CN1901890B - Generally linear effervescent oral fentanyl dosage form and method of administration - Google Patents

Abstract

Dosage forms containing fentanyl and methods of using the same are disclosed. These dosage forms contain significantly less fentanyl by weight than known oral formulations and have advantages in terms of cost and side effects. The dosage form is intended for oral administration of fentanyl through the oral mucosa.

Description

Generally linear effervescent oral fentanyl dosage form and method of administration

Background technique

Fentanyl (CAS Reg. No. 437-38-7) N-phenyl-N-[1-(2-phenyl-ethyl)-4-piperidinyl]propionamide and its salts, especially its lemon Oxygenate (CAS Registration No. 990-73-8) is an opiate, a controlled substance, and is an extremely effective narcotic analgesic. Fentanyl and its citrate salt are currently marketed by various companies in a variety of delivery methods. For example, fentanyl citrate is available as an injection and as an oral lozenge on a stick, the latter marketed under the trademark ACTIQ. Three patents in the FDA publication Approved Drug Products With Therapeutic Equivalence Evaluations (hereinafter "Yellow Book") relate to ACTIQ: US Patent Nos. 4,671,953, 4,863,737 and 5,785,989. A second form of ACTIQ is also available. This form may be a compressed tablet on a stick. Similar to the original ACTIQ lozenge, it is believed that this second form exhibits the same disintegration rate, _Tmax , _Cmax and AUC as the original lozenge. Accordingly, they will be discussed collectively unless otherwise indicated, or where the context dictates otherwise.

Package insert information for ACTIQ sold by Cephalon, Inc., 145 Brandy Wine Parkway West, Chester, PA 19380, is available from Physician's DeskReference, 57th ed. severity of pain. According to its label, ACTIQ "is indicated only for the management of breakthrough cancer pain in patients with malignancies who have received and are resistant to opioid therapy for their underlying persistent cancer pain" (Id., emphasized in the original text ). The text of the ACTIQ label is incorporated herein by reference.

In the ACTIQ clinical trial, breakthrough cancer pain was defined as a transient episode of moderate to severe pain occurring in cancer patients experiencing persistent cancer pain controlled with maintenance dose opiate medication , including at least 60 mg morphine/day, 50 μg transdermal fentanyl/hour, or an equivalent analgesic dose of another opiate for a week or more. Thus, patients receiving ACTIQ are those with sudden intolerable pain that flares up despite long-term analgesic therapy. Providing pain relief for this breakthrough pain is inexorably linked to the patient's immediate quality of life. And, for these patients, providing breakthrough pain relief may be the only thing medical science can offer.

As with many things in medicine, there is always room for improvement. Fentanyl is an expensive drug, costing $100/gram or more to produce. Although cost is not an overriding issue, the cost of medication is a consideration. A formulation that reduces the amount of fentanyl used could reduce the overall cost of patient care.

More importantly, reducing the dose of this potent opiate while still achieving effective control of breakthrough pain in cancer patients has very far-reaching and desirable consequences in terms of overall patient care. Opioid mu-agonists, including fentanyl, produce dose-dependent respiratory depression. Severe or fatal respiratory depression may occur in susceptible individuals even at recommended doses. Like other potent opiates, fentanyl has been associated with severe and fatal cases of respiratory depression in opiate-intolerant individuals. Therefore, the initial dose of ACTIQ for the treatment of onset in patients with breakthrough cancer should be 200 μg and adjusted individually for each patient to provide adequate analgesia while minimizing side effects. At the same time, side effects, even those that are not life-threatening, can be significant.

In addition, fentanyl as a mu-opioid agonist may produce drug dependence and tolerance. Medication dependence by itself is not necessarily a problem for patients with these types of cancer. However, fentanyl can also be used to treat other types of pain. Dependence and tolerability can be important issues in such treatment regimens. In addition, cancer patients often receive onerous drug therapy, and lower doses of drug therapy can be provided for as long as possible.

U.S. Patent 6,200,604, issued March 13, 2001 to CIMA LABS INC., 10000 Valley View Road, Eden Prairie, MN 55344, exemplifies two formulations of fentanyl, each containing 36% effervescent and 1.57 mg of fentanyl Ni salt. See Example I at column 5, line 60 to column 6, line 30 of this patent. The '604 patent specifically discloses the use of effervescent agents as penetration enhancers for affecting the absorption of oral drugs. See also US Patents 6,759,059 and 6,680,071.还可参见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.

If lower doses of fentanyl could be achieved to provide similar pain relief, patients could reap comparable benefit with much less drug at lower cost, and with reduced risk of side effects. Accordingly, there remains a desire to improve the administration of fentanyl.

Summary of the invention

，取而代之包括可在口中崩解溶解的片剂，胶囊，囊片，凝胶，乳膏和薄膜等。所述剂型优选是泡腾片剂。另外，它们可以包括pH调节物质和崩解剂。一般，将所述剂型应用或者放置在口腔中的特定部位，并且在它们崩解和/或溶解期间保持在那儿，通常大约10-30分钟时间。The present invention relates to a dosage form that disintegrates/dissolves in the mouth, a method for preparing the dosage form, a method for treating pain using the dosage form, and the use for the manufacture of a medicament, wherein fentanyl, or one or more thereof A pharmaceutically acceptable salt (wherein, when "fentanyl" is mentioned herein, it should be considered to include all pharmaceutically acceptable salts, unless the context indicates otherwise) is administered orally, and existing non-effervescent The dose contains at least about 45% less fentanyl than lollipop formulations (lozenges and compressed tablets). Despite the lower dose, the _Cmax of these orally disintegrable dosage forms of the invention is comparable to the _Cmax of other dosage forms containing much more, eg about twice as much drug. As used herein, "comparable" means that the _Cmax of the dosage form of the invention is at least about 75% that of ACTIQ with about 2 times as much fentanyl. Thus, if a 400 μg tablet of the invention is compared to a 400 μg ACTIQ lollipop, and both are compared to an 800 μg ACTIQ lollipop, the _Cmax of the tablet of the invention is at least about 75% to about 125% of the _Cmax of the 800 μg ACTIQ formulation. %. The 400 μg ACTIQ formulation had a much lower C _max . The same is true for doses up to about 800 [mu]g based on the weight of free form fentanyl. Note that "about" in this context (dosage) means ± 10%. Thus, about 100-about 800 μg is 90-880 μg. More preferably, "comparable" in the context of the present invention may also mean that the _Cmax of the dosage form of the present invention is about 80 to about 120% of the _Cmax of ACTIQ. This may also be referred to as "height comparable". More preferably, "comparable" in the context of the present invention may also mean that the _Cmax of the dosage form of the present invention is from about 5 to about 115% of the _Cmax of ACTIQ with about 2 times the weight of fentanyl. This may also be referred to as "very highly comparable". "Oral dosage form" in the context of the present invention preferably excludes lollipop-like lozenges such as ACTIQ

, which instead include tablets, capsules, caplets, gels, creams and films that disintegrate in the mouth. The dosage form is preferably an effervescent tablet. Additionally, they may include pH adjusting substances and disintegrants. Typically, the dosage forms are applied or placed at a specific site in the oral cavity and remain there while they disintegrate and/or dissolve, usually for a period of about 10-30 minutes.

产品相比，所述剂型包括至少大约45％更少的芬太尼(基于它以游离碱材料的形式计算的重量)，更优选大约45％-大约55％更少的芬太尼。然而，它们在Cmax方面是相当的，优选高度相当的，更优选非常高度相当的，以及大体上相等效力的。In another preferred aspect of the present invention there is provided an effervescent orally disintegrating dosage form designed for oral administration of fentanyl and/or a pharmaceutically acceptable salt thereof, such as buccal, gingival or The sublingual route of administration, rather than being swallowed. The formulation preferably does not include a stick or other such device to allow easy gripping in the patient's hand or removal from the mouth once the dosage form is wet in the mouth. Alternatively, with the corresponding ACTIQ

The dosage form comprises at least about 45% less fentanyl (based on its weight as free base material), more preferably from about 45% to about 55% less fentanyl, than product. However, they are comparable in terms of Cmax, preferably highly comparable, more preferably very highly comparable, and substantially equally potent.

制剂中提供1600μg的芬太尼的话，本发明相应的剂型将包括大约880μg的芬太尼或更少。更优选的是，它将包括大约800μg的芬太尼。尽管药物量显著减少，所测定的各种药物的至少一种或多种传统药物动力学特性，如C_max，将是相似的，如果不是更好的话。例如，与含有至少80％更多重量芬太尼的相应ACTIQ

产品相比，根据本发明，制剂可以具有更短的T_max(达到最大浓度所需要的时间)和/或相当(如果不是更好的话)的C_max(在施用之后在患者血液中观察到的最高浓度)。对于在预计的剂量范围内的芬太尼含量增加的剂型，AUC或曲线下面积将大体上是线性的。Therefore, if in ACTIQ

For formulations providing 1600 μg of fentanyl, a corresponding dosage form of the present invention would comprise about 880 μg of fentanyl or less. More preferably, it will include about 800 μg of fentanyl. Despite the significantly reduced amount of drug, at least one or more traditional pharmacokinetic properties, such as _Cmax , will be similar, if not better, measured for each drug. For example, with the corresponding ACTIQ containing at least 80% greater by weight of fentanyl

Formulations according to the invention may have a shorter T _max (time required to reach maximum concentration) and/or equivalent (if not better) C _max (observed in the patient's blood after administration) compared to the product. highest concentration). For dosage forms with increasing fentanyl content over the predicted dose range, the AUC or area under the curve will be approximately linear.

In a particularly preferred aspect of the invention, it has been found that formulations produced have an approximately linear relationship between the dose of fentanyl (measured by weight of free base) and _Cmax , especially at about 100-800 μg/dose. within the dose range. "Linear" should be understood to mean that, when formulated as part of a series of at least 3 dosage forms having different doses of 90-880 μg of fentanyl, within the dose range of 90-880 μg (more preferably 100-810 μg), the dose is standardized C _max was not significantly different, using ANOVA, p was in the range of 0.15 (p less than or equal to 0.15). This is the preferred method for determining the linearity of the invention. In other words, the slope of ln(C _max ) vs. ln(dose) should be 1 ± 15% (0.85-1.15). As noted in the studies discussed herein, doses of 200, 500 and 810 μg were "linear" according to the invention. The 1080 [mu]g dose, while far superior to the prior art, was not "linear" as defined herein in terms of _Cmax vs. dose compared to the other doses.

Within this dosage range, the _Cmax to dose ratio will be from about 2.0 to about 4.0 pg/mL/μg. That is, picograms of fentanyl base per mL of serum or proportional amounts (if measured in blood or other fluid) are normalized to each μg dose. The term "between/-" in the present invention includes endpoints. More preferably, the ratio is from about 2.5 to about 3.5, more preferably from about 2.7 to about 3.5 picograms/mL/μg. The range is an average calculated from at least 10 patients in a suitable clinical trial. In contrast, experiments have determined that ACTIQ provides a ratio of approximately 1.4 pg/mL/μg. Thus, for a dosage form containing the same amount of fentanyl, the present invention can provide approximately twice the _Cmax (if not more), up to a dose of 880 μg, eg, about 800 μg, with the present invention. In another embodiment, the dosage form will also provide a linear relationship between dose and _Cmax when formulated in the range of about 100 to about 800 μg of fentanyl (free base) or a proportional amount of salt. Of course for a single dose strength this means that the ratio of dose to _Cmax for that dose will have a linear relationship to the series produced by simply varying the same formulation within the above range to include more or less fentanyl .

Also preferred as an aspect of the present invention are effervescent dosage forms of fentanyl, designed for buccal, gingival or sublingual administration, containing 880 μg or less by weight of fentanyl (based on free base material). weight), and it has a _Tmax of less than about 1.5 hours, most preferably less than about 1 hour. However, these dosage forms will ideally have a _Cmax of about 2.0 to about 4.0 picograms/mL/[mu]g as described above. Also contemplated are methods of administering the dosage forms for the treatment of pain.

In a particularly preferred embodiment of the invention, the formulation includes an effervescent agent, acting as a penetration enhancer, with or without, but preferably with, an additional pH-adjusting substance. Most preferably, the pH adjusting substance is a different substance than one of the ingredients, compounds or molecules used to generate the effervescence. Particularly preferred dosage forms also include disintegrants which allow for dose reduction, linearity and/or _Cmax and dose scaling as described herein. A particularly preferred example of a disintegrant is starch glycolate. Also preferred are dosage forms that include fillers that promote the same properties as the disintegrants described above. Most preferably, the filler is mannitol.

的大约25％以内，优选大约20％以内，更优选其大约15％以内。In a particularly preferred embodiment of the invention there is provided an oral dosage form suitable for buccal, gingival or sublingual administration containing up to 1 mg, more preferably 100, 200, 300, 400, 600 or 800 μg of fentanyl, Weight is measured as free base and also includes at least one effervescent couple, at least one pH adjusting substance and suitable excipients. Preferably, the formulation will be capable of providing a T _max of 1.5 hours or less and/or a C _max of about 2.0 to about 4.0 picograms/mL/μg. In other words, the _Cmax of the dosage form of the present invention is comparable to that of ACTIQ containing at least about 80% more fentanyl by weight. The C _max of the formulations were comparable. In another preferred embodiment, the _Cmax of the dosage form is ACTIQ with at least about 80% greater by weight fentanyl free base

Within about 25%, preferably within about 20%, more preferably within about 15% of

In another particularly preferred embodiment of the invention there is provided an orally disintegrating tablet suitable for buccal, gingival or sublingual administration containing about 100, 200, 300, 400, 600 or 800 μg of Fentanyl (measured as free base), at least one effervescent agent pair, and at least one pH adjusting substance, and suitable excipients, in a dosage form capable of providing a _Tmax of about 1.5 hours or less and/or Or a C _max of about 2.7 to about 3.5 pg/mL/μg.

In another embodiment of the invention, any of the formulations mentioned hereinbefore may consist essentially of fentanyl, preferably in an amount of about 800 μg or less (i.e., up to 880 μg), an effervescent pair, At least one pH adjusting substance and suitable excipients capable of providing a _Cmax of about 2.0 to about 4.0 pg/mL/μg, more preferably about 2.5 to about 3.5 pg/mL/μg, most preferably about 2.7-approximately 3.5 pg/mL/μg, and provides comparable C _max than ACTIQ The dosage form contains at least about 45% less fentanyl. As used herein, "consisting essentially of/consisting essentially of" means excluding any excipient or combination of excipients, or any amount of any excipient or combination of excipients where appropriate, and Any pH adjusting substance or any amount of pH adjusting substance, such excipients and pH adjusting substances would alter the basic and novel features of the present invention. Therefore, specific excipients or mixtures of excipients that would increase _Tmax to 2.5 hours or more will be excluded. Similarly, and again for exemplary purposes only, combinations of excipients provided in specific amounts that would alter _Cmax to an undesired level are excluded. Small amounts of cross-linked PVP and/or lactose monohydrate, although generally undesirable, may still be used as long as it does not significantly alter the _Tmax or _Cmax of the dosage form of the invention. However, if used together, and at levels of 5% and 20%, respectively, they can adversely alter the above properties. Accordingly, said amounts of the aforementioned excipients in combination would be excluded.

In a particularly preferred embodiment of this aspect of the invention, the dosage form provided consists essentially of: 90-880 μg of fentanyl (calculated as fentanyl free base) or a salt thereof, sodium starch glycolate, manna A sugar alcohol, at least one pH adjusting substance and at least one effervescent agent pair. Preferably, the dosage form has a _Tmax of about 1.5 hours or less, a _Cmax to dose ratio of about 2.0 to about 4.0 picograms/mL/μg, a _Cmax linear to dose and/or as defined herein The _dosage form is suitable for buccal, sublingual or gingival administration. More preferably, the amount of fentanyl measured in free base form is 100-800 μg.

Another aspect of the invention also relates to methods of administering fentanyl to patients experiencing pain, generally including but not limited to: back pain, lower back pain, joint pain, arthritic pain of any form, pain due to trauma or accident Pain, neuropathic pain, surgical or postoperative pain, pain resulting from a disease or condition other than cancer, cancer pain, and breakthrough pain especially due to cancer. A preferred method comprises the step of administering to a patient in need thereof any of the orally disintegrable effervescent tablets disclosed herein for buccal, gingival or sublingual administration comprising a dose of about 100-800 μg Fentanyl (measured as the free base) and the dosage form is held in the patient's mouth for a sufficient period of time to allow the dose (or a therapeutically meaningful and/or effective portion thereof) to be transported from the mouth into the bloodstream . Preferably, the patient is instructed, trained or observed to ensure that the dose is not swallowed but, to the extent practicable, the fentanyl enters the body through the mouth and one or more surfaces within the oral cavity. The method also preferably includes the step of maintaining said dosage form in the mouth without substantially moving it within the oral cavity. In another preferred aspect, the dose dissolves/disintegrates or has an average residence time of 5-30 minutes.

One such method is a method of treating breakthrough cancer pain episodes comprising the steps of: providing an initial dose of about 100 μg of fentanyl (calculated as fentanyl free base) or a salt thereof in an equivalent amount, in a A dosage form comprising an effervescent agent in an amount of about 5 to about 85% by weight of the dosage form; a pH adjusting substance in an amount of about 0.5 to about 25% by weight of the dosage form; and starch glycolate in an amount of 0.25 to about 20% by weight. The dosage form is suitable for delivering the fentanyl through the oral mucosa of a patient. "Providing" is understood to include removal of the dosage form from packaging or distribution or distribution of said dosage form by someone. The method also includes placing the dosage form in the patient's mouth, between the cheek and the upper or lower gum, for a time sufficient to deliver a therapeutically effective amount of the fentanyl across the oral mucosa. Other types of pain can be treated in the same way, including any type of back pain, surgical or post-operative pain, and neuropathic pain.

Unexpectedly, it is possible to produce an orally disintegrating tablet designed for oral administration of fentanyl that provides a _Tmax of 1.5 hours or less, containing 880 μg of fentanyl Tenyl or less (measured as free base), preferably with a desirable _Cmax Although some literature on ACTIQ lozenges suggests a _Tmax of about 45 minutes, testing has shown that this time is more likely to be two hours .

剂型相比，包含至少大约45％更少的芬太尼。Unexpectedly, it was possible to produce an orally disintegrating dosage form designed for oral administration of fentanyl by buccal, sublingual, or gingival routes that provided comparable _Cmax data to ACTIQ

Contains at least about 45% less fentanyl compared to a dosage form.

It is also unexpected that an orally disintegrating dosage form can be produced and used to treat pain, particularly breakthrough pain experienced by cancer patients, wherein a therapeutically effective amount (capable of providing some degree of pain relief) amount), usually more than 75%, more preferably more than 80%, and most preferably 90% or more of a fentanyl dose is absorbed from the oral cavity into the bloodstream through the oral mucosa.

It is also unexpected that the _Cmax of a dosage form with so little active drug compared to currently marketed products can be linear in _Cmax versus dose, e.g., between about 100-about 800 μg (90-880 μg ) with a confidence interval of ±15%.

According to another aspect of the present invention, there is provided a method of preparing a buccal, gingival or sublingual effervescent fentanyl dosage form capable of providing one or more of the following characteristics: Linear relationship between dose and _Cmax over range; comparable to non-effervescent formulations such as ACTIQ at the same dose Comparable _Cmax at doses of at least about 45% less fentanyl; and _Cmax to dose ratios of 2.0-4.0 picograms/mL/μg. This is accomplished by mixing the following: fentanyl in an amount of about 100 to about 800 μg/dosage (based on the weight of the free base) and an effective amount of an effervescent agent that, once placed in the patient's mouth, An effective amount that alters the local pH ("local pH") of the microenvironment ("local pH") of the dosage form in the area of contact with the oral mucosal surface (by at least 0.5 pH units as compared to the same formulation without the pH adjusting substance) pH adjusting substances, and disintegrants, which allow to achieve the above described dose reduction, linear relationship and ratio of _Cmax and dose. These materials are compressed into tablets or otherwise formulated using conventional techniques. This process is preferably accomplished without granulation, although the various materials used may be granulated prior to mixing. Thus, moist granulated sugar can be used as filler in otherwise dry and direct compression processes.

More preferably, the method is used to prepare a dosage form, preferably a tablet, which produces a linear relationship between dose and _Cmax in the range of about 100 to about 800 μg, at least about 50 compared to the same dose of ACTIQ. % less fentanyl doses with highly comparable _Cmax and/or _Cmax to dose ratios of about 2.7 to about 3.5 pg/mL/μg. This is accomplished by mixing the following ingredients: fentanyl or its salts suitable to provide a predetermined amount of dosage forms each having from about 100 to about 800 μg of fentanyl; and an effervescent pair in an amount of about 5 to about 5 by weight of the finished dosage form 85% (w/w); pH adjusting substance in an amount of about 0.5 to about 25% w/w; starch glycolate in an amount of about 0.25 to about 20% w/w; with or without mannitol; and The mixture is compressed into tablets in the dry state. Preferably, the pH adjusting substance will provide a localized pH change of at least about 1 pH unit compared to the same formulation without the adjusting substance.

Detailed description

Throughout the specification, including the claims, the word "comprise" and variations of that word, such as "comprising" and "comprises", as well as "have", "having", "Includes", "include" and "including" and their variations, means that the mentioned steps, elements or materials are essential, but other steps, elements or materials may be added and still constitute the claims or schemes within the scope of the disclosure. When cited in describing the invention and claims, it means that the invention and claims are considered to be what follows and possibly more. These terms, especially when used in the claims, are inclusive or open-ended and do not exclude other unrecited elements or method steps.

For the purposes of the present invention, unless otherwise defined in connection with a particular property, characteristic or variable, the term "substantially/substantially" when applied to any criterion, such as a characteristic, characteristic or variable, means that the indicated Criteria, such that a benefit to be obtained, or a desired condition or value of a property is met, will be understood by those skilled in the art.

In one aspect, the invention includes a dosage form comprising about 100 to about 800 micrograms (micrograms) of fentanyl (calculated as fentanyl free base) or a salt thereof, suitable for buccal, sublingual or gingival administration. The dosage form is capable of providing a _Tmax of 1.5 hours or less when properly administered by contact with the oral mucosa for a sufficient period of time. Additionally or alternatively, a _Cmax to dose ratio of about 2.0 to about 4.0, more preferably about 2.3 to about 3.5, most preferably about 2.7 to about 3.5 picogram/mL/μg can be achieved. Most preferably, the relationship between dose and _Cmax is linear for doses of about 100 to about 800 [mu]g compared to other doses formulated in the same manner.

The dosage form preferably also comprises at least one pH adjusting substance and at least one effervescent couple. They are provided in amounts sufficient to provide the desired _Tmax and/or _Cmax , respectively. The dosage form also preferably comprises at least one excipient selected and used in such an amount as to provide the desired _Tmax and/or _Cmax in combination with the at least one pH adjusting substance and at least one effervescent agent pair.

Another aspect of the invention is a method of administering fentanyl to a patient experiencing pain, which method may comprise the step of contacting the oral mucosa of the patient in need thereof with an orally disintegrable dosage form. The dosage form includes a dose of about 100-800 (90-880) μg (measured as free base) per dosage form of fentanyl, or a salt thereof. The dosage form is capable of providing a _Tmax of 1.5 hours or less, and/or a _Cmax to dose ratio of about 2.0 to about 4.0, more preferably about 2.3 to about 3.5, most preferably about 2.7 to about 3.5 picograms/mL /μg, and/or a linear relationship between _Cmax and dose, is preferred for a dosage form that includes at least 45% less fentanyl than is prescribed using commercially known delivery forms. The dosage form is kept in contact with the patient's oral mucosa for a period of time long enough that a therapeutically meaningful or effective fraction of the fentanyl, preferably greater than 75%, more preferably greater than 80%, and most preferably 90% or more of the dose, passes through the oral mucosa Transported from the mouth into the bloodstream.

制剂的C_max的至少大约75-大约125％，更优选为大约80-大约120％，最优选为大约85％-大约115％，其中，所述后者包括重量至少80％更多的芬太尼。优选的是，该剂型还包括至少一种pH调节物质和至少一种泡腾剂对，其用量足以提供所述C_max。更优选的是，所述剂型还包含一定量的至少一种赋形剂，与所述至少一种pH调节物质和/或至少一种泡腾剂对相组合足以提供理想的C_max。Another aspect of the invention provides a dosage form comprising: about 100 to about 800 μg of fentanyl per dosage form, calculated as fentanyl free base. When used, the fentanyl salt is used in an amount to provide an equivalent by weight of fentanyl free base. The dosage form is suitable for buccal, sublingual or gingival administration. The dosage form, when properly administered through contact with the oral mucosa for a sufficient period of time, is capable of providing a _Cmax of ACTIQ

At least about 75% to about 125%, more preferably about 80% to about 120%, most preferably about 85% to about 115% of the _Cmax of the formulation, wherein the latter includes at least 80% more fentai by weight Ni. Preferably, the dosage form further comprises at least one pH adjusting substance and at least one effervescent pair in amounts sufficient to provide said _Cmax . More preferably, the dosage form further comprises an amount of at least one excipient sufficient to provide the desired _Cmax in combination with the at least one pH adjusting substance and/or at least one effervescent agent pair.

Also relates to a method of administering fentanyl to a patient experiencing pain comprising the steps of contacting the oral mucosa of a patient in need thereof with an orally disintegrable dosage form comprising a dose of fentanyl of approximately 100-800 μg (measured in the form of free base), or the equivalent amount of its salt. The dosage form exhibits a _Cmax of ACTIQ comprising at least 80% more fentanyl by weight At least about 75% to about 125% of the formulation, more preferably about 80% to about 120%, most preferably about 85% to about 115%. The dosage form remains in contact with the patient's oral mucosa long enough to deliver a therapeutically meaningful or effective fraction of the fentanyl, preferably more than 75%, more preferably more than 80%, most preferably 90% or more of the dose, by The oral mucosa enters the bloodstream from the mouth.

It has now been found that the use of effervescent and pH adjusting substances, especially in combination with starch glycolate, can provide significant advantages, particularly in terms of the amount of fentanyl required for administration. It has also been found that certain excipients in combination with effervescent couples and pH adjusting substances provide even better and very unexpected results.

To determine whether a particular formulation is capable of achieving the results disclosed herein, one need only conduct a routine human clinical study of that formulation in at least ten patients. Suitable clinical studies can use any conventional model. Examples of suitable studies include the following:

Clinical Study Design and Operation

This study and the Informed Consent Form (ICF) were approved by the Institutional Review Board (IRB). All subjects read and signed the IRB-approved ICF prior to study initiation. Keep signed and notarized ICF on file.

For the first two phases, the study employed single doses of the designated test and reference products, a randomized, open-label, two-way crossover design, and subjects were randomized during phase 3 to receive one of three additional test formulations. All subjects were randomized and were in the fasted state after a 10 hour overnight fast. There was a washout interval of 7 days between the three administered doses. The subjects were confined to the clinic until 36 hours after fentanyl administration.

The subjects were screened within 21 days prior to study enrollment. The screening program included medical history, physical examination (height, weight, body shape, vital signs, and ECG), and clinical laboratory tests (hematology, serum chemistry, urinalysis, HIV antibody screen, HBsAg screen, hepatitis C Antibody screen, serum pregnancy test [for women only]), and screen for cannabinoids and opioids.

All subjects enrolled in this study met the inclusion/exclusion criteria listed in the protocol. The study involved a total of 42 subjects, 17 males and 25 females, with 39 subjects, 17 males and 22 females, completing the study.

Subjects reported to the clinic the morning before each dose and had lunch 19 hours before the dose, dinner 14 hours before the dose, and a snack 11 hours before the dose. The subjects then followed a 10 hour overnight fast. On Day 1, a standardized meal schedule was initiated with lunch 4.5 hours post-dose, dinner 9.5 hours post-dose, and snack 13 hours post-dose. On day 2, breakfast was eaten 24.5 hours after dosing, lunch 28.5 hours after dosing, and dinner 33 hours after dosing.

Subjects were not to consume any food or drink containing alcohol, broccoli, citrus, caffeine, or xanthines for 48 hours prior to and during each session of containment. Subjects were nicotine and tobacco abstinent for at least 6 months prior to participation in the study. Additionally, over-the-counter medications were prohibited 7 days prior to dosing and during the study. No prescription medications (except female hormonal contraceptives) were allowed 14 days prior to dosing and during the study.

During the study, the subjects remained seated for 4 hours after taking the fentanyl citrate. Restrict drinking from 0 hours to 4 hours after taking the drug. Restrict food intake from 10 hours before the dose to 4 hours after the dose. During the study, the subjects were not allowed to engage in any strenuous exercise.

The naltrexone subjects received in each phase are detailed below:

50mg(盐酸纳曲酮片剂)Adm 1: ReVia

50mg (naltrexone hydrochloride tablet)

Manufactured by Bristol-Myers Squibb

Batch number: 5C269A

Product validity period: April 2004

Batch number: TB1798

Product validity period: March 2005

Subjects assigned to Treatments A, B, C, and D received oral doses of one 50 mg naltrexone tablet taken with 240 mL of water 15 hours and 3 hours before and 12 hours after administration of the fentanyl dose of.

Subjects assigned to Treatment E received an oral dose of one 50 mg naltrexone tablet taken with 240 mL of water 15 and 3 hours before the fentanyl dose.

Subjects received one of the following fentanyl treatments in each of the three phases:

A: Ora Vescent Fentanyl citrate tablet 1080 μg (as fentanyl base)

Produced by CIMA LABS

Batch number: 930502

″表示本发明的制剂和剂型。Subjects randomized to Treatment A received a single oral dose of one 1080 μg fentanyl tablet placed between the upper gum and cheek, over the molars, and allowed to disintegrate for 10 minutes. Note, "OraVescent

"Denotes formulations and dosage forms of the invention.

(口服经粘膜柠檬酸芬太尼)相当于1600μgB: Actiq

(oral transmucosal fentanyl citrate) equivalent to 1600 μg

Manufactured by Cephalon or Anesta

Batch number: 02689W3

Subjects randomized to Treatment B received a single oral dose of Actiq 1600 μg flat, placed between the cheek and lower gum. Use the handle to move the unit from side to side and let it dissolve for 15 minutes.

C: OraVescent Fentanyl citrate tablet 1300 μg (as fentanyl base)

Produced by CIMA LABS

Batch number: 930503

Subjects randomized to Treatment C received a single oral dose of one 1300 μg fentanyl tablet placed between the upper gum and cheek, over the molars, and allowed to disintegrate for 10 minutes.

柠檬酸芬太尼片剂810μg(作为芬太尼碱)D: OraVescent

Fentanyl citrate tablet 810 μg (as fentanyl base)

Produced by CIMA LABS

Batch number: 930501

Subjects randomized to Treatment D received a single oral dose of one 810 μg fentanyl tablet placed between the upper gum and cheek, over the molars, and allowed to disintegrate for 10 minutes.

柠檬酸芬太尼片剂270μg(作为芬太尼碱)E: OraVescent

Fentanyl citrate tablet 270 μg (as fentanyl base)

Produced by CIMA LABS

Batch number: 930500

Subjects randomized to Treatment E received a single oral dose of one 270 μg fentanyl tablet placed between the upper gum and cheek, over the molars, and allowed to disintegrate for 10 minutes.

The composition of each of the above fentanyl citrate tablets is disclosed in Examples 1-4.

Every morning before medication (0 hours) and after medication 0.25, 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, Sedentary vital signs (blood pressure, pulse, and respiration) were assessed at 10, 24, and 36 hours. Continuous pulse oximetry was performed for the first 8 hours after dosing. A 12-lead electrocardiogram, clinical laboratory evaluation (hematology, serum chemistry, and urinalysis), and physical examination with comprehensive vital signs were performed at the conclusion of the study. Oral irritation assessments were performed 4 hours after dosing. Subjects were told to notify the study physician and/or nurse of any adverse events that occurred during the study.

Blood samples (7 mL) were collected from subjects assigned to Treatments A-D at the following times: pre-dose (0 hour), and 10, 20, 30, and 45 minutes post-dose; and post-dose 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, and 36 hours. Blood samples (7 mL) were collected from subjects assigned to Treatment E at the following times: pre-dose (0 hour), and 10, 20, 30, and 45 minutes post-dose; and post-dose 1, 2, 4, 6, 8, 9, 10, 11, 12, 14, 16, 20, and 24 hours. A total of 54 blood samples (378 mL) were drawn for drug analysis during the study. Samples were collected and processed under fluorescent illumination at room temperature. Serum samples were allowed to clot, separated by centrifugation, frozen at -20°C, and kept frozen until analysis.

Analytical method

LC-MS/MS (Liquid Chromatography-Mass Spectrometry/Mass Spectrometry) of Fentanyl in Human Serum.

Pharmacokinetic and Statistical Methods

Pharmacokinetic and statistical analyzes are based on guidance for industry issued by the Food and Drug Administration, Center for Drug Evaluation and Research (CDER), January 2001, titled "Statistical Approaches to Establishing Bioequivalence", and industry guidance issued March 2003 Guidelines, entitled "Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations".

Based on the fentanyl concentration-time data for each treatment, the following noncompartmental pharmacokinetic parameters were calculated using WinNonlinStandard Edition version 2.1. Actual (rather than nominal) sampling times were used for the analysis.

AUC(0-t) is calculated using linear trapezoidal summation from time zero to time t in Fenty

The area under the Ni concentration-time curve, where t is the last measurable

Time to constant concentration (Ct).

AUC(0-inf) lies below the fentanyl concentration-time curve from time zero to infinity

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

Kel is the terminal elimination rate constant.

AUC(0-t)/AUC The ratio of AUC(0-t) to AUC(0-inf). Also known as AUCR. (0-inf)

AUC(0-tmax) is the fractional area from time zero to the median _Tmax of the reference formulation, which is the

Computed using linear trapezoidal summation.

Kel through the linearity of the terminal linear part of the logarithmic concentration vs. time curve

Terminal elimination rate constant calculated by regression, where Kel=-slope.

The terminal linear portion is determined by visual inspection.

T1/2 Elimination half-life calculated as ln(2)/Kel.

C _max Maximum observed fentanyl concentration.

T _max Time to maximum fentanyl concentration (obtained without interpolation

have to).

The study was a single-dose, randomized, open-label, two-way crossover (Treatment A and Treatment B, Phases 1 and 2) of the designated test and reference products, with subjects randomized in Phase 3 to receive one of three other test agents ( Treatment C, treatment D, or treatment E). Due to the large number of subjects, this study was conducted in two groups. The primary comparison in this study was Treatment A versus Treatment B. To compare the ANOVA of the above two treatments, only two sequences (AB, BA), two stages (1, 2), and two treatments (A, B) were considered.

A parametric (normal-theoretical) general linear model was used for log-transformed AUC(0-inf), AUC(0-t), and _Cmax values ^5-7 from Treatments A and B. The full analysis of variance (ANOVA) model considers groups in the model and includes the following factors: group, stage within group, treatment, sequence, sequence/group, subject/group in sequence, and treatment/group. Since treatment/group interactions were not apparent, the model was reduced to sequence, subject within sequence, stage, and treatment. The order effect was tested using the subject mean square within order and all other main effects were tested using the residuals (error mean square). Two one-way hypotheses were tested at the 5% level for AUC(0-t), AUC(0-inf), and _Cmax , and 90% confidence intervals were constructed for the ratio of the test and reference means (treatment A vs. Processing B).

The difference in T _max between Treatment A and Treatment B was evaluated by Wilcoxon Signed Ranks Test (α = 0.05).

柠檬酸芬太尼制剂的剂量比例性(proportionality)，将混合线性模型用于来自处理A，C，D，和E的剂量标准化C_max和AUC参数^5-7。完整的模型考虑分组并且包括以下事项：组，组内阶段，处理，顺序，顺序/分组，顺序内的对象/分组，和处理/分组。对于三种参数中的两种[C_max和AUC(0-t)]来说，处理/分组相互作用不显著，并且将模型减为具有处理因素的单向ANOVA。如果发现了总的处理效果，用处理A作对照进行成对比较。In Treatment C, Treatment D, and Treatment E (1300 μg, 810 μg, and 270 μg OraVescent After fentanyl citrate tablets), serum fentanyl concentrations and pharmacokinetic parameters were also measured. To evaluate OraVescent

Dose proportionality of fentanyl citrate formulations using mixed linear models for dose normalized C _max and AUC parameters from treatments A, C, D, and E ^5-7 . The full model considers grouping and includes the following: group, phase within group, processing, sequence, sequence/grouping, object/grouping within sequence, and processing/grouping. For two of the three parameters [ _Cmax and AUC(0-t)], the treatment/group interaction was not significant and the model was reduced to a one-way ANOVA with a treatment factor. If an overall treatment effect was found, pairwise comparisons were made using Treatment A as the control.

Residence time values (the length of time the formulation was present in the oral cavity) were calculated by subtracting the treatment application time from the time to perceived and confirmed disappearance of the formulation. The above values are tabulated and summarized statistics are presented.

result

Object Demographics and Configuration

A total of 42 subjects (17 males and 25 females) participated in the study and 39 subjects (17 males and 22 females) completed the study.

Three subjects were terminated/withdrawn from the study. One subject withdrew before the second period because the subject did not wish to continue the study. A second subject withdrew prior to Phase 3 because the subject did not wish to continue the study. A third subject withdrew prior to the second period because the subject was taking antibiotics.

The average age of the subjects was 27 years (age range 19-55), the average height of the subjects was 68 inches (range 62-74 inches), and the average weight of the subjects was 152.1 lbs (range 109.0 -197.0 lbs range).

Protocol Deviations and Adverse Events

The following protocol deviations occurred during the conduct of this study.

According to the protocol, subjects had respiration measured at the 3.5-hour vital sign time point. One subject did not measure respiration at the 3.5-hour time point during the second period. Two subjects were not rechecked for vital signs at the 3-hour time point of the second period. One subject did not have a vital sign recheck at the 2.25-hour time point of Phase III. Blood samples from these two subjects were not properly labeled at the .33-hour time point of Phase 1 (Treatment A). The above samples were not analyzed. According to this protocol, subjects have their pulse measured at the 3.5-hour vital sign time point. One subject did not have a pulse measured at the 3.5-hour time point during the first period. No subject was exposed to more than one of the aforementioned deviations. No serious adverse events were reported.

A total of 15 batches of clinical samples from this study required processing. Of the 15 lots, 14 were acceptable. Back calculated standard concentrations of 14 batches of acceptable human serum used in this study covered the range of 50.0-5000.0 pg/mL (picograms/mL) with a limit of quantitation of 50.0 pg/mL. The coefficient of variation of the quality control samples analyzed with each batch of acceptable samples was less than or equal to 7.89%.

dwell time

Residence time data is summarized in the table below.

Overview of Tablet/Lozenge Dwell Time

Processing A Processing B Processing C Processing D Processing E number of objects time (minutes) time (minutes) Time (minutes) Time (minutes) Time (minutes) average value twenty one 34 19 25 twenty two 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 value 48 77 33 50 62

Treatment A = 1 x 1080 mcg OraVescent Fentanyl Citrate Tablets: Trial

Treatment B = 1 x 1600mcg oral transmucosal fentanyl citrate (Actiq): control

Treatment C = 1 x 1300mcg OraVescent Fentanyl Citrate Tablets: Trial

Treatment D = 1 x 810mcg OraVescent Fentanyl Citrate Tablets: Trial

Treatment E = 1 x 270mcg OraVescent Fentanyl Citrate Tablets: Trial

SD = standard deviation; CV = coefficient of variation; SEM = standard error of the mean;

N = number (of observations)

One subject reported mild oral irritation (Grade 2 on a scale of 1-10) following Treatment C. The irritation, located on the right side of the mouth, occurred after the third phase of application of the test product. Researchers visually inspecting the area reported one case of redness, which occurred after treatment of E. The redness appeared on the right upper cheek after the third period of application of the test product.

Of the 42 enrolled subjects, 40 subjects completed Phases 1 and 2 and were included in the summary statistics, ANOVA analysis, and treatment A and B mean numbers. Thirty-nine subjects completed Phases 1, 2 and 3 and were included in the statistical analysis of dose proportionality.

The arithmetic mean and standard deviation and statistical comparison of serum fentanyl pharmacokinetic parameters after treatment A and treatment B are summarized in the following table.

Summary of Pharmacokinetic Parameters of Serum Fentanyl for Treatments A and B

----------Serum Fentanyl----------

* = Based on LS averages from Table 13.

Treatment A = 1 x 1080 mcg OraVescent Fentanyl Citrate Tablets: Trial

Treatment B = 1 x 1600mcg oral transmucosal fentanyl citrate (Actiq): control

The results of Wilcoxon Signed Rank Test showed that the median T _max of Treatment A (0.998 hours) was significantly earlier than that of Treatment B (1.999 hours) (p<0.0001).

Individual and mean serum fentanyl pharmacokinetic parameters were calculated for Treatments C, D, and E. Kel for 5 subjects in E could not be calculated. Therefore, AUC(0-inf), AUCR, and T1/2 cannot be calculated in these cases.

The arithmetic mean and standard deviation of serum fentanyl pharmacokinetic parameters after treatments C, D, and E are summarized in the following table.

Summary of Pharmacokinetic Parameters of Serum Fentanyl by Treatments C, D, and E

----------Serum Fentanyl----------

Process C = 1 x 1300mcg OraVescent Fentanyl Citrate Tablets

Treatment D = 1 x 810mcg OraVescent Fentanyl Citrate Tablets

Treatment E = 1 x 270mcg OraVescent Fentanyl Citrate Tablets

AUCR is the ratio of AUC _0-t /AUC _0-infinity

Dose proportionality assessments including p-values for Treatments A, C, D, and E are summarized in the table below.

Summary of serum fentanyl dose normalization parameters for Treatments A, C, D, and E

----------------- Serum Fentanyl --------------------

Treatment A = 1 x 1080mcg OraVescent Fentanyl Citrate Tablets

Process C = 1 x 1300mcg OraVescent Fentanyl Citrate Tablets

Treatment D = 1 x 810mcg OraVescent Fentanyl Citrate Tablets

Treatment E = 1 x 270mcg OraVescent Fentanyl Citrate Tablets

The time interval in which the Kel value is exceeded is determined.

柠檬酸芬太尼片剂(处理A，试验)与市场上销售的1600μg口服经粘膜柠檬酸芬太尼，Actiq

(处理B，对照)相比的生物等效性。本研究是第1和2阶段的单一剂量随机化，开放标记，双向交叉设计。所有对象同样回到第三阶段，施用三种OraVescent柠檬酸芬太尼测试制剂之一：1300μg(处理C)，810μg(处理D)，或270μg(处理E)。评估了OraVescent

柠檬酸芬太尼片剂制剂(处理A，C，D，和E)的剂量比例性。The primary objective of this study was to evaluate a 1080 μg dose of OraVescent from CIMALABS under fasting conditions

Fentanyl citrate tablets (treatment A, trial) with 1600 μg of the marketed oral transmucosal fentanyl citrate, Actiq

(treatment B, control) compared to bioequivalence. This study is a single-dose randomized, open-label, two-way crossover design in phases 1 and 2. All subjects also return to Phase 3 with three doses of OraVescent One of the fentanyl citrate test formulations: 1300 μg (treatment C), 810 μg (treatment D), or 270 μg (treatment E). OraVescent was evaluated

Dose Proportionality of Fentanyl Citrate Tablet Formulations (Treatments A, C, D, and E).

A total of 42 healthy subjects initially participated in this study. Thirty-nine subjects completed all three phases of the study. And 40 subjects completed Treatments A and B (Phase 1 and 2). Data from the 40 subjects who completed Treatment A and B were included in the pharmacokinetic and statistical analyses.

For treatment A and treatment B, the ratio of fentanyl C _max , AUC(0-t), and AUC(0-inf) geometric least square mean (test/control) was 123.4%, 101.4%, respectively. %, and 101.1%. The above data show that the mean fentanyl exposures are similar, but the peak exposures are higher for Treatment A compared to Treatment B. Treatment A's _Tmax (0.998 hours) occurred 1 hour earlier than Treatment B's (2.00 hours), and _Cmax was 23% higher, indicating a significantly faster rate of fentanyl absorption in Treatment A compared to Treatment B .

制剂提供的重量百分比少大约30-35％的芬太尼的剂量与1600μgACTIQ

制剂相比产生了统计学上明显更高的C_max。为了获得在C_max方面的生物等效结果，实际上为获得相当的结果，人们需要使用OraVescent芬太尼制剂，它包括相当于参照物Actiq片剂中的用量而言至少大约45％，更优选大约47.5％，更优选大约50％更少的芬太尼(是以游离芬太尼的重量计算的)。在这种场合下，大约800-880μg与1600μg ACTIQ相当。The 90% confidence interval of C _max was 111.82%-136.20%, the AUC(0-t) was 94.42%-108.86%, and the AUC(0-inf) was 93.60%-109.23%, indicating that treatment A and treatment B had significant effects on AUC( However, the bioequivalence requirement was not met for Cmax). In fact, the _Cmax for Treatment A shows that the OraVescent exemplified by Example 1

The formulation provided a dose of approximately 30-35% less fentanyl by weight with 1600 μg ACTIQ

Formulations produced a statistically significantly higher _Cmax compared to . In order to obtain bioequivalent results in terms of C _max , indeed to obtain comparable results, one needs to use OraVescent Fentanyl preparations which include the equivalent of the reference Actiq At least about 45%, more preferably about 47.5%, more preferably about 50% less fentanyl (calculated by weight of free fentanyl) is present in the tablet. In this case, approximately 800-880 μg is equivalent to 1600 μg ACTIQ.

It has thus been found that, using the present invention, comparable _Cmax can be obtained with less fentanyl than originally thought for dosage forms of 1 mg or less. A fast T _max is achieved. This enables a further reduction in the expected dose, with the advantages disclosed herein before, which result from a dose reduction that is not accompanied by a decrease in potency.

柠檬酸芬太尼片剂制剂之后，芬太尼AUC在270-1300μg的范围随着剂量成比例地增加(在这里被定义为线性增加)。4种OraVescent

剂量在剂量标准化AUC(0-t)或AUC(0-inf)方面没有显著差异。在比较剂量标准化C_max时发现了显著的总体处理效果。用处理A作对照进行成对比较，因为所有对象都接受了处理A。通过成对比较没有发现任何模式。发现了处理D(810μg)和处理A(1080μg)之间的显著差异。While administering OraVescent

Following the fentanyl citrate tablet formulation, the fentanyl AUC increased proportionally (defined here as a linear increase) with dose in the range of 270-1300 μg. 4 types of OraVescent

The doses did not differ significantly in dose-normalized AUC(0-t) or AUC(0-inf). Significant overall treatment effects were found when comparing dose-normalized _Cmax . Pairwise comparisons were performed using Treatment A as the control since all subjects received Treatment A. No patterns were found by pairwise comparisons. A significant difference was found between treatment D (810 μg) and treatment A (1080 μg).

(34分钟)短13分钟。其它3种剂量的OraVescent

柠檬酸芬太尼片剂制剂的平均停留时间(19，25，和22分钟)与1080μg OraVescent

制剂的平均停留时间类似。1080 μg OraVescent Fentanyl citrate tablets had an average residence time (21 minutes) longer than Actiq

(34 minutes) 13 minutes short. 3 other doses of OraVescent

Mean residence times (19, 25, and 22 minutes) of fentanyl citrate tablet formulations compared with 1080 μg OraVescent

The average residence time of the formulations was similar.

柠檬酸芬太尼片剂之后，一名对象报导了口腔粘膜的轻微刺激，一名对象经历了发红。在服用Actiq之后没有报导刺激或发红。Taking OraVescent

Following the fentanyl citrate tablets, one subject reported mild irritation of the oral mucosa and one subject experienced redness. Taking Actiq No irritation or redness was reported afterwards.

)之后，比较血清芬太尼药物动力学发现，平均芬太尼暴露类似，但是这两种产品的吸收速度不同。AUC(0-t)和AUC(0-inf)的几何最小二乘方(″ LS″)平均值比例接近100％，并且90％置信区间在80％-125％以内。几何LS平均C_max对于1080μgOraVescent柠檬酸芬太尼高23％，并且处理/对照比例的90％置信区间的上限超过125％，这表明该参数不满足生物等效标准。因此，可实现进一步的剂量降低。OraVescent

柠檬酸芬太尼片剂的T_max明显更早(早1小时)。After administration of 1080 μg OraVescent Fentanyl citrate tablet and 1600 μg oral transmucosal fentanyl citrate (Actiq

), comparison of serum fentanyl pharmacokinetics found that mean fentanyl exposures were similar, but the rates of absorption of the two products were different. The geometric least squares ("LS") mean ratios for AUC(0-t) and AUC(0-inf) were close to 100% and 90% confidence intervals were within 80%-125%. Geometric LS mean C _max for 1080 μg OraVescent Fentanyl citrate was 23% higher and the upper limit of the 90% confidence interval for the treatment/control ratio exceeded 125%, suggesting that this parameter did not meet the bioequivalence criteria. Thus, further dose reductions can be achieved. Ora Vescent

The T _max was significantly earlier (1 hour earlier) for the fentanyl citrate tablet.

For OraVescent For fentanyl citrate formulations, fentanyl AUC increased proportionally with dose in the range of 270-1300 μg, but not perfectly linear over the entire dose range.

的平均停留时间(34分钟)短13分钟。根据本发明的“停留时间”是开始使用剂型(插入口中)到所有肉眼可识别的剂型消失的时间数量。1080 μg OraVescent Fentanyl citrate tablets had an average residence time (21 minutes) longer than Actiq

The average residence time (34 minutes) was 13 minutes shorter. The "dwell time" according to the present invention is the amount of time from the start of use of the dosage form (insertion into the mouth) until the disappearance of all visually identifiable dosage forms.

No serious or unexpected adverse events occurred during the study. Both formulations were well tolerated by the oral mucosa.

references

；p.405-409.1. Physician's Desk Reference. 56th ed. Montvale, NJ: Medical Economics Company, Inc.; 2002. Actiq

; p.405-409.

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

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

4. Naitrexone.Micromedex.[online] Vol.107: Health Series Integrated 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.

Procedures guide，Ver.6，3rded.Cary，NC：SAS Institute；1990.7. SAS Institute, Inc., SAS

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

A second study was also conducted. This study demonstrated an approximately linear relationship between dose and _Cmax over the dose range of 100-800 μg.

This study was carried out to assess the range of therapeutic applications formulated into tablets according to the invention (referred to herein as OraVescent Tablets) of fentanyl citrate (AUC and C _max ) and confirmed the C _max observations from the study described above.

The Institutional Review Board (IRB) approved the experimental protocol and informed consent. All subjects read and signed the IRB-approved ICF prior to study initiation. This study has a single-dose, randomized, open-label, 4-treatment, 4-period, crossover design.

The subjects were screened within 21 days prior to study enrollment. The screening program included medical history, physical examination (height, weight, body shape, vital signs, and electrocardiogram [ECG]), and clinical laboratory tests (hematology, serum chemistry, urinalysis, HIV antibody screen, hepatitis A antibody screen, B Hepatitis surface antigen screen, hepatitis C antibody screen, and serum pregnancy test [for women only]), as well as a screen for cannabinoids and opioids.

All subjects participating in this study met the inclusion/exclusion criteria enumerated in the protocol, and the principal investigator reviewed the medical history, clinical laboratory evaluation, and physical examination prior to subjects' participation in the study. A total of 28 subjects, 16 males and 12 females, were involved in this study and 25 subjects, 14 males and 11 females, completed the study.

Subjects reported to the clinic in the early afternoon before each dose and had lunch at 14 o'clock, dinner at 19 o'clock and a snack at 22 o'clock. The subjects then followed a 10 hour overnight fast. On day 1, a standardized meal regimen was started, with lunch at 13:30, dinner at 18:30, and a snack at 22:00. On day 2, a standardized meal regimen (including breakfast) was started.

Subjects were not to consume any food or drink containing alcohol, broccoli, caffeine, or xanthines for 48 hours prior to and during each session of containment. Subjects were restricted from eating grapefruit for 10 days prior to dosing and during the study. Subjects were abstained from nicotine and tobacco for at least 6 months prior to study entry until completion of the study. In addition, over-the-counter drug treatments (including herbal supplements) were prohibited 7 days prior to dosing and during the study. No prescription medications (including MAO inhibitors) were allowed 14 days prior to dosing and during the study.

During the study, the subjects remained upright for 4 hours after taking the fentanyl citrate. Restrict drinking water from the time of dosing until 4 hours after dosing. Food was restricted from 10 hours before the dose to 4 hours after the dose. During the study, the subjects were not allowed to engage in any strenuous exercise.

Randomize subjects to the following treatments:

(盐酸纳曲酮片剂)50mgAdml: ReVia

(Naltrexone Hydrochloride Tablets) 50mg

Manufactured by Duramed Pharmaceuticals

Batch number: 402753001T

Product validity period: June 2006

50mg片剂，在处理A的用药之前15小时和3小时用240mL的水服用。Subjects receive an oral dose of one ReVia

50 mg tablet, taken with 240 mL of water 15 hours and 3 hours before the administration of treatment A.

Subjects receive an oral dose of one ReVia 50 mg tablet to be taken with 240 ml of water 15 hours and 3 hours before and 12.17 hours after the administration of Treatments B, C, and D.

柠檬酸芬太尼200μg片剂A: Oravescent

Fentanyl citrate 200μg tablet

Produced by CIMA LABS

Batch number: 930859

Subjects randomized to Treatment A received a single oral dose of one Oravescent Fentanyl citrate 200 μg tablets were placed between the upper gum and cheek, above the molars, and allowed to disintegrate for 10 minutes.

B: Oravescent Fentanyl citrate 500μg tablet

Produced by CIMA LABS

Batch number: 930860

柠檬酸芬太尼500μg片剂，放置在上齿龈和面颊之间，位于臼齿上方，并且让它崩解10分钟。Subjects randomized to Treatment B received a single oral dose of one Oravescent

Fentanyl citrate 500 μg tablets were placed between the upper gum and cheek, above the molars, and allowed to disintegrate for 10 minutes.

柠檬酸芬太尼810μg片剂C: OraVescent

Fentanyl Citrate 810μg Tablet

Produced by CIMA LABS

Batch number: 930501

Subjects randomized to Treatment C received a single oral dose of one Oravescent Fentanyl citrate 810 μg tablet was placed between the upper gum and cheek, above the molars, and allowed to disintegrate for 10 minutes.

D: Oravescent Fentanyl citrate 1080μg tablet

Produced by CIMA LABS

Batch number: 930502

Subjects randomized to Treatment D received a single oral dose of one Oravescent Fentanyl citrate 1080 μg tablet was placed between the upper gum and cheek, above the molars, and allowed to disintegrate for 10 minutes.

Every morning before and after medication 0.25, 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 36 hours to assess vital signs (blood pressure, pulse, and respiration) while sitting still. Continuous pulse oximetry was performed during the first 8 hours after dosing and during the first 12 hours after dosing while the subject was attempting to sleep. A 12-lead electrocardiogram, clinical laboratory evaluation (hematology, serum chemistry, and urinalysis), and a brief physical examination with comprehensive vital signs were performed at the conclusion of the study. Oral irritation assessments were performed 4 hours after dosing. At each check-in, the mouth was inspected to ensure that the subject had no aphthous sores at the application site. Subjects were told to notify the study doctor or nurse of any adverse events that occurred during the study.

Blood samples (7 mL) were collected from subjects belonging to Treatment A at the following times: pre-dose (0 hour), 10, 20, 30, and 45 minutes post-dose; and 1, 2, 4, 6, 8, 9, 10 post-dose , 11, 12, 14, 16, 20 and 24 hours. Blood samples (7 mL) were collected from subjects belonging to Treatments B, C, and D at the following times: pre-dose (0 hour), 10, 20, 30, and 45 minutes post-dose; and 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, and 36 hours.

Human serum samples were analyzed for fentanyl concentrations by a sensitive and specific LC-MS/MS method.

The following noncompartmental pharmacokinetic parameters were calculated using WinNonlin Standard Edition version 2.1 from the fentanyl concentration-time data for each treatment. Actual (rather than nominal) sample times were used in this analysis.

AUC(0-t) The area under the fentanyl concentration-time curve calculated using linear trapezoidal summation from time zero to time t, where t is the time of the last available concentration (Ct).

AUC(0-inf) is the area under the fentanyl concentration-time curve from time zero to infinity,

AUC(0-inf)=AUC(0-t)±Ct/Kel, where Kel is the terminal elimination rate constant.

AUC(0-t) The ratio of AUC(0-t) to AUC(0-inf). Also known as AUCR. Kel/AUC(0-inf) is the terminal elimination rate constant calculated by linear regression of the terminal linear portion of the log concentration vs. time curve, where Kel=-efficiency. The terminal linear portion was determined by visual inspection.

T1/2 is the elimination half-life calculated as ln(2)/Kel.

C _max Maximum observed fentanyl concentration.

T _max Time to reach maximum fentanyl concentration (obtained without interpolation).

Plasma concentration values for fentanyl are listed and summarized by treatment and time point, using descriptive statistics (mean, standard deviation [SD], coefficient of variation [CV], standard error of the mean [SEM], sample size, minimum, maximum, and median) ^9-11 . Values below the lower limit of quantitation (LOQ) were set to zero. Mean and individual concentration-time profiles are provided. Fentanyl pharmacokinetic parameters and dose-normalized pharmacokinetic parameters were tabulated by treatment and inductive statistics were calculated.

Dose proportionality from 200 μg to 1080 μg was assessed by the method described by Smith et ^al.8 . First, log-transformed parameters were analyzed using a mixed-effects model, including the log-transformation of dose and the fixed and random effects of the intercept. The model was fitted using SAS Proc ^Mixed9-11 .

The 90% confidence interval (CI) of the fixed effect of the slope (β ₁ ) was calculated and compared to the range (0.8677, 1.1323), which is an appropriate cut-off range for the dose range investigated in this study.

The conclusion is based on the following:

1) If the 90% CI of _β1 is completely included in this range (0.8677, 1.1323), it is considered to be dose proportional.

2) If the 90% CI of _β1 lies completely outside this range, dose proportionality is considered to be lacking.

3) If the 90% CI of _β1 is partly within the range and partly outside the range, such a result is considered "indeterminate". In such cases, the value of _β1 can serve as the best estimate of deviation from ideal proportionality, and the lower and upper bounds of the 90% CI can be considered in terms of drug safety, efficacy, or pharmacological effect data8 ^.

Where inconclusive results were observed, the maximum dose ratio for which the 90% CI of _β1 was well within the critical range and the dose ratio for which the 90% CI for β1 was well outside the critical range were calculated. Smith et al. refer to these dose ratios as ρ1 and ρ2, respectively.

ρ1=θ _H^ [1/max(1-L, U-1)], where, θ _H =1.25,

L = lower limit of 90% CI

U = upper limit of 90% CI.

ρ2=θ _H^ [1/max(L-1, 1-U)], where θ _H , L, and U are as defined above.

A second analysis was performed to examine differences in dose-normalized _Cmax between the three lowest dose levels (200 μg, 500 μg, and 810 μg). A parametric (normal theory) GLM was applied to the dose-normalized _Cmax values from Treatments A, B, and C after log transformation. Analysis of variance (ANOVA) models included the following factors: treatment, sequence, subject within sequence, and stage. A p-value of less than 0.05 was considered statistically significant.

Residence time values (the length of time the formulation is present in the oral cavity) are calculated by subtracting the time of drug treatment administration from the perceived and confirmed disappearance time of the formulation. The above values are tabulated and inductive statistics are provided.

Three subjects terminated/withdrawn from the study. Two of them withdrew before Phase III because they did not wish to continue the study. One subject withdrew after Phase 2 dosing because of an adverse event. The mean age of the subjects was 33 years (age range 19-55 years). The average height of the subjects was 68.6 inches (range 60-76 inches) and the average weight of the subjects was 160.9 pounds (range 110-215 pounds).

The following protocol deviations occurred during the conduct of this study. One subject did not have a vital sign recheck at 0.5 hours of the second period. One subject did not have a vital sign recheck at 2.5 hours into the third period. One subject did not have her serum pregnancy test results prior to Phase III - 15-hour naltrexone administration. This result was obtained prior to the -3-hour naltrexone dose. One subject's 36-hour ECG misplacement in the fourth period. One subject did not complete the early termination procedure. Subject considered lost to follow-up. Also, in the third period all subjects were supposed to have an oral irritation assessment at 3.83 hours after dosing. The nurse in charge recalled making the assessment but stated that the oral irritation assessment form had not been completed at the time of the incident. Accordingly, said assessment information cannot be verified and should be deemed not to have been performed.

The dwell time data are summarized in the table below.

Processing A Processing B Processing C Processing D number of objects time (minutes) time (minutes) time (minutes) time (minutes) Average 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 value 37 33 41 60

Treatment A = 200 μg

Treatment B = 500 μg

Treatment C = 810 μg

Treatment D = 1080 μg

It was noted during the oral evaluation at check-in that one subject had an aphthous sore on the lower right inner cheek at the start of Phase 4, but was administered the trial product in Phase 3 on the upper right cheek. The Principal Investigator confirmed that the aphthous ulcer was not an aphthous ulcer and approved the subject for Phase 4 medication.

Two subjects reported mild oral irritation (grades 2 and 3 on a scale of 1-10) following treatment A. Irritation in both subjects appeared on the left side of the mouth following Phase 2 application of the test product; one of the two subjects also showed redness when the site was visually inspected by the researcher. Another subject reported pain at the gum line in the left upper cheek area 11 minutes after treatment C. No serious or unexpected adverse events were reported.

Of the 28 subjects enrolled in the study, 25 subjects completed Treatment A, 26 subjects completed Treatment B, and 27 subjects completed Treatments C and D. All subjects underwent statistical analysis of pharmacokinetic data. Elimination rate constant calculations were not possible for one subject in Treatment A due to limited data points in the terminal phase. Therefore, AUC(0-inf), AUCR, and T1/2 cannot be calculated for this subject.

The arithmetic mean and standard deviation of the serum fentanyl pharmacokinetic parameters after all treatments are summarized in the table below.

Summary of Pharmacokinetic Parameters of Serum Fentanyl

----------------- Serum Fentanyl --------------------

* Median and min-max of T _max are reported

Treatment A = 1 x 200mcg OraVescent Fentanyl Citrate Tablets

Treatment B = 1 x 500mcg OraVescent Fentanyl Citrate Tablets

Treatment C = 1 x 810mcg OraVescent Fentanyl Citrate Tablets

Treatment D = 1 x 1080mcg OraVescent Fentanyl Citrate Tablets

The slopes of ln[AUC(0-t)]vs.ln(dose) and ln[AUC(0-inf)]vs.ln(dose) were 1.0574 and 0.9983, 1, and the 90% CI of each parameter was complete Contained within the critical range required for dose proportionality of 200 μg-1080 μg. The slope of ln(C _max ) vs. ln(dose) was 0.8746, less than 1, and the 90% CI (0.8145-0.9347) was not well contained within the critical range required to draw dose proportionality conclusions. The maximum dose ratio that puts the 90% CI of _β1 well within the critical range was 3.33. The maximum dose ratio that put the 90% CI of _β1 completely outside the critical range was 30.48. ANOVA results of dose normalized C _max for treatments A, B, and C showed no statistically significant differences in dose normalized C _max over the dose range of 200 μg-810 μg (p=0.13).

柠檬酸芬太尼片剂之后有关C_max的观察结果。本研究是单一剂量，随机化，开放标记，4-阶段交叉设计。The primary objective of this study was to evaluate OraVescent at the following doses of fentanyl Dose-proportionality of fentanyl AUC and C _max following fentanyl citrate tablets was present for: 200 μg (Treatment A), 500 μg (Treatment B), 810 μg (Treatment C), and 1080 μg (Treatment D). In addition, this study was performed to confirm the previous experience with OraVescent at doses of 810 μg and 1080 μg

Observations regarding _Cmax following fentanyl citrate tablets. This study was a single-dose, randomized, open-label, 4-stage crossover design.

Of the 28 subjects who participated in the study, 25 subjects completed Treatment A, 26 subjects completed Treatment B, and 27 subjects completed Treatments C and D. Statistical analysis was performed on the pharmacokinetic data for all subjects.

柠檬酸芬太尼片剂的每一增加剂量水平而成比例地增加。The slopes of ln[AUC(0-t)]vs.ln(dose) and ln[AUC(0-inf)]vs.ln(dose) are 1.0574 and 0.9983, close to 1, and 90% of each parameter The CI was well contained within the critical range required for dose proportionality. The above results show that the AUC of fentanyl increases significantly with the dose of OraVescent between 200μg-1080μg

Each incremental dose level of fentanyl citrate tablets increases proportionally.

The slope of ln(C _max ) vs. ln(dose) was 0.8746, less than 1, indicating that the increase in fentanyl C _max was less than dose proportional. The 90% CI (0.8145-0.9347) was not completely contained within the critical range. This less than proportional increase was observed at the highest dose (1080 μg) and to a lesser extent (±11% confidence interval) at the next highest dose (810 μg). From 200 μg to 500 μg, _Cmax increased proportionally. The value of p1 (maximum dose ratio that puts the 90% CI of β1 well within the borderline range) was 3.33, while the ratio of 810 μg:200 μg was 4.05. This shows that the formulation is linear according to the invention up to a dose of about 800 μg.

柠檬酸芬太尼片剂的平均停留时间是类似的，分别为14分钟，14分钟，17分钟，和15分钟。The second analysis compared the dose normalized C _max from the 200 μg, 500 μg and 810 μg doses using ANOVA and showed no statistically significant difference between these dose levels (p=0.13). The LS means of ln( _Cmax /dose) were 1.06 (200 μg), 1.06 (500 μg), and 0.94 (810 μg), showing no significant difference between the 200 and 500 μg doses, and the 810 μg dose was not significantly different from the lower dose There is only a small (less than 15%) difference in comparison. The lack of significant difference in the ANOVA, coupled with the small difference between the 810 μg dose and the two lower doses indicated that there was no clinically important deviation in the dose proportionality of _Cmax from 200 μg to 810 μg. Therefore, they are "linear" as defined herein. 200 μg, 500 μg, 810 μg and 1080 μg OraVescent

The mean residence times for the fentanyl citrate tablets were similar at 14 minutes, 14 minutes, 17 minutes, and 15 minutes, respectively.

柠檬酸芬太尼片剂之后，有2名对象报导了口腔粘膜的微弱刺激，有1名对象经历了发红。Taking OraVescent

Following the fentanyl citrate tablets, 2 subjects reported mild irritation of the oral mucosa and 1 subject experienced redness.

Fentanyl AUC increased proportionally with dose in the range of 200 μg-1080 μg. The increase in fentanyl _Cmax at the two highest dose levels was less than dose proportional. However, at all doses (except greater than 1 mg) the increase was linear as defined herein. The mean In( _Cmax /dose) for the 810 μg dose was 10-11% lower than for the 200 μg and 500 μg doses. The mean ln( _Cmax /dose) of the 1080 μg dose was 20-21% lower than that of 200 μg and 500 μg. There were no clinically important deviations in dose proportionality of _Cmax from 200 μg to 810 μg. 200 μg, 500 μg, 810 μg, and 1080 μg OraVescent The mean residence times for the fentanyl citrate tablets were similar at 14 minutes, 14 minutes, 17 minutes, and 15 minutes, respectively.

No serious or unexpected adverse events occurred during the study. Each formulation was well tolerated by the oral mucosa.

references

8. Smith BP et al., Confidence Interval Criteria for Assessment of Dose Proportionality. Pharmaceutical Research 17: 1278-1283, 2000.

/STAT User’s guide，Ver.6.4thed.Vol.1.Cary，NC：SAS Institute；1989.9. SAS Institute, Inc., SAS

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

/STAT Users guide，Ver.6，4th ed.Vol.2.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 In Institute, Inc., SAS Procedures guide, Ver.6, 3rd ed. Cary, NC: SAS Institute; 1990.

)。Approvaldate November 4，1998，Clinical Pharmacology andBiopharmaceutics Review pp 6.12. Summary Basis of Approval NDA 20-747 (Actiq

). Approval date November 4, 1998, Clinical Pharmacology and Biopharmaceutics Review pp 6.

Any formulation comprising sufficient effervescent material and pH adjusting substance, preferably containing a suitable disintegrant, to provide a dosage form useful for buccal, gingival or sublingual administration of fentanyl at dosage levels as contemplated herein may be used , and provide dose reductions and/or dose versus _Cmax relationships disclosed herein. Most preferably, for dosage forms containing about 100-800 μg of fentanyl (calculated as free base), any effervescent couple and/or pH adjusting substance may be used in an amount that produces a dosage form whose _Tmax 1.5 hours or less and/or a _Cmax to dose ratio of about 2.0 to about 4.0 pg/mL/μg, more preferably about 2.5 to about 3.5, more preferably about 2.7 to about 3.5 pg/mL/μg . Preferably, the dosage form also exhibits the linear relationship between _Cmax and dose as disclosed herein. This means that the ratio of _Cmax to dose will fall on a curve (p≤0.15) generated for a series of at least three different doses of fentanyl according to the invention between 100-800 μg fentanyl, said dosage forms having the same composition except for fentanyl The amount of tenyl varies.

Similarly, any amount of effervescent pair and pH adjusting substance is expected to provide a dosage form with comparable _Cmax as compared to an ACTIQ formulation with at least about 80% more fentanyl. That is, it has a _Cmax of at least 75% to 125% of the _Cmax of the ACTIQ formulation, more preferably from about 80% to about 125% of the ACTIQ formulation (p less than or equal to 0.15), most preferably of the ACTIQ formulation. About 85% - about 115%, albeit with at least 45% less fentanyl (calculated as free base). In particularly preferred embodiments, these formulations will not contain any disintegrant or excipient or combination of excipients in significant amounts that would interfere with this performance profile. Spray dried mannitol is a preferred filler. Another preferred excipient is a disintegrant which is starch glycolate, especially sodium starch glycolate. The former are generally characterized as fillers, while the latter are disintegrants. However, the characterization is not controlling.

The formulations in the '604 patent include both lactose monohydrate in an amount greater than 20% and/or microcrystalline cellulose in an amount of at least about 20% and cross-linked PVP in an amount of 5% or more, and are considered A formulation with ideal linear behavior of dose vs. _Cmax at the levels discussed here cannot be provided, despite the presence of pH adjusting substances and effervescent pairs. The formulation in the '604 patent also has over 880 μg of fentanyl.

A preferred effervescent orally disintegrating dosage form according to the present invention is a dosage form comprising about 100-800 μg of fentanyl (90-880) based on the weight of the free base material, or A pharmaceutically acceptable salt thereof in proportion to weight. Additionally, the above figures are intended to include normal processing variability such as assay consistency, etc. Particularly preferred doses are about 100 μg, about 200 μg, about 300 μg, about 400 μg, about 600 μg and about 800 μg, respectively.

Preferably, the fentanyl used in the formulations of the present invention has an average particle size as determined by laser diffraction techniques of from about 0.2 to about 150 microns, more preferably from about 0.5 to about 100 microns, most preferably from about 1 to about 20 microns .

As effervescent agent or effervescent agent pair any known combination can be used. These include those disclosed in US Patent No. 5,178,878 and US Patent No. 5,503,846, which are hereby incorporated by reference to the extent they discuss various effervescent agent pairs and the construction of effervescent agent pairs. Effervescent pairs are usually water- or saliva-activated materials, usually kept in an anhydrous state with little or no absorbed moisture or in a stable hydrated form. Typically, these effervescent pairs comprise at least one acid source and at least one active base source, the latter usually being a carbonate or bicarbonate salt. Each component of the effervescent pair can be any component that is safe for human consumption.

Such acids generally include food acids, anhydrides and acid salts. Food acids include citric, tartaric, malic, fumaric, adipic, ascorbic, and succinic. Anhydrides or salts of the above acids may be used, and the salts herein may include any known salts, but particularly sodium dihydrogen phosphate, disodium dihydrogen phosphate, acid citrate and sodium acid sulfate. Bases that can be used in the present invention generally include sodium bicarbonate, potassium bicarbonate, and the like. Sodium carbonate, potassium carbonate, and magnesium carbonate, etc. can also be used as part of the effervescent agent. However, it is more preferred to use them as pH adjusting substances. Preferably, stoichiometrically equivalent amounts of acid, anhydride or acid salt and base are used. However, some excess acid or base may be used. However, caution should be exercised in so formulating formulations, especially in view of the overall pH adjusting effect of this ingredient, if any. Excess may affect absorption.

The amount of effervescent material useful in the present invention is an effective amount and is determined based on properties other than those necessary to achieve disintegration of the tablet in the oral cavity. Instead, effervescent agents are used as the basis for enhancing the transmission of fentanyl in the oral cavity via buccal, gingival or sublingual administration across the oral mucosa. Therefore, based on the weight of the total formulation, the effervescent agent should be used in an amount of about 5 to about 85%, more preferably about 15 to 60%, more preferably about 30 to 45%, most preferably about 35 to about 40% %. Of course, the relative proportions of acids and bases will depend on the particular components (eg, whether the acid is monobasic, dibasic or ternary) relative molecular weights, etc. However, it is preferred to provide stoichiometric amounts of each, although, of course, excess is acceptable.

Preferably, the formulations according to the invention comprise at least one pH adjusting substance. Without wishing to be bound by any particular theory, this allows a drug that is sensitive to a change in ionization state to be administered by ensuring appropriate conditions for its dissolution and transport through one or more membranes or tissues within the oral cavity, such as through the oral mucosa. If the ideal delivery conditions for a particular drug are alkaline, it may not be appropriate to add a sufficient excess of an appropriate strong acid as part of the production of an effervescent pair or as a pH adjusting substance. It would be preferable to choose another pH adjusting substance, such as anhydrous sodium carbonate, which is capable of acting alone and away from the effervescent agent.

The pH adjusting substances of the present invention can be used to provide further penetration enhancement. Selection of a suitable pH-adjusting substance depends on the drug to be administered, and in particular the pH at which the drug is ionized or non-ionized, and whether the ionized or non-ionized form facilitates delivery across the oral mucosa. For fentanyl and its salts, basic substances are preferred for delivery of fentanyl. The pH adjusting substances of the present invention may include, but are not limited to, any substance capable of modulating local pH to facilitate transmembrane transport in the oral cavity in an amount that results in a pH generally in the range of about 3-10, more preferably about 4-about 9. The pH is the "local pH" in the microenvironment of the patient's mouth in the area of oral mucosa in contact with the surface of the dosage form or any part thereof, such as when it disintegrates. For the purposes of the present invention, local pH can be determined as follows: In order to characterize the dynamic pH change exhibited by the relevant tablet, an in vitro pH measurement was employed. The method involves the use of 0.5-10 mL of phosphate-buffered saline in an appropriately sized test tube or similar container. The amount of vehicle used will depend on tablet size and dosage. For example, when determining the pH profile of a fentanyl tablet, a volume of 1 mL is used for a tablet weighing 100 mg. Immediately after contacting the tablets with the medium, the pH profile of the solution was monitored as a function of time using a micro-combination pH electrode. Preferably, materials usable as the pH adjusting substance in the present invention include carbonates, such as sodium carbonate, potassium carbonate or calcium carbonate, or phosphates, such as calcium phosphate or sodium phosphate. Most preferred is sodium carbonate. The amount of pH adjusting substance that can be used in the present invention can vary with the type of pH adjusting substance used, the amount of any excess acid or base from the effervescent, the nature of the remaining ingredients, and of course the drug (here drug is fentanyl).

Most preferably, the pH adjusting substance will be present in an amount of about 0.5 to about 25 wt%, more preferably about 2 to about 20 wt%, more preferably about 5 to about 15 wt%, most preferably about 7 to about 12 wt%. The most preferred pH adjusting substances are carbonates, bicarbonates or phosphates. Also preferred are those pH adjusting substances which, when provided in suitable amounts, can alter the local pH by at least about 0.5 pH units, more preferably about 1.0 pH units, compared to an otherwise identical formulation without the pH adjusting substances , more preferably about 2.0 pH units.

Any filler, or any amount of filler, can be used so long as the resulting dosage form achieves the results described herein. Most preferred among fillers are sugars and sugar alcohols, and these may include indirect compression and direct compression fillers, indirect compression fillers generally, at least when formulated, have properties that make them suitable for use in high-speed tableting without fortification or conditioning. Flow and/or compression characteristics that are impractical for the process. For example, a formulation may not flow well enough, therefore, it may be necessary to add a glidant, eg, silicon dioxide.

In contrast, direct compression fillers do not require similar tolerance. They generally have compressibility and flowability characteristics that make them ready for immediate use. It is to be noted that, depending on the method of preparation of the formulation, fillers that are not directly compressed can be given the properties of direct compression fillers, and vice versa. In general, non-direct compression fillers tend to have relatively smaller particle sizes compared to direct compression fillers. However, certain fillers such as spray-dried mannitol have smaller particle sizes and are still often directly compressible, depending on how they are further processed. There are also relatively large indirect compression packings.

Preferred fillers of the present invention include mannitol, lactose, sorbitol, dextrose, sucrose, xylitol and glucose, so long as their use provides the results disclosed herein. It is more preferred according to the invention that the filler is not lactose monohydrate in an amount of 20% or more by weight of the formulation, and more preferably no lactose monohydrate is used. Most preferred in the present invention is the use of spray-dried mannitol. The filler may be present in an amount of 10-80%, more preferably about 25-about 80%, most preferably 35-about 60%, by weight of the formulation.

(标准等级)，可以从Roquette of Lestrem France获得。实际上，更优选的是所述制剂既不包括微晶纤维素也不包括交联PVP。Disintegrants may also be used in the present invention as long as they allow or even facilitate dose reduction, linearity and/or _Cmax to dose ratio as described herein. Disintegrants may also include binders with disintegrating properties. The disintegrant according to the present invention may include microcrystalline cellulose, cross-linked polyvinylpyrrolidone (PVP-XL), sodium starch glycolate, cross-linked sodium carmellose, cross-linked hydroxypropyl cellulose, and the like. The choice of disintegrant will of course depend on whether the results described herein are achievable in a particular system. More preferably, the formulations do not contain more than about 20% microcrystalline cellulose and crospovidone in an amount of about 5% or more, especially in formulations that include an additional 20% lactose monohydrate. Most preferred for use as a disintegrant is starch glycolate, especially sodium starch glycolate. In fact, it has been found that the use of sodium starch glycolate in the formulations of the present invention provides a significant improvement in the degree of dose reduction while still providing comparable _Cmax compared to effervescent formulations including pH adjusting substances and other disintegrants. . A particularly useful sodium starch glycolate is GLYCOLYS

(standard grade), available from Roquette of Lestrem France. Indeed, it is more preferred that the formulation comprises neither microcrystalline cellulose nor cross-linked PVP.

The amount of disintegrant will vary according to known factors, such as the size of the dosage form, the nature and amount of other ingredients employed, and the like. Generally speaking, however, the amount should be about 0.25 to about 20% by weight of the final formulation, more preferably about 0.5 to about 15% w/w, more preferably 0.5 to about 10% w/w, more preferably about 1 - about 8% by weight. This is also based on the weight of the finished formulation.

Also commonly used in the present invention are tableting or spraying lubricants. The most well-known lubricant is magnesium stearate, and magnesium stearate is preferably used. In general, the conventional wisdom behind tableting lubricants is that less is better. In most cases, it is preferred to use less than about 1% of tableting lubricant. Generally, the amount should be 0.5% or less. However, magnesium stearate may be used in excess of 1.0%. In fact, more than about 1.5% is preferred, most preferably from about 1.5% to about 3%. Most preferably about 2% magnesium stearate is used. Other conventional tableting lubricants, such as stearic acid and calcium stearate, may also be used in place of some or all of the magnesium stearate.

The effervescent tablets of the present invention may be relatively soft or firm. For example, they can be produced as disclosed in US Patent No. 5,178,878, and generally have a hardness of less than 15 Newtons. Unlike the formulations disclosed in the '878 patent, the active ingredient here will not have to be coated with a protective material. Indeed, it is preferred not to coat the fentanyl active ingredient. When the tablets are soft and pliable/friable as manufactured, they may advantageously be packaged in blister packs, see eg US Patent 6,155,423. They can also be strong, with a hardness in excess of about 15 Newtons, produced as taught in US Patent 6,024,981. In a preferred embodiment, the fentanyl dosage form of the present invention is provided in a child resistant blister pack. See, eg, US Patent 6,155,423 to Katzner et al., issued December 5, 2000 and assigned to CIMA LABS, Inc., the contents of which are incorporated herein by reference. Most preferably, the packaging meets the standards set forth in 16 U.S.C. §1700.15 and .20 (2003). Packages also preferably include those commonly referred to in the industry as so-called "F1" and "F2" packages. "F1" packaging is most preferred.

Tablets according to the invention may be of slightly different designs for buccal, gingival or sublingual administration. However, in each instance, the oral disintegration time (mean residence time) achieved by the formulation is preferably less than 30 minutes. The oral disintegration time/dissolution (residence time) achieved by the tablet is preferably less than about 30 minutes, most preferably about 20 minutes or less. It is usually longer than 5 minutes, most often 10 minutes or longer. This is based on a subjective determination of the patient's response.

According to a particularly preferred embodiment of the present invention, there is provided an effervescent orally disintegrable tablet, designed for buccal, sublingual or gingival administration of fentanyl or a pharmaceutically acceptable salt thereof, comprising about 100 to about 800 μg of fentanyl (weight based on the weight of free base), an effective amount of an effervescent agent and an effective amount of a pH adjusting substance and sodium starch glycolate. The formulation may also include mannitol.

而言至少大约45％芬太尼重量的剂量减少。特别是，优选乳糖一水合物或微晶纤维素不超过制剂重量的大约10％，并且交联的PVP不超过大约4％。更优选的是，除了偶然附带量之外，所述制剂不含所有这些赋形剂。根据本发明，最优选的是将羟乙酸淀粉钠用作崩解剂，和将甘露糖醇用作填料。最优选的填料包括喷雾干燥的甘露糖醇。In a particularly preferred aspect of this embodiment of the invention, the aforementioned formulation does not contain an amount of lactose monohydrate and/or cross-linked PVP which would render the formulation incapable of obtaining a relative ACTIQ

For a dose reduction of at least about 45% by weight of fentanyl. In particular, it is preferred that lactose monohydrate or microcrystalline cellulose does not exceed about 10% by weight of the formulation, and that cross-linked PVP does not exceed about 4%. More preferably, the formulation is free of all but incidental amounts of such excipients. According to the present invention it is most preferred to use sodium starch glycolate as disintegrant and mannitol as filler. The most preferred filler comprises spray dried mannitol.

The formulations of the present invention may include other conventional excipients in generally known amounts, so long as they do not detract from the advantages described herein. These excipients may include, but are not limited to, binders, sweeteners, coloring components, fragrances, glidants, lubricants, preservatives, and disintegrants.

Tablets, the preferred dosage form of the invention, can be produced by any known tabletting technique. Preferably, however, the materials used are dry mixed and directly compressed. Although the tablet can be produced by granulation, this is not preferred. Certain excipients and materials used in the formulations of the invention may, of course, be wet or dry granulated. For example, granulated mannitol can be used as filler. It may also be desirable to granulate or premix certain portions of the formulation prior to final mixing and compression. Relevant materials are preselected to provide correct dose and content uniformity as well as dose reduction, _Cmax /dose ratio and/or dose linearity as described herein. Therefore, an appropriate amount of effervescent pair, an appropriate and appropriate pH adjusting substance and an appropriate disintegrant are selected, provided in a predetermined amount, and formulated into a dosage form, preferably a tablet.

Preferred pH adjusting substances are carbonates, bicarbonates or phosphates and preferred disintegrants are starch glycolate. Amounts of each are disclosed elsewhere herein. However, it is preferred that the disintegrant is selected and used in such an amount as to provide a further dose reduction in the amount of fentanyl that would otherwise be the same preparations in comparison. Preferably the pH adjusting substance is selected and used in an amount sufficient to provide a localized pH change of at least 0.5 pH units, more preferably 1.0 pH units, most preferably about 2.0 pH units or more. Although the tablet can be compressed to any hardness and/or friability, this result should not be negatively impacted on residence time and drug release and transport through the oral mucosa. Where possible, it is desirable to provide the fentanyl dosage form in the form of a compressed tablet having a hardness of from about 5 to about 100 Newtons, more preferably from about 10 to about 50 Newtons.

The dosage forms of the present invention can be used to treat any type of pain, especially pain that is commonly prescribed opiates. Like all opiates, fentanyl products, especially the products of the present invention, should always be taken under the direction and strict management and supervision of a physician. General guidance on the use of said ACTIQ products can be found on the label in the Physician's Desk Reference referred to above, and the warnings and contraindications therein apply broadly to the use of the dosage forms of the present invention. This usually involves titrating the patient with smaller doses before increasing the dose.

The dosage forms of the invention are administered by placing them in the patient's mouth, preferably under the tongue or between the cheeks or gums, where they remain until their dissolution/disintegration is substantially complete and they are no longer recognizable as dosage form. Preferably, swallowing is minimized to help facilitate maximal transfer of fentanyl through the adjacent oral mucosa.

Use additional doses as needed. As noted above, a single dose, e.g., 800 μg of fentanyl, may be administered in one dosage form of the invention, or may be administered in multiple dosage forms, e.g., two dosage forms of the invention, each containing 400 μg of fentanyl, or Four dosage forms of the invention, each containing about 200 μg of fentanyl. Preferably, such multiple dosage forms involve administration of all dosage forms within one hour, more preferably at about the same time (if not simultaneously).

In particular, a method for preparing a tablet of the invention for buccal, gingival or sublingual administration comprises providing fentanyl in an amount of about 100 to about 800 μg/dose (measured as fentanyl base). or its salt, or an equivalent amount of its salt. Also provided is an effervescent agent pair in an amount of 5 to about 85% by weight of the dosage form, at least one pH adjusting substance, and at least one disintegrant, preferably a hydroxyl Starch acetate is used in an amount of about 0.25% to about 20% by weight of the dosage form. The above ingredients are mixed and compressed into tablets. In a preferred embodiment, fillers are also used. In particularly preferred embodiments, a portion of the filler may be premixed with fentanyl or other excipients such as coloring agents.

Additionally, one of the excipients commonly used in the present invention is a lubricant, such as magnesium stearate. Usually, it is added near the end of the mixing phase. Blending is usually interrupted and the magnesium stearate is added, after which blending is continued for a few minutes.

In a preferred embodiment, the blister pack containing the dosage form of the invention should be opened immediately before the product is used. The patient should place the dosage form in his or her mouth, preferably between the cheek and the upper or lower gum. The dosage form should not be sucked or chewed. As with many opiates, fentanyl is preferably titrated from relatively low starting doses. The starting dose of the fentanyl dosage forms of the invention, especially those used to treat breakthrough cancer pain episodes, should be 100 μg. Patients should be provided with a limited initial titration supply of the 100 μg dosage form, thereby limiting the number of units used at home during the titration. Then, the dose can be gradually increased under the guidance of a doctor.

Example

production method

In each case in Examples 1-7 and 9-11, the material was screened prior to use, filled into a V-blender, or could be mixed with any suitable low shear mixer, and mixed with the appropriate time. After discharge from the mixer, the material was compressed on a standard rotary tablet press to achieve a target hardness of 13 Newtons and a target weight of 100 or 200 mg as disclosed in each example.

Embodiment 1-dosage form A

Ora Vescent Fentanyl, 1080mcg, 5/16″ Tablet, Red

Ingredient name Quantity (mg/tablet) Fentanyl Citrate, USP 1.688 Mannitol, USP* 95.312 Sodium bicarbonate, 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 iron oxide, NF 1.000

Total 200.000

*Spray drying (Mannogem EX from SPI Pharma)

Embodiment 2-dosage form C

芬太尼，1300mcg，5/16″片剂，红色0ra Vescent

Fentanyl, 1300mcg, 5/16″ Tablet, Red

Ingredient name Quantity (mg/tablet) Fentanyl Citrate, USP 2.042 Mannitol, USP* 94.958 Sodium bicarbonate, 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 iron oxide, NF 1.000 Total 200.000

*Spray drying

Embodiment 3-dosage form D

芬太尼，810mcg，5/16″片剂，黄色Ora Vescent

Fentanyl, 810mcg, 5/16″ Tablet, Yellow

Ingredient name Quantity (mg/tablet) Fentanyl Citrate, USP 1.266 Mannitol, USP* 95.734 Sodium bicarbonate, 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 iron oxide, NF 1.000 Total 200.000

*Spray drying

Embodiment 4-dosage form E

芬太尼，270mcg，5/16″片剂，白色   成分名称   量(mg/片)   柠檬酸芬太尼，USP   0.422   甘露糖醇，USP*   97.578   碳酸氢钠，USP/EP/JP   42.000   柠檬酸，USP/EP/JP   30.000   碳酸钠，USP/NF   20.000   羟乙酸淀粉钠，NF/EP   6.000   硬脂酸镁，NF/EP/JP   4.000   总计   200.000 Ora Vescent

Fentanyl, 270mcg, 5/16″ Tablet, White ingredient name Quantity (mg/tablet) Fentanyl Citrate, USP 0.422 Mannitol, USP* 97.578 Sodium bicarbonate, 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 total 200.000

*Spray drying

Example 5

芬太尼，500mcg，5/16″片剂，橙色Ora Vescent

Fentanyl, 500mcg, 5/16″ Tablet, Orange

Ingredient name Quantity (mg/tablet) Fentanyl Citrate, USP 0.786 Mannitol, USP* 96.214 Sodium bicarbonate, 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 iron oxide, NF 0.600 Red iron oxide, NF 0.400 Total 200.000

*Spray drying

Example 6

芬太尼，200mcg，5/16″片剂，白色Ora Vescent

Fentanyl, 200mcg, 5/16″ Tablet, White

Ingredient name Quantity (mg/tablet) Fentanyl Citrate, USP 0.315 Mannitol, USP* 97.685 Sodium bicarbonate, 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 Total 200.000

*Spray drying

Example 7

芬太尼，100mcg，1/4″片剂，白色Ora Vescent

Fentanyl, 100mcg, 1/4″ tablet, white

Ingredient name Quantity (mg/tablet) Fentanyl Citrate, USP 0.157 Mannitol, USP* 48.843 Sodium bicarbonate, 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 Total 100.000

*Spray drying

Example 8

The material can be screened, filled into a V-blender or other suitable low shear mixer, and mixed for an appropriate time prior to use. After exiting the mixer, the material can be compressed on a standard rotary tablet press to a target hardness of 13 Newtons and a target weight of 200 mg/tablet.

Ora Vescent Fentanyl, 300mcg, 5/16″ Tablet, Pale Yellow

Ingredient name Quantity (mg/tablet) Fentanyl Citrate, USP 0.472 Mannitol, USP* 97.328 Sodium bicarbonate, 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 iron oxide, NF 0.200 Total 200.000

*Spray drying

Example 9

芬太尼，400mcg，5/16″片剂，粉红色Ora Vescent

Fentanyl, 400mcg, 5/16″ Tablet, Pink

Ingredient name Quantity (mg/tablet) Fentanyl Citrate, USP 0.629 Mannitol, USP* 97.171 Sodium bicarbonate, 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 iron oxide, NF 0.200 Total 200.000

*Spray drying

Example 10

Ora Vescent Fentanyl, 600mcg, 5/16″ Tablet, Orange

Ingredient name Quantity (mg/tablet) Fentanyl Citrate, USP 0.943 Mannitol, USP* 96.057 Sodium bicarbonate, 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 iron oxide, NF 0.600 Red iron oxide, NF 0.400 Total 200.000

*Spray drying

Example 11

芬太尼，800mcg，5/16″片剂，黄色Ora Vescent

Fentanyl, 800mcg, 5/16″ Tablet, Yellow

Ingredient name Quantity (mg/tablet) Fentanyl Citrate, USP 1.257 Mannitol, USP* 95.743 Sodium bicarbonate, 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 iron oxide, NF 1.000 Total 200.000

*Spray drying

Example 12

Weigh and sieve the following materials.

# illustrate Amount/piece (%w/w) Quantity/batch (kg) 1 Fentanyl Citrate 0.6285 502.8g* 2a. Mannitol EZ 23.875 19.1 2b. Mannitol EZ 24.014 19.2 3. Sodium bicarbonate, No.1 21.0000 16.8 4. Citric acid, anhydrous, fine grain 15.0000 12.0 5. Sodium carbonate, anhydrous 10.0000 8.000 6. Sodium starch glycolate 3.0000 2.400 7. Yellow 10 iron oxide 0.5000 0.400 8. Magnesium Stearate, Non-Bovine 2.0000 1.600 Total 100.0000 80.0

Mannitol EZ (2a.) and yellow 10 iron oxide were transferred to the V-blender and mixed for 30 minutes. Drain and grind premix. Add the total amount of premix, fentanyl citrate, sodium bicarbonate, citric acid, sodium carbonate, and sodium starch glycolate to the V-blender and mix for 30 minutes. Mannitol (2b) was charged into the V-blender and mixed for 13 minutes. Magnesium stearate was filled into the V-blender and mixed for 5 minutes. Tablets are compressed from this final blend. The tablets were 1/4" round, flat surfaced, white, with beveled edges. The tablets were compressed to an average hardness of 13 Newtons on a fully equipped 36 station Fette tablet press.

Claims (18)

1. A compressed tablet dosage form, comprising: 90-880 μg of fentanyl or its salt of equivalent, calculated as fentanyl free base; consumption is an effervescent agent accounting for 5-85% of the dosage form weight, so Said effervescent agent is selected from food acids and carbonates or bicarbonates, wherein said acid and said carbonates or bicarbonates are present in stoichiometric equivalent amounts in said tablet; 0.5-25% of a pH-adjusting substance, the pH-adjusting substance being selected from carbonates, bicarbonates or phosphates; an amount of 10-80% mannitol by weight of the dosage form; and an amount of 0.25% by weight of the dosage form -20% starch glycolate. 2. The dosage form of claim 1, wherein the pH adjusting substance is selected and used to provide a localized pH change of at least 0.5 pH units. 3. The dosage form of claim 1 is used for the preparation of the medicine for the treatment of pain in patients. 4. The use of claim 3, wherein the pain is selected from the group consisting of breakthrough cancer pain, back pain, neuropathic pain, surgical pain, or post-operative pain. 5. The dosage form of claim 1 is used for the preparation of medicines for the treatment of breakthrough cancer pain attacks. 6. A method for preparing a tablet for buccal administration, gingival administration or sublingual administration of fentanyl, comprising the steps of: providing fentanyl or a salt thereof in an amount of 90-880 μg/dose, measured with fentanyl base , or an equivalent amount of its salt; providing an effervescent agent in an amount of 5-85% by weight of the dosage form, said effervescent agent being selected from food acids and carbonates or bicarbonates, wherein said acid and said carbon Acid salts or bicarbonates are present in stoichiometrically equivalent amounts in the tablet; pH adjusting substances are used in an amount of 0.5-25% by weight of the dosage form, and the pH adjusting substances are selected from carbonates, bicarbonates or phosphoric acid Salt, mannitol in an amount of 10-80% by weight of the dosage form; and starch glycolate in an amount of 0.25-20% by weight of the dosage form; mixing the fentanyl, effervescent, pH adjusting substance, mannose alcohol and said starch glycolate; and compressing the resulting mixture into at least one tablet. 7. The method of claim 6, further comprising the step of adding a lubricant to the resulting mixture prior to compressing the resulting mixture into at least one tablet. 8. The method of claim 7, further comprising the step of mixing said lubricant with said fentanyl, effervescent agent, pH adjusting substance, starch glycolate and said filler, and then compressing the resulting mixture into at least one tablet. 9. The method of claim 8, wherein the tablet is compressed to a hardness of 5-100 Newtons. 10. The method of claim 6, wherein the tablet is compressed to a hardness of 15-100 Newtons. 11. The dosage form of claim 1, wherein the dosage form comprises no more than 10% by weight lactose monohydrate. 12. The dosage form of claim 1, wherein the dosage form comprises no more than 10% by weight microcrystalline cellulose. 13. The dosage form of claim 1, wherein the dosage form comprises no more than 4% by weight of cross-linked PVP. 14. The dosage form of claim 1, wherein the dosage form is free of lactose monohydrate, microcrystalline cellulose, or cross-linked PVP. 15. The method of claim 6, wherein said tablet comprises no more than 10% by weight lactose monohydrate. 16. The method of claim 6, wherein said tablet comprises no more than 10% by weight microcrystalline cellulose. 17. The method of claim 6, wherein said tablet comprises no more than 4% by weight of cross-linked PVP. 18. The method of claim 6, wherein the tablet is free of lactose monohydrate, microcrystalline cellulose, or cross-linked PVP.