example, be used for the sufentanil that preparation of the present invention to child's administration can contain the 0.25 μ g that has an appointment, 0.5 μ g, 1 μ g, 2.5 μ g, 4 μ g, 5 μ g, 6 μ g, 8 μ g, 10 μ g, 15 μ g, 20 μ g, 40 μ g, 60 μ g or 120 μ g and be used for oral transmucosal delivery.Its exemplary dose scope of following for pediatric patients is at least about 0.02 μ g/kg to about 0.5 μ g/kg, and preferred range is that about 0.05 μ g/kg is to about 0.1 μ g/kg.

Be used for containing the sufentanil of 2.5 μ g of having an appointment in each dosage form to about 200 μ g to the exemplary formulation of the present invention of adult's administration.For example, be used for to contain the 2.5 μ g that have an appointment, 3 μ g, 5 μ g, 7.5 μ g, 10 μ g, 15 μ g, 20 μ g, 40 μ g, 60 μ g, 80 μ g, 100 μ g, 120 μ g, 140 μ g, 180 μ g or 200 μ g or higher sufentanil is used for oral transmucosal delivery to the preparation of the present invention of adult's administration.

Dosage form of the present invention contains the fentanyl of 2 μ g to about 1500 μ g of having an appointment in the dosage form that each is used for oral transmucosal delivery.Skilled person in the art will appreciate that this dosage for the low side of child, and, depend on body quality, especially when long term administration is grown up in tolerance to class Opium for adult high-end in this scope in this scope.

Be used for containing the fentanyl of 2 μ g of having an appointment in each dosage form to about 900 μ g to the exemplary dosage forms of the present invention of child's (pediatric patients) administration.For example, be used for the fentanyl that preparation of the present invention to child's administration can contain the 2 μ g that have an appointment, 3.75 μ g, 7.5 μ g, 18.75 μ g, 30 μ g, 37.5 μ g, 45 μ g, 60 μ g, 75 μ g, 112.5 μ g, 150 μ g, 300 μ g, 450 μ g or 900 μ g and be used for oral transmucosal delivery.

Be used for containing the fentanyl of 18.75 μ g of having an appointment in each dosage form to about 1500 μ g to the exemplary formulation of the present invention of adult's administration.For example, be used for to contain the 18.75 μ g that have an appointment, 22.5 μ g, 37.5 μ g, 56 μ g, 75 μ g, 112.5 μ g, 150 μ g, 300 μ g, 450 μ g, 600 μ g, 750 μ g, 900 μ g, 1050 μ g, 1350 μ g or 1500 μ g or higher sufentanil is used for oral transmucosal delivery to the dosage form of the present invention of adult's administration.

Dosage form of the present invention contains the alfentanil of 10 μ g to about 10000 μ g of having an appointment in the dosage form that each is used for oral transmucosal delivery.Skilled person in the art will appreciate that this dosage for the low side of child, and, depend on body quality, especially when long term administration is grown up in tolerance to class Opium for adult high-end in this scope in this scope.

The exemplary dosage forms of the present invention that is used for the alfentanil administration contains the alfentanil of 10 μ g to about 10mg of having an appointment in each dosage form.For example, the preparation of the present invention that the is used for administration alfentanil that can contain the 10 μ g that have an appointment, 25 μ g, 50 μ g, 150 μ g, 200 μ g, 300 μ g, 400 μ g, 600 μ g, 800 μ g, 1000 μ g, 2000 μ g, 3000 μ g, 5000 μ g, 7000 μ g, 9000 μ g or 10000 μ g is used for oral transmucosal delivery.

In different exemplary, the dosage form that is used for the treatment of pain can comprise the sufentanil to about 0.25 μ g of the fentanyl combination of about 1500 μ g to about 200 μ g with about 2 μ g, perhaps with about 0.25 μ g of one or more other drug regimens fentanyl to the sufentanil of about 200 μ g or about 2 μ g to about 1500 μ g.

Remifentanil, lofentanil, carfentanil, trefentanil and mirfentanil are effective fentanyl congeners, its through bioadhesion through mucous membrane formulation delivered of the present invention the time applicable to management of acute pain.The exemplary formulation of these congeners can comprise 0.25 μ g to 99.9mg for the dosage range of adult and pediatric patients.Can be to repeat these dosage at interval for the defined appropriate time of each molecule.

Alfentanil also is effective fentanyl congener, its tachymetabolism and can be suitable for using through bioadhesion through mucous membrane formulation delivered of the present invention the time.For adult and the suitable alfentanil dosage range of pediatric patients is 10 μ g to 10mg.Can repeat these dosage at interval with appropriate time.

The pain of suffering from the patient of chronic pain morbid state also can intermittently worsen, and treats its basic chronic pain except the class Opium that discharges in time that uses slow onset, also needs the explosive class Opium of acute use snap action.

Explosive pain or operation pain can be as short as 1 minute or 2 minutes or grow to 30 minutes or very strong in longer short time, therefore provide to produce to have class Opiate between more constant and predictable action period, quicker clinical effective plasma levels and have significant advantage.

Class Opium remains the most effective form of analgesic, yet need have minimal side effect and can be so that the doctor can be easy to follow the tracks of the improved form that mode that the patient uses provides.

Use present Therapeutic Method, attempt with multiple interference technique pain management, described interference technique generally includes: control of nursing pain and the control of family health care patient pain are controlled, alleviated to the acute pain of the analgesia (PCA) of intravenous patient control, continuous epidural infusion (CEI), other type.These methods are obtaining success in various degree with respect to side effect aspect the convenience of controlling persistent period, treatment and the safety.

Need quick management of acute pain under different clinical settings, these clinical settings comprise that postoperative recovery, rheumatoid arthritis, back are impaired, terminal cancer etc.For example, the patient is subjected to the torment of serious pain in postoperative initial a couple of days, tormented by slight pain to medium level.

Being used for the treatment of medium the most frequently used analgesia to serious postoperative pain is the IV morphine.This or give the patient or place PCA pump and patient to carry out opioid self administration the injection of morphia device usually by the IV injected delivery based on " needs " by the nurse by pressing button with lock-in feature.Other class Opium such as hydromorphone and fentanyl also can use by this way.

Also be necessary management of acute pain for the patient in outpatient's arrangement.For example, many patients are tormented by chronic pain and need use class Opium to treat its pain by week or by the sky.Although they have long-acting oral or percutaneous class Opiate to treat its chronic potential pain level, they often need fugitive effective class Opium to treat its serious explosive pain level.

" scene " management of acute pain also is necessary under extremely not good enough condition.Often need nursing staff or military doctor to treat serious acute pain under non-conditions for sterilization, the pin that be used for IV or intramuscular administration this moment can cause unintentional pricking wound, infection risk etc.Oral class dream-stick often needs 60 minutes so that alleviation to be provided, and this is oversize for the people of the serious pain of experience.

In various clinical is provided with, use and in the reasonable time section, provide preparation to the pain relief of serious burst or intermittent pain but need produce effective pain relief safe and convenient in titratable mode obviously.

V. The purposes of preparation of the present invention

It is simple, non-invasive and can be by nursing staff or patient with minimum uncomfortable administration that the oral transmucosal medicine is sent.Usually use the oral transmucosal delivery of realizing medicine such as the solid dosage forms of lozenge or tablet, yet also can use liquid, spray, gel, natural gum, powder and thin film.

For some drugs, those medicines that have relatively poor bioavailability via the GI road for example, for example many lipotropy class Opium, oral transmucosal (OT) are sent can provide than GI and are sent better route of delivery.For such as opioid medicine, oral transmucosal delivery has than oral GI to be sent shorter onset time (promptly from being administered to the time of therapeutic effect) and the bioavailability of remarkable improvement is provided.

Pharmacokinetics (PK) and formulation characteristics

Medicine causes comparing more constant sending with most of medicine that can get at present via the oral transmucosal dosage forms of GI approach picked-up between individual dose and the individual patient from the picked-up of bioadhesion through mucous membrane preparation of the present invention.

Bioadhesion through mucous membrane preparation of the present invention is designed to effectively work in the unique environments in oral cavity, makes the relative short time of limited amount liquid in the oral cavity, medicine dissolution and pH level not produce otherwise impact to drug absorption.Described dosage form also is designed to improve dissolving, dissolubility and the stability of medicine.The higher level drug absorption and the constant dosage effect time that can provide via oral transmucosal delivery is provided advantage of the present invention, makes this preparation significantly improve acute or explosive treatment of pain.

Oral transmucosal preparation of the present invention be designed to by use hypoglossis mucous membrane and by independent control disintegration of tablet (or erosion) and medicine dissolution and in time from the release of tablet provide safer sending to compose to avoid intravenous dosage form the peak value blood plasma level.Oral transmucosal preparation of the present invention provides the individual repeated doses of the activating agent that contains specified rate, thereby allows the amount of the medicine that the accurate titration of patient sent and suitably regulate this amount in mode safely and effectively.

The advantage of bioadhesion oral transmucosal preparation of the present invention is, it shows the bioavailability of constant height and can with remarkable lower fluctuation plasma drug level be kept than the longer time of dosage form that can get at present, no matter and be solid dosage forms or IV dosage form in the treatment window of targeting.Can be weakened along with the administration of the preparation of the present invention that is characterized as medicine controlled releasing for the common observed peak value blood plasma level of IV dosage form.In addition,, therefore can avoid the rapid decline of blood plasma level, have the drug plasma kinetics that prolongs platform status thereby provide to compare with the IV route of administration because medicine can continue to enter blood flow through the oral cavity in the time span of tablet dissolved and longer time.In addition, dosage form of the present invention can be improved the treatment safety by potential deleterious side effect is minimized, this side effect is because the reduction of drug plasma kinetics Zhong Feng and paddy, and it jeopardizes the treatment safety and is very common for the dosage form that can get at present.

With respect to the various liquid forms that are used for opioid Sublingual or intranasal administration, the advantage of solid sublingual formulation of the present invention comprises that the part of controlling solid dosage forms discharges and avoids swallowing via the liquid dosage form Chinese medicine of nose or mouthful administration.The disclosed pharmacokinetic data of people's intranasal sufentanil liquid administration (15 μ g) is shown 78% bioavailability (Helmers et al.Comparison of intravenous and intranasal sufentanil absorption andsedation (intravenous and intranasal sufentanil absorb and abirritative contrasts) .Canadian Journalof Anaesthesia36:494-497,1989).The sublingual liquid sufentanil administration of beagle (5 μ g) (embodiment 8) causes 40% bioavailability.These bioavailability all are lower than uses sufentanil with the present invention in people volunteer

75% the bioavailability (embodiment 7-12 hereinafter) that 91% meansigma methods that the form sublingual administration of preparation is obtained or surpass is obtained in the zooscopy.

Oral transmucosal dosage forms of the present invention be designed to cosily to be positioned over dosage form that the Sublingual makes that load has a medicine fully slowly disintegrate significantly descend then for the viewed peak plasma level that produces at once of preparation of the prior art avoiding, described preparation of the prior art such as United States Patent (USP) the 6th, 759, No. 059 (Rapinyl) is described, wherein with fentanyl via the tablet administration that contains 400 μ g fentanyls, this causes the peak plasma level of 2.5ng/mL, and blood plasma level descends at once subsequently.Fentora (fentanyl cheek tablet) also stands not have platform phase, rises to C but have very steep oblique line _Max, the remarkable decline of blood plasma level (Fentora package insert) then.

Bioadhesion through mucous membrane preparation of the present invention is designed to form the concrete delivery vector of two classes: hydrogel and aggressivity tablet.From the hydrogel diffusion with (ii) from erosion of corrosion type tablet and diffusion, they follow two kinds of different disintegrates and drug release mechanism based on (i).Use these basic engineerings, preparation of the present invention can be designed to quick, medium or slow disintegrate.These architectures are different from greatly by using carbonate-type (or other) excipient to be designed to broken fast foaming matrix agent.In addition, they be fundamentally different than be designed to disintegrate Cheng Jing " in order " mix back " carrying " less (being generally micron-scale) drug particles than the particulate dosage form of larger vector.The structure of through mucous membrane preparation of the present invention has no requirement to the concrete particle diameter of medicine and excipient granule, does not require that also disintegrate becomes " the pharmaceutical pack quilt " carrier granular to reach the performance of expectation.

Bioadhesion through mucous membrane preparation of the present invention can be designed to regulate and control the pharmacokinetics spectrum of active medicine.Equally, provide the quick medicament of snap action onset kinetics spectrum to reach the release of quick disintegrate and quick medicament and to reach, keep other performance characteristic of tablet simultaneously, biological example adhesion, the repeatability of effect, the C that weakens thereby can regulate described preparation _MaxDeng.Such rapid disintegration tablet can be designed to from height in 30 seconds to disintegrate in 20 minutes and be able to according to the pharmacokinetics spectrum that changes between 10 minutes to 1-2 hour action period.Perhaps, preparation of the present invention can be adjusted to reach " medium " thus erosion time and drug release and reaching provides more " medium " pharmacokinetics spectrum of continuous action.The preparation of even now still can provide the snap action onset, but mainly it is designed to reach other performance characteristic that longer continuous action keeps tablet simultaneously, biological example adhesion, the repeatability of effect, the C that weakens _MaxDeng." medium " disintegrating tablet like this can be designed to from height in 30 seconds to disintegrate in 30 minutes and reach the pharmacokinetics spectrum of respective change.At last, preparation of the present invention can be adjusted to and reach " slowly " disintegration time (and erosion dynamic learn spectrum) thereby and slow drug release and reach to provide and continue the pharmaceutically-active very PK of prolongation.The preparation of even now can be designed as still provides quick acting, but expects that mainly it reaches lasting medicine PK and effect, keeps other performance characteristic of tablet simultaneously, biological example adhesion, the repeatability of effect, the C that weakens _MaxDeng.Slow disintegrating tablet like this can be designed to from height in 15 minutes to disintegrate in 8 hours and reach the pharmacokinetics spectrum of respective change.

In addition, bioadhesion through mucous membrane dosage particles of the present invention can enough multiple physicochemical properties on a large scale that have, for example water solublity, partition coefficient etc., active medicine show aforementioned properties.

At last, the performance of bioadhesion through mucous membrane preparation of the present invention and feature and manufacture process are irrelevant.Can use in multiple this area conventional, established make preparation of the present invention (for example wet method and non-slurry pelletizing, directly compression etc.) with known method, and do not influence performance in the physicochemical properties of described dosage form or the body.

Interior medicine dynamics-zooscopy

Thereby the dosage form of test selected representative aggressivity preparation and aquogel type preparation is to estimate the interior medicine dynamics behind the sublingual administration and the character of explanation preparation of the present invention in appropriate animal model.The oral transmucosal medicine that uses preparation of the present invention is sent with respect to the liquid sublingual administration and swallowed

Compare to estimate its performance.The result supports that our claimed biologic adhesion preparation of the present invention is that the Sublingual tolerates well in dog, cause bioavailability and the more constant pharmacokinetics spectrum higher than other the oral transmucosal dosage forms that comprises instillation liquid.In addition, they show that through mucous membrane preparation of the present invention can weaken absorption C _MaxAnd change the drug absorption spectrum to reach absorption quick, medium or that prolong.

In order to show the broad applicability of bioadhesion transmucosal dosage forms of the present invention, prepared preparation with three kinds of different class Opium: sufentanil citrate, fentanyl citrate and alfentanil hydrochlorate.Although these molecules are members of identical class Opium analgesic family, have large-scale physicochemical properties, as shown in table 1.The ability that preparation of the present invention is handled the interior medicine dynamics of these different moleculars similarly shows the broad applicability of preparation of the present invention to molecule on a large scale with different physicochemical properties in vivo.

The selected opioid physicochemical properties of table 1.

As embodiment 7 (table 12) in greater detail, carried out a research to compare Sublingual 5 μ g sufentanils

Preparation and IV sufentanil.Studied 3 beagles altogether and the Fig. 3 that the results are shown in of pharmacokinetic analysis has been listed in table 13.To tablets all after dog administration disintegrate in＜20 minutes.Compare with IV, sufentanil is from the Sublingual

The bioavailability of preparation is 74.8 ± 10.7, thereby has confirmed the superior performance of described preparation with respect to other dosage form or preparation type (foaming dosage form etc.).With respect to other commercially available transmucosal dosage forms, the coefficient of variation of bioavailability lower (CV=14.4%), this shows very repeatably and effectively unexpectedly sends.From the Sublingual

The absorption of preparation is very fast, its average T _MaxBe about 12 minutes, simultaneously the onset of sending in 7 minutes in administration.Yet opposite with the IV administration, described preparation makes and absorbs maximum with respect to IV decline 2-3 doubly.In addition, absorb half-life significant prolongation (IV 3.3 times), show more lasting absorption spectra.

Treatment time, ratio was important mathematics ratio, and it shows the platform phase of the prolongation of the sufentanil blood plasma level that records after the administration of through mucous membrane biologic adhesion preparation, and it is defined as the last eventually C that removes half-life compensation by known drug IV _MaxThe time that is spent more than 50%.

The treatment time ratio of the Sublingual sufentanil preparation of this embodiment is 0.28, and is 0.05 (use disclosed sufentanil in dog 139 minutes IV remove the half-life) for this ratio of IV sufentanil.Therefore, compare with the IV sufentanil, through mucous membrane preparation (#44) causes the treatment time ratio of 5.6 times of increases, show send from Sublingual of the present invention biologic adhesion preparation after, sufentanil reaches treatment level and compares with IV and remains on the longer time within the effective treatment level.This embodiment has given prominence to some advantage of Sublingual of the present invention sufentanil preparation, and it comprises that (i) effectively and repeatably sends the absorption C that (ii) quick acting (iii) weakens _MaxAnd the absorption spectra that (iv) prolongs.These features show, through mucous membrane preparation of the present invention can cause the medication effect that improves, makes side effect minimize and improve the safety of administration simultaneously.

In beagle, carried out another research to estimate the advantage of sublingual formulation with respect to the sublingual liquid administration.Describe this research among the embodiment 8 (table 14) in detail.Result's (being shown in table 15 and Fig. 4) shows cause T fast although send in the Sublingual that sufentanil (5 μ g) instils via liquid dosage form _Max, this medication causes comparing with the Sublingual sufentanil preparation of embodiment 7 the high fluctuation (83.1%CV) of extremely low absorption (F=40.0 ± 32.5%) and absorption.This may be because the part of instillation liquid is swallowed the part oral absorption of medicine afterwards.Use this medication, C _MaxAlso alterable height shows 72% high coefficient of variation.The liquid sufentanil treatment time ratio that instils is calculated as 0.04 ± 0.02, is very similar to IV sufentanil arm.Therefore, instil in the Sublingual of liquid does not provide for the viewed favourable treatment platform of sublingual formulation.These discoveries show, are not that described molecule is inherent for the high bioavailability in the viewed Sublingual of the present invention's biologic adhesion preparation required for protection, but the direct result of the unique design of described dosage form and preparation thereof.Described through mucous membrane preparation to the chamber, Sublingual the surf zone that can be used for absorbing that sticks to by force the fluctuation under the liquid solution situation is minimized, thereby improve molecule sending to systemic circulation.In addition, because its unique design and less size,

Do not cause the generation of significant saliva, thereby reduce the probability of medicine that absorption discharges.These two kinds of factors help the higher and absorption of more consistent of medicine from the chamber, Sublingual.

In another part (being shown in embodiment 9) of same research, in same animal model, measured and swallowed

The bioavailability of back sufentanil.The bioavailability of estimating this route of administration is very important with the following observed result of further support: come the medicine of self-preparing agent sublingual administration can not swallowed and keep high bioavailability because about the data in literature of GI sufentanil bioavailability seldom or do not have.Shown in the PK analytical data of table 15, cause extremely low drug bioavailability (F=12.2 ± 16.3%) from the oral absorption of the sufentanil of bioadhesion tablet.Low absorption causes drug absorption and the kinetics (C that absorbs the drug _Max, T _Max) high fluctuation, (134.2%CV) as shown in Table 15.These data further show, almost take place via the Sublingual exclusively rather than absorb from the absorption of the biologic adhesion preparation of embodiment #7 via GI, in contrast, in the class Opium transmucosal dosage forms that commerce can get the medicine of a great deal of be delivered to the GI road (

-75%;

-50% oral absorption).These find to support following results: bioadhesion sublingual formulation of the present invention with the mode strong adhesion that do not move in the oral cavity, thereby avoid oral absorption and avoid the height fluctuation of blood plasma level, and when medicine absorbs via the GI approach height to fluctuate be typical.

In certain embodiments, can modify bioadhesion through mucous membrane preparation of the present invention to regulate and control pharmacokinetics spectrum.As an example, thereby can regulate said preparation to reach quick disintegrate and drug release and to reach quick medicament kinetics spectrum, it reaches quick acting, keeps other performance characteristic of tablet simultaneously, biological example adhesion, the repeatability of effect, the C that weakens _MaxDeng.Such rapid disintegration tablet can be designed to from height in 30 seconds to disintegrate in 20 minutes and be able to according to the pharmacokinetics spectrum that changes between 10 minutes to 1-2 hour action period.Perhaps, can regulate preparation of the present invention to reach " medium " erosion time (learning spectrum) with erosion dynamic thereby and drug release and reaching provide more " medium " pharmacokinetics of continuous action to compose.The preparation of even now still can provide the snap action onset, but mainly it is designed to reach other performance characteristic that longer continuous action keeps tablet simultaneously, biological example adhesion, the repeatability of effect, the C that weakens _MaxDeng." medium " disintegrating tablet like this can be designed to from height in 30 seconds to disintegrate in 30 minutes and reach the pharmacokinetics spectrum of respective change.At last, preparation of the present invention can be adjusted to reach " slowly " disintegration time (and erosion dynamic learn spectrum) thereby and slowly drug release and reaching provide and continue the pharmaceutically-active pharmacokinetics that prolongs very much and compose.The preparation of even now can be designed as still provides quick acting, but expects that mainly it reaches lasting medicine PK and effect, keeps other performance characteristic of tablet simultaneously, biological example adhesion, the repeatability of effect, the C that weakens _MaxDeng.Slow disintegrating tablet like this can be designed to from height in 15 minutes to disintegrate in 8 hours and reach the pharmacokinetics spectrum of respective change.

In addition, the pharmacokinetics spectrum that obtains from such bioadhesion sublingual formulation can be according to variations such as dosage form design, geometry, compositionss.The example of such PK spectrum comprises the rising pharmacokinetics that is similar to bell shaped curve, show more than unimodal spectrum, on the surface that prolongs between whole action period smooth PK spectrum or middle spectrum.What especially pay close attention to is to show rapid release part and the two stage absorption spectras of extending the release stage slowly subsequently.

Should be noted that the non-foaming also not disintegrate of bioadhesion through mucous membrane preparation as herein described (no matter quick, medium or slow disintegrate type) becomes to comprise the individual carrier granular of described dosage form.

Reach the ability that different like this pharmacokinetics is composed in order to illustrate bioadhesion through mucous membrane preparation of the present invention, in embodiment 10, prepared some preparations (#54-#58) of representing aquogel type preparation and corrosion type preparation.They be with sufentanil citrate preparation and be designed to provide medicine to put from quick, the medium gentle slow release of described dosage form.By 1 described direct compression prepares preparation as described in Table 16 as embodiment, except preparation #56, it is by as the described wet granulations preparation of embodiment 3, and as described in embodiment 10 and the table 17 with as described in preparation in healthy, clear-headed beagle model, estimate.

The sufentanil administration of A. quick and medium disintegrating preparations (#55,54).Analysis result is shown in Fig. 5 and pharmacokinetic analysis the results are summarized in table 18.The tablet of preparation #55 after administration＜5 minutes in disintegrate, and the tablet of preparation #54 disintegrate in＜20 minutes.Show after the preparation #54 administration and act on onset (T fast _Onset=7.1 ± 0.5min) with relative T fast _Max(early to 10 minutes).Although very fast effect onset is arranged, said preparation causes C _MaxWeaken, though this weakens the durative action preparation less than embodiment 7, and said preparation (26.7 ± 2.2min) show that it causes the effect that prolongs a little with respect to the longer plasma half-life of IV.The performance of the performance reaction embodiment 7 of said preparation, because compare with other commercially available transmucosal dosage forms, sufentanil bioavailability (comparing F=90.4 ± 25.3% with IV) that the said preparation maintenance is high and low coefficient of variation (CV=28%).At last, compare with IV, TTR has increased by 3 times, thereby having confirmed that preparation of the present invention can reach repeatably and effectively with respect to other dosage form or preparation type sends.

Preparation #54 shows similarly (although being slower than preparation #55) effect onset (T fast _Onset=9.2 ± 4.3min) with relative slower T _Max(25.0 ± 8.7min), it can reach the C of increase simultaneously _MaxWeaken.In addition, its shows the effect that more prolongs, as the plasma half-life long with respect to IV (as indicated in 49.2 ± 22min).Said preparation still shows the high bioavailability (F=88.2 ± 28.9%) and the enhanced therapeutic effect of sufentanil, as indicated in almost 6 times TTR (0.28 ± 0.13) increases with respect to IV.

B. the slowly sufentanil administration of disintegrating preparations (#58).The tablet of said preparation is slowly disintegrate in 35 minutes to 120 minutes after administration.The said preparation demonstration acts on onset (T very slowly _Onset=48.0 ± 34.1min) and even administration after the sufentanil pharmacokinetics that also show to continue in 8 hours (plasma half-life is 205 ± 93.1min).The PK that prolongs causes the C that compares with IV _MaxRemarkable (almost 2.4 times) weaken and the remarkable increase (almost 22.6 times) of TTR (scope of 8.8-36.4).These embodiment are used to illustrate the bioadhesion through mucous membrane preparation of the present invention pharmacokinetics effect of modification and control drug release and medicine in vivo.

Can not rely on drug type and physicochemical properties thereof and revise and control pharmacokinetics in order to further specify bioadhesion through mucous membrane preparation of the present invention, prepared several formulations with two kinds of other class Opium fentanyl and alfentanils

Shown in embodiment 11, prepared (by direct compression) several formulations (#59-#62) with the fentanyl citrate, its medium gentle slow release of representing aquogel type and corrosion type and being designed to reach medicine is put.It is estimated in the beagle model that health is regained consciousness, shown in table 21.PK analyzes the results are summarized in table 22 and analysis result is shown in Fig. 7 and 8.

The fentanyl administration of A. medium disintegrating preparations (#59,60).The disintegrate in 20 minutes to 50 minutes of the tablet of preparation #59, with preparation #60 after administration in 20 minutes disintegrate similar.These two kinds of preparations show that all comparatively faster effect onset (is respectively 16.2 ± 6.8min and 9.0 ± 2.6min) and the C that weakens _MaxThough, its degree difference: be 2.4 times and be 6.7 times for preparation #60 for preparation #59.In addition, with respect to other commercially available transmucosal dosage forms, they reach high drug bioavailability (being about 95% with respect to IV) and low absorption fluctuation (being respectively 8.4% and 10.5% for preparation #59 and #60).In addition, the two kinds of equal significant prolongation medicine of preparation PK.Preparation #59 shows more significant absworption peak and shows 75.5 ± 32.5 minutes plasma half-life (having prolonged 7.5 times with respect to IV).On the contrary, preparation #60 shows the absorption spectra that more prolongs, shown in 12.1 times of prolongations of plasma half-life (121.5 ± 19.1 minutes).The increase of TTR has reflected that also this effect prolongs, and TTR has increased by 6 times for preparation #59, has increased by 11.5 times for preparation #60.This data acknowledgement fentanyl cause very repeatably and effectively sending through the absorption of bioadhesion through mucous membrane preparation of the present invention with respect to other dosage form or preparation type (foaming agent etc.).

B. the slowly fentanyl administration of disintegrating preparations (#62).Slowly the more medium disintegrating preparations of erosion of the tablet of disintegrating preparations #62 is slow; Erosion was finished at 35 minutes to 65 minutes.Opposite with medium disintegrating preparations, and the slowly effect onset of preparation display delay (43.6 ± 20.7min), though keep very high bioavailability (F=99.0 ± 4.4%) and low-down fluctuation (CV=4.5%) with respect to other commercially available transmucosal dosage forms.Said preparation provides even absorbs with respect to the fentanyl that more prolongs of medium disintegrating preparations; Plasma half-life extends to 154.4 ± 52.6 minutes, and the drug absorption that representative prolongs is very much composed-compared with IV between action period and prolongs near 15.5 times.Compare C with IV _MaxReduction has also reflected this point near 4 times.At last, compare the treatment time ratio with IV and also increase to 0.46 ± 0.12, represent 11.5 times increase.

In addition, shown in embodiment 12, prepared bioadhesion through mucous membrane preparation (#63) and in the clear-headed beagle model of health, it has been estimated with alfentanil (table 23), as described in Table 24.Pharmacokinetic analysis the results are summarized in table 25 and the PK analysis result is shown in Fig. 9.

The disintegrate of two kinds of tablets of preparation #63 occurred in after the administration in 20 minutes.Alfentanil causes comparing with the IV alfentanil 94% high bioavailability and for 15% coefficient of variation of bioavailability, for C from the administration of biologic adhesion preparation _Max7% coefficient of variation and for T _Max28% coefficient of variation.The onset that alfentanil absorbs from said preparation is very fast, occurs in after the administration in 5 minutes.Said preparation makes absworption peak weaken almost 4 times.Generally, said preparation reaches the lasting absorption spectra of medicine, as by shown in 8 to 10 times of increases (40.8 minutes with respect to 4.4 minutes) of plasma half-life.With compare for 0.04 of the IV alfentanil arm of this research, TTR is calculated as 0.33 (use in the disclosed dog 104 minutes IV of alfentanil to remove the half-life and calculate).Therefore, compare with IV alfentanil arm, alfentanil through mucous membrane preparation (shown in embodiment 12) produces the TTR of 8 times of improvement.The high bioavailability of said preparation has been supported following opinion equally: use Can produce minimum medicine swallows.

These embodiment have illustrated that multiple molecule effectively sends from the height of bioadhesion through mucous membrane preparation, and this reaches higher drug bioavailability for three kinds of medicines being studied with lower fluctuation.Also with enhanced treatment time ratio described total efficacy of drugs, show send from sublingual formulation of the present invention after, medicine reaches effective treatment level and keeps the longer time of this level than intravenous administration.In addition, above-mentioned data are supported following opinion: through mucous membrane biologic adhesion preparation of the present invention can control drug release and is reached the pharmacokinetics spectrum of multiple modification, and its scope be from quick, medium drug absorption extremely slowly.

Interior medicine dynamics-people's clinical research

Intersect estimated selected biologic adhesion preparation (the described #46 of table 9, #47 and #48) sublingual administration in the clinical research after the pharmacokinetics of sufentanil, this research as embodiment 13 detaileds description, relate to human volunteer health, that naltrexone seals.

The through mucous membrane preparation corrodes in during 10 minutes to 30 minutes in all individualities.In addition, in 72 tablet administrations, only have an example to remove to snack made with traditional Chinese medicines tablet taking place promptly altogether, this shows that tablet adheres to Johnson ﹠ Johnson's thing in chamber, Sublingual.The Sublingual sufentanil administration of biologic adhesion preparation causes remarkable constant pharmacokinetics spectrum, sums up with table 26 as shown in figure 10.Compare with IV (for individually dosed), the bioavailability meansigma methods of all three dosage is 91%, this result who is far superior to record for commercially available fentanyl through mucous membrane preparation Actiq and Fentora (be respectively 47% and 65%-Fentora package insert).Although reach high bioavailability may be because multiple factor, but its reduction that can mainly swallow (if having) owing to medicine, this reduction be because: (i) tablet adheres to the Johnson ﹠ Johnson thing of hypoglossis mucous membrane and does not allow it to remove and swallowing subsequently, and (ii) lacks the saliva generation that the small size because of dosage form causes and increase.Opposite with these discoveries, two kinds of commercial product Fentora and Actiq (described in its package insert) claim respectively at least 50% and 75% drug dose via the saliva picked-up and swallow, thereby cause the bioavailability lower than the present invention preparation.This discovery has reflected the result of embodiment 7 to 12 described zooscopies, and it shows the very high bioavailability of through mucous membrane preparation of the present invention.Such conclusion is supported in all researchs of the present invention: the medicine above 75% is that through mucous membrane absorbs.Therefore, be less than 25% medicine and swallowed, this is significantly less than reports above-mentioned commercial product.

With compare for 20.1% of IV, 24.7% to 34.1% low coefficient of variation of three kinds of preparation bioavailability being estimated very importantly show this high bioavailability also with send high repeatable relevant.This is significantly less than (Fentora package insert) that Fentora (CV=45%) and Actiq (CV=41%) are reported.Therefore the accumulated dose of sending to patient/individuality not only for sufentanil preparation of the present invention more biology can utilize, and more constant between patient and patient.Although as indicated above this may be because multiple factor, this mainly be since (i) among all patients Johnson ﹠ Johnson's thing of transmucosal dosage forms adhere to, thereby reduce moving and therefore reducing the fluctuation that absorbs of tablet, and the (ii) medicine reduction of swallowing.

Aspect the constant medicine blood plasma level at initial stage, the sufentanil sublingual formulation also is preferably after administration.C with preparation #48 acquisition _MaxBe 27.5 ± 7.7pg/ml, its CV only is 28%.On the contrary, the C of Fentora and Actiq _MaxFluctuation with increase, its CV is respectively 41-56% and 33% (Fentora package insert).

Except bioavailability and constant plasma concentration preferably, T _MaxBe unusual important parameters, this be since in management of acute pain the requirement for the quick and constant onset of pain relief be very important.The T of through mucous membrane preparation #48 _MaxBe 40.8 ± 13.2 minutes (19.8 minutes to 60 minutes scopes), the average T of the Fentora that this is better than reporting _MaxThe average T of (46.8min, scope is 20 minutes to 240 minutes) and Actiq _Max(90.8min, scope is 35 minutes to 240 minutes) (Fentora package insert).Therefore bioadhesion through mucous membrane preparation of the present invention provides the onset that significantly improves than Fentora and Actiq and the homeostasis of pain disappearance onset, the T of slow onset _MaxDescend 400%.

In management of acute pain, especially acute explosive pain, it is important constant and relative low drug half-life.10 μ g sufentanils

The plasma clearance half-life be 1.71 ± 0.4 hours, this allows medicine all is titratable for the pain of various levels.If explosive pain events continues to surpass 1.5 hours, then the patient can take another

The half-life of Actiq and Fentora lowest dose level was respectively 3.2 hours and 2.63 hours.For these medicines, the half-life of higher dosage significantly increases, thereby limits the titratable property of these medicines.

The PK curve that tested Sublingual sufentanil preparation is produced in the human research be platform phase on the other hand, this allows the constant blood plasma level of a period of time, this all is very important for safety and efficient.Compare with 10 minutes IV infusions (embodiment 13) that IV injects among administration (referring to zooscopy embodiment 7-12) or the human research, the PK spectrum of sufentanil preparation is obviously safer, because it causes C _MaxWeakening of blood plasma level.Because class Opium can produce respiration inhibition, thereby the peak value of avoiding these PK to compose is favourable.

For 12 volunteers,, surpass C for the dose intensity of 2.5 μ g, 5 μ g and 10 μ g _Max50% time average be respectively 110 minutes, 111 minutes and 106 minutes, causing scope is the TTR (for all sufentanil preparations of being estimated in clinical research) of 0.72-0.75.The value (0.14-1.13) that is obtained with the sufentanil preparation in these values and the zooscopy is consistent well.When the through mucous membrane preparation being modified when reaching shorter or longer disintegration time, the treatment time ratio of philtrum sufentanil can be changed and be about 0.2-2.0.

In addition, ratio is how fugitive medicine successfully to be configured to produce the increase of treatment time and by avoiding the peak value plasma C treatment time _MaxConcentration and increase measuring of safety.For example, as a comparison, human research's sufentanil IV arm shows that the treatment time ratio is 0.067.Therefore should low rate value be measuring and showing that said preparation does not produce significant platform phase of the peak value that produces of the IV infusion by sufentanil for the IV arm.On the contrary, the bioadhesion through mucous membrane preparation of estimating in the clinical research shows the treatment time ratio higher 10 times than IV, thereby has supported the treatment platform spectrum that these preparations prolong.

In a word, clinical and data zooscopy show significantly all that bioadhesion through mucous membrane preparation of the present invention is sent with respect to intravenous and with respect to the advantage of sending from the commercially available product based on routine techniques.The embodiment that this paper provided provides very convictive data, and it shows that (i) effectively and repeatably sends, (ii) snap action onset, the absorption C that (iii) weakens _Max, and the absorption spectra that (iv) prolongs.These features show, biologic adhesion preparation of the present invention can cause the medication effect that improves, makes side effect minimize and improve the safety of administration simultaneously.

External preparation characterizes

The external biological adhesion

Shown in embodiment 5, through mucous membrane preparation of the present invention can be designed to prove bioadhesive in various degree.In the exemplary formulation of this embodiment, the through mucous membrane preparation is shown as 0.03N/cm to the adhesion of porcine mucosa substrate ²To 0.18N/cm ²The adhesion of measuring is big or small directly related with the interior adhesion of body.Notice that the separating force that specific experiment condition (for example time of contact, drip washing etc.) the meeting appreciable impact of expection has been write down is very important; Interact and the increase adhesion thereby for example increase to cause time of contact increasing.In order to measure, the time of contact of selecting 2 minutes is to reflect the time of contact of fast disintegrating preparations.

The result who is summarized in table 11 shows that the adhesion strength of embodiment 5 selected through mucous membrane preparations changes in 6 times of scopes.Yet, expect that preparation of the present invention shows the adhesion strength that can extend beyond this measuring scope.Expectation can be revised as 0.005N/cm with the bioadhesion intensity of preparation of the present invention ²To 1.0N/cm ²Scope (500-10 ⁵Dyn/cm ²).

External medicine dissolution kinetics

According to the Higuchi law, the sufentanil citrate is followed diffused kinetics from the dissolving (Fig. 2) of preparation #46-#48.It is the distinct characteristic of aquogel type system that this class discharges.In addition, Korsmeyer and Peppas equation have been described these data (Korsmeyer, R.W. well, Gurney, R., Doecker, E., Buri, P., Peppas, N.A., Mechanisms of soluterelease from hydrophilic polymers (mechanism that solute discharges from hydrophilic polymer), J.Pharm.Sci.15:25-35,1983), its R ²Value is 0.96-0.98.The match of solubility curve shows, medicine does not rely on the amount that medicine loads from the release of all three kinds of systems, and index n provides match value 0.566 ± 0.109 (0.068%w/w sufentanil citrate tablet), 0.673 ± 0.123 (0.163%w/w sufentanil citrate tablet) and 0.446 ± 0.116 (0.273%w/w sufentanil citrate tablet).Notice that all n values level off to 0.5, this shows the release of Fickian DIFFUSION CONTROLLED, and this is subjected to a little, and tablet is expansible to be influenced, and has further confirmed to discharge from the aquogel type of these preparations.

(embodiment 7-12) also illustrates in the body, expects that preparation of the present invention can show the multiple dissolving spectrum from several minutes (2-4 minute) to a few hours (6-8).In addition, physicochemical properties, preparation compositions and tablet design (for example number of the existence of physical size, coating, coatings etc.) according to medicine, the external medicine dissolution spectrum that obtains can show multiple dissolution kinetics, for example one-level or secondary spread or corrode control or follow blended erosion-diffusion mechanism.

Expansion ratio

Term used herein " expansion ratio " means the mass ratio of the dosage form that is exposed to fully behind the water quality of its dried state before expose.Expansion ratio (SR) can define and be expressed as ratio or percent based on the special time that is exposed to water, as is expressed as SR=(being exposed to the quality-initial dry mass behind the water)/(initial dry mass) * 100 of percent.

Perhaps such " expansion ratio " may be defined as with water and contacts back dosage form of the present invention than contact the volume ratio of same dosage form before with water.Expansion ratio (SR) can define and be expressed as ratio or percent based on the special time that is exposed to water or steam, as is expressed as SR=(exposing the preceding tablet volume of back tablet volume-exposure)/(tablet volume before exposing) * 100 of percent.When controlling the radius size of such experiment well, same expansion ratio can be according to defining such as the variable-sized of thickness, as be expressed as SR=(expose back tablet thickness-exposures before tablet thickness)/(exposing preceding tablet thickness) * 100 of percent.

Bioadhesion through mucous membrane preparation of the present invention can be used to measure its expansion ratio by the specific period (for example 2 hours or longer) of next section of relative humidity (for example 100%RH) that is exposed to rising.Can be before being exposed to dampness and measure tablet sizes and weight afterwards to calculate expansion ratio as mentioned above.

The dosage form disintegrate

Can observe sublingual dosage forms disappearance in time by visual inspection and monitor the dosage form erosion.High to 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours or grew to 8 hours or can be observed by visual inspection in longer time the erosion fully of dosage form at about 30 seconds.Oral transmucosal preparation of the present invention is usually designed to high in about 60 minutes at 1 minute, promptly reaching in the time of effect level, disintegrate (or all corroding), this effect level be held grow to 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours or longer, depend on patient and administration environment and inherent pharmacokinetics.The compositions that should be appreciated that scalable oral transmucosal preparation of the present invention is to provide multiple dosage and multiple dissolution time to adapt to specific clinical setting.

Embodiment

It is in order to illustrate that the following example is provided, rather than the invention of requirement for restriction protection.Except as otherwise noted, hereinafter the gross mass of all tablets of preparation is 5.5mg.In addition, with all tablets demonstrations higher content uniformity of active drug substance, as by the defined %RSD of American Pharmacopeia＜10% by directly compression or wet granulation preparation.

Embodiment 1: by the exemplary erosion preparation of direct compression preparation

For illustrative purposes, show to provide among the 1-4 multiple exemplary erosion placebo preparation hereinafter by direct compression method preparation.For each preparation, with all excipient weigh, with mortar with grind mallet and grind 1-2 minute, manual mixing; Preparation comprises the substitute of a small amount of coloring agent (aluminum is blue to form sediment) as active drug substance.Take by weighing the mummification compound of 5.5-8.0mg equal portions, be loaded in the loading unit of special tectonic and in the Carver forcing press in 5-20K psi lower compression to form dosage form.%w/w compositions with excipient among the table 2-5 hereinafter provides the exemplary formulation of using this method preparation, and its invading the

exterior

6 and 7 provides the exemplary hydrogel preparation.

Table 2. is by directly compressing the exemplary erosion preparation of preparation

Table 3. is by directly compressing the exemplary erosion preparation of preparation

Table 4. is by directly compressing the exemplary erosion preparation of preparation

Table 5. is by directly compressing the exemplary erosion preparation of preparation

Embodiment 2: by the exemplary hydrogel preparation of direct compression preparation

For illustrative purposes, provide the various exemplary hydrogel placebo preparation for preparing by the method for directly compressing among the table 6-7 hereinafter.For each preparation, with all excipient weigh, with mortar with grind mallet and ground 1-2 minute and manual mixing; Preparation comprises the substitute of a small amount of coloring agent (aluminum is blue to form sediment) as active drug substance.Take by weighing the mummification compound of 5.5-8.0mg equal portions, be loaded in the loading unit of special tectonic and in the Carver forcing press in 5-20K psi lower compression to form dosage form.%w/w compositions with excipient among the table 6-7 hereinafter provides the exemplary formulation for preparing by this method.

Table 6. is by directly compressing the exemplary hydrogel preparation of preparation

Embodiment 3: by the exemplary corrosion type and the aqueogel of wet granulation preparation

For illustrative purposes, provide the various exemplary aggressivity placebo preparation for preparing by wet granulation in the table 8.In common preparation, used complete wet granulation.In such method, with aluminum is blue form sediment (as the medicine substitute) be dissolved in the suitable dilution agent (water-alcohol mixture of water, EtOH or multiple ratio) and and be added on the dry mixture of all the other excipient by directly toppling over or spraying.Then wet mixture is mixed in the high speed shear blender, and in high speed shear comminutor (for example KG-5), handle the granule that forms the expectation size.Then with the granule dry and mixing in the disc type baking box that forms.Final mixture is loaded in the Piccola rotational pressure machine (or β forcing press) of the loading unit that particular design is housed to realize the preparation of dosage form.In order to reach this point, with the dried particles of about 5.5-8.0mg in 1KN to 20KN lower compression.For some embodiment hereinafter, be poured over and also comprise other excipient, for example binding agent or bioadhesive polymer in the solution on the excipient dry mixture.

In addition, can use the mannitol of multiple different brackets and particle diameter to help to optimize granulation process.Among the embodiment that provides hereinafter, the mannitol grade is (Pearlitol 100SD, Pearlitol 200SD or the Pearlitol 160C) granule (size, distribution etc.) to obtain different qualities that changes.

As well known to those skilled in the art, can use several different methods to change in this method.In a kind of such variation, use the part wet granulation with the preparation dosage form.Only some excipient is used to form granule (mixing in the granule) in the method.In such method, remaining excipient is added to granule outside granule, and with mixture mixed number minute to produce the substrate of homogeneous.The example of formulations (table 8) that hereinafter provides has also reflected the part prilling process.

Table 7. is by the exemplary corrosion type and the aqueogel of complete wet granulation preparation

Table 8. is by the exemplary hydrogel preparation of part wet granulation preparation

Embodiment 4: with the exemplary hydrogel preparation of active substance sufentanil citrate preparation

For illustrative purposes, prepared several formulations with active drug substance.Used drug substance is the sufentanil citrate among these embodiment.For illustrative purposes, the described preparation that is described in the table 9 is to use identical part processes for wet granulation mentioned above to prepare according to the detailed description in the table.

The exemplary hydrogel preparation that table 9. prepares with the sufentanil citrate

The in-vitro evaluation of through mucous membrane preparation

Use directly compression and/or wet granulation to prepare the placebo preparation of multiple corrosion type and aquogel type and use above-outlined operation evaluation its external biological adhesiveness and the dynamic (dynamical) character of external medicine dissolution.

Table 10. is used for the exemplary placebo preparation of in-vitro evaluation

Embodiment 5: the in-vitro evaluation of bioadhesive

By the bottom and the mensuration that tablet are adhered to suspension platform preparation is measured mucosal adhesive intensity from the required power of pig buccal mucosa substrate separation.(GS-500Tranducer techniques, Temecula CA) form with hook-shaped adnexa the mucosal adhesive test macro by accurate loading unit.Loading unit produces analogue signal, and it is converted to digital signal by the data collecting system that A/D converter and computer are housed; Use EasyLx software (Keithley Metrabyte) analytical data.Suspension platform is connected with loading unit, and it comprises the slide that is connected with plastic piston (8cm) on top and the circular steel ridge (0.5cm) with platform surface of bottom.The tablet mould of platform surface is as low fixed platform.Use screw-pincers that mucosal tissue is installed on the low platform.To have the suspension platform reduction of thin film and the specific time of top experience that places mucomembranous surface with the known power that applies.Mensuration is with N/cm ²For the separating force of unit and compare.Between each is measured, with mucomembranous surface 4mL pure water drip washing.Excessive water is wiped and mucosa is used away the phosphate-buffered liquid wetting of the pH6.8 of known volume with softish cotton paper.Research is carried out three times in room temperature (23 ℃ to 25 ℃).Adhesion and peak separation power can be used in the bioadhesion intensity of estimating the dosage form that comprises the various preparations of the present invention.Dosage form of the present invention shows above 100 dyne/cm ²Bioadhesion power, as 500 dyne/cm ²Bioadhesion power.

Estimate the bioadhesion intensity of placebo preparation and in table 11, provided the result.

The bioadhesion power of table 11. placebo preparation

Preparation #	Bioadhesion power, N/cm ²
Preparation #	Bioadhesion power, N/cm ²	49	0.040±0.01
47	0.046±0.01	49	0.040±0.01
47	0.046±0.01	52	0.162±0.15
50	0.030±0.00	52	0.162±0.15
50	0.030±0.00	51	0.056±0.01
53	0.180±0.08	51	0.056±0.01

Embodiment 6: estimate the external sufentanil dissolving of preparation.

Use through suitably revising to hold a small amount of sufentanil that contains of small size

II type USP dissolution apparatus measure the sufentanil dissolution kinetics of preparation #46, #47 and #48.By of the release of LC/MS monitoring medicine from bioadhesion through mucous membrane preparation.Dissolve medium is defined as the phosphate buffer that pH is 6.5-7.8.It is high to about 60 minutes that the dissolution time of dosage form of the present invention is generally, yet dissolve just more obvious in some cases after height was to about 120 minutes or 240 minutes.The results are shown in Fig. 2.

Embodiment 7: the preparation bioavailability of sufentanil and pharmacokinetics behind the sublingual administration in the healthy dogs model.

The bioavailability of sufentanil is as described in Table 12 estimated the sublingual administration of comparing preparation #44 with intravenous in the clear-headed beagle animal model of health after.Intravenous administration be will via the sterilization syringe needle of suitable size and syringe with the dosage of 5 μ g sufentanil alkali by injecting

50 μ g/mL individually dosed (n=3) are to a lateral vein.For sublingual administration (group 2), by measured matter (preparation #44, the intensity of 5 μ g sufentanil alkali) is placed the Sublingual of contiguous frenulum and carries out sublingual administration (n=3) with tweezers.Blood sample is gathered from jugular vein or other suitable vein in about 1 minute, 3 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours before administration and after the administration.At each time point about 2mL blood collecting is gone into to contain K ₂In the refrigerative in advance test tube of EDTA.With sample in refrigerated centrifuger 3, under the 000g centrifugal about 10 minutes.Collect blood plasma in centrifugal back 20 minutes and be chilled in approximately-70 ℃ down and keep this temperature until analyzing.Use attested LC/MS/MS method to carry out sample analysis to analyze the sufentanil in the dog plasma.

Table 12. (i) is by the sublingual administration of Sublingual biologic adhesion preparation #44 and the administration parameter of (ii) carrying out the sufentanil administration by intravenous solution.

A=represents with free alkali.

B=uses identical animal, at least 2 days flushing time between the administration for group 1 to 3.

Blood plasma PK spectrum is shown in Fig. 3.The PK analysis result is summarized in table 13.

The PK of the sufentanil sublingual formulation (#44) that table 13. is compared with the intravenous sufentanil analyzes

Group	F(％)	Absorb fluctuation (%CV)	C _max (pg/mL)	T _onset(min) ¹	T _max (min)	Plasma half-life (min)	Treatment time ratio ²
Group	F(％)	Absorb fluctuation (%CV)	C _max (pg/mL)	T _onset(min) ¹	T _max (min)	Plasma half-life (min)	Treatment time ratio ²	The intravenous sufentanil	-	22.8	536.7±186.1	0.05±0.06	1.6±0.6	10.3±4.5	0.05±0.02
Sublingual sufentanil preparation #44	74.8±10.7	14.4	222.7±25.9	7.1±4.0	11.7±2.5	33.3±5.8	0.28±0.16	The intravenous sufentanil	-	22.8	536.7±186.1	0.05±0.06	1.6±0.6	10.3±4.5	0.05±0.02

¹Reach C _MaxTime of 50%

²The expression medicine reaches treatment level and (surpasses 50%C _Max) relative time, be defined as the drug plasma concentration of removing half-life compensation with intravenous drug and keep surpassing C _MaxTime of 50% and its calculate by following formula: TTR=(surpasses C _MaxTime of 50%)/(intravenous of medicine end is eventually removed the half-life).The denominator that obtains from the literature research of sufentanil in the beagle is 139 minutes.

Embodiment 8: the bioavailability and the pharmacokinetics of sufentanil behind the Sublingual solution infusion in the healthy dogs model

For with the sufentanil dosage form relatively, estimated sufentanil solution and compared via the bioavailability of infusion sublingual administration (n=6) back sufentanil citrate and pharmacokinetics and with IV (n=6).In the beagle animal model that health is regained consciousness, estimated the bioavailability after the sufentanil of comparing with the intravenous bioavailability carries out sublingual administration from solution, as described in Table 14.In two arms of this research, used commercially available sufentanil citrate preparation (

50 μ g/mL) and with the accumulated dose administration of 5 identical μ g sufentanil alkali.Intravenous administration be will via the sterilization syringe needle of suitable size and syringe by injecting

50 μ g/mL individually dosed (n=3) are to a lateral vein.Dosage slowly is applied to the Sublingual of contiguous frenulum via the disinfectant syringe.With condition identical described in the embodiment #7 under gather and storing blood; Use attested LC/MS/MS method to carry out sample analysis to analyze the sufentanil in the dog plasma.

Table 14. (i) passes through through the sublingual administration of instillation sufentanil solution with (ii) by oral absorption

Preparation and the administration parameter of (ii) carrying out the sufentanil administration by intravenous solution

Group	Treatment	Dosage level (μ g) ^a	Route of administration	The animal total number, n
Group	Treatment	Dosage level (μ g) ^a	Route of administration	The animal total number, n	1	Sufentanil solution	5.0	IV	3
2	Sufentanil solution ^c	5.0	The Sublingual	6 ^b	1	Sufentanil solution	5.0	IV	3
2	Sufentanil solution ^c	5.0	The Sublingual	6 ^b	3	The preparation #44 that takes in	5.0	Oral	6 ^b

A=represents with free alkali.

B=is to ading up to 6

group

2 and 3 animals administers 2 times, at least 2 days flushing time.

C=use normal saline solution with measured matter (

50 μ g/mL) be diluted to expectation concentration.

Analysis result is shown in Fig. 4.The PK analysis result is summarized in table 15.

The solution that instils in table 15. and (i) Sublingual and (ii) taking in

The PK of the sufentanil that the intravenous of comparing is given analyzes

¹Reach C _MaxTime of 50%

Embodiment 9: the bioavailability of sufentanil and the evaluation of pharmacokinetics behind the oral absorption sufentanil through mucous membrane preparation

As described in previous embodiment, in the beagle animal model that health is regained consciousness, estimated the bioavailability of the absorption of comparing with intravenous bioavailability bioadhesion tablet of the present invention (preparation #44) back sufentanil.For n=6 altogether, will be with the single biologic adhesion preparation oral administration of the overall strength preparation of 5.0 μ g sufentanils (alkali unit) 2 times, at least 2 days washing time (table 14) between each dosage.The bioadhesion tablet is manually placed as far as possible after examination position of throat, and the water flushing is to promote the response of swallowing of animal.

Embodiment 10: the exemplary sufentanil preparation and the interior medicine dynamics of control drug release.

For illustrative purposes, prepared drug release rate and the interior medicine dynamics of several formulations with the sufentanil citrate to estimate various dosage forms.By 1 described direct compression has prepared corrosion type as described in Table 16 and based on the preparation of hydrogel as embodiment, except preparation #56, it is by as embodiment 3 described wet granulations preparations.

Table 16. is used to estimate the exemplary sufentanil dosage form of interior medicine dynamics

The pharmacokinetics of sufentanil is as described in Table 17 estimated preparation #54-58 sublingual administration in the beagle animal model that health is regained consciousness after.Intravenous administration be will via the sterilization syringe needle of suitable size and syringe by injecting 50 μ g/mL individually dosed (accumulated dose is the sufentanil alkali of 5 μ g) are to a lateral vein.For sublingual administration, measured matter (n=2 or 3) is placed the Sublingual of contiguous frenulum with tweezers.With condition identical described in the embodiment #7 under gather and storing blood; Use attested LC/MS/MS method to carry out sample analysis to analyze the sufentanil in the dog plasma.

Table 17. sufentanil (i) is via fast (#55), medium (#54) and slowly (#58) preparation sublingual administration and the administration parameter of (ii) passing through the intravenous solution administration

^aRepresent with free alkali.

The results are shown in Fig. 5 and 6.PK the results are summarized in table 18 and 19.

Table 18. and intravenous administration

The PK of the sufentanil preparation of the quick and medium disintegrate in the Sublingual of comparing analyzes

Group	F(％)	Absorb fluctuation (% CV)	T _onset(min) ¹	T _max (min)	C _max(pg/mL)	Plasma half-life (min)	Treatment time ratio ²
Group	F(％)	Absorb fluctuation (% CV)	T _onset(min) ¹	T _max (min)	C _max(pg/mL)	Plasma half-life (min)	Treatment time ratio ²	The intravenous sufentanil	-	5.4	0.6±0.0	1.0±0.0	1002.1±149.1	7.9±2.5	0.05±0.02
Sublingual formulation #54	88.2±28.9	32.8	9.2±4.3	25±8.7	727.2±256.3	49.2±22.0	0.28±0.13	The intravenous sufentanil	-	5.4	0.6±0.0	1.0±0.0	1002.1±149.1	7.9±2.5	0.05±0.02
Sublingual formulation #54	88.2±28.9	32.8	9.2±4.3	25±8.7	727.2±256.3	49.2±22.0	0.28±0.13	Sublingual formulation #55	90.4±25.3	28	7.1±0.5	13.3±2.9	819.1±100.1	26.7±2.2	0.14±0.02

¹Reach C _MaxTime of 50%

Table 19. and intravenous administration

The PK of the sufentanil preparation of the slow disintegrate of comparing in Sublingual analyzes

Group	T _onset (min) ¹	T _max(min)	C _max(pg/mL)	Plasma half-life (min)	Treatment time ratio ²
Group	T _onset (min) ¹	T _max(min)	C _max(pg/mL)	Plasma half-life (min)	Treatment time ratio ²	The intravenous sufentanil	0.6±0.0	1.0±0.0	1002.1±149.1	7.9±2.5	0.05±0.02
Sublingual formulation #58	48±34.1	70±45.8	420.9±298.4	205±93.1	1.13±0.69	The intravenous sufentanil	0.6±0.0	1.0±0.0	1002.1±149.1	7.9±2.5	0.05±0.02

¹Reach C _MaxTime of 50%

Embodiment 11. the interior evaluating of Sublingual Sublimaze in the canine model.

For illustrative purposes, prepared drug release rate and the interior medicine dynamics of multiple through mucous membrane preparation with the fentanyl citrate to estimate various dosage forms.Estimated corrosion type as described in Table 20 and based on the preparation of hydrogel; All dosage forms are all by 1 described direct compression prepares as embodiment.

Table 20. is used for the exemplary Sublimaze of interior evaluating

In the clear-headed beagle animal model of health, estimated the pharmacokinetics of fentanyl behind the sublingual administration of the several formulations that aims to provide the PK spectrum different with intravenous, shown in table 21.Use commercially available fentanyl citrate preparation ( 50 μ g/mL) and with its identical accumulated dose administration with 70 μ g fentanyl alkali.Intravenous administration be will via the sterilization syringe needle of suitable size and syringe by injecting

50 μ g/mL individually dosed (n=3) are to a lateral vein.Having developed hydrogel and corrosion type preparation puts from the medium gentle slow release of dosage form so that medicine to be provided.For sublingual administration, measured matter is placed the Sublingual of contiguous frenulum and carries out sublingual administration (n=2 or 3) with tweezers.With condition identical described in the embodiment #7 under gather and storing blood; Use attested LC/MS/MS method to carry out sample analysis to analyze the fentanyl in the dog plasma.

Table 21. fentanyl (i) is via medium (#59,60) and the slow administration parameter that acts on (#62) preparation sublingual administration and (ii) pass through the intravenous solution administration

^aRepresent with free alkali.

The results are shown in Fig. 7 and 8.Pharmacokinetic analysis the results are summarized in table 22.

Table 22. and intravenous

The PK of the Sublimaze of the sublingual administration of comparing analyzes

Group	F(％)	Absorb fluctuation (% CV)	T _onset (min) ¹	T _max (min)	C _max (pg/mL)	Plasma half-life (min)	Treatment time ratio ²
Group	F(％)	Absorb fluctuation (% CV)	T _onset (min) ¹	T _max (min)	C _max (pg/mL)	Plasma half-life (min)	Treatment time ratio ²	The intravenous fentanyl	-	13.7	0.6±0.0	1.0±0.0	7895.9±6096	10.5±9.6	0.04±0.04
Sublingual formulation #59	96.9±8.2	8.4	16.2±6.8	45±21.2	3304.5±2398	75.5±32.5	0.24±0.16	The intravenous fentanyl	-	13.7	0.6±0.0	1.0±0.0	7895.9±6096	10.5±9.6	0.04±0.04
Sublingual formulation #59	96.9±8.2	8.4	16.2±6.8	45±21.2	3304.5±2398	75.5±32.5	0.24±0.16	Sublingual formulation #60	95.4±10	10.5	9.0±2.6	22.5±10.6	1188.2±42.4	121.5±19.1	0.46±0.07
Sublingual formulation #62	99.0±4.4	4.5	43.6±20.7	50±17.3	2226.9±811.5	154.4±52.6	0.46±0.12	Sublingual formulation #60	95.4±10	10.5	9.0±2.6	22.5±10.6	1188.2±42.4	121.5±19.1	0.46±0.07

¹Reach C _MaxTime of 50%

²The expression medicine reaches treatment level and (surpasses 50%C _Max) relative time, be defined as the drug plasma concentration of removing half-life compensation with intravenous drug and keep surpassing C _MaxTime of 50% and its calculate by following formula: TTR=(surpasses C _MaxTime of 50%)/(intravenous of medicine end is eventually removed the half-life).The denominator that obtains from the literature research of fentanyl in the beagle is 244 minutes.

Medium disintegrate

Sublingual fentanyl pharmacokinetics be shown in Fig. 7.Slowly disintegrate

Sublingual fentanyl pharmacokinetics be shown in Fig. 8.

Embodiment 12: interior evaluating Sublingual alfentanil HCl preparation in canine model.

For illustrative purposes, prepared the erosion dosage form with the proof described dosage form adjusting of the application and control drug release and the final dynamic (dynamical) ability of drug disposition with alfentanil HCl.Described preparation compositions is described in table 23; All tablets are by directly compression preparation, as described in embodiment 1.

Table 23. is used to estimate the exemplary alfentanil preparation of interior medicine dynamics

The bioavailability and the pharmacokinetics of alfentanil are shown in table 24 estimated the preparation sublingual administration of comparing with intravenous in the beagle animal model that health is regained consciousness after.Intravenous administration be by alfentanil HCl individually dosed (n=3) (by will

500 μ g/mL inject to a lateral vein via the sterilization syringe needle and the syringe of suitable size with the dosage of 253 μ g alfentanil alkali).For sublingual administration, place the Sublingual of contiguous frenulum to carry out sublingual administration (n=2) measured matter (preparation #63, intensity is 239 ± 16.2 μ g alfentanil alkali) with tweezers.With condition identical described in the embodiment #7 under gather and storing blood; Use attested LC/MS/MS method to carry out sample analysis to analyze the alfentanil in the dog plasma.

The sublingual administration of table 24. alfentanil (i) preparation and the administration parameter of (ii) passing through the intravenous solution administration

Group	Handle	Dosage level (μ g) ^a	Route of administration	Animal number (male)
Group	Handle	Dosage level (μ g) ^a	Route of administration	Animal number (male)	1	Alfentanil solution	253	IV	3
2	The alfentanil preparation	239.0±16.2	The Sublingual	2	1	Alfentanil solution	253	IV	3

A=represents with free alkali.

The results are shown in Fig. 9.The PK analysis result is summarized in table 25.

The PK of the alfentanil sublingual formulation that table 25. is compared with the intravenous alfentanil analyzes

Group	F(％)	Absorb fluctuation (% CV)	T _onset(min) ¹	T _max (min)	C _max (pg/mL)	Plasma half-life (min)	Treatment time ratio ²
Group	F(％)	Absorb fluctuation (% CV)	T _onset(min) ¹	T _max (min)	C _max (pg/mL)	Plasma half-life (min)	Treatment time ratio ²	The intravenous alfentanil	-	10.5	0.5±0.05	1±0	139.1±76.4	4.4±2.4	0.04±0.02

Sublingual alfentanil preparation

94.1±4.6

4.9

11.7±1.3

15.0±4.2

35.5±2.6

40.8±8.5

0.33±0.07

¹Reach C _MaxTime of 50%

²The expression medicine reaches treatment level and (surpasses 50%C _Max) relative time, be defined as the drug plasma concentration of removing half-life compensation with intravenous drug and keep surpassing C _MaxTime of 50% and its calculate by following formula: TTR=(surpasses C _MaxTime of 50%)/(intravenous of medicine end is eventually removed the half-life).The denominator that obtains from the literature research of alfentanil in the beagle is 104 minutes.

Embodiment 13: estimate bioadhesive in human volunteer

The sufentanil pharmacokinetics of preparation

In 12 human volunteers, estimated bioadhesion through mucous membrane preparation #46, #47 as described in Table 9 and #48 (dosage is respectively 2.5 μ g, 5.0 μ g and 10.0 μ g sufentanil alkali units separately) in the human clinical research intersecting, had the cleaning phase to than the low dosage conversion time from higher.With individual every day with the side effect of naltrexone sealing to avoid class Opium to cause.Use tweezers with sufentanil

Preparation carries out sublingual administration in the bottom of frenulum.For relatively, with commercially available (intensity is 50 μ g/mL) thus the cumulative volume preparation accumulated dose that is diluted to 20mL in 0.9% saline is the intravenous sufentanil of 5 μ g and with its administration by IV conduit continuous infusion 10 minutes.For all groups ,-5.0 minutes (infusion begin before), 2.5 minutes, 5 minutes, 7.5 minutes, 10 minutes, 12.5 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, 160 minutes, 320 minutes, 480 minutes and 640 minutes are from all individual plasma samples of gathering after administration.

In addition, with 5.0mg preparation (#47) in 12 identical volunteers, to have estimated the pharmacokinetics of sufentanil behind 10 minutes the interval repeat administration 4 times.As indicated abovely carry out administration.Gather plasma sample at following time point from all individualities :-5.0 (for the first time

Before the administration), (be right after in 5 minutes, 7.5 minutes, 10 minutes for the second time

Before the administration), (be right after in 15 minutes, 17.5 minutes, 20 minutes for the third time

Before the administration), (be right after in 25 minutes, 27.5 minutes, 30 minutes at the 4th time

Before the administration), 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 190 minutes, 350 minutes, 510 minutes and 670 minutes.Use the LC-MS/MS sufentanil determination of plasma that confirms fully to measure the concentration of sufentanil in blood plasma.

Monitoring in this research

The disintegrate of preparation in the people.Used owning in this research

Disintegrate in 10 minutes to 30 minutes time in all individualities.With each sufentanil Sublingual

Place after 12 healthy volunteers' the chamber, Sublingual, all obtain remarkable constant pharmacokinetics spectrum, reach as shown in figure 10 that table 26 sums up for three kinds of dosage.

Compare with IV (n=12) among the table 26. people volunteer

Preparation (#46, intensity is 2.5 μ g; #47, intensity is 5.0 μ g; And #48, intensity is 10 μ g; Be n=12) pharmacokinetic analysis of sufentanil behind the sublingual administration

Group	F (％)	Absorb fluctuation (% CV)	C _max (pg/mL)	T _max (min)	Plasma half-life (hr)	Treatment time ratio ¹
Group	F (％)	Absorb fluctuation (% CV)	C _max (pg/mL)	T _max (min)	Plasma half-life (hr)	Treatment time ratio ¹	The intravenous sufentanil	-	20.7	0.0813±0.0281	0.16±0.03	1.19±0.18	0.067
Sublingual sufentanil preparation #46	97.8	24.7	0.0068±0.0021	0.73±0.13	1.65±0.43	0.74	The intravenous sufentanil	-	20.7	0.0813±0.0281	0.16±0.03	1.19±0.18	0.067
Sublingual sufentanil preparation #46	97.8	24.7	0.0068±0.0021	0.73±0.13	1.65±0.43	0.74	Sublingual sufentanil preparation #47	76.7	34.1	0.0109±0.0035	0.77±0.29	1.54±0.57	0.75
Sublingual sufentanil preparation #48	98.2	27.5	0.0275±0.0077	0.68±0.22	1.71±0.40	0.72	Sublingual sufentanil preparation #47	76.7	34.1	0.0109±0.0035	0.77±0.29	1.54±0.57	0.75
Sublingual sufentanil preparation #48	98.2	27.5	0.0275±0.0077	0.68±0.22	1.71±0.40	0.72	Per 10 minutes * 4 the repeat administration of #47NanoTab	96.4	25.7	0.0464±0.0124	1.04±0.23	1.97±0.30	NA

¹The expression medicine reaches treatment level and (surpasses 50%C _Max) relative time, and it calculates by following formula: TTR=(surpasses C _MaxTime of 50%)/(IV end eventually removes the half-life).Obtaining denominator from the literature research of sufentanil is 148 minutes.

Claims

1. the bioadhesion pharmaceutical dosage form that is used for the oral transmucosal administration, it comprises the soluble agents preparation, wherein said preparation contains the class Opium and the bioadhesive material of the pharmaceutically active of scheduled volume, described class Opium is selected from sufentanil, alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil or mirfentanil, and described bioadhesive material provides the adhesion to the oral mucosa of described individuality.

2. bioadhesion pharmaceutical dosage form as claimed in claim 1, wherein said oral mucosa are the Sublingual films.

3. bioadhesion pharmaceutical dosage form as claimed in claim 1, wherein said oral mucosa are the cheek films.

4. bioadhesion pharmaceutical dosage form as claimed in claim 2, wherein said dosage form become hydrogel and expand when contacting with waterborne liquid.

5. bioadhesion pharmaceutical dosage form as claimed in claim 2, wherein said dosage form are to corrode dosage form, and wherein when contacting with waterborne liquid, the surface of described dosage form hydration takes place and corrodes, and does not form hydrogel.

6. the bioadhesion pharmaceutical dosage form that is used for the oral transmucosal administration, it comprises the soluble agents preparation, wherein said preparation contains the pharmaceutically active medicament and the bioadhesive material of scheduled volume, and described bioadhesive material provides becomes hydrogel and expansion to the adhesiveness of the oral mucosa of individuality and wherein said dosage form when contacting with waterborne liquid.

7. the bioadhesion that is used for the oral transmucosal administration corrodes pharmaceutical dosage form, it comprises the soluble agents preparation, wherein said preparation contains the pharmaceutically active medicament and the bioadhesive material of scheduled volume, the amount of described active agents is selected from 10 μ g, 15 μ g, 25 μ g, 50 μ g, 100 μ g, 500 μ g, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg and 10mg, and described bioadhesive material provides the adhesiveness to the oral mucosa of individuality, wherein when contacting with waterborne liquid, hydration takes place and corrodes in the surface of described dosage form, and does not form hydrogel.

8. bioadhesion pharmaceutical dosage form as claimed in claim 1, the mucosal adhesive intensity of wherein said dosage form surpasses 500 dyne/cm ²

9. bioadhesion pharmaceutical dosage form as claimed in claim 6, the mucosal adhesive intensity of wherein said dosage form surpasses 500 dyne/cm ²

10. bioadhesion pharmaceutical dosage form as claimed in claim 7, the mucosal adhesive intensity of wherein said dosage form surpasses 500 dyne/cm ²

11. bioadhesion pharmaceutical dosage form as claimed in claim 1, the erosion time of wherein said dosage form is for high to being selected from the following time from 30 seconds: 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours or 8 hours or longer.

12. bioadhesion pharmaceutical dosage form as claimed in claim 6, the erosion time of wherein said dosage form is for high to being selected from the following time from 30 seconds: 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours or 8 hours or longer.

13. bioadhesion pharmaceutical dosage form as claimed in claim 7, the erosion time of wherein said dosage form is for high to being selected from the following time from 30 seconds: 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours or 8 hours or longer.

14. bioadhesion pharmaceutical dosage form as claimed in claim 1, wherein the amount at the described soluble agents preparation of Chinese medicine that absorbs via oral mucosa is selected from least 35%, 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% of described dosage form Chinese medicine.

15. bioadhesion pharmaceutical dosage form as claimed in claim 6, wherein the amount of the described soluble agents preparation of Chinese medicine that absorbs via oral mucosa is selected from the described dosage form at least 35%, 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% medicine.

16. bioadhesion pharmaceutical dosage form as claimed in claim 7, wherein the amount of the described soluble agents preparation of Chinese medicine that absorbs via oral mucosa is selected from the described dosage form at least 35%, 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% medicine.

17. comprising the opioid amount of described pharmaceutically active, bioadhesion pharmaceutical dosage form as claimed in claim 1, wherein said dosage form be selected from 10 μ g, 15 μ g, 25 μ g, 50 μ g, 100 μ g, 500 μ g, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg or 10mg.

18. comprising the opioid amount of described pharmaceutically active, bioadhesion pharmaceutical dosage form as claimed in claim 4, wherein said dosage form be selected from 10 μ g, 15 μ g, 25 μ g, 50 μ g, 100 μ g, 500 μ g, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg or 10mg.

19. comprising the amount of described pharmaceutically active medicament, bioadhesion pharmaceutical dosage form as claimed in claim 6, wherein said dosage form be selected from 10 μ g, 15 μ g, 25 μ g, 50 μ g, 100 μ g, 500 μ g, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg or 10mg.

20. bioadhesion pharmaceutical dosage form as claimed in claim 6, wherein said pharmaceutically active medicament are the class Opium that is selected from sufentanil, alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil or mirfentanil.

21. bioadhesion pharmaceutical dosage form as claimed in claim 7, wherein said pharmaceutically active medicament are the class Opium that is selected from sufentanil, alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil or mirfentanil.

22. bioadhesion pharmaceutical dosage form as claimed in claim 1, it comprises the sufentanil of pharmaceutically active amount.

23. bioadhesion pharmaceutical dosage form as claimed in claim 20, it comprises the sufentanil of pharmaceutically active amount.

24. bioadhesion pharmaceutical dosage form as claimed in claim 21, it comprises the sufentanil of pharmaceutically active amount.

25. bioadhesion pharmaceutical dosage form as claimed in claim 22, it comprises the sufentanil of about 0.25 μ g to 200 microgram (μ g).

26. bioadhesion pharmaceutical dosage form as claimed in claim 23, it comprises the sufentanil of about 0.25 μ g to 200 microgram (μ g).

27. bioadhesion pharmaceutical dosage form as claimed in claim 24, it comprises the sufentanil of about 0.25 μ g to 200 microgram (μ g).

28. bioadhesion pharmaceutical dosage form as claimed in claim 22, it comprises the sufentanil of about 2.5 μ g to 100 μ g.

29. bioadhesion pharmaceutical dosage form as claimed in claim 23, it comprises the sufentanil of about 2.5 μ g to 100 μ g.

30. bioadhesion pharmaceutical dosage form as claimed in claim 24, it comprises the sufentanil of about 2.5 μ g to 100 μ g.

31. bioadhesion pharmaceutical dosage form as claimed in claim 22, it comprises the sufentanil of about per kilogram 0.02 μ g to 5 microgram (μ g/kg).

32. bioadhesion pharmaceutical dosage form as claimed in claim 23, it comprises the sufentanil of about per kilogram 0.02 μ g to 5 microgram (μ g/kg).

33. bioadhesion pharmaceutical dosage form as claimed in claim 24, it comprises the sufentanil of about per kilogram 0.02 μ g to 5 microgram (μ g/kg).

34. bioadhesion pharmaceutical dosage form as claimed in claim 22, it comprises the sufentanil of about 2 μ g, 5 μ g or 10 μ g.

35. bioadhesion pharmaceutical dosage form as claimed in claim 23, it comprises the sufentanil of about 2 μ g, 5 μ g or 10 μ g.

36. bioadhesion pharmaceutical dosage form as claimed in claim 24, it comprises the sufentanil of about 2 μ g, 5 μ g or 10 μ g.

37. bioadhesion pharmaceutical dosage form as claimed in claim 1, it comprises the alfentanil of about 10 μ g to 10mg.

38. bioadhesion pharmaceutical dosage form as claimed in claim 20, it comprises the alfentanil of about 10 μ g to 10mg.

39. bioadhesion pharmaceutical dosage form as claimed in claim 21, it comprises the alfentanil of about 10 μ g to 10mg.

40. bioadhesion pharmaceutical dosage form as claimed in claim 1, it comprises the fentanyl of about 2 μ g to 1500 μ g.

41. bioadhesion pharmaceutical dosage form as claimed in claim 20, it comprises the fentanyl of about 2 μ g to 1500 μ g.

42. bioadhesion pharmaceutical dosage form as claimed in claim 21, it comprises the fentanyl of about 2 μ g to 1500 μ g.

43. bioadhesion pharmaceutical dosage form as claimed in claim 1, it comprises the fentanyl of about 50 μ g to 1500 μ g.

44. bioadhesion pharmaceutical dosage form as claimed in claim 20, it comprises the fentanyl of about 50 μ g to 1500 μ g.

45. bioadhesion pharmaceutical dosage form as claimed in claim 21, it comprises the fentanyl of about 50 μ g to 1500 μ g.

46. bioadhesion pharmaceutical dosage form as claimed in claim 1, it comprises the fentanyl of about 200 μ g to 1500 μ g.

47. bioadhesion pharmaceutical dosage form as claimed in claim 20, it comprises the fentanyl of about 200 μ g to 1500 μ g.

48. bioadhesion pharmaceutical dosage form as claimed in claim 21, it comprises the fentanyl of about 200 μ g to 1500 μ g.

49. bioadhesion pharmaceutical dosage form as claimed in claim 1, it comprises the lofentanil of about 0.25 μ g to 99.9mg.

50. bioadhesion pharmaceutical dosage form as claimed in claim 20, it comprises the lofentanil of about 0.25 μ g to 99.9mg.

51. bioadhesion pharmaceutical dosage form as claimed in claim 21, it comprises the lofentanil of about 0.25 μ g to 99.9mg.

52. bioadhesion pharmaceutical dosage form as claimed in claim 1, it comprises the carfentanil of about 0.25 μ g to 99.9mg.

53. bioadhesion pharmaceutical dosage form as claimed in claim 20, it comprises the carfentanil of about 0.25 μ g to 99.9mg.

54. bioadhesion pharmaceutical dosage form as claimed in claim 21, it comprises the carfentanil of about 0.25 μ g to 99.9mg.

55. bioadhesion pharmaceutical dosage form as claimed in claim 1, it comprises the remifentanil of about 0.25 μ g to 99.9mg.

56. bioadhesion pharmaceutical dosage form as claimed in claim 20, it comprises the remifentanil of about 0.25 μ g to 99.9mg.

57. bioadhesion pharmaceutical dosage form as claimed in claim 21, it comprises the remifentanil of about 0.25 μ g to 99.9mg.

58. bioadhesion pharmaceutical dosage form as claimed in claim 1, it comprises the trefentanil of about 0.25 μ g to 99.9mg.

59. bioadhesion pharmaceutical dosage form as claimed in claim 20, it comprises the trefentanil of about 0.25 μ g to 99.9mg.

60. bioadhesion pharmaceutical dosage form as claimed in claim 21, it comprises the trefentanil of about 0.25 μ g to 99.9mg.

61. bioadhesion pharmaceutical dosage form as claimed in claim 1, it comprises the mirfentanil of about 0.25 μ g to 99.9mg.

62. bioadhesion pharmaceutical dosage form as claimed in claim 20, it comprises the mirfentanil of about 0.25 μ g to 99.9mg.

63. bioadhesion pharmaceutical dosage form as claimed in claim 21, it comprises the mirfentanil of about 0.25 μ g to 99.9mg.

64. bioadhesion pharmaceutical dosage form as claimed in claim 1 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 70% bioavailability.

65. bioadhesion pharmaceutical dosage form as claimed in claim 20 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 70% bioavailability.

66. bioadhesion pharmaceutical dosage form as claimed in claim 21 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 70% bioavailability.

67. bioadhesion pharmaceutical dosage form as claimed in claim 1 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 75% bioavailability.

68. bioadhesion pharmaceutical dosage form as claimed in claim 20 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 75% bioavailability.

69. bioadhesion pharmaceutical dosage form as claimed in claim 21 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 75% bioavailability.

70. bioadhesion pharmaceutical dosage form as claimed in claim 1 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 85% bioavailability.

71. bioadhesion pharmaceutical dosage form as claimed in claim 20 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 85% bioavailability.

72. bioadhesion pharmaceutical dosage form as claimed in claim 21 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 85% bioavailability.

73. bioadhesion pharmaceutical dosage form as claimed in claim 1 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 90% bioavailability.

74. bioadhesion pharmaceutical dosage form as claimed in claim 20 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 90% bioavailability.

75. bioadhesion pharmaceutical dosage form as claimed in claim 21 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 90% bioavailability.

76. bioadhesion pharmaceutical dosage form as claimed in claim 1 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 94% bioavailability.

77. bioadhesion pharmaceutical dosage form as claimed in claim 20 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 94% bioavailability.

78. bioadhesion pharmaceutical dosage form as claimed in claim 21 wherein carries out single to individuality or repeats the oral transmucosal administration causing surpassing 94% bioavailability.

79. bioadhesion pharmaceutical dosage form as claimed in claim 1 wherein carries out single to individuality or repeats the oral transmucosal administration causing coefficient of variation to be lower than 30% bioavailability.

80. bioadhesion pharmaceutical dosage form as claimed in claim 20 wherein carries out single to individuality or repeats the oral transmucosal administration causing coefficient of variation to be lower than 30% bioavailability.

81. bioadhesion pharmaceutical dosage form as claimed in claim 21 wherein carries out single to individuality or repeats the oral transmucosal administration causing coefficient of variation to be lower than 30% bioavailability.

82. bioadhesion pharmaceutical dosage form as claimed in claim 1 wherein carries out single to individuality or repeats the oral transmucosal administration causing coefficient of variation to be lower than 40% bioavailability.

83. bioadhesion pharmaceutical dosage form as claimed in claim 20 wherein carries out single to individuality or repeats the oral transmucosal administration causing coefficient of variation to be lower than 40% bioavailability.

84. bioadhesion pharmaceutical dosage form as claimed in claim 21 wherein carries out single to individuality or repeats the oral transmucosal administration causing coefficient of variation to be lower than 40% bioavailability.

85. soluble agents dosage form as claimed in claim 1, wherein said pharmaceutical dosage form are carried out single oral transmucosal administration to individuality and are caused coefficient of variation to be lower than 30% C _Max

86. soluble agents dosage form as claimed in claim 20, wherein said pharmaceutical dosage form are carried out single oral transmucosal administration to individuality and are caused coefficient of variation to be lower than 30% C _Max

87. soluble agents dosage form as claimed in claim 21, wherein said pharmaceutical dosage form are carried out single oral transmucosal administration to individuality and are caused coefficient of variation to be lower than 30% C _Max

88. soluble agents dosage form as claimed in claim 1, wherein said pharmaceutical dosage form are carried out single oral transmucosal administration to individuality and are caused coefficient of variation to be lower than 40% C _Max

89. soluble agents dosage form as claimed in claim 20, wherein said pharmaceutical dosage form are carried out single oral transmucosal administration to individuality and are caused coefficient of variation to be lower than 40% C _Max

90. soluble agents dosage form as claimed in claim 21, wherein said pharmaceutical dosage form are carried out single oral transmucosal administration to individuality and are caused coefficient of variation to be lower than 40% C _Max

91. soluble agents dosage form as claimed in claim 1, wherein said pharmaceutical dosage form are carried out single oral transmucosal administration to individuality and are caused about 5 minutes to about 2 hours T _Max

92. soluble agents dosage form as claimed in claim 20, wherein said pharmaceutical dosage form are carried out single oral transmucosal administration to individuality and are caused about 5 minutes to about 2 hours T _Max

93. soluble agents dosage form as claimed in claim 21, wherein said pharmaceutical dosage form are carried out single oral transmucosal administration to individuality and are caused about 5 minutes to about 2 hours T _Max

94. soluble agents dosage form as claimed in claim 1, the single oral transmucosal administration of wherein said pharmaceutical dosage form cause blood plasma level being selected from about 3 minutes to 2 hours, about 3 minutes to 30 minutes, about 3 minutes to 20 minutes or reaching C in about 3 minutes to 10 minutes time _Max50%.

95. soluble agents dosage form as claimed in claim 20, the single oral transmucosal administration of wherein said pharmaceutical dosage form cause blood plasma level being selected from about 3 minutes to 2 hours, about 3 minutes to 30 minutes, about 3 minutes to 20 minutes or reaching C in about 3 minutes to 10 minutes time _Max50%.

96. soluble agents dosage form as claimed in claim 21, the single oral transmucosal administration of wherein said pharmaceutical dosage form cause blood plasma level being selected from about 3 minutes to 2 hours, about 3 minutes to 30 minutes, about 3 minutes to 20 minutes or reaching C in about 3 minutes to 10 minutes time _Max50%.

97. soluble agents dosage form as claimed in claim 1, the single oral transmucosal administration of wherein said pharmaceutical dosage form cause about 5 minutes to about 6 hours plasma half-life.

98. soluble agents dosage form as claimed in claim 20, the single oral transmucosal administration of wherein said pharmaceutical dosage form cause about 5 minutes to about 6 hours plasma half-life.

99. soluble agents dosage form as claimed in claim 21, the single oral transmucosal administration of wherein said pharmaceutical dosage form cause about 5 minutes to about 6 hours plasma half-life.

100. soluble agents dosage form as claimed in claim 1, the single oral transmucosal administration of wherein said pharmaceutical dosage form cause surpassing 0.07 treatment time ratio.

Soluble agents dosage form as claimed in claim 20, the single oral transmucosal administration of wherein said pharmaceutical dosage form cause surpassing 0.07 treatment time ratio.

Soluble agents dosage form as claimed in claim 21, the single oral transmucosal administration of wherein said pharmaceutical dosage form cause surpassing 0.07 treatment time ratio.

Soluble agents dosage form as claimed in claim 1, the single oral transmucosal administration of wherein said pharmaceutical dosage form causes about 0.5 to about 2.0 treatment time ratio.

Soluble agents dosage form as claimed in claim 20, the single oral transmucosal administration of wherein said pharmaceutical dosage form causes about 0.5 to about 2.0 treatment time ratio.

Soluble agents dosage form as claimed in claim 21, the single oral transmucosal administration of wherein said pharmaceutical dosage form causes about 0.5 to about 2.0 treatment time ratio.

Soluble agents dosage form as claimed in claim 1, wherein said pharmaceutical dosage form have the onset time (T that the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds causes about 3 minutes to about 23 minutes or 30 minutes _Onset).

Soluble agents dosage form as claimed in claim 6, wherein said pharmaceutical dosage form have the onset time (T that the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds causes about 3 minutes to about 23 minutes or 30 minutes _Onset).

Soluble agents dosage form as claimed in claim 7, wherein said pharmaceutical dosage form have the onset time (T that the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds causes about 3 minutes to about 23 minutes or 30 minutes _Onset).

Soluble agents dosage form as claimed in claim 1, wherein said pharmaceutical dosage form have the oral transmucosal administration to about 8 hours disintegration time and described pharmaceutical dosage form in about 15 minutes and cause extremely about 100 minutes onset time (T of about 14 minutes to about 82 minutes or about 10 minutes _Onset).

110. having the oral transmucosal administration to about 8 hours disintegration time and described pharmaceutical dosage form in about 15 minutes, soluble agents dosage form as claimed in claim 6, wherein said pharmaceutical dosage form cause extremely about 100 minutes onset time (T of about 14 minutes to about 82 minutes or about 10 minutes _Onset).

111. having the oral transmucosal administration to about 8 hours disintegration time and described pharmaceutical dosage form in about 15 minutes, soluble agents dosage form as claimed in claim 7, wherein said pharmaceutical dosage form cause extremely about 100 minutes onset time (T of about 14 minutes to about 82 minutes or about 10 minutes _Onset).

112. soluble agents dosage form as claimed in claim 22, wherein said pharmaceutical dosage form have the onset time (T that the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds causes about 3 minutes to about 13.5 minutes or 15 minutes _Onset).

113. soluble agents dosage form as claimed in claim 23, wherein said pharmaceutical dosage form have the onset time (T that the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds causes about 3 minutes to about 13.5 minutes or 15 minutes _Onset).

114. soluble agents dosage form as claimed in claim 24, wherein said pharmaceutical dosage form have the onset time (T that the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds causes about 3 minutes to about 13.5 minutes or 15 minutes _Onset).

115. having the oral transmucosal administration to about 8 hours disintegration time and described pharmaceutical dosage form in about 15 minutes, soluble agents dosage form as claimed in claim 22, wherein said pharmaceutical dosage form cause extremely about 100 minutes onset time (T of about 14 minutes to about 82 minutes or about 10 minutes _Onset).

116. having the oral transmucosal administration to about 8 hours disintegration time and described pharmaceutical dosage form in about 15 minutes, soluble agents dosage form as claimed in claim 23, wherein said pharmaceutical dosage form cause extremely about 100 minutes onset time (T of about 14 minutes to about 82 minutes or about 10 minutes _Onset).

117. having the oral transmucosal administration to about 8 hours disintegration time and described pharmaceutical dosage form in about 15 minutes, soluble agents dosage form as claimed in claim 24, wherein said pharmaceutical dosage form cause extremely about 100 minutes onset time (T of about 14 minutes to about 82 minutes or about 10 minutes _Onset).

118. having the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds, soluble agents dosage form as claimed in claim 37, wherein said pharmaceutical dosage form cause about 10 minutes to about 30 minutes onset time (T _Onset).

119. having the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds, soluble agents dosage form as claimed in claim 38, wherein said pharmaceutical dosage form cause about 10 minutes to about 30 minutes onset time (T _Onset).

120. having the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds, soluble agents dosage form as claimed in claim 39, wherein said pharmaceutical dosage form cause about 10 minutes to about 30 minutes onset time (T _Onset).

121. having the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds, soluble agents dosage form as claimed in claim 1, wherein said pharmaceutical dosage form cause about 20 minutes to about 140 minutes plasma half-life.

122. having the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds, soluble agents dosage form as claimed in claim 6, wherein said pharmaceutical dosage form cause about 20 minutes to about 140 minutes plasma half-life.

123. having the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds, soluble agents dosage form as claimed in claim 7, wherein said pharmaceutical dosage form cause about 20 minutes to about 140 minutes plasma half-life.

124. having the oral transmucosal administration to about 8 hours disintegration time and described pharmaceutical dosage form in about 15 minutes, soluble agents dosage form as claimed in claim 1, wherein said pharmaceutical dosage form cause about 100 minutes to about 300 minutes plasma half-life.

125. having the oral transmucosal administration to about 8 hours disintegration time and described pharmaceutical dosage form in about 15 minutes, soluble agents dosage form as claimed in claim 6, wherein said pharmaceutical dosage form cause about 100 minutes to about 300 minutes plasma half-life.

126. having the oral transmucosal administration to about 8 hours disintegration time and described pharmaceutical dosage form in about 15 minutes, soluble agents dosage form as claimed in claim 7, wherein said pharmaceutical dosage form cause about 100 minutes to about 300 minutes plasma half-life.

127. having the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds, soluble agents dosage form as claimed in claim 22, wherein said pharmaceutical dosage form cause extremely about 80 minutes plasma half-life of about 27 minutes to about 71 minutes or about 20 minutes.

128. having the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds, soluble agents dosage form as claimed in claim 23, wherein said pharmaceutical dosage form cause extremely about 80 minutes plasma half-life of about 27 minutes to about 71 minutes or about 20 minutes.

129. having the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds, soluble agents dosage form as claimed in claim 24, wherein said pharmaceutical dosage form cause extremely about 80 minutes plasma half-life of about 27 minutes to about 71 minutes or about 20 minutes.

130. having the oral transmucosal administration to about 8 hours disintegration time and described pharmaceutical dosage form in about 15 minutes, soluble agents dosage form as claimed in claim 22, wherein said pharmaceutical dosage form cause extremely about 300 minutes plasma half-life of about 112 minutes to about 298 minutes or about 100 minutes.

131. having the oral transmucosal administration to about 8 hours disintegration time and described pharmaceutical dosage form in about 15 minutes, soluble agents dosage form as claimed in claim 23, wherein said pharmaceutical dosage form cause extremely about 300 minutes plasma half-life of about 112 minutes to about 298 minutes or about 100 minutes.

132. having the oral transmucosal administration to about 8 hours disintegration time and described pharmaceutical dosage form in about 15 minutes, soluble agents dosage form as claimed in claim 24, wherein said pharmaceutical dosage form cause extremely about 300 minutes plasma half-life of about 112 minutes to about 298 minutes or about 100 minutes.

133. having the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds, soluble agents dosage form as claimed in claim 37, wherein said pharmaceutical dosage form cause extremely about 100 minutes plasma half-life of about 32 minutes to about 50 minutes or about 25 minutes.

134. having the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds, soluble agents dosage form as claimed in claim 38, wherein said pharmaceutical dosage form cause extremely about 100 minutes plasma half-life of about 32 minutes to about 50 minutes or about 25 minutes.

135. having the oral transmucosal administration to about 30 minutes disintegration time and described pharmaceutical dosage form in about 30 seconds, soluble agents dosage form as claimed in claim 39, wherein said pharmaceutical dosage form cause extremely about 100 minutes plasma half-life of about 32 minutes to about 50 minutes or about 25 minutes.

136. having, soluble agents dosage form as claimed in claim 1, wherein said pharmaceutical dosage form caused about 0.08 to about 0.48 or about 0.05 to about 0.5 treatment time ratio to the about 30 minutes disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 30 seconds.

137. having, soluble agents dosage form as claimed in claim 6, wherein said pharmaceutical dosage form caused about 0.08 to about 0.48 or about 0.05 to about 0.5 treatment time ratio to the about 30 minutes disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 30 seconds.

138. having, soluble agents dosage form as claimed in claim 7, wherein said pharmaceutical dosage form caused about 0.08 to about 0.48 or about 0.05 to about 0.5 treatment time ratio to the about 30 minutes disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 30 seconds.

139. having, soluble agents dosage form as claimed in claim 1, wherein said pharmaceutical dosage form caused about 0.34 to about 1.82 or about 0.3 to about 2.0 treatment time ratio to the about 8 hours disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 15 minutes.

140. having, soluble agents dosage form as claimed in claim 6, wherein said pharmaceutical dosage form caused about 0.34 to about 1.82 or about 0.3 to about 2.0 treatment time ratio to the about 8 hours disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 15 minutes.

141. having, soluble agents dosage form as claimed in claim 7, wherein said pharmaceutical dosage form caused about 0.34 to about 1.82 or about 0.3 to about 2.0 treatment time ratio to the about 8 hours disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 15 minutes.

142. having, soluble agents dosage form as claimed in claim 22, wherein said pharmaceutical dosage form caused about 0.12 to about 0.44 or about 0.05 to about 0.5 treatment time ratio to the about 30 minutes disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 30 seconds.

143. having, soluble agents dosage form as claimed in claim 23, wherein said pharmaceutical dosage form caused about 0.12 to about 0.44 or about 0.05 to about 0.5 treatment time ratio to the about 30 minutes disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 30 seconds.

144. having, soluble agents dosage form as claimed in claim 24, wherein said pharmaceutical dosage form caused about 0.12 to about 0.44 or about 0.05 to about 0.5 treatment time ratio to the about 30 minutes disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 30 seconds.

145. having, soluble agents dosage form as claimed in claim 22, wherein said pharmaceutical dosage form caused about 0.42 to about 1.82 or about 0.4 to about 2.0 treatment time ratio to the about 8 hours disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 15 minutes.

146. having, soluble agents dosage form as claimed in claim 23, wherein said pharmaceutical dosage form caused about 0.42 to about 1.82 or about 0.4 to about 2.0 treatment time ratio to the about 8 hours disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 15 minutes.

147. having, soluble agents dosage form as claimed in claim 24, wherein said pharmaceutical dosage form caused about 0.42 to about 1.82 or about 0.4 to about 2.0 treatment time ratio to the about 8 hours disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 15 minutes.

148. having, soluble agents dosage form as claimed in claim 37, wherein said pharmaceutical dosage form caused about 0.26 to about 0.4 or about 0.1 to about 0.5 treatment time ratio to the about 30 minutes disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 30 seconds.

149. having, soluble agents dosage form as claimed in claim 38, wherein said pharmaceutical dosage form caused about 0.26 to about 0.4 or about 0.1 to about 0.5 treatment time ratio to the about 30 minutes disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 30 seconds.

150. having, soluble agents dosage form as claimed in claim 39, wherein said pharmaceutical dosage form caused about 0.26 to about 0.4 or about 0.1 to about 0.5 treatment time ratio to the about 30 minutes disintegration time and the oral transmucosal administration of described pharmaceutical dosage form in about 30 seconds.

151. treatment shows the method for the individuality of symptomatic medical condition, it comprises the administration of the described soluble agents dosage form of claim 1, and wherein said pharmaceutical dosage form comprises effective reduction or eliminates the medicine of the pharmaceutically active amount of symptom described in the described individuality.

152. treatment shows the method for the individuality of symptomatic medical condition, it comprises the administration of the described soluble agents dosage form of claim 20, and wherein said pharmaceutical dosage form comprises effective reduction or eliminates the medicine of the pharmaceutically active amount of symptom described in the described individuality.

153. treatment shows the method for the individuality of symptomatic medical condition, it comprises the administration of the described soluble agents dosage form of claim 21, and wherein said pharmaceutical dosage form comprises effective reduction or eliminates the medicine of the pharmaceutically active amount of symptom described in the described individuality.

154. as the described method of claim 103, wherein said symptomatic medical condition is a pain.

155. as the described method of claim 104, wherein said symptomatic medical condition is a pain.

156. as the described method of claim 105, wherein said symptomatic medical condition is a pain.

157. the method for treatment pain in individuality, it comprises the administration of the described soluble agents dosage form of claim 1, wherein said pharmaceutical dosage form comprises the medicine of the pharmaceutically active amount of effective reduction or eliminate pain symptom, wherein reduces after described pharmaceutical dosage form administration or eliminates pain symptom in the described individuality.

158. the method for treatment pain in individuality, it comprises the administration of the described soluble agents dosage form of claim 20, wherein said pharmaceutical dosage form comprises the medicine of the pharmaceutically active amount of effective reduction or eliminate pain symptom, wherein reduces after described pharmaceutical dosage form administration or eliminates pain symptom in the described individuality.

159. the method for treatment pain in individuality, it comprises the administration of the described soluble agents dosage form of claim 21, wherein said pharmaceutical dosage form comprises the medicine of the pharmaceutically active amount of effective reduction or eliminate pain symptom, wherein reduces after described pharmaceutical dosage form administration or eliminates pain symptom in the described individuality.

160. as the described method of claim 158, wherein said symptomatic medical condition is an acute pain.

161. as the described method of claim 158, wherein said symptomatic medical condition is explosive pain.

162. as the described method of claim 158, wherein said symptomatic medical condition is a postoperative pain.

163. as the described method of claim 159, wherein said symptomatic medical condition is an acute pain.

164. as the described method of claim 159, wherein said symptomatic medical condition is explosive pain.

165. as the described method of claim 159, wherein said symptomatic medical condition is a postoperative pain.

166. as the described method of claim 160, wherein said symptomatic medical condition is an acute pain.

167. as the described method of claim 160, wherein said symptomatic medical condition is explosive pain.

168. as the described method of claim 160, wherein said symptomatic medical condition is a postoperative pain.