CN1901890B - Generally linear effervescent oral fentanyl dosage form and methods of administering - Google Patents

Abstract

Fentanyl containing dosage forms and methods using same are described. These dosage forms include substantially less fentanyl by weight than know oral formulation and have advantages in terms of cost and side effects. These dosage forms are intended for oral administration of fentanyl across the oral mucosa.

Description

The effervescent oral fentanyl dosage form and application process of generally linear

Background technology

Fentanyl (CAS Registry Number 437-38-7) N- phenyl-N- [1- (2- phenyl-ethyl groups) -4- piperidyls] propionamides and its salt, particularly its citrate CAS Registry Number 990-73-8) it is opiate (opiate), it is controlled substance, and is extremely effective narcotic analgesics.Fentanyl and its citrate are listed by many companies with a variety of mode of movements at present.For example, citric acid fentanyl can be with injection and on rod oral lozenge form obtain, the sales trademark of the latter is ACTIQ.There are three patents to be related to ACTIQ in FDA publication Approved Drug ProductsWith Therapeutic Equivalence Evaluations (following to be referred to as to make " yellow book ")：U.S. Patent number 4,671,953,4,863,737 and 5,785,989.The ACTIQ of second of form can also be obtained.This form can be the compressed tablets being located on rod.It is similar with original ACTIQ lozenge, it is believed that second of form is shown and original lozenge identical disintegration rate, T_max, C_maxAnd AUC.Therefore, they will be carried out with unified discussion, unless otherwise indicated, or specially pointed out within a context.

By Cephalon, Inc., 145 Brandy Wine Parkway West, Chester, the package insert information for the ACTIQ that PA 19380 is sold, can be obtained from Physician ' s DeskReference, 57th ed.2003, page 1184, therefrom it is recognized that taking the painful order of severity of its patient.According to its label, ACTIQ " indication be only be used for controlReceive already and be resistant to opiate therapy its basic persistent cancer painMalignant tumor patient break-through cancer pain " (Id. is emphasized in original text).The word of ACTIQ labels is incorporated herein by reference.

In ACTIQ clinical trials, break-through cancer pain is defined as appearing in the moderate in cancer patient to the transient flare of severe pain, the cancer pain of the patient experience continuation, it is controlled with the opiate medications of maintenance dose, including at least 60mg morphines/day, 50 μ g percutaneous fentanyl/hours or another opiate for waiting analgesic dose, continue one week or the longer time.Therefore, the patient for receiving ACTIQ is the patient with the insupportable pain that happens suddenly, although carrying out chronic analgesic treatment, still burst aggravation.It is unfeelingly related to the direct quality of life of patient that pain relief is provided to this breakthrough pain.Also, it is probably unique thing that medical science can be provided there is provided breakthrough pain relief for these patients.

As many things of medical domain, room for improvement is constantly present.Fentanyl is a kind of expensive medicine, and its production cost is up to 100/ gram of $ or more.Although the problem of cost is not above all, the problem of cost of drug therapy is to be considered.The preparation of fentanyl consumption, which can be reduced, can reduce the totle drilling cost of patient care.

Importantly, reducing the dosage of this effective opiate, while effective control to the breakthrough pain of cancer patient still can be realized, there is very far-reaching and preferable consequence in terms of the overall care of patient.Opiate mu-receptor activator, including fentanyl, can produce dose dependent respiration inhibition.Even if at the recommended dose, it is also possible to occur serious or fatal respiration inhibition in susceptible individual.Such as other effective opiates, it is related that fentanyl does not tolerate respiration inhibition case serious and fatal in individual to opiate.Therefore, the predose of the ACTIQ for treating breakthrough cancer patients' breaking-out should be 200 μ g, and each patient should adjust respectively, to provide appropriate analgesic effect, while side effect will be arrived into minimum.Meanwhile, side effect, even will not life-threatening side effect, it is also possible to it is important.

In addition, fentanyl is as mu- opiate agonists, there may be drug dependence and tolerance.Drug dependence itself might not turn into problem for the cancer patient of these types.But, fentanyl can also be used to treat other types of pain.In such therapeutic scheme, the problem of dependence and tolerance are probably important.In addition, cancer patient generally receives heavy drug therapy, it is possible to provide the time of the drug therapy of relatively low-dose, the longer the better.

CIMA LABS INC. are authorized on March 13rd, 2001,10000 Valley ViewRoad, Eden Prairie, MN 55344 United States Patent (USP) 6,200,604 illustrates two kinds of Sublimazes, each the fentanyl salt containing 36% effervescent agent and 1.57 milligrams.Referring to the patent the row of the 5th column the 60th to the row of the 6th column the 30th embodiment I.' No. 604 patents especially disclose effervescent agent to be used to influence the purposes of oral drug absorption as penetration enhancer.Referring also to United States Patent (USP) 6,759,059 and 6,680,071.Referring also to Brendenberg, S., 2003 New Concepts in Administration of Drugs in TabletsForm：Formulation and Evaluation of a Sublingual Tablets forRapid Absorption, and Presentation of an Individualized DoseAdministration System, Acta Universitiatis Upsaliensis.Comprehensive Summaries of Uppsala Dissertations from theFaculty of Pharmacy, 287,83pp.Uppsala ISBN 91-554-5600-6.

Similar pain relief effect is provided if the fentanyl of relatively low-dose can be realized, the medicine of patient's much less can obtain suitable benifit with relatively low cost, and with the side effect risk of reduction.Therefore, it is still desired to improve the administration of fentanyl.

Summary of the invention

The present invention relates to can in mouth disintegration/dissolving formulation, the method for preparing the formulation, the method that pain is treated using the formulation, and for producing the purposes of medicine, wherein, fentanyl, or its one or more officinal salts are (wherein, when mentioning " fentanyl " herein, it will be understood that including all officinal salts, unless the article pointed out other implications up and down) it is oral administration, compared with existing non-effervesce lollipop preparation (lozenge and compressed tablets), its dosage contains at least about 45% less fentanyl.Although dosage is relatively low, the C of these formulations that can be disintegrated in mouth of the invention_maxWith comprising it is much more for example approximately twice as so drug other formulations C_maxQuite.Herein, the C of the formulation of the present invention " quite " is represented_maxFor at least about 75% of the ACTIQ with about 2 times of so much fentanyls.Therefore, if the tablet of the 400 μ g present invention is compared with 400 μ gACTIQ lollipops, and both is compared with 800 μ g ACTIQ lollipops, then the C of Tablets_maxFor the C of 800 μ g ACTIQ preparations_maxAt least about 75%- about 125%.400 μ g ACTIQ preparations have much lower C_max.For the weight based on free form fentanyl be up to about 800 μ g dosage for be also such.Note, ± 10% " about " is represented in the context (dosage).Therefore, the μ g of about 100- about 800 are 90-880 μ g.It is further preferred that " quite " in the context of the invention also may indicate that the C of formulation of the present invention_maxFor ACTIQ C_maxAbout 80- about 120%.This can also be referred to as " highly suitable ".It is further preferred that " quite " in the context of the invention also may indicate that the C of formulation of the present invention_maxFor the C of the ACTIQ with about 2 times of weight fentanyls_maxAbout 5- about 115%.This can also be referred to as " very highly suitable "." peroral dosage form " in the context of the invention preferably excludes lollipop-sample lozenge such as ACTIQ

, replace including the tablet of dissolving, capsule, caplet, gel, emulsifiable paste and film etc. can be disintegrated in mouth.The formulation is preferably effervescent tablet.In addition, they can include pH Auto-regulators and disintegrant.Typically, privileged site in the oral cavity is applied or placed to the formulation, and they be disintegrated and/or dissolving during be maintained at there, generally about 10-30 minutes.

In another preferred aspect of the invention there is provided the effervesce formulation that can be disintegrated in mouth, it such as by buccal, gums administration or sublingual administration route, rather than is swallowed to be designed by oral administration fentanyl and/or its officinal salt.Once said preparation preferably do not include rod or it is other it is this kind of make its easily grip in patient's hand or formulation moisten in the oral cavity after the device that is taken out from mouth.In addition, with corresponding ACTIQ

Product is compared, and the formulation includes at least about 45% less fentanyl (based on it with the weight of the form calculus of free base material), the less fentanyls of more preferably from about 45%- about 55%.However, they are suitable in terms of Cmax, and it is preferably highly suitable, it is more preferably very highly suitable, and substantially equal effect.

Therefore, if in ACTIQ

If the fentanyl that 1600 μ g are provided in preparation, the corresponding formulation of the present invention is by the fentanyl including about 880 μ g or less.It is further preferred that it will include about 800 μ g fentanyl.Although medication amount is substantially reduced, at least one or more of traditional pharmacokinetic characteristic of the various medicines determined, such as C_max, will be similar, if not in better words.For example, to the corresponding ACTIQ containing at least 80% more weight fentanyl

Product is compared, according to the present invention, and preparation can have shorter T_max(reaching the time required for Cmax) and/or the quite C of (if not in better words)_max(maximum concentration observed after administration in blood samples of patients).For the increased formulation of fentanyl content in estimated dosage range, AUC or TG-AUC will be substantially linear.

In the particularly preferred aspect of the present invention, it has been found that dosage (by the weight of free alkali) and C of the preparation produced in fentanyl_maxBetween have substantial linear relation, particularly in the dosage range of about 100-800 μ g/ dosage." linear " is to be understood as representing, when an a series of part for the formulation as at least three with 90-880 μ g fentanyl various doses is prepared, in 90-880 μ g (more preferably 100-810 μ g) dosage range, dose normalized C_maxIt is not significantly different, using ANOVA, p (p is less than or equal to 0.15) in the range of 0.15.This is to determine the linear method for optimizing of the present invention.In other words, ln (C_max) vs.ln (dosage) slope should be 1 ± 15% (0.85-1.15).As what is noticed in the research being discussed herein, 200,500 and 810 μ g dosage is " linear " according to the present invention.Although 1080 μ g dosage is far better than prior art, in C compared with other dosage_maxWith not being " linear " defined herein in terms of dosage.

In the dosage range, C_maxIt is about 2.0- about 4.0 piks/mL/ μ g with the ratio between dosage.The picogram or proportional amount (if being determined in blood or other liquid) of fentanyl alkali i.e. per mL serum are standardized relative to every μ g dosage.Described in the present invention " between/- " include end points.It is further preferred that the ratio is about 2.5- about 3.5, more preferably about 2.7- about 3.5 piks/mL/ μ g.The scope is according to the average value that at least 10 patients calculate in appropriate clinical trial.By contrast, experiment is it has been determined that the ratio that ACTIQ is provided is about 1.4 piks/mL/ μ g.Therefore, for the formulation containing same amount of fentanyl, the present invention can provide approximately twice as C_max(if more), until 880 μ g dosage, for example, about 800 μ g, using the present invention.In another embodiment, when being prepared in the range of the μ g of about 100- about 800 fentanyl (free alkali) or the salt of proportional amount, the formulation will also provide dosage and C_maxBetween linear relationship.Certainly, for single dose intensity, it means that the dosage and C of the dosage_maxThe ratio between by with the series produced including more or less fentanyls there is linear relationship by only changing identical preparation within the above range.

Also preferred as one aspect of the invention be fentanyl effervesce formulation, it be in order to buccal, gums apply or sublingual administration and design, be 880 μ g or less fentanyl (weight based on free base material) containing weight, and its T_maxLess than about 1.5 hours, most preferably less than about 1 hour.But these formulations will have preferable C as described above_max, it is about 2.0- about 4.0 piks/mL/ μ g.Further relate to apply method of the formulation to treat pain.

In particularly preferred embodiment of the invention, the preparation includes effervescent agent, plays a part of penetration enhancer, is with or without but preferably comprises additional pH Auto-regulators.Most preferably, the pH Auto-regulators are and the composition for generating effervescent agent, the different material of one of compound or molecule.Particularly preferred formulation also includes disintegrant, and it allows for dosage reduction as described herein, linear and/or C_maxWith the ratio of dosage.A kind of more preferred example of disintegrant is starch glycolate.It is also preferred that including promoting the formulation with the filler of disintegrant identical performance described above.Most preferably, the filler is mannitol.

In particularly preferred embodiment of the invention, buccal there is provided being adapted to, the peroral dosage form of gums administration or sublingual administration contains at most 1 milligram, more preferably 100,200,300,400,600 or 800 μ g fentanyl, weight is the measure as free alkali, and also includes at least one effervescent agent pair, at least one pH Auto-regulators and suitable excipient.Preferably, the preparation is possible to provide the T of 1.5 hours or less_maxAnd/or about 2.0- about 4.0 piks/mL/ μ g C_max.In other words, the C of formulation of the present invention_maxWith the ACTIQ containing at least about 80% more weight fentanylThe C of preparation_maxQuite.In another preferred embodiment, the C of the formulation_maxFor the ACTIQ with least about 80% more weight fentanyl free base

About 25% within, within preferably approximately 20%, more preferably it is within about 15%.

In another particularly preferred embodiment of the present invention, buccal there is provided being adapted to, the tablet that can be disintegrated in mouth of gums administration or sublingual administration contains about 100,200,300,400,600 or 800 μ g fentanyl (being determined in the form of free alkali), at least one effervescent agent pair, with at least one pH Auto-regulators, and suitable excipient, the formulation can provide the T of about 1.5 hours or less_maxAnd/or about 2.7- about 3.5 piks/mL/ μ g C_max。

In another embodiment of the invention, any preparation previously mentioned herein can be consisted of the following composition substantially：Fentanyl, preferable amount is about 800 μ g or following (that is, at most 880 μ g), effervescent agent pair, at least one pH Auto-regulators and suitable excipient, and it can provide about 2.0- about 4.0 piks/mL/ μ g C_max, more preferably about 2.5- about 3.5 piks/mL/ μ g, most preferably about 2.7- about 3.5 piks/mL/ μ g, and than providing suitable C_maxACTIQFormulation contains at least about 45% less fentanyl.Herein, " substantially by ... constitute/constitute substantially " represents to eliminate the combination of any excipient or excipient, or how properly, any excipient of any amount or the combination of excipient, and any pH Auto-regulators or the pH Auto-regulators of any amount, excipient and the pH Auto-regulator can change the present invention basic and new feature.Therefore, will exclude can be by T_maxIncrease to the specific excipient of 2.5 hours or more or the mixture of excipient.Similarly, and equally it is only used for purpose of illustrating, can be by C_maxChanging to the combination for not expecting the horizontal excipient provided with specified quantitative to be left out.A small amount of cross-linked pvp and/or lactose monohydrate is although be usually to be not intended to, as long as it will not significantly change the T of formulation of the present invention_maxOr C_max, still can use.But, if be used together, and respectively with 5% and 20% level use, they can bring unfavorable change to above-mentioned characteristic.Therefore, the above-mentioned excipient of the amount of combination will be excluded.

In the particularly preferred embodiment of this aspect of the present invention there is provided formulation basic composition is：90-880 μ g fentanyl (being calculated with fentanyl free base) or its salt, sodium starch glycolate, mannitol, at least one pH Auto-regulators and at least one effervescent agent pair.Preferably, the T of the formulation_maxIt is about 1.5 hours or less, C_maxIt is about 2.0- about 4.0 piks/mL/ μ g, the linear C with dosage with the ratio between dosage_maxAnd/or suitable C as defined herein_max, the formulation is adapted to buccal, and sublingual administration or gums are applied.It is further preferred that determining the amount of fentanyl in the form of free alkali as 100-800 μ g.

Another aspect of the present invention further relates to the method for applying fentanyl to the patient of experience pain, generally comprises but is not limited to：Backache, low back pain, arthralgia, any type of arthritis ache, due to the pain that wound or accident are caused, neuropathic pain, operation or postoperative pain, the pain caused by the disease or illness beyond cancer, cancer pain, and especially because the breakthrough pain that cancer is caused.It is preferred that method comprise the following steps：To patient in need using described herein for buccal, gums administration or any effervescent tablet that can be disintegrated in mouth of sublingual administration, it includes the fentanyl that dosage is about 100-800 μ g (being determined in the form of free alkali), and the formulation is maintained at the sufficiently long time in patient mouthful, to cause the dosage (or it treats meaningful and/or live part) to be transported from oral cavity into blood flow.Preferably, the patient is instructed, trains or observe, to ensure that the dosage is not swallowed, but in feasible degree, fentanyl enters internal by mouth and intraoral one or more surfaces.This method further preferably includes the formulation being maintained in mouth, the step of moving it generally not in oral cavity.In another preferred aspect, the dosage dissolving/disintegrating or mean residence time are 5-30 minutes.

A kind of such method is the method for treating break-through cancer pain breaking-out, is comprised the following steps：The fentanyl (being calculated with fentanyl free base) of about 100 μ g initial doses or the salt of its equal parts are provided, in a kind of formulation, it includes effervescent agent pair, and consumption is the about 5- about 85% of the formulation weight；PH Auto-regulators, consumption is the about 0.5- about 25% of the formulation weight；And starch glycolate, consumption is the 0.25- about 20% of the formulation weight.The formulation is adapted to the oral mucosa that the conveying fentanyl passes through patient." offer " is understood as that including being taken out formulation from the package or someone's distribution or distributing the formulation.Methods described also includes the formulation being put into patient mouthful, between cheek and upper gums or lower gums, keeps the fentanyl for being enough to convey therapeutically effective amount to pass through the time of the oral mucosa.Other types of pain, including any kind of backache, operation or postoperative pain and neuropathic pain can be treated with identical method.

It is surprising that the tablet that can be disintegrated in mouth can be produced, this tablet using fentanyl in order to design in the oral cavity, and it can provide the T of 1.5 hours or less_max, wherein the fentanyl comprising 880 μ g or less (being determined with free alkali), preferably with preferable C_maxAlthough having pointed out its T about some documents of ACTIQ lozenge_maxIt it is about 45 minutes, test is it has been shown that this time is more likely two hours.

It is surprising that the formulation that can be disintegrated in mouth can be produced, it is in order to which by buccal, sublingual administration or gingival administration route are designed, the formulation C suitable with offer using fentanyl in the oral cavity_maxThe ACTIQ of data

Formulation is compared, and includes at least about 45% less fentanyl.

Equally unexpectedly, the formulation that can be disintegrated in mouth can be produced, and treat pain with it, the breakthrough pain that particularly treating cancer patient is undergone, wherein, therapeutically effective amount (amount that pain relief to a certain degree can be provided), usually more than 75%, more preferably above 80%, most preferably 90% or more fentanyl dosage by from oral cavity by oral mucosal absorption into blood flow.

Equally it is surprising that having the C of the formulation of so few active medicine compared with the product sold in the market_maxIn C_maxWith dose relationship in terms of can be linear, for example, in the range of the μ g of about 100- about 800 (90-880 μ g) ± 15% confidential interval.

Buccal there is provided preparing according to another aspect of the present invention, the method for the effervesce fentanyl dosage form of gums administration or sublingual administration, the formulation can provide one or more following features：Dosage and C in the range of the μ g of about 100- about 800_maxBetween linear relationship；With the non-effervescent formulation such as ACTIQ of same doseCompare, the suitable C under the dosage of at least about 45% less fentanyl_max；With 2.0-4.0 piks/mL/ μ g C_maxThe ratio between with dosage.This is by the way that following material mixing is completed：Effervescent agent pair of the fentanyl (being calculated according to the weight of free alkali) of the amount of the μ g/ formulations of about 100- about 800 with effective dose, the local pH (" local pH ") being once placed in described in patient mouthful in formulation and the microenvironment of oral mucosa surface area contact can be made to change (as described herein to determine, compared with the same preparation without pH Auto-regulators, change at least 0.5 pH unit) effective dose pH Auto-regulators, and disintegrant, it allows for above-described dosage reduction, linear relationship and C_maxThe ratio between with dosage.These materials are tabletted or formulation is otherwise made using routine techniques.The process does not preferably use granulation and realized, although used various materials can be granulated before mixing.Therefore, moist granulating sugar can be used in addition dry and direct pressing process as filler.

It is further preferred that methods described be used for prepare formulation, preferred tablet, it is in the range of the μ g of about 100- about 800 in dosage and C_maxBetween produce linear relationship, compared with the ACTIQ of same dose, there is the suitable C of height under at least about 50% less fentanyl dosage_maxAnd/or C_maxIt is about 2.7- about 3.5 piks/mL/ μ g with the ratio between dosage.This is realized by mixing following component：It is adapted to provide for the fentanyl or its salt of each formulation with the μ g fentanyls of about 100- about 800 of predetermined quantity；Effervescent agent pair, consumption is the about 5- about 85% (w/w) of finished dosage forms weight；PH Auto-regulators, consumption is about 0.5- about 25%w/w；Starch glycolate, consumption is about 0.25- about 20%w/w；It is with or without mannitol；And the mixture is pressed into the tablet of drying regime.Preferably, compared with the same preparation without Auto-regulator, the pH Auto-regulators change the local pH for providing at least about 1 pH unit.

Describe in detail

Including in the entire disclosure including claims, the deformation of word " include/include (comprise) " and the word, such as " comprising " and " comprises ", and " have/contain (have) ", " having ", " including (includes) ", " include " and " including " and their version, the step of expression is previously mentioned, element or material are required, other steps, element or material can but be increased, and still constitute the scheme in claims or scope of disclosure.When being quoted from the description present invention and claims, what it represented that the present invention and claim be claimed is considered as following and is possible to include more.These terms, are to include property or open, and be not excluded for other elements or method and step do not mentioned particularly when in for claims.

For the purposes of the present invention, except non-binding special properties, feature or variable are defined otherwise, term " substantially/generally " for any standard such as characteristic, when feature or variable, represent to meet the pointed standard of this measurement, so, it will be appreciated by persons skilled in the art that the benefit to be obtained is met, or desired condition or characteristic value.

On the one hand, the present invention includes a kind of formulation, and it includes the μ g (microgram) of about 100- about 800 fentanyl (being calculated with fentanyl free base) or its salt, is adapted to buccal, sublingual administration or gums administration.The formulation is by contacting time enough with oral mucosa when suitably applying, using the teaching of the invention it is possible to provide the T of 1.5 hours or less_max.In addition or it the substitute is, it is possible to achieve C_maxIt is about 2.0- about 4.0, more preferably about 2.3- about 3.5, most preferably about 2.7- about 3.5 piks/mL/ μ g with the ratio between dosage.Most preferably, compared with the other dosage prepared in the same manner, for the μ g of about 100- about 800 dosage, dosage and C_maxBetween relation be linear.

The formulation is preferably also comprising at least one pH Auto-regulators and at least one effervescent agent pair.They are the T to be enough required for providing respectively_maxAnd/or C_maxAmount provide.The formulation is further preferably comprising at least one excipient, and its selection and consumption make it that the T of needs can be provided to combining with least one pH Auto-regulators and at least one effervescent agent_maxAnd/or C_max。

Another aspect of the present invention is the method for applying fentanyl to the patient of experience pain, and this method may include following steps：Allow the oral mucosa and the dosage form contacts that can be disintegrated in mouth of patient in need.The formulation includes the fentanyl that dosage is about 100-800 (90-880) μ g (measure in the form of free alkali)/formulation, or its salt.The formulation can provide the T of 1.5 hours or less_max, and/or C_maxIt is about 2.0- about 4.0, more preferably about 2.3- about 3.5, most preferably about 2.7- about 3.5 piks/mL/ μ g, and/or C with the ratio between dosage_maxLinear relationship between dosage, is preferably to include the formulation of at least 45% less fentanyl compared with using commerce known transporting pattern prescription.The formulation is allowed to keep contacting the sufficiently long time with patient's oral mucosa so that meaningful or live part the fentanyl for the treatment of, preferably greater than 75%, more preferably above 80%, most preferably 90% or more dosage is transported into blood flow by oral mucosa from oral cavity.

Another aspect provides a kind of formulation, it is included：The μ g of about 100- about 800 fentanyl/formulation, with the form calculus of fentanyl free base.When in use, fentanyl salt is used with the amount for providing the fentanyl free base of equivalent weight.The formulation is adapted to buccal, sublingual administration or gums administration.The formulation by contacted with oral mucosa time enough suitably apply when, using the teaching of the invention it is possible to provide C_maxFor ACTIQ

The C of preparation_maxAt least about 75- about 125%, more preferably about 80- about 120%, most preferably about 85%- about 115%, wherein, described the latter include the more fentanyls of weight at least 80%.Preferably, the formulation also includes at least one pH Auto-regulators and at least one effervescent agent pair, and its consumption is enough to provide the C_max.It is further preferred that the formulation also includes a certain amount of at least one excipient, it is enough to provide preferable C to combined with least one pH Auto-regulators and/or at least one effervescent agent_max。

The method for further relating to apply fentanyl to the patient of experience pain, comprises the following steps：Allow the oral mucosa and the dosage form contacts that can be disintegrated in mouth of patient in need, the fentanyl dosage that the formulation is included is each formulation about 100-800 μ g (being determined in the form of free alkali), or equivalent its salt.The C that the formulation is shown_maxIt is to include the ACTIQ of the more fentanyls of weight at least 80%At least about 75%- about 125% of preparation, more preferably about 80- about 120%, most preferably about 85%- about 115%.The formulation is kept contacting the sufficiently long time with patient's oral mucosa, and meaningful or live part fentanyl is treated to transport, and the 75% of preferably greater than described dosage, more preferably above 80%, most preferably 90% or more, blood flow is entered from oral cavity by oral mucosa.

It has now been found that using effervescent agent and pH Auto-regulators, particularly when being combined with starch glycolate, using the teaching of the invention it is possible to provide in terms of the fentanyl amount that remarkable advantage, particularly medication need.It has also been discovered that some excipient are combined with effervescent agent pair and pH Auto-regulators, it is possible to provide even preferably and unusual unexpected result.

Determine whether particular formulations result in result described herein, people only need to carry out routine human clinical's research to said preparation at least ten patients.Suitable clinical research can use any conventional model.The example properly studied is as follows：

Clinical study design and operation

This research and informed consent form (ICF) have obtained Institutional Review Board (IRB) accreditation.Before the study starts, all objects are all read and signed on the ICF that IRB- approves.The ICF of signature and just mistake is achieved.

For the first two stage, the research receives one of three kinds of additional test formulations using the single dose for specifying experiment and reference product, randomization, open-label, bidirectional crossed design, and object are random during the 3rd stage.All objects are carried out with randomization, and fasting state is in afterwards overnight within 10 hours in fasting.There is the wash-off interval time of 7 days between three application dosages.The object is limited in clinic until applying after fentanyl 36 hours.

The object is screened within 21 days before research is added.Screening sequence includes medical history, physical examination (height, body weight, the bodily form, vital sign, and ECG), (hematology is detected with clinical labororatory, serum chemistry, urinalysis, HIV antibody screening, hepatitis B surface antibody is screened, antibody to hepatitis C is screened, serum pregnancy [being only applicable to women]), and the screening to cannboid and opioid.

All objects for adding this research all meet cited selected/exclusion standard in scheme.This research is related to 42 objects altogether, 17 males and 25 women, has 39 objects, 17 males and 22 women, completes this research.

Early morning of the object before each medication is reported to clinic, and 19 hours before medication have lunch, and uses within 14 hours before medication dinner, and 11 hours eat a piece before medication.Then the object follows 10 hours overnight fasts.At the 1st day, start standardized meal schedule, have lunch within 4.5 hours after medication, use within 9.5 hours after medication dinner, and 13 hours after medication eat a piece.At the 2nd day, eat the breakfast within 24.5 hours after medication, have lunch within 28.5 hours after medication, and 33 hours after medication use dinner.

48 hours and the period object can not consume any containing alcohol before each stage is closed, broccoli, citrus, the food or beverage of caffeine or xanthine.Before research is participated in, object does not contact nicotine and tobacco at least six month.In addition, forbidding non-prescribed medicine drug therapy during 7 days and this research before medication.Before medication during 14 days and this research, Prescription medications (except female hormonal contraception medicine) are not allowed.

During this research, the object keeps taking one's seat 4 hours after citric acid fentanyl is taken.0 hour to the 4 hours water restriction after medication.Fed to limitation in 4 hours after medication within 10 hours before medication.During this research, the object does not allow to be engaged in any strenuous exercise.

Details are as follows for the naltrexone that object receives in each stage：

Adm 1：ReVia

50mg (Naltrexone Hydrochloride tablet)

Produced by Bristol-Myers Squibb companies

Lot number：5C269A

Keeping life：In April, 2004

Lot number：TB1798

Keeping life：In March, 2005

Distribution to processing A, B, C, and D object receives a 50mg naltrexone tablet of oral dose, 15 hours and 3 hours and is taken after administration together with 240mL water within 12 hours before fentanyl dosage is taken.

Distribution receives a 50mg naltrexone tablet of oral dose to processing E object, is to be taken together with 240mL water for 15 hours and 3 hours before fentanyl dosage is taken.

Object receives one of following fentanyl treatment in each stage of three phases：

A：OraVescentThe μ g of citric acid fentanyl tablet 1080 (being used as fentanyl alkali)

Produced by CIMA LABS companies

Lot number：930502

The object for being randomized to processing A receives a 1080 μ g fentanyl tablets of single oral dose, is placed between gums and cheek, above molar, and allows it to be disintegrated 10 minutes.Note, " OraVescent

" represent the preparation and formulation of the present invention.

B：Actiq

(oral transmucosal citric acid fentanyl) is equivalent to 1600 μ g

Produced by Cephalon companies or Anesta

Lot number：02689W3

The object for being randomized to processing B receives a 1600 μ g Actiq of single oral doseUnit, is placed between cheek and lower gums.The unit is moved to another side from one side with handle, and allow it to dissolve 15 minutes.

C：OraVescentThe μ g of citric acid fentanyl tablet 1300 (being used as fentanyl alkali)

Produced by CIMA LABS companies

Lot number：930503

The object for being randomized to processing C receives a 1300 μ g fentanyl tablets of single oral dose, is placed between gums and cheek, above molar, and allows it to be disintegrated 10 minutes.

D：OraVescent

The μ g of citric acid fentanyl tablet 810 (being used as fentanyl alkali)

Produced by CIMA LABS companies

Lot number：930501

The object for being randomized to processing D receives a 810 μ g fentanyl tablets of single oral dose, is placed between gums and cheek, above molar, and allows it to be disintegrated 10 minutes.

E：OraVescent

The μ g of citric acid fentanyl tablet 270 (being used as fentanyl alkali)

Produced by CIMA LABS companies

Lot number：930500

The object for being randomized to processing E receives a 270 μ g fentanyl tablets of single oral dose, is placed between gums and cheek, above molar, and allows it to be disintegrated 10 minutes.

The composition of each above-mentioned citric acid fentanyl tablet is disclosed in embodiment 1-4.

Daily early morning is before medication 0.25,0.5,0.75,1,1.25,1.5,1.75,2 after (0 hour) and medication, 2.25,2.5,2.75,3,3.25,3.5,3.75,4,5,6,8,10,24, and the vital sign (blood pressure, pulse, and breathing) assessed when sitting quietly for 36 hours.Preceding 8 hours carry out continuous pulse oximetry after medication.12- lead electrocardiogram, clinical laboratory assessments (hematology, serum chemistry, and urinalysis), and the physical examination containing complete vital signs are carried out at the end of this research.Carry out Oral irritation assessments within 4 hours after medication.Tell object that any adverse events occurred during this research are notified to the doctor and/or nurse of this research.

Distribution is gathered in the following time to the blood sample (7mL) of processing A-D object：Before medication (0 hour), and 10,20,30 and 45 minutes after medication；With after medication 1,2,4,6,8,10,12,16,20,24,28,32, and 36 hours.Distribution is gathered in the following time to the blood sample (7mL) of processing E object：Before medication (0 hour), and 10,20,30 and 45 minutes after medication；And 1 after medication, 2,4,6,8,9,10,11,12,14,16,20, and 24 hours.Having extracted 54 blood samples (378mL) altogether during this research is used for Pharmaceutical Analysis.Sample is gathered under fluorescence irradiation and be processed at room temperature.Allow blood serum sample to solidify, by centrifuging, freezed at -20 DEG C, and keep freezing state until analysis.

Analysis method

The LC-MS/MS (liquid chromatography-mass spectral analysis/mass spectral analysis) of fentanyl in human serum.

Pharmacokinetics and statistical method

Pharmacokinetics and statistical analysis are affixed one's name to based on food and medication management, assessing drug actions and research center (CDER), the industry guide that in January, 2001 promulgates, entitled " StatisticalApproaches to Establishing Bioequivalence ", the industry guide promulgated with March, 2003, entitled " Bioavailability and BioequivalenceStudies for Orally Administered Drug Products-GeneralConsiderations ".

According to the fentanyl concentration v. time data of each processing, following non-chamber pharmacokinetic parameter is calculated using WinNonlinStandard Edition version 2.1.Actual (rather than nominal) sample time is used for the analysis.

AUC (0-t) is located at sweet smell too using linear trapezoidal read group total from the zero-time to the t times

Area below Buddhist nun's concentration time curve, wherein, t is can finally to survey

Determine concentration (Ct) time.

AUC (0-inf) is from the zero-time to infinitely below fentanyl concentration time curve

Area, AUC (0-inf)=AUC (0-t)+Ct/Kel, wherein

Kel is whole last elimination rate constant.

The ratio between AUC (0-t)/AUC AUC (0-t) and AUC (0-inf).Also referred to as AUCR.(0-inf)

Intermediate value Ts of the AUC (0-tmax) from zero-time to reference preparation_maxArea, be profit

With linear trapezoidal read group total.

The terminal linear portion vs. time graphs that Kel passes through log concentration it is linear

Return the elimination rate constant last eventually calculated, wherein Kel=- slopes.

Terminal linear portion is determined by visual inspection.

The elimination half-life period that T1/2 is calculated with ln (2)/Kel.

C_maxIt was observed that maximum fentanyl concentration.

T_maxThe time of maximum fentanyl concentration (is obtained under conditions of no interpolation

).

This research is the single dose for specifying experiment and reference product, randomization, bidirectional crossed (processing A and the processing B of open-label, 1st and 2 stages), object receives one of three kinds of other test preparations in phase III randomization (processing C handles D, or processing E).Due to the object with greater number, this research is divided to two groups of progress.Primarily comparing for this research is that processing A handles B relatively.In order to compare the variance analysis of both the above processing, two kinds of orders (AB, BA), two stages (1,2), and two kinds of processing (A, B) are only considered.

Parameter (normal-theory) general linear model is used for AUC (0-inf), AUC (0-t), and the C of the Logarithm conversion from processing A and B_maxValue^5-7.Complete variance analysis (ANOVA) model considers the group in the model, and including following factor：Object/group in stage in group, group, processing, order, order/group, order, and processing/group.Because processing/group interaction is not obvious, the model is kept to the object in order, order, stage, and processing.Using the square checkout sequence effect of the object in order, all other main effects are examined using residual error (error mean square).Two kinds are unidirectionally assumed in 5% level to AUC (0-t), AUC (0-inf), and C_maxTest, to testing and building 90% confidential interval with reference to the ratio between average value (processing A vs. handle B).

Processing A and processing B T are assessed by Wilcoxon Signed Ranks Test_maxDifference (α=0.05).

In processing C, D, and processing E (respectively 1300 μ g, 810 μ g, and 270 μ g OraVescent are handledCitric acid fentanyl tablet) after, also measured were serum fentanyl concentration and pharmacokinetic parameter.In order to assess OraVescent

The dose proportionality (proportionality) of citric acid Sublimaze, is used for the dose normalized C from processing A, C, D, and E by mixed linear model_maxWith AUC parameters^5-7.Complete model considers packet and including following item：Object/packet in stage in group, group, processing, order, order/packet, order, and processing/packet.For two kinds of [C in three kinds of parameters_maxWith AUC (0-t)] for, processing/packet interaction is not notable, and model is kept into the unidirectional ANOVA with processing factor.If it find that total treatment effect, is compared with processing A and is compared in pairs.

Dwell time values are calculated by deducting processing time of application from the time for the preparation disappearance felt and confirmed (preparation has time span in the oral cavity).Values above is carried out to make table, and the statistics of conclusion are presented.

As a result

The demography of object and configuration

One has 42 objects (17 males and 25 women) to take part in this research, and has 39 objects (17 males and 22 women) to complete this research.

There are three objects to terminate/exit from this research.One object is exited before second stage, because the object is not intended to continue this research.Second place object is exited before the phase III, because the object is not intended to continue this research.Third object is exited before second stage, because the object has taken antibiotic.

The average age of the object is 27 years old (the range of age is 19-55 Sui), the average height of the object is 68 inches (in 62-74 inch ranges), and the average weight of the object is 152.1 pounds (in the range of 109.0-197.0 pounds).

Protocol Deviations and adverse events

Following scheme deviation is occurred in that during this research is carried out.

According to the scheme, object determined breathing in the vital signs time point of 3.5- hours.One object is not determined in 3.5- hours point in second stage and breathed.There are two objects not carry out reexamining for vital sign in the 3- hours point of second stage.2.25- hours point of one object in the phase III does not carry out vital sign and reexamined.The .33- hours point that the blood sample of this two objects (handles A) in the first stage is not marked correctly.Above-mentioned sample is not analyzed.According to the program, object determined pulse in 3.5- hours vital signs time points.One object does not determine pulse in 3.5- hours point in the first stage.It is exposed to without an object and exceedes more than one above-mentioned deviation.Serious adverse events are not reported.

From this research have altogether 15 batches need handle clinical sample.In this is 15 batches, it is acceptable to have 14 batches.The normal concentration that Back for 14 batches of acceptable human serums of this research is calculated covers the scope of 50.0-5000.0pg/mL (pik/mL), is quantitatively limited to 50.0pg/mL.It is less than or equal to 7.89% with the coefficient of variation of the quality-control sample per a collection of acceptable sample analysis.

Residence time

Duration data is summarized in following table.

The general introduction of tablet/lozenge residence time

	Handle A	Handle B	Handle C	Handle D	Handle E
						Object number	Time (minute)	Time (minute)	Time (minute)	Time (minute)	Time (minute)
Average value	21	34	19	25	22
						SD	12	15	11	14	17
CV	58	44	56	57	75
						SEM	2	2	3	4	4
N	40	42	12	13	14
						Minimum value	3	9	4	4	4
Maximum	48	77	33	50	62

Handle A=1 × 1080mcg OraVescent citric acid fentanyl tablets：Experiment

Handle B=1 × 1600mcg oral transmucosal citric acid fentanyls (Actiq)：Control

Handle C=1 × 1300mcg OraVescent citric acid fentanyl tablets：Experiment

Handle D=1 × 810mcg OraVescent citric acid fentanyl tablets：Experiment

Handle E=1 × 270mcg OraVescent citric acid fentanyl tablets：Experiment

SD=standard deviations；The CV=coefficient of variation；The standard error of SEM=average values；

N=(observation) number

One object occurs in that slight oral stimulation (belonging to 2 grades in 1-10 grade) after being reported in processing C.Described stimulate is located on the right side of oral cavity, occurs after the phase III is using test products.Researcher's visual inspection region report one is rubescent, and this occurs after processing E.It is described it is rubescent be the phase III apply test products after upper right cheek occur.

Added at 42 in object, there are 40 objects to complete for the 1st and 2 stages, and be included in the statistics of conclusion, in ANOVA analyses, and processing A and B average number.There are 39 objects to complete for the 1st, 2 and 3 stage, and be included in the statistical analysis of dose proportionality.

The arithmetic mean of instantaneous value and standard deviation and statistics of serum fentanyl pharmacokinetic parameter after processing A and processing B compare conclusion in the following table.

Handle the overview of pharmacokinetic parameters of A and B serum fentanyl

--- --- ----serum fentanyl --- --- ----

*=based on the LS average values from table 13.

Handle A=1 × 1080mcg OraVescent citric acid fentanyl tablets：Experiment

Handle B=1 × 1600mcg oral transmucosal citric acid fentanyls (Actiq)：Control

Wilcoxon Signed Rank Test result is shown, handles A intermediate value T_max(0.998 hour) with processing B (1.999 hours) compared to it is obvious earlier (p ＜ 0.0001).

Calculate processing C, D, and E individual and average serum fentanyl pharmacokinetic parameter.The Kel of 5 objects fails to calculate in processing E.Therefore, AUC (0-inf), AUCR, and T1/2 can not be calculated in these cases.

The arithmetic mean of instantaneous value and standard deviation of serum fentanyl pharmacokinetic parameter are concluded in the following table after processing C, D, and E.

Handle the overview of pharmacokinetic parameters of C, D, and E serum fentanyl

--- --- ----serum fentanyl --- --- ----

Handle C=1 × 1300mcg OraVescent citric acid fentanyl tablets

Handle D=1 × 810mcg OraVescent citric acid fentanyl tablets

Handle E=1 × 270mcg OraVescent citric acid fentanyl tablets

AUCR is AUC_0-t/AUC_0-infinityThe ratio between

Dose proportionality is assessed the p- values for including handling A, C, D, and E and concluded in the following table.

Handle the general introduction of A, C, D and the E dose normalized parameter of serum fentanyl

--- --- --- --- --- ----serum fentanyl --- --- --- --- --- --- --

Handle A=1 × 1080mcg OraVescent citric acid fentanyl tablets

Handle C=1 × 1300mcg OraVescent citric acid fentanyl tablets

Handle D=1 × 810mcg OraVescent citric acid fentanyl tablets

Handle E=1 × 270mcg OraVescent citric acid fentanyl tablets

The time interval more than Kel values is determined.

The main purpose of this research is the OraVescent for the CIMALABS companies for assessing 1080 μ g dosage in fasted condition

Citric acid fentanyl tablet (processing A, experiment) and 1600 μ g oral transmucosal citric acid fentanyls on the market, Actiq

The bioequivalence that (processing B, control) is compared.This research is the single dose randomization in the 1st and 2 stages, open-label, bidirectional crossed design.All objects turn also to the phase III, using three kinds of OraVescentOne of citric acid fentanyl test formulation：1300 μ g (processing C), 810 μ g (processing D), or 270 μ g (processing E).It has evaluated OraVescent

The dose proportionality of citric acid fentanyl tablet formulation (processing A, C, D, and E).

Initially have altogether 42 health objects take part in this research.39 objects complete all three stages of this research.And there are 40 objects to complete processing A and B (the 1st and 2 stage).The data for completing processing A and B 40 objects include pharmacokinetics and statistical analysis.

For processing A and processing B, fentanyl C_max, AUC (0-t), and the ratio of AUC (0-inf) geometry least square average value (experiment/control) is respectively 123.4%, 101.4%, and 101.1%.Data above shows that average fentanyl exposure is similar, but the peak exposure that A is handled compared with handling B is higher.Handle A T_maxRatio processing B (2.00 hours) early 1 hour occurred for (0.998 hour), and C_max23% is higher by, this shows that compared with handling B, the fentanyl infiltration rate for handling A is considerably more rapid.

C_max90% confidential interval be 111.82%-136.20%, AUC (0-t) is 94.42%-108.86%, and AUC (0-inf) is 93.60%-109.23%, show that processing A and processing B meet bioequivalence requirement for AUC (but not to Cmax).In fact, processing A C_maxIndicate by the OraVescent illustrated in embodiment 1

The percentage by weight dosage of about 30-35% fentanyl and 1600 μ gACTIQ less that preparation is provided

Preparation is compared and generates statistically significantly higher C_max.In order to obtain in C_maxThe bioequivalent results of aspect, are actually to obtain suitable result, people need to use OraVescentSublimaze, it is included equivalent to object of reference ActiqAt least about 45% for consumption in tablet, more preferably from about 47.5%, more preferably from about 50% less fentanyl (being calculated with the weight for the fentanyl that dissociates).In this case, about 800-880 μ g are suitable with 1600 μ g ACTIQ.

Consequently found that,, can be with than being initially considered that less fentanyl obtains suitable C for 1 milligram or less of formulation using the present invention_max.Realize quick T_max.This makes it possible to the further expected dosage of reduction, has the advantages that disclosed herein above, and the advantage is to reduce what is produced by the dosage for being not accompanied by effect decline.

Applying OraVescent

After citric acid fentanyl tablet formulation, fentanyl AUC increases with dose proportional and (is defined herein as linearly increasing) in 270-1300 μ g scope.4 kinds of OraVescent

Dosage is not significantly different in terms of dose normalized AUC (0-t) or AUC (0-inf).In more dose normalized C_maxWhen be found that significant overall treatment effect.Compared and compared in pairs with processing A, because all objects all receive processing A.Any pattern is less found in contrast with.It is found that the significant difference between processing D (810 μ g) and processing A (1080 μ g).

1080μg OraVescentThe mean residence time (21 minutes) of citric acid fentanyl tablet compares Actiq

(34 minutes) are short 13 minutes.The OraVescent of other 3 kinds of dosage

The mean residence time (19,25, and 22 minutes) of citric acid fentanyl tablet formulation and 1080 μ g OraVescent

The mean residence time of preparation is similar.

Taking OraVescent

After citric acid fentanyl tablet, an object has reported the minimal irritation of oral mucosa, and an object experienced rubescent.Taking ActiqStimulation or rubescent is not reported afterwards.

Applying 1080 μ g OraVescentCitric acid fentanyl tablet and 1600 μ g oral transmucosal citric acid fentanyls (Actiq

) after, compare the discovery of serum fentanyl pharmacokinetics, average fentanyl exposure is similar, but the infiltration rate of both products is different.AUC (0-t) and AUC (0-inf) geometry least square (" LS ") toaverage ratio are close to 100%, and 90% confidential interval within 80%-125%.The average C of geometry LS_maxFor 1080 μ gOraVescentCitric acid fentanyl is high by 23%, and handle/compare ratio 90% confidential interval the upper limit more than 125%, this shows that the parameter is unsatisfactory for bioequivalence criteria.Therefore, further dosage reduction can be achieved.OraVescent

The T of citric acid fentanyl tablet_maxSubstantially earlier (early 1 hour).

For OraVescentCitric acid Sublimaze, in 270-1300 μ g ranges, fentanyl AUC increases with dose proportional, but the endless full linear in whole dosage range.

1080μg OraVescentThe mean residence time (21 minutes) of citric acid fentanyl tablet compares Actiq

Mean residence time (34 minutes) it is short 13 minutes.It is the time quantity for beginning to use formulation (inserting into the mouth) to be disappeared to the formulation that all naked eyes can recognize that according to " residence time " of the present invention.

There is no serious or adverse events beyond expectation occur during this research.Both preparations are that oral mucosa is resistant to well.

Bibliography

1.Physician ' s Desk Reference.56th ed.Montvale, NJ：MedicalEconomics Company, Inc.；2002.Actiq

；p.405-409.

2.Fentanyl.Micromedex [online] Vol.107：Health SeriesIntegrated Index；2002 [Date Accessed：2003/Jun/371.http://www.tomescps.com

3.Streisand YB, et al. Dose Proportionality andPharmacokinetics of Oral Transmucosal Fentanyl Citrate.Anesthesiology 88：305-309,1998

4.Naitrexone.Micromedex.[online] Vol.107：Health SeriesIntegrated Index；2002 [Date Accessed：2003/JunI6].http：//www.tomescps.com

5.SAS Institute, Inc., SAS/ STAT User ' s guide, Ver.6.4thed.Vol.1.Cary, NC：SAS Institute；1989.

6.SAS Institute, Inc., SAS/ STAT User ' s guide, Ver.6,4th ed.Vol.2.Cary, NC：SAS Institute；1989.

7.SAS Institute, Inc., SAS

Procedures guide, Ver.6,3rded.Cary, NC：SAS Institute；1990.

Section 2 research is also carried out.The research confirms dosage and C in 100-800 μ g dosage ranges_maxBetween generally linear relation.

This research is carried out, can be configured to assessing in the range for the treatment of use according to Tablets (herein referred to as OraVescentTablet) citric acid fentanyl dose proportionality (AUC and C_max), and confirm the C of research described above_maxObserve result.

Institutional Review Board (IRB) have approved experimental program and informed consent form.All objects are all read and endorsed the ICF of IRB- approvals before the study starts.This research has single dose, randomization, open-label, 4- processing, 4- stages, cross-over design.

The object is screened within 21 days before research is added.Screening sequence includes medical history, physical examination (height, body weight, the bodily form, vital sign, and electrocardiogram [ECG]), (hematology, serum chemistry, urinalysis are detected with clinical labororatory, HIV antibody is screened, Hepatitis A Antibody is screened, hepatitis B surface antibody screening, antibody to hepatitis C screening, with serum pregnancy [being only applicable to women]), and the screening to cannboid and opioid.

All objects for participating in this research all meet the selected/exclusion standard enumerated in this embodiment, and Principal Investigator has checked medical history, clinical laboratory assessments, and are checked UP before object participates in this research.This research is related to 28 objects altogether, 16 males and 12 women, and has 25 objects, 14 males and 11 women, completes this research.

Afternoon before each medication of object is reported to clinic, and is had lunch at 14 points, at 19 points with dinner, and is eaten a piece at 22 points.Then the object follows 10 hours overnight fasts.At the 1st day, start standardized meal schedule, have lunch within 30 minutes at 13 points, use within 30 minutes dinner at 18 points, and eat a piece at 22 points.At the 2nd day, start standardized meal schedule (including breakfast).

48 hours and the period object can not absorb any containing alcohol before each stage is closed, broccoli, the food or beverage of caffeine or xanthine.Before medication during 10 days and this research, limitation object table grapes shaddock.At least six month is to complete cost study before research is participated in, and object does not contact nicotine and tobacco.In addition, before medication during 7 days and this research, forbidding OTC treatment (including Chinese herbal medicine additive agent).Before medication during 14 days and this research, Prescription medications (including MAO inhibitor) are not allowed.

During this research, the object keeps straight position to take one's seat 4 hours after citric acid fentanyl is taken.From during medication up to 4 hours water restrictions after medication.Limit food within 10 hours to 4 hours after medication before medication.During this research, the object does not allow to be engaged in any strenuous exercise.

Receive following processing with allowing object randomization：

Adml：ReVia

(Naltrexone Hydrochloride tablet) 50mg

Produced by Duramed Pharmaceuticals companies

Lot number：402753001T

Keeping life：In June, 2006

Object receives a ReVia of oral dose

50mg tablets, are taken for 15 hours and 3 hours before processing A medication with 240mL water.

Object receives a ReVia of oral dose50mg tablets, are taken for 15 hours and 3 hours and 12.17 hours after medication before processing B, C, and D medication with 240ml water.

A：Oravescent

The μ g tablets of citric acid fentanyl 200

Produced by CIMA LABS companies

Lot number：930859

The object for being randomized to processing A receives an Oravescent of single oral doseThe μ g tablets of citric acid fentanyl 200, are placed between gums and cheek, above molar, and allow it to be disintegrated 10 minutes.

B：OravescentThe μ g tablets of citric acid fentanyl 500

Produced by CIMA LABS companies

Lot number：930860

The object for being randomized to processing B receives an Oravescent of single oral dose

The μ g tablets of citric acid fentanyl 500, are placed between gums and cheek, above molar, and allow it to be disintegrated 10 minutes.

C：OraVescent

The μ g tablets of citric acid fentanyl 810

Produced by CIMA LABS companies

Lot number：930501

The object for being randomized to processing C receives an Oravescent of single oral doseThe μ g tablets of citric acid fentanyl 810, are placed between gums and cheek, above molar, and allow it to be disintegrated 10 minutes.

D：OravescentThe μ g tablets of citric acid fentanyl 1080

Produced by CIMA LABS companies

Lot number：930502

The object for being randomized to processing D receives an Oravescent of single oral doseThe μ g tablets of citric acid fentanyl 1080, are placed between gums and cheek, above molar, and allow it to be disintegrated 10 minutes.

Daily early morning 0.25 before medication and after medication, 0.5,0.75,1,1.25,1.5,1.75,2,2.25,2.5,2.75,3,3.25,3.5,3.75,4,5,6,8,10,24, and the vital sign (blood pressure, pulse, and breathing) assessed when sitting quietly for 36 hours.Preceding 8 hours and object attempts to carry out continuous pulse blood oxygen assay during sleep during first 12 hours after medication after medication.12- lead electrocardiogram, clinical laboratory assessments (hematology, serum chemistry, and urinalysis), and the brief physical inspection containing complete vital signs are carried out at the end of this research.Carry out Oral irritation assessments within 4 hours after medication.When registering every time, oral cavity is checked, to ensure that the object does not have aphthous ulcer in agents area.Tell object that any adverse events occurred during this research are notified to the doctor or nurse of this research.

The blood sample (7mL) for the object for belonging to processing A is gathered in the following time：Before medication (0 hour), 10 after medication, 20,30, and 45 minutes；With 1,2,4,6,8,9,10,11,12,14,16,20 and 24 hour after medication.The blood sample (7mL) for the object for belonging to processing B, C and D is gathered in the following time：Before medication (0 hour), 10,20,30 and 45 minutes after medication；And 1 after medication, 2,4,6,8,10,12,16,20,24,28,32, and 36 hours.

The fentanyl concentration of human serum sample is analyzed by sensitive and specific LC-MS/MS methods.

Following non-chamber pharmacokinetic parameter is calculated using WinNonlin StandardEdition version 2.1 according to the fentanyl concentration v. time data of every kind of processing.Actual (rather than nominal) sampling time has been used in this analysis.

The areas that is located at fentanyl concentration time curve below of the AUC (0-t) from the zero-time to t time utilization linear trapezoidal read group totals, wherein, t is can finally to determine concentration (Ct) time.

AUC (0-inf) from the zero-time to the unlimited area below fentanyl concentration time curve,

AUC (0-inf)=AUC (0-t) ± Ct/Kel, wherein, Kel is whole last elimination rate constant.

The ratio between AUC (0-t) AUC (0-t) and AUC (0-inf).Also referred to as AUCR.Kel/AUC (0-inf) is the elimination rate constant last eventually calculated by the linear regression of the terminal linear portion of log concentration vs. time graphs, wherein, Kel=- efficiency.The terminal linear portion is determined by visual inspection.

The elimination half-life period that T1/2 is calculated as ln (2)/Kel.

C_maxIt was observed that maximum fentanyl concentration.

T_maxReach the time (being obtained under conditions of no interpolation) of maximum fentanyl concentration.

The plasma concentration value of fentanyl is listed, and is concluded by processing and time point, descriptive statistics (average value, standard deviation [SD] is employed, the coefficient of variation [CV], the standard error [SEM] of average value, sample size, minimum value, maximum, and intermediate value)^9-11.The value that will be less than quantitative lower bound (LOQ) is set as zero.There is provided average and individual concentration time curve figure.Carry out making table, and computation induction statistics by handling remifentanil pharmacokinetic parameter and dose normalized pharmacokinetic parameter.

Pass through Smith etc.⁸Disclosed method assesses 200 μ g-1080 μ g dose proportionality.First, immixture model analysis Logarithm conversion parameter, including the Logarithm conversion of dosage and the fixation of intercept and stochastic effects are utilized.The model is fitted using SAS Proc Mixed^9-11。

Slope calculations (β₁) fixed effect 90% confidential interval (CI), and be compared with the scope (0.8677,1.1323), it is the suitable critical range of the dosage range for being inquired into this research.

Conclusion is based on following：

If 1) β₁90%CI be completely contained in the scope (0.8677,1.1323), be considered as possessing dose proportionality.

If 2) β₁90%CI be fully located at outside the scope, be considered as lack dose proportionality.

If 3) β₁90%CI part be located at should in the range of, partly outside the scope, such result is considered as " uncertain ".In this case, β₁Value can be as the best estimate to deviateing desired proportions, and 90%CI lower bound and the upper bound can take in terms of drug safety, effect, or pharmacological effect data⁸。

In the case where observing uncertain result, calculating makes β₁The maximum doses that are completely disposed in the critical range of 90%CI than the dose ratio that is completely disposed in the 90%CI for making β 1 beyond the critical range.These dose ratios are referred to as ρ 1 and ρ 2 by Smith etc..

ρ 1=θ_H^[1/max (1-L, U-1)], wherein, θ_H=1.25,

L=90%CI lower limit

The U=90%CI upper limit.

ρ 2=θ_H^[1/max (L-1,1-U)], wherein, θ_H, L, and U definition are same as above.

Second of analysis is carried out, to check dose normalized C between three kinds of lowest dosage levels (200 μ g, 500 μ g, and 810 μ g)_maxDifference.(normal-theory) GLM of parameter is applied to the dose normalized C from processing A, B, and C after Logarithm conversion_maxValue.Variance analysis (ANOVA) model includes following factor：Object and stage in processing, order, order.P- values less than 0.05 are considered as being statistically significant.

By deducting medication administration time from the preparation extinction time for perceiving and confirming, calculate dwell time values (preparation has time span in the oral cavity).Values above is carried out to make table, and inductive statistics is provided.

Have three objects terminate/exited this research.Two therein are exited before the phase III, because they are not intended to continue this research.One object second stage medication backed off after random because there are adverse events.The average age of the object is 33 years old (the range of age is 19-55 Sui).The average height of the object is 68.6 inches (in 60-76 inch ranges), and the average weight of the object is 160.9 pounds (in the range of 110-215 pounds).

Following scheme deviation is occurred in that during this research is carried out.One object is reexamined in the vital sign that do not carry out for 0.5 hour of second stage.2.5 hour do not carry out vital sign of one object in the phase III is reexamined.One object does not obtain her serum pregnancy test result before phase III -15- hour naltrexone administration.At -3- hours the result was obtained before naltrexone dosage.One object is misplaced in the ECG of 36 hours of fourth stage.One object does not complete premature termination program.The object is considered as lost to follow-up.Also, it should carry out Oral irritation assessments within 3.83 hours after medication in phase III all objects.The nurse for being responsible for relevant issues, which remembers, has carried out the assessment, but statement does not complete oral irritation assessment forms at that time in relevant event.Therefore, the assessment information can not be verified, and should be considered as not carrying out.

Duration data is summarized in following form.

	Handle A	Handle B	Handle C	Handle D
					Object number	Time (minute)	Time (minute)	Time (minute)	Time (minute)
Average value	14	14	17	15
					SD	8	6	10	11
CV	59	45	57	72
					SEM	2	1	2	2
N	25	26	27	27
					Minimum value	4	6	5	4
Maximum	37	33	41	60

Handle A=200 μ g

Handle B=500 μ g

Handle C=810 μ g

Handle D=1080 μ g

It is noted that object right lower quadrant in cheek when fourth stage starts has aphthous ulcer during the oral cavity carried out when registering is assessed, but the test products medication in the phase III is the upper right quarter in cheek.Principal Investigator confirms that the aphthous ulcer is not aphtha, and ratifies the object in fourth stage medication.

There are two objects to be reported in the slight oral stimulation (belonging to 2 and 3 grades in 1-10 grade) for carrying out occurring after processing A.The stimulation of this two objects is all the left side that oral cavity is appeared in after second stage applies test products；One when researcher's visual inspection is about position in this two objects also show it is rubescent.Also one object reports the pain in upper left buccal area gum line for 11 minutes after processing C is carried out.Serious or beyond expectation adverse events are not reported.

In 28 objects for participating in research, 25 objects complete processing A, and 26 objects complete processing B, and 27 objects complete processing C and D.All objects all carry out the statistical analysis of pharmacokinetic data.An object in processing A fails to carry out elimination rate constant calculating, because there was only limited data point in the last stage eventually.Therefore, it is impossible to calculate AUC (0-inf), AUCR, and the T1/2 of the object.

The arithmetic mean of instantaneous value of serum fentanyl pharmacokinetic parameter and standard deviation are concluded in the following table after all processing.

The overview of pharmacokinetic parameters of serum fentanyl

--- --- --- --- --- ----serum fentanyl --- --- --- --- --- --- --

* T has been reported_maxIntermediate value and min-max

Handle A=1 × 200mcg OraVescent citric acid fentanyl tablets

Handle B=1 × 500mcg OraVes cent citric acid fentanyl tablets

Handle C=1 × 810mcg OraVescent citric acid fentanyl tablets

Handle D=1 × 1080mcg OraVescent citric acid fentanyl tablets

Ln [AUC (0-t)] vs.ln (dosage) and ln [AUC (0-inf)] vs.ln (dosage) slope is respectively 1.0574 and 0.9983,1, the 90%CI of each parameter are completely contained in the critical range required for 200 μ g-1080 μ g dose proportionalities.ln(C_max) vs.ln (dosage) slope is 0.8746, less than 1, and 90%CI (0.8145-0.9347) is not fully contained in the critical range drawn required for dose proportionality conclusion.Make β₁90%CI to be completely disposed in maximum dose ratio in the critical range be 3.33.Make β₁90%CI to be completely disposed in maximum dose ratio outside critical range be 30.48.Handle A, B, and C dose normalized C_maxANOVA results indicate in 200 μ g-810 μ g dosage range be not present dose normalized C_maxStatistically-significant difference (p=0.13).

The main purpose of this research is to assess applying the OraVescent of following fentanyl dosageFentanyl AUC and C after citric acid fentanyl tablet_maxDose proportionality there is degree：200 μ g (processing A), 500 μ g (processing B), 810 μ g (processing C), and 1080 μ g (processing D).In addition, it is previous in 810 μ g of administration and the OraVescent of 1080 μ g dosage in order to confirm to carry out this research

Relevant C after citric acid fentanyl tablet_maxObservation result.This research is single dose, randomization, open-label, 4- period crossover designs.

In 28 objects for participating in research, 25 objects complete processing A, and 26 objects complete processing B, and 27 objects complete processing C and D.Statistical analysis is carried out to the pharmacokinetic data of all objects.

Ln [AUC (0-t)] vs.ln (dosage) and ln [AUC (0-inf)] vs.ln (dosage) slope is respectively 1.0574 and 0.9983, close to 1, and the 90%CI of each parameter is completely contained within the critical range required for dose proportionality.Result above shows that fentanyl AUC is between the μ g-1080 μ g of dosage 200 of this research with OraVescent

Each incremental dose level of citric acid fentanyl tablet and proportionally increase.

ln(C_max) vs.ln (dosage) slope be 0.8746, less than 1, show fentanyl C_maxIncrease be less than increase with dose proportional.90%CI (0.8145-0.9347) is not fully contained in the critical range.This proportional increase that is less than is observed in maximum dose level (1080 μ g), and appears in time maximum dose level (810 μ g) with relatively low degree (± 11% confidential interval).μ g, C from 200 μ g to 500_maxProportionally increase.ρ 1 (making β 1 90%CI be completely in the maximum dose ratio of critical range) value is 3.33, and the μ g of 810 μ g: 200 ratio is 4.05.This shows that the preparation is linear according to the present invention, until about 800 μ g dosage.

Second of analysis and utilization ANOVA compares the dose normalized C from 200 μ g, 500 μ g and 810 μ g dosage_max, show not having between these dosage levels difference (p=0.13) statistically significantly.ln(C_max/ dosage) LS averages be 1.06 (200 μ g), 1.06 (500 μ g), with 0.94 (810 μ g), show and be not significantly different between 200 and 500 μ g dosage, and 810 μ g dosage compared with relatively low dosage the only difference of (be less than 15%) of very little.Lack significant difference in ANOVA, the difference by a small margin added between 810 μ g dosage and two relatively low-doses shows, in 200 μ g-810 μ g C_maxDose proportionality in terms of without clinically important deviation.Therefore, they are " linear " as herein defined.200 μ g, 500 μ g, 810 μ g and 1080 μ g OraVescent

The mean residence time of citric acid fentanyl tablet be it is similar, respectively 14 minutes, 14 minutes, 17 minutes, and 15 minutes.

Taking OraVescent

After citric acid fentanyl tablet, there are 2 objects to report the faint stimulation of oral mucosa, there is 1 object experienced rubescent.

Fentanyl AUC proportionally increases in the range of 200 μ g-1080 μ g with the increase of dosage.In the horizontal fentanyl C of two maximum dose levels_maxIncrease be less than increase with dose proportional.But, in the dosage of all (but except be more than 1mg), this increase is linear as herein defined.Average ln (the C of 810 μ g dosage_max/ dosage) than 200 μ g and the 500 low 10-11% of μ g dosage.Average ln (the C of 1080 μ g dosage_max/ dosage) than 200 μ g and the 500 low 20-21% of μ g.In 200 μ g-810 μ g C_maxDose proportionality in terms of clinically important deviation is not present.200 μ g, 500 μ g, 810 μ g, and 1080 μ g OraVescentThe mean residence time of citric acid fentanyl tablet be it is similar, respectively 14 minutes, 14 minutes, 17 minutes, and 15 minutes.

There is no serious or adverse events beyond expectation occur during this research.Every kind of preparation is all resistant to very well for oral mucosa.

Bibliography

8.Smith BP etc., Confidence Interval Criteria for Assessmentof Dose Proportionality.Pharmaceutical Research 17：1278-1283,2000.

9.SAS Institute, Inc., SAS

/ STAT User ' s guide, Ver.6.4thed.Vol.1.Cary, NC：SAS Institute；1989.

10.SAS Institute, Inc., SAS

/ STAT Users guide, Ver.6,4th ed.Vol.2.Cary, NC：SAS Institute；1989.

11.SAS InStitute, Inc., SASProcedures guide, Ver.6,3rd ed.Cary, NC：SAS Institute；1990.

12.Summary Basis of Approval NDA 20-747(Actiq

).The Pharmacology andBiopharmaceutics Review pp 6. of Approvaldate November 4,1998, Clinical

Any preparation comprising enough effervescent materials and pH Auto-regulators can be used, preferably comprise suitable disintegrant, it can be provided available for the buccal of fentanyl, gums administration or the formulation of sublingual administration, dosage level as contemplated herein, and provides dosage reduction and/or dosage and C described herein_maxRelation.Most preferably, for the formulation containing about 100-800 μ g fentanyls (being calculated according to free alkali), any effervescent agent pair and/or pH Auto-regulators for the consumption for producing following formulation, the T of the formulation can be used_maxFor 1.5 hours or less and/or C_maxIt is about 2.0- about 4.0 piks/mL/ μ g, more preferably about 2.5- about 3.5, more preferably about 2.7- about 3.5 piks/mL/ μ g with the ratio between dosage.Preferably, the formulation also shows C described herein_maxLinear relationship between dosage.It means that C_maxIt will fall between 100-800 μ g fentanyls of the present invention on a series of curve of at least three kinds various doses generations (p≤0.15) with the ratio between dosage, the formulation has identical composition, and simply the amount of fentanyl is different.

Similarly, it is contemplated that the effervescent agent pair and pH Auto-regulators of any amount, compared with the ACTIQ preparations with least about 80% more fentanyls, it can be provided with suitable C_maxFormulation.That is, its C_maxFor the C of this ACTIQ preparations_maxAt least 75%-125%, the more preferably about 80%- about 125% of ACTIQ preparations (p is less than or equal to 0.15), the most preferably about 85%- about 115% of ACTIQ preparations, although with least 45% less fentanyl (being calculated with free alkali form).In particularly preferred embodiments, these preparations are by any disintegrant or excipient or excipient composition not comprising the significant quantity that can disturb this performance characteristic.The mannitol of spray drying is preferred filler.Another preferred excipient is disintegrant, and it is starch glycolate, particularly sodium starch glycolate.The former is generally characterized as filler, and the latter is disintegrant.But, described characterize is not controlling.

Preparation in ' No. 604 patents includes both cross-linked pvps that consumption is 5% or more for the lactose monohydrate more than 20% and/or microcrystalline cellulose and consumption that consumption is at least about 20%, and said preparation is considered as providing dosage and C with level described herein_maxIdeal linearity behavior preparation, despite the presence of pH Auto-regulators and effervescent agent pair.Preparation in ' No. 604 patents also has the fentanyl more than 880 μ g.

It is such a formulation according to a kind of formulation that can be disintegrated in mouth of preferred effervesce of the present invention, based on the weight of free base material, it includes about 100-800 μ g fentanyl (90-880), or proportional weight a kind of its officinal salt.In addition, numbers above is intended to include normal processing variabilities, such as content uniformity.Particularly preferred dosage is respectively about 100 μ g, about 200 μ g, about 300 μ g, about 400 μ g, about 600 μ g and about 800 μ g.

Preferably, the particle mean size of the fentanyl being used in invention formulation determined by laser diffraction technology is about 150 microns of about 0.2-, about 100 microns of more preferably about 0.5-, about 20 microns of most preferably about 1-.

As effervescent agent or effervescent agent pair, any of combination can be used.Including in United States Patent (USP) 5,178,878 and United States Patent (USP) 5, those disclosed in 503,846, document above with they discuss various effervescent agents pair and effervescent agent pair structure degree be incorporated as herein with reference to.Effervescent agent to be typically water-or saliva-activation material, be generally held under anhydrous state, the moisture of absorption be with or without less or is existed with stable hydrated form.Generally, these effervescent agents comprising at least one acid source and at least one active alkali to originating, and the latter is typically carbonate or bicarbonate.Each composition of effervescent agent pair may each be any composition safe for human consumption.

The acid generally includes food acids, acid anhydrides and acid salt.Food acids include citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, ascorbic acid and butanedioic acid.Above-mentioned sour acid anhydrides or salt can be used, salt mentioned here can include any of salt, but particularly sodium dihydrogen phosphate, disodium dihydrogen, acid citrate and sodium acid sulfate.Alkali available for the present invention generally includes sodium acid carbonate and saleratus etc..Sodium carbonate, potassium carbonate, and magnesium carbonate etc. can also be used the degree of a part for use as effervescent agent.But, pH Auto-regulators are more preferably used them as.Preferably, using the acid of equivalent, acid anhydrides or acid salt and alkali in stoichiometry.But, some excess of acid or alkali can be used.But, to be subject in such formulated carefully, particularly in view of the overall pH adjustment effects (if any) of this composition.It may excessively influence to absorb.

The amount for the effervescent materials that can be used in the present invention is effective dose, and be according to except realize the tablet be disintegrated in the oral cavity must in addition to other characteristics determine.It the substitute is, effervescent agent is used as enhancing fentanyl in the oral cavity via buccal, the basis that gums is applied or sublingual administration is transmitted by oral mucosa.Therefore, calculated according to the weight of total preparation, the consumption of effervescent agent pair should be about 5- about 85%, more preferably about 15-60%, more preferably about 30-45%, most preferably about 35- about 40%.Certainly, the relative scale of soda acid depends on special component (for example, acid is unitary, binary or ternary) relative molecular weight etc..But, each of stoichiometric amount is preferably provided, is excessively acceptable certainly.

Preferably, preparation of the invention includes at least one pH Auto-regulators.It is not intended to be bound by any particular theory, this allows to change ionization state sensitive medicine and dissolves by ensuring it and can such as apply by the felicity condition that oral mucosa is transmitted by one or more films or tissue in oral cavity.If the preferable transmission condition of certain drug is alkaline, addition fully excessive appropriate strong acid is probably unfavorable to a part for production or as pH Auto-regulators as effervescent agent.It can be preferred to select another pH Auto-regulators such as natrium carbonicum calcinatum, and it can work individually and away from effervescent agent.

The pH Auto-regulators of the present invention, which can be used for providing, further penetrates humidification.The selection of suitable pH Auto-regulators depends on the medicine to be applied, and particularly medicine ion or non-ionic pH, and whether ionization or non-ionised form promote to transmit by oral mucosa.For fentanyl and its salt, alkaline matter is preferred for delivering fentanyl.The pH Auto-regulators of the present invention including but not limited to can adjust local pH to promote any material of transmembrane transport in oral cavity, and its amount will cause pH general scope to be about 3-10, more preferably about 4- about 9.The pH is oral mucosa in the patient's mouth and " local pH " in formulation or the microenvironment of the surface area contact of its any part (such as when it is disintegrated).For the purposes of the present invention, local pH can be identified below：In order to characterize the dynamic ph change showed by related tablet, employ external pH and determine.This method is included in the phosphate buffered saline (PBS) that 0.5-10mL is used in the test tube of suitable size or similar containers.The consumption of medium depends on tablet size and dosage.For example, when determining the pH features of fentanyl tablet, 1mL volumes are used for into the tablet that weight is 100mg.After tablet is contacted with the medium, the pH curves of the solution are monitored at once, as the function of time, micro-combination pH electrode are used.Preferably, can be used as the material of the pH Auto-regulators of the present invention includes carbonate, such as such as sodium carbonate, potassium carbonate or calcium carbonate, or phosphate, calcium phosphate or sodium phosphate.Most preferably sodium carbonate.The amount for the pH Auto-regulators that can be used in the present invention can be with the type of used pH Auto-regulators, the amount of any excessive acid or alkali from effervescent agent, the property of remaining composition, certainly also medicine (medicine is fentanyl herein) and change.

Most preferably, the consumption of pH Auto-regulators will account for about 0.5- about 25wt%, more preferably about 2- about 20wt%, more preferably about 5- about 15wt%, most preferably about the 7- about 12wt% of total preparation weight.Most preferred pH Auto-regulators are carbonate, bicarbonate or phosphate.Further preferably those pH Auto-regulators：When being provided with suitable amount, with local pH compared with other identical preparations, can be made to change at least about 0.5 pH unit, more preferably from about 1.0 pH units, more preferably from about 2.0 pH units without pH Auto-regulators.

Any filler or the filler of any amount can be used, as long as resulting formulation can obtain result described herein.In filler most preferably sugar and sugar alcohol, and these may include indirect compression and the filler directly compressed, indirect compressible filler generally, at least prepare when, with cause they to for without reinforcing or adjustment high speed tablet making technology for be unpractical flowing and/or compressive features.For example, a kind of preparation may be without mobility good enough, accordingly, it may be desirable to glidant be added, for example, silica.

On the contrary, the filler directly compressed does not need similar tolerance.They, which generally have, allows the compressibility and flowable feature that they are directly used.It is noted that according to the method for preparation of preparation, the filler of indirect compression can be endowed the characteristic of direct compressible filler, and vice versa.In general, compared with direct compressible filler, indirect compressible filler tends to relatively small granularity.But, some fillers such as mannitol being spray-dried has smaller particle size, and is still often what can directly be compressed, and this depends on how to make further processing to them.Also there is relatively large indirect compressible filler.

Currently preferred filler includes mannitol, lactose, D-sorbite, dextrose, sucrose, xylose alcohol and glucose, as long as their use can provide result described herein.It is still further preferred according to the invention that filler is not based on the lactose monohydrate that weight of formulation consumption is 20% or more, and more preferably without using lactose monohydrate.The present invention is most preferably using the mannitol of spray drying.The amount of filler can be to account for weight of formulation 10-80%, more preferably from about 25- about 80%, most preferably 35- about 60%.

Disintegrant can also be used in the present invention, as long as they allow or are even conducive to dosage as described herein to reduce, linear and/or C_maxThe ratio between with dosage.Disintegrant can also include the adhesive with disintegration properties.Microcrystalline cellulose, PVPP (PVP-XL), sodium starch glycolate, cross-linked carboxymethyl cellulose sodium, cross-linked hydroxypropyl base cellulose etc. can be included according to the disintegrant of the present invention.The selection of certain disintegrant depends on whether result described herein can be obtained in particular system.It is further preferred that the PVPP that the preparation is free of the microcrystalline cellulose more than about 20% and consumption is about 5% or more, particularly in the preparation including 20% other lactose monohydrate.What it is as disintegrant is most preferably starch glycolate, particularly sodium starch glycolate.In practice it has been found that using sodium starch glycolate in the preparation of the present invention, using the teaching of the invention it is possible to provide dosage reduces significantly improving for degree, while suitable C compared with the effervescent formulation including pH Auto-regulators and other disintegrants still can be provided_max.Particularly useful sodium starch glycolate is GLYCOLYS

(standard class), can be obtained from Roquette of Lestrem France.In fact, more preferably described preparation neither includes microcrystalline cellulose nor including cross-linked pvp.

The amount of disintegrant changes according to known facts, the size of such as formulation, property and consumption of used other compositions etc..But, in general, the consumption should account for the about 0.25- about 20% of final preparation weight, the weight % of more preferably about 0.5- about 15%w/w, more preferably 0.5- about 10%w/w, more preferably about 1- about 8.This same weight based on finished product preparation.

It is film-making or injection lubricant to be equally usually used in the present invention.Most commonly known lubricant is magnesium stearate, and preferably uses magnesium stearate.Typically, the Conventional wisdom of tableting lubricant behind is more few better.In most circumstances, it is preferred to use the tableting lubricant less than about 1%.Generally, the consumption should be 0.5% or less.But, the consumption of magnesium stearate can be more than 1.0%.In fact it is preferred to more than about 1.5%, most preferably about 1.5%- about 3%.Most preferably use about 2% magnesium stearate.Other conventional tableting lubricants, for example, stearic acid and calcium stearate etc. can also be used for replacing all or part of magnesium stearate.

The effervescent tablet of the present invention can be flexible relative or firm.For example, they can be according in United States Patent (USP) 5, the method disclosed in 178,878 is produced, and hardness is typically smaller than 15 newton.Different from the preparation disclosed in ' No. 878 patents, active component in this need not be coated with protectiveness material.In fact it is preferred to which remifentanil active component is not coated.When tablet is soft and submissive/frangible as production, it may be advantageous to they are packaged in blister package, for example, with reference to United States Patent (USP) 6,155,423.They can also be firm, and hardness exceedes about 15 newton, be produced according to the method provided in United States Patent (USP) 6,024,981.In preferred embodiments, fentanyl dosage form of the invention is provided in the blister package for preventing children from eating by mistake.For example, with reference to the United States Patent (USP) 6 for authorizing Katzner etc., 155,423, grant date is on December 5th, 2000, and transfers CIMA LABS companies, and the content of the patent is incorporated herein by reference.Most preferably, the packaging meets the standard proposed in 16U.S.C. § 1700.15 and .20 (2003).Packaging further preferably includes those packagings that commonly known as so-called " F1 " in this industry and " F2 " is packed." F1 " packaging is most preferred.

The tablet of the present invention can be used for buccal, gums administration or sublingual administration with slightly different design.But, in each example, disintegration time (mean residence time) is preferably smaller than 30 minutes in the mouth realized by the preparation.Disintegration time/dissolving (residence time) is preferably less than about 30 minutes, most preferably from about 20 minutes or shorter in the mouth realized by the tablet.It is usually more than 5 minutes, most commonly 10 minutes or longer.This is the subjective determination based on patient's reaction.

According to particularly preferred embodiment of the invention, there is provided the tablet of effervescent oral disintegratable, designed for buccal, sublingual or gums applies fentanyl or its officinal salt, fentanyl (weight of the weight based on free alkali) comprising the μ g of about 100- about 800, the effervescent agent pair of effective dose and the pH Auto-regulators and sodium starch glycolate of effective dose.The preparation can also include mannitol.

At the particularly preferred aspect of the embodiment of the present invention, above-mentioned preparation does not include a certain amount of lactose monohydrate and/or the PVP of crosslinking, and the material prevents preparation from obtaining relative ACTIQ

For at least about 45% fentanyl weight dosage reduce.In particular it is preferred that lactose monohydrate or microcrystalline cellulose are no more than about the 10% of weight of formulation, and the PVP being crosslinked is no more than about 4%.It is further preferred that in addition to accidentally subsidiary amount, the preparation is free of all these excipient.According to the invention it is most preferred that be by sodium starch glycolate be used as disintegrant, and by mannitol be used as filler.Most preferred filler includes the mannitol of spray drying.

The preparation of the present invention can include other conventional excipient, and usage amount is generally known consumption, as long as they do not detract advantage as described herein.These excipient may include but be not limited to adhesive, sweetener, coloring components, aromatic, glidant, lubricant, preservative, and disintegrant etc..

Tablet, preferred dosage form of the invention can be produced by any of tabletting technology.It is preferred, however, that, by used material dry-mixing and direct pressing.Although the tablet can be produced by granulation, this is not preferred.Certainly, can be wet method or dry granulation for the specific excipient and material in invention formulation.For example, the mannitol of granulation can be used as into filler.Before final mixing and compacting, it may be desirable that some parts of the preparation are granulated or are pre-mixed.The material of correlation is pre-selected, is reduced with providing correct dosage and content uniformity and dosage as described herein, C_max/ dose ratio and/or dose linear.Therefore, proper amount of effervescent agent pair is selected, suitable and appropriate pH Auto-regulators and suitable disintegrant are provided, and be configured to formulation, preferred tablet with predetermined consumption.

It is preferred that pH Auto-regulators be carbonate, bicarbonate or phosphate, disintegrant preferably is starch glycolate.The amount of each is disclosed in this paper other places.It is preferred, however, that, the selection of the disintegrant and consumption, which make it possible to provide further dosage in terms of fentanyl consumption, to be reduced, this be with other identical preparations containing effervescent agent pair and pH Auto-regulators but without disintegrant Comparatively speaking.It is preferred that the selection of pH Auto-regulators and consumption are sufficient to provide the local pH change of at least 0.5 pH unit, more preferably 1.0 pH units, most preferably from about 2.0 pH units or more.Although can be by tablet press to any hardness and/or fragility, while this result is obtained, it is impossible to had a negative impact to residence time and insoluble drug release and by the transmission of oral mucosa.If possible, it is necessary to provide fentanyl dosage form in the form of compressed tablets, its hardness is the newton of about 5- about 100, the newton of more preferably about 10- about 50.

The formulation of the present invention can be used for treating any kind of pain, the pain of particularly usual prescription opiate therapy.Such as all opiates, the product of fentanyl product, the particularly present invention should be taken under the guidance of doctor and under the strict control and supervision of doctor always.The label in Physician ' sDesk Reference mentioned above is may refer to using the general guide of the ACTIQ products, and warning therein and contraindication are widely used in the use of formulation of the present invention.This be typically included in escalated dose before with less dose titration patient.

The formulation of the present invention is that, by being put into patient mouthful, being preferably placed at sublingual or be placed on what is applied between cheek or gums, they are remained there, until their dissolving/disintegrating is substantially complete, and they can no longer be identified as formulation.Preferably, it will swallow and be minimized, to help lend some impetus to maximum transfer of the fentanyl by adjacent oral mucosa.

Extra dosage is used as needed.As indicated above, single dose such as 800 μ g fentanyl can be taken with a formulation of the invention, or can be taken with multiple formulations, for example, two formulations of the invention, the respective fentanyl containing 400 μ g, or 4 formulations of the invention, each contain about 200 μ g fentanyl.Preferably, this multi-form medication, which was related in one hour, takes all formulations, more preferably substantially takes simultaneously (if not simultaneously).

Specifically, it is a kind of be used to prepare be used for buccal, gums is applied or the method for Tablets of sublingual administration includes the fentanyl or its salt that offer amount is the μ g/ agent of about 100- about 800 (being determined as fentanyl alkali), or equivalent its salt.Effervescent agent pair of the consumption for the 5- about 85% of the formulation weight is also provided, consumption is the about .5- about 25% of the formulation weight at least one pH Auto-regulators, with at least one disintegrant, preferably starch glycolate, consumption is the about 0.25- about 20% of the formulation weight.Mix above composition and be pressed into tablet.In preferred embodiments, filler is also used.In particularly preferred embodiments, a part of filler can be pre-mixed with fentanyl or other excipient such as colouring agent.

In addition, one of excipient being usually used in the present invention is lubricant, such as magnesium stearate.Generally, it is added at the end of blending period.Mixing is generally interrupted, magnesium stearate is then added, the mixed for several minutes time is further continued for afterwards.

In preferred embodiments, the blister package equipped with formulation of the present invention should at once be opened before product use.The formulation should be placed in his or her mouth by patient, be preferably positioned between cheek and up or down gums.The formulation should not be sucked or chew.Such as many opiates, fentanyl is preferably titrated with the initial dose of relative low dose.Sublimaze formulation of the present invention, the initial dose of particularly those preparation formulations for treating break-through cancer pain breaking-out should be 100 μ g.The limited initial titration supply of the μ g formulations of patient 100 should be provided, the units used at home during titration is thus limited in.It is then possible to be gradually increased dosage under the guidance of doctor.

Embodiment

Production method

In the case of each in embodiment 1-7 and 9-11, material is filled into V- blenders using preceding sieving, or can be mixed with any suitable low shear mixer, and mixes reasonable time.After being discharged from blender, the material is suppressed on standard rotary tablet press, to reach the aimed hardness and the target weight as 100 disclosed in each example or 200mg of 13 newton.

Embodiment 1- formulations A

OraVescentFentanyl, 1080mcg, 5/16 " tablet is red

Components Name	Measure (mg/ pieces)
		Citric acid fentanyl, USP	1.688
Mannitol, USP*	95.312
		Sodium acid carbonate, USP/EP/JP	42.000
Citric acid, USP/EP/JP	30.000
		Sodium carbonate, USP/NF	20.000
Sodium starch glycolate, NF/EP	6.000
		Magnesium stearate, NF/EP/JP	4.000
Red ferric oxide, NF	1.000

Amount to

200.000

* it is spray-dried (SPI Pharma Mannogem EX)

Embodiment 2- formulations C

0raVescent

Fentanyl, 1300mcg, 5/16 " tablet is red

Components Name	Measure (mg/ pieces)
		Citric acid fentanyl, USP	2.042
Mannitol, USP*	94.958
		Sodium acid carbonate, USP/EP/JP	42.000
Citric acid, USP/EP/JP	30.000
		Sodium carbonate, USP/NF	20.000
Sodium starch glycolate, NF/EP	6.000
		Magnesium stearate, NF/EP/JP	4.000
Red ferric oxide, NF	1.000
		Amount to	200.000

* it is spray-dried

Embodiment 3- formulations D

OraVescent

Fentanyl, 810mcg, 5/16 " tablet, yellow

Components Name	Measure (mg/ pieces)
		Citric acid fentanyl, USP	1.266
Mannitol, USP*	95.734
		Sodium acid carbonate, USP/EP/JP	42.000
Citric acid, USP/EP/JP	30.000
		Sodium carbonate, USP/NF	20.000
Sodium starch glycolate, NF/EP	6.000
		Magnesium stearate, NF/EP/JP	4.000
Yellow ferric oxide, NF	1.000
		Amount to	200.000

* it is spray-dried

Embodiment 4- formulations E

OraVescent

Fentanyl, 270mcg, 5/16 " tablet, white

Components Name	Measure (mg/ pieces)
		Citric acid fentanyl, USP	0.422
Mannitol, USP*	97.578
		Sodium acid carbonate, USP/EP/JP	42.000
Citric acid, USP/EP/JP	30.000
		Sodium carbonate, USP/NF	20.000
Sodium starch glycolate, NF/EP	6.000
		Magnesium stearate, NF/EP/JP	4.000
Amount to	200.000

* it is spray-dried

Embodiment 5

OraVescent

Fentanyl, 500mcg, 5/16 " tablet is orange

Components Name	Measure (mg/ pieces)
		Citric acid fentanyl, USP	0.786
Mannitol, USP*	96.214
		Sodium acid carbonate, USP/EP/JP	42.000
Citric acid, USP/EP/JP	30.000
		Sodium carbonate, NF	20.000
Sodium starch glycolate, NF/EP	6.000
		Magnesium stearate, NF/EP/JP	4.000
Yellow ferric oxide, NF	0.600
		Red ferric oxide, NF	0.400
Amount to	200.000

* it is spray-dried

Embodiment 6

OraVescent

Fentanyl, 200mcg, 5/16 " tablet, white

Components Name	Measure (mg/ pieces)
		Citric acid fentanyl, USP	0.315
Mannitol, USP*	97.685
		Sodium acid carbonate, USP/EP/JP	42.000
Citric acid, USP/EP/JP	30.000
		Sodium carbonate, NF	20.000
Sodium starch glycolate, NF/EP	6.000
		Magnesium stearate, NF/EP/JP	4.000
Amount to	200.000

* it is spray-dried

Embodiment 7

OraVescent

Fentanyl, 100mcg, 1/4 " tablet, white

Components Name	Measure (mg/ pieces)
		Citric acid fentanyl, USP	0.157
Mannitol, USP*	48.843
		Sodium acid carbonate, USP/EP/JP	21.000
Citric acid, USP/EP/JP	15.000
		Sodium carbonate, NF	10.000
Sodium starch glycolate, NF/EP	3.000
		Magnesium stearate, NF/EP/JP	2.000
Amount to	100.000

* it is spray-dried

Embodiment 8

Material can be filled into V- blenders or other suitable low shear mixers, and mix reasonable time using preceding sieving.After being discharged from blender, the material can be pressed into the aimed hardness of 13 newton and the target weight of 200mg/ pieces on standard rotary tablet press.

OraVescentFentanyl, 300mcg, 5/16 " tablet is light yellow

Components Name	Measure (mg/ pieces)
		Citric acid fentanyl, USP	0.472
Mannitol, USP*	97.328
		Sodium acid carbonate, USP/EP/JP	42.000
Citric acid, USP/EP/JP	30.000
		Sodium carbonate, NF	20.000
Sodium starch glycolate, NF/EP	6.000
		Magnesium stearate, NF/EP/JP	4.000
Yellow ferric oxide, NF	0.200
		Amount to	200.000

* it is spray-dried

Embodiment 9

OraVescent

Fentanyl, 400mcg, 5/16 " tablet, pink

Components Name	Measure (mg/ pieces)
		Citric acid fentanyl, USP	0.629
Mannitol, USP*	97.171
		Sodium acid carbonate, USP/EP/JP	42.000
Citric acid, USP/EP/JP	30.000
		Sodium carbonate, NF	20.000
Sodium starch glycolate, NF/EP	6.000
		Magnesium stearate, NF/EP/JP	4.000
Red ferric oxide, NF	0.200
		Amount to	200.000

* it is spray-dried

Embodiment 10

OraVescentFentanyl, 600mcg, 5/16 " tablet is orange

Components Name	Measure (mg/ pieces)
		Citric acid fentanyl, USP	0.943
Mannitol, USP*	96.057
		Sodium acid carbonate, USP/EP/JP	42.000
Citric acid, USP/EP/JP	30.000
		Sodium carbonate, NF	20.000
Sodium starch glycolate, NF/EP	6.000
		Magnesium stearate, NF/EP/JP	4.000
Yellow ferric oxide, NF	0.600
		Red ferric oxide, NF	0.400
Amount to	200.000

* it is spray-dried

Embodiment 11

OraVescent

Fentanyl, 800mcg, 5/16 " tablet, yellow

Components Name	Measure (mg/ pieces)
		Citric acid fentanyl, USP	1.257
Mannitol, USP*	95.743
		Sodium acid carbonate, USP/EP/JP	42.000
Citric acid, USP/EP/JP	30.000
		Sodium carbonate, NF	20.000
Sodium starch glycolate, NF/EP	6.000
		Magnesium stearate, NF/EP/JP	4.000
Yellow ferric oxide, NF	1.000
		Amount to	200.000

* it is spray-dried

Embodiment 12

Weigh and the following material that sieves.

#	Explanation	Amount/piece (%w/w)	Amount/crowd (kg)
				1	Citric acid fentanyl	0.6285	502.8g*
2a.	Mannitol EZ	23.875	19.1
				2b.	Mannitol EZ	24.014	19.2
3.	Sodium acid carbonate, No.1	21.0000	16.8
				4.	Citric acid, anhydrous, fine grained	15.0000	12.0
5.	Sodium carbonate, it is anhydrous	10.0000	8.000
				6.	Sodium starch glycolate	3.0000	2.400
7.	The iron oxide of yellow 10	0.5000	0.400
				8.	Magnesium stearate, non-ox	2.0000	1.600
	Amount to	100.0000	80.0

Mannitol EZ (2a.) and the iron oxide of yellow 10 are transferred in V- blenders, and mixed 30 minutes.Discharge and grind premixing.By the premix of total amount, citric acid fentanyl, sodium acid carbonate, citric acid, sodium carbonate and sodium starch glycolate are added in V- blenders, and mix 30 minutes.Mannitol (2b) is filled into V- blenders, and mixed 13 minutes.Magnesium stearate is filled into V- blenders, and mixed 5 minutes.By this final mixture compressed tablets.These tablets are 1/4 " circular, flat surface, it is white, with hypotenuse.By the tablet press to average hardness it is 13 newton on 36 complete station Fette tablet press machines of equipment.

Claims (18)

1. a kind of compressed tablets formulation, it is included：90-880 μ g fentanyl or its salt of equivalent, are calculated with fentanyl free base；Consumption is the effervescent agent for accounting for formulation weight 5-85%, and the effervescent agent is selected from food acid plus carbonate or bicarbonate, wherein described sour and described carbonate or bicarbonate exist in the tablet with stoichiometry equivalent；Consumption is the pH Auto-regulators for accounting for formulation weight 0.5-25%, and the pH Auto-regulators are selected from carbonate, bicarbonate or phosphate；Consumption is the mannitol for accounting for formulation weight 10-80%；It is the starch glycolate that accounts for formulation weight 0.25-20% with consumption.

2. the formulation of claim 1, wherein, the selection of the pH Auto-regulators and consumption can provide the local pH change of at least 0.5 pH unit.

3. the formulation described in claim 1 is used for the purposes for preparing the medicine of the pain for the treatment of patient.

4. the purposes of claim 3, wherein, the pain is selected from following one group：Break-through cancer pain, backache, neuropathic pain, surgical pain, or postoperative pain.

5. the formulation described in claim 1 is used for the purposes for preparing the medicine for the treatment of break-through cancer pain breaking-out.

6. preparing the method for the tablet for buccal, gums administration or sublingual administration fentanyl, comprise the following steps：Fentanyl or its salt are provided, consumption is 90-880 μ g/ agent, with its salt of the measurement of fentanyl alkali, or equivalent；Effervescent agent of the consumption for the 5-85% of the formulation weight is provided, the effervescent agent is selected from food acid plus carbonate or bicarbonate, wherein described sour and described carbonate or bicarbonate exist in the tablet with stoichiometry equivalent；Consumption is the 0.5-25% of formulation weight pH Auto-regulators, and the pH Auto-regulators are selected from carbonate, bicarbonate or phosphate, and consumption is the mannitol for accounting for formulation weight 10-80%；With starch glycolate of the consumption for the 0.25-20% of the formulation weight；Mix the fentanyl, effervescent agent, pH Auto-regulators, mannitol and the starch glycolate；And resulting mixture is pressed at least one tablet.

7. the method for claim 6, is additionally included in before resulting mixture is pressed into at least one tablet lubricant being added to the step in the mixture.

8. the method for claim 7, also comprises the following steps：By the lubricant and the fentanyl, effervescent agent, pH Auto-regulators, starch glycolate and the filler are mixed, and resulting mixture then is pressed into at least one tablet.

9. the method for claim 8, wherein, the tablet is pressed into hardness for 5-100 newton.

10. the method for claim 6, wherein, the tablet is compressed to hardness for 15-100 newton.

11. the formulation of claim 1, wherein the formulation includes the lactose monohydrate no more than weight 10%.

12. the formulation of claim 1, wherein the formulation includes the microcrystalline cellulose no more than weight 10%.

13. the formulation of claim 1, wherein the formulation includes 4% cross-linked pvp no more than weight.

14. the formulation of claim 1, wherein the formulation is free of lactose monohydrate, microcrystalline cellulose or cross-linked pvp.

15. the method for claim 6, wherein the tablet includes the lactose monohydrate no more than weight 10%.

16. the method for claim 6, wherein the tablet includes the microcrystalline cellulose no more than weight 10%.

17. the method for claim 6, wherein the tablet includes 4% cross-linked pvp no more than weight.

18. the method for claim 6, wherein the tablet is free of lactose monohydrate, microcrystalline cellulose or cross-linked pvp.