TWI387466B - Generally linear effervescent oral fentanyl dosage form and methods of administering - Google Patents

Description

Ordinary linear foaming oral fentanyl (FENTANYL) dosage form and administration method

The present invention describes dosage forms containing fentanyl and methods of using such dosage forms. Such dosage forms include substantially less weight of phenanthrene than known oral formulations and are advantageous in terms of cost and side effects. These dosage forms are intended to be administered phenanthrene in an oral manner through the oral mucosa.

Phentani (CAS Registry Number 437-38-7) N-phenyl-N-[1-(2-phenyl-ethyl)-4-piperidyl]propanamide and its salts, especially for its lemon The acid salt (CAS Registry Number 990-73-8) is an anesthetic, a controlled substance and a very potent anesthetic analgesic. Many companies currently sell a variety of delivery forms of phenanthrene and its citrate. For example, fentanyl citrate is commercially available as an injectable preparation and as an oral lozenge with a stick which is sold under the trade name ACTIQ. Three patents on ACTIQ were identified in the Approved Drug Products With Therapeutic Equivalence Evaluations (hereafter referred to as "the Orange Book"): US Patent 4,671,953 4,863,737 and 5,785,989. The second form of ACTIQ is also available. This form can be a rod-shaped compressed tablet. Similar to the original ACTIQ lozenge, it is believed that this second form will exhibit the same disintegration rate, T _{m a x} , C _{m a x} and AUC as the original lozenge. Therefore, unless otherwise specified or as indicated by the context, they will be discussed intensively.

A review of the internal pages of the ACTIQ available from Cephalon, Inc., 145 Brandy Wine Parkway West, Chester, PA 19380, available from the Physician's Desk Reference, 57th Edition, 2003, page 1184. The patient’s pain severity presents a direct perspective. According to its label, ACTIQ "is stated to be used only for the treatment of sudden cancer pain in patients with malignant tumors who have been treated with anesthesia and are resistant to their potential refractory cancer pain " (ibid. Emphasize). The original text of the ACTIQ label is incorporated herein by reference.

In the ACTIQ clinical trial, sudden cancer pain is defined as a transient episode of moderate to severe pain in a cancer patient undergoing refractory cancer pain, controlled by a maintenance dose of anesthetic, including daily Another anesthetic with at least 60 mg of morphine, 50 mg per hour of transdermal fentanyl or an equivalent analgesic dose of one week or more. Therefore, patients who receive ACTIQ are patients with sudden and unbearable pain, and although they are receiving chronic pain relief treatment, the pain will suddenly erupt. Providing relief from this sudden cancer pain is absolutely associated with the patient's immediate quality of life. And for these patients, providing relief from sudden cancer pain is the only thing that medical science can provide.

There are always room for improvement in many things in medicine. Bentani is an expensive drug that costs manufacturers as much as $100 or more per gram. Although cost is by no means the most important issue, the cost of drugs is an issue to be considered. Allowing a reduction in the amount of fentanyl can reduce the total cost of patient care.

More importantly, reducing the dose of this potent anesthetic can still achieve beneficial treatment of sudden pain in cancer patients, with very long-term and promising results for overall patient care. Anesthetic μ-receptor agonists (including fentanyl) produced dose-dependent respiratory depression. Severe or fatal respiratory depression can occur in vulnerable individuals even at the recommended dose. In conjunction with other potent anesthetics, phenanthrene has been implicated in severe and fatal respiratory depression in individuals without anaesthesia resistance. Therefore, the initial ACTIQ dose for the onset of a sudden cancer patient should be 200 mg and each patient should be individually dosed to provide adequate pain relief while minimizing side effects. And even these non-life threatening side effects are still important.

In addition, phenanthrene as a μ-anaesthetic agonist can produce drug dependence and drug resistance. Drug dependence itself is not necessarily a problem for these types of cancer patients, but phenanthrene can also be used to treat other types of pain. In these experimental protocols, dependence and drug resistance can become major problems. In addition, cancer patients generally receive a large number of drug treatments, and the longer the drug can be provided, the better.

U.S. Patent No. 6,200,604 to CIMA LABS INC., 10000 Valley View Road, Eden Prairie, MN 55344, issued March 13, 2001, exemplifies two types of phenanthrene containing 36% of a foaming agent and 1.57 milligrams of phenanthrene salt. Nepalese compounding. See Example I, line 5, ln. 60 up to line 6 ln. The '604 patent describes the use of a foaming agent as a penetration enhancer to affect the absorption of an oral drug. See also U.S. Patent Nos. 6,759,059 and 6,680,071. See also Brendenberg, S., 2003 New Concepts in Administration of Drugs in Tablet Form: Formulation and Evaluation of a Sublingual Tablet for Rapid Absorption, and Presentation of an Individualized Dose Administration System, Acta Universitiatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty Of Pharmacy, 287, page 83 Uppsala ISBN 91-554-5600-6.

If phenanthrene, which achieves a low dose while providing a similar pain relief, patients can achieve similar benefits with a much lower risk of lower cost and reduced side effects. Therefore, I still hope that the improvement of the administration of fentanyl.

The present invention relates to an orally disintegrable/dissolvable dosage form, a method of making the same, a method of using the same to treat pain, and a medicament for the manufacture of a medicament, wherein the phenanthrene or one or more of the medicaments is pharmaceutically acceptable Accepted salts (when "Bentene" is stated herein, unless the context indicates otherwise, it shall be considered to include all pharmaceutically acceptable salts) to contain non-foaming rod-like formulations currently available (containing tablets) And compressed lozenges) are administered orally in a reduced dose of at least about 45% of the fentanyl dose. Despite the lower dosage, the orally disintegrating dosage forms of the invention should have a _{Cm a x} that can be compared to other dosage forms containing much more (e.g., about two times) the drug. By "comparison" in this context is meant that the _{Cm a x} of the dosage form of the invention is at least about 75% of an ACTIQ having about twice the fentanyl. Thus, when compared to a rod 400 microgram ACTIQ lozenge according to 400 micrograms of the present invention, and compared with both a rod 800 microgram ACTIQ formulation, C _m lozenges of the present invention will have _{a x} 800 The microgram ACTIQ formulation has a _{Cm a x} of at least about 75% to about 125%. 400 microgram ACTIQ formulation will have a much low C _{m a x.} This is extremely true for doses up to about 800 micrograms by weight of free form fentanyl. It should be noted that "about" (dose) in this context means ±10%. Therefore, about 100 to about 800 μg is 90 to 880 μg. More preferably, "comparison" in the context of the present invention may also mean that the _{Cm a x of the} dosage form of the present invention is between about 80 and about 120% of ACTIQ C _{m a x} having a weight of about twice the number of fentanyl. This can also be called "height comparison". Even more "comparative" in the context of the present invention may also mean that the _{Cm a x of the} dosage form of the present invention is between about 85 and about 115% of ACTIQ C _{m a x} having a weight of about twice the number of fentanyl. This can also be called "very high height comparison".

An "oral dosage form" in the context of the present invention preferably excludes a lozenge-like tablet (such as ACTIQ). And vice versa, including orally disintegrating soluble lozenges, capsules, caplets, gels, emulsions, films and the like. Preferably, the dosage forms are foaming tablets. Further, it may include a pH adjuster and a disintegrant. Generally, the dosage forms are applied to or placed in a particular location in the oral cavity and remain there during disintegration and/or dissolution for substantially about 10 to 30 minutes.

In another preferred aspect of the invention, there is provided an orally disintegrating foaming dosage form designed to administer phenanthrene and/or a pharmaceutically acceptable salt thereof via the oral cavity, for example via the oral cavity, Gingival or sublingual route of administration rather than swallowing. Preferably, the formulation should not include a stick or other device that allows for convenient gripping in the patient's hand or removal from the mouth once the dosage form has been moistened in the mouth. In addition, the dosage form will include the corresponding ACTIQ The product is at least about 45% less (based on the weight of the free base material based on its weight) and more preferably between about 45% and about 55% of the phenanthrene. However, in terms of C _{m a x} , the two should be compared, the preferred heights are compared and even better than the extreme heights and they are substantially equally effective.

So if ACTIQ There are 1600 micrograms of phenanthrene in the formulation, and the corresponding dosage form according to the invention will comprise about 880 micrograms of phenanthrene or less. More preferably, it may comprise about 800 micrograms of fentanyl. However, despite the significant reduction in the amount of drug, at least one or more of the traditional pharmacokinetic properties (e.g., C _{m a x} ) measured for various drugs will be similar if not higher. For example, according to the present invention, the formulation may have a shorter T _{m a x} , ie, the time to reach the maximum concentration, and/or C _{m a x} , ie the highest concentration observed in the blood of the patient after administration, the C _{m a x} with corresponding ACTIQ containing at least 80% by weight of phenanthrene Compare products (if not higher). For dosage forms with increased phenanthrene content, the area under the AUC or curve is generally linear over the range of doses covered.

In a particularly preferred aspect of the invention, it has been found that a dose of fentanyl (measured as a free base in weight) and C _{m a x} can be produced, particularly in the dosage range of about 100-800 micrograms per dose. A linear relationship formulation. It should be understood that "linear" means that in a dose of 90 to 880 micrograms (more preferably 100-810 micrograms), when formulated as a fraction of at least three dosage forms having one of 90 different doses in the range of 880 micrograms of phenanthrene, There was no significant difference in dose normalized C _{m a x} using ANOVA with p in 0.15 (p less than or equal to 0.15). This is a preferred method of determining the linearity of the present invention. In other words, the slope of ln(C _{m a x} ) to ln (dose) should be 1 ± 15% (0.85-1.15). As described in the studies discussed herein, doses of 200, 500, and 810 μg are "linear" in accordance with the present invention. Although the dosage 1080μg of the prior art greatly exceeded, but compared with other doses to C _{m a x} dose in terms not defined herein as the "linear."

The ratio of C _{m a x} to dose in the dosage range is between about 2.0 and about 4.0 pg/ml/μg. It is the number of picograms of phenanthrene base per milliliter of serum or proportional amount per microgram of dose as normalized in blood or other fluids. "Inter" as used in accordance with the invention includes endpoint values. More preferably, the ratio is from about 2.5 to about 3.5 and even more preferably from about 2.7 to about 3.5 picograms per milliliter per microgram. These ranges are based on an average calculated for at least 10 patients in a suitable clinical trial. In contrast, the assay has determined that ACTIQ provides a ratio of about 1.4 picograms per milliliter per microgram. Thus, for dosage forms containing the same amount of fentanyl, the present invention can provide doses up to 880 micrograms, if using about 800 micrograms of the present invention, about twice as much _{Cm a x} if not more. In another embodiment, when the dosage forms are formulated in a range of from about 100 to about 800 micrograms of phenanthrene (free base) or a proportional amount of salt, they will also provide _a linear relationship between the dose and C _{m a x} . . Of course, for a single dose strength, this means that the dose to _{Cm a x} ratio of the dose should be linear with one of the series produced by only the same formulation to include more or less phenanthrene in the range described. relationship.

Also preferred according to one aspect of the invention is a styrene foaming dosage form designed for oral, gingival or sublingual administration comprising phenidani at a weight of 880 micrograms or less based on the weight of the free base material and having less than about 1.5. hours and most preferably less than about 1 hour T _{m a x.} And such dosage forms will have an ideal _{Cm a x of} from about 2.0 to about 4.0 picograms per milliliter per microgram as discussed above. Methods of treating pain with such dosage forms are also contemplated.

In a particularly preferred embodiment according to the invention, the dosage forms comprise a foaming agent which acts as a penetration enhancer, with or without, but preferably with an additional pH adjusting agent. Preferably, the pH adjusting agent is other substance than one of the components, compounds or molecules used to generate the foaming. Particularly preferred dosage forms also include disintegrants which permit the dosage reduction rates, C _{m a x} and dose linearity and/or ratios described herein. A particularly preferred example of one of the disintegrants is a glycolic acid starch salt. Also preferred is a dosage form comprising a filler that promotes the same efficacy as the disintegrant just described. Most preferably the filler is mannitol.

In a particularly preferred embodiment according to the present invention, there is provided an oral dosage form suitable for oral, sublingual or gingival administration, which comprises up to one milligram and more preferably 100, 200, 300 by weight in the form of a free base. 400, 600 or 800 micrograms of phenanthrene and additionally comprising at least one blister coupling agent, at least one pH adjusting agent and suitable excipients. Preferably, the formulation is capable of providing _{a Tm a x of} 1.5 hours or less and/or _a C _{m a x} between about 2.0 and about 4.0 pg/ml/μg. In other words, the C _{m a x of the} dosage form of the invention and the ACTIQ containing at least about 80% by weight of phenanthrene The C _{m a x} of the formulation is compared. In another preferred embodiment, the _{Cm a x of the} dosage forms will be at an ACTIQ having at least about 80% by weight of the phenanthrene free base. C _{m a x is} within about 25%, preferably within about 20% and even more preferably within 15% thereof.

In another preferred embodiment of the present invention, there is provided an orally disintegrating lozenge suitable for administration to the oral cavity, sublingual or gums, which comprises measuring about 100, 200, 300, 400, 600 in the form of a free base. Or 800 micrograms of phenanthrene, at least one foaming coupler, and at least one pH adjusting agent and a suitable excipient capable of providing _{a Tm a x} and/or from about 2.7 to about 3.5 for about 1.5 hours or less. C _{m a x} between picogram/ml/μg.

In another embodiment in accordance with the invention, any of the formulations previously mentioned herein may comprise substantially at least about 800 micrograms or less (i.e., up to 800 μg) of phenanthrene, a foaming coupler, at least one A pH adjusting agent and a suitable excipient which is capable of providing between about 2.0 and about 4.0 picograms per milliliter per microgram, more preferably between about 2.5 and about 3.5 picograms per milliliter per microgram, and most preferably from about 2.7 to about 3.5 skins. C _{m a x} between gram/ml/μg and contains at least ACIQ compared to the supplied C _{m a x} The dosage form is at least about 45% less phenanthrene. In the context of the present invention, "consisting essentially of" means excluding any excipient or combination of excipients or, if appropriate, any excipient or excipient that would alter the basic and novel characteristics of the present invention. Combination of agents and any pH adjusting agent or any amount of pH adjusting agent. Thus, the mixture will increase the T _{m a x} to 2.5 hours or more of the specific excipient or will be excluded. Similarly, and for purposes of example only, _a particular combination of excipients provided that will change _{Cm a x} to an uncovered level will be excluded. It is still possible to use _a small amount of crosslinked PVP and/or lactose monohydrate which does not significantly alter _{Tm a x} or C _{m a x} of the dosage form of the invention, although it is generally undesirable. However, if used together and at 5% and 20%, respectively, they can adversely alter these properties. Thus, a combination of such equivalent amounts of such excipients can be excluded.

In a particularly preferred embodiment of this aspect of the invention, it is provided that substantially 90 to 880 micrograms of phenanodamine or a salt thereof, sodium starch glycolate, mannitol, at least one pH adjustment is calculated from the phenanthroline free base form And a dosage form consisting of at least one foaming coupler. Such preferred dosage form provides about 1.5 hours or less of the T _{m a x,} C _m of between about 2.0 and about 4.0 picograms / mL / microgram dose of the ratio of _{a x,} with a linear dose-relationship of C _{m a x} And/or C _{m a x} as compared herein as defined herein, the dosage form being suitable for administration to the oral cavity, sublingual or gums. More preferably, the amount of phenanthrene measured in the form of the free base is from 100 to 800 micrograms.

Another aspect of the invention also encompasses methods of administering phenentramine to a patient suffering from pain, including, but not limited to, back pain, low back pain, joint pain, arthritic pain of any form, Pain due to trauma or accident, neuralgia, pain after surgery or surgery, pain from non-cancer diseases or conditions, cancer pain and especially sudden pain caused by cancer. A preferred method comprises the steps of: administering to a patient in need thereof any of the orally disintegrating foaming lozenges disclosed herein for oral, gingival or sublingual administration comprising from about 100 to about 800 micrograms (as free base) The dose of phenanthrene is measured and the dosage form is maintained in the patient's mouth for a time sufficient to allow the dosage form (or a therapeutically significant and/or effective portion thereof) to be transported from the oral cavity into the bloodstream. Preferably, the patient is instructed, trained, or cared for to ensure that the agent is not swallowed, and instead the fentanyl enters the body through one or more surfaces in the mouth and mouth to a practical extent. The method also preferably includes the step of maintaining in the mouth that the dosage form does not substantially move within the oral cavity. In another preferred embodiment, the agent dissolves/disintegrates or has an average residence time of 5 to 30 minutes.

A method of treating an onset of sudden onset of cancer pain comprising the step of providing an initial dose of about 100 micrograms of fentanyl or an equivalent amount of a salt thereof in the form of a fentanyl free base in a dosage form, the dosage form comprising The foaming coupler is present in an amount of from about 5 to about 85% by weight of the dosage form, the pH adjusting agent in an amount of from about 0.5 to about 25% by weight of the dosage form, and the glycolic acid starch salt in an amount of from 0.25 to about 20% by weight of the dosage form. The dosage form is adapted to deliver the fentanyl through the oral mucosa of the patient. It should be understood that "providing" includes removing the dosage form from the package or allowing someone to dispense or dispense the dosage form. The method also includes placing the dosage form between the cheeks of the patient's mouth and the upper gums or the lower gums, experiencing a sufficient amount to deliver the therapeutically effective amount of the fentanyl through the oral mucosa. The same method can be used to treat other types of pain, including any type of back pain, postoperative or postoperative pain and neuralgia.

It is not anticipated that it would be possible to produce an orally disintegrating tablet designed to administer phenanthrene in the oral cavity, which is capable of providing _{Tm a x} for 1.5 hours or less and containing 880 micrograms as a free base. Or less phenanodene, preferably having the desired C _{m a x} . Although some of the literature on ACTIQ lozenges revealed T _{m a x of} about 45 minutes, tests have shown that this time is about two hours.

It is not anticipated that it would be possible to produce an oral disintegrating tablet that is designed to be administered orally in the mouth via the mouth, sublingual or gums, which contains ACTIQ compared to the _{Cm a x} data provided. At least 45% less phenanodamine.

It is also not expected that it will be possible to produce an orally disintegrating dosage form and use it for the treatment of pain, and especially for sudden onset of pain experienced by cancer patients, which are generally greater than 75%, more preferably greater than 80% and optimally 90% or More therapeutically effective doses of phenanthrene dose (which provide a degree of pain relief) are absorbed from the oral cavity into the bloodstream through the oral mucosa.

Nor expected to have lower than the currently marketed product C _m so many active pharmaceutical dosage form of linearly on _{a x a x} C _m ratio in terms of dose, e.g., from about 100 to about 800μg (90-880μg) in the range of ±15% confidence interval.

According to another aspect of the present invention, there is provided a method of making an oral, gingival or sublingual foaming phenentramine dosage form which is capable of providing one or more of the following parameters: a dose and a C _{m a x} ranging from about 100 to about 800 micrograms a linear relationship within; C _{m a x} ; and 2.0 to 4.0 pg/ml/μg compared to _a dose of at least 45% phenanthrene compared to the same dose of non-foaming formulation (eg, ACTIQ) The ratio of C _{m a x} to dose. By reducing the amount of phenanthrene (by weight of the free base) in an amount of from about 100 to about 800 micrograms per dosage form with an effective amount of a foaming coupler, an effective amount of a pH adjusting agent, and a permissible dose, as described above. _{m a x} is achieved by mixing with a dose linearity and ratio of disintegrant; once placed in the patient's mouth, the dosage is measured as described herein, and the pH adjuster is capable of contacting the microenvironment and dosage form of the surface of the oral mucosa A local pH change ("local pH") of at least 0.5 pH units is produced as compared to the same formulation without the pH adjusting agent. These materials are compressed into tablets or formed into dosage forms using conventional techniques. Preferably, the process is accomplished without granulation, although the individual materials used may be granulated prior to mixing. Therefore, wet granulated sugar can be used as a filler in other drying and direct compression processes.

Preferably, the method is used to produce a dosage form, preferably a tablet, which produces _a linear relationship between the dose and _{Cm a x in} the range of from about 100 to about 800 micrograms, at least 50% less than the same dose of ACTIQ. The ratio of _{Cm a x} and/or C _{m a x} to dose between about 2.7 to about 3.5 picograms per milliliter per microgram at _a dose of Tenny. This is accomplished by providing a quantity of fentanyl or a salt thereof in a predetermined number of dosage forms each having between about 100 and about 800 micrograms of phenanthrene, in a final dosage form from about 5 to 85% by weight (w/w). a blistering agent, a pH adjuster in an amount of from about 0.5 to about 25% w/w, a glycolic acid starch salt in an amount of from about 0.25 to about 20% by weight, or not mixed with mannitol, and dried The tablet is compressed into a tablet. Preferably, the pH adjusting agent should provide a local pH change of at least about 1 pH unit compared to the same formulation without the pH adjusting agent.

Throughout the specification, including the scope of the patent application, the words "comprise" and variations of the word and "have", "include" and variants thereof mean the specified steps of the reference, The elements or materials are necessary, but other steps, elements or materials may be added and still form within the scope of the patent application or disclosure. When the invention is described and referenced in the claims, it is intended that the present invention The terms are used in the context of the patent application, and are not intended to be inclusive or open and do not exclude additional unrecited elements or method steps.

For the purposes of the present invention, the term "substantially" used in relation to any standard (such as a property, feature, or variable), unless otherwise defined for a particular property, feature, or variable, is meant to the extent that the standard is The skilled artisan will understand that the benefits or desired conditions or properties are to be met.

In one aspect of the invention, a dosage form suitable for oral, sublingual or gingival administration comprising from about 100 to about 800 [mu]g (micrograms) of fentanyl or a salt thereof is included in the form of the phenanthroline free base. The dosage form is capable of providing _{Tm a x} for 1.5 hours or less when properly administered by contact with the oral mucosa for a sufficient period of time. Additionally or vice versa, C _{m a} ratio of _x to dose should reach from about 2.0 to about 4.0, more preferably from about 2.3 to about 3.5, and most preferably about between 2.7 to about 3.5 picograms / mL / microgram. Preferably, the dose is linear with respect to _{Cm a x for} doses between about 100 and about 800 micrograms compared to other doses otherwise formulated in the same manner.

Preferably, the dosage form further comprises at least one pH adjusting agent and at least one foaming coupling agent. Each of these materials to an amount sufficient to provide a _{m a x} and / or C _{m a x} of the T to be provided. The dosage form also preferably comprises at least one selected and provided amount of excipient which, in combination with at least one pH adjusting agent and at least one foaming coupling agent, provides the desired _{Tm a x} and/or C _{m a x} .

A method of administering phenanthrene to a patient suffering from pain is another aspect of the invention. The method can include the step of contacting the oral mucosa of the patient in need thereof with an orally disintegrating dosage form. The dosage form comprises about 100-800 (90-880) micrograms of phenanthrene (measured as the free base) or a salt thereof per dosage form. Preferably, the dosage form comprises at least 45% phenanthrene less than a dosage form prepared using a commercially known delivery form, the dosage form being capable of providing _{a Tm a x of} 1.5 hours or less, and/or from about 2.0 to about 4.0 More preferably, the ratio of _{Cm a x} to dose and/or C _{m a x} to dose is between about 2.3 and about 3.5, and most preferably between about 2.7 and about 3.5 picograms per milliliter per microgram. The dosage form is maintained in contact with the oral mucosa of the patient sufficient to permit delivery of a therapeutically significant or effective portion of fentanyl from the oral cavity through the oral mucosa to the bloodstream, preferably greater than 75%, more preferably greater than 80%. % and optimally 90% or more of the dose.

Another aspect of the invention provides a dosage form comprising from about 100 to about 800 micrograms of fentanyl per dosage form in the form of a phenanthroline free base. When a phenanthrene salt is used, it is used in an amount that provides an equivalent weight of fentanyl free base. The dosage form is suitable for administration to the mouth, sublingual or gums. The dosage form can provide C _{m a x} as ACTIQ when it is properly administered by contact with the oral mucosa for a sufficient period of time. The formulation has a _{Cm a x} of at least about 75 to about 125%, more preferably from about 80 to about 120%, and most preferably from about 85% to about 115%, with the latter comprising at least 80% by weight of phenanthrene. Preferably, the dosage form also includes at least one pH adjusting agent and at least one foaming coupling agent in an amount sufficient to provide said C _{m a x} . Even more preferably, the dosage form further comprises at least one excipient in an amount sufficient to provide the desired _{Cm a x in} combination with at least one pH adjusting agent and/or at least one foaming coupler.

Also contemplated is a method of administering phenanthrene to a patient suffering from pain comprising the step of contacting an oral mucosa of a patient in need thereof with an orally disintegrating dosage form comprising from about 100 to 800 micrograms per dosage form (in the form of a free base) Measure the dose of fentanyl or its equivalent salt. The dosage form exhibits C _{m a x} as an ACTIQ comprising at least 80% by weight of phenanthrene The formulation has a C _{m a x} of at least about 75 to about 125%, more preferably from about 80 to about 120%, and most preferably from about 85% to about 115% of C _{m a x} . The dosage form remains in contact with the oral mucosa of the patient for a time sufficient to permit a portion of the phenanthrene that is therapeutically significant or effective, preferably greater than 75%, more preferably greater than 80%, and most preferably 90% or greater. From the oral cavity through the oral mucosa to the bloodstream.

It has now been found that the use of foaming agents and pH adjusting agents, especially when combined with glycolic acid starch salts, provides significant advantages, particularly in the amount of phenanthrene required for administration. Combinations of specific excipients with sudsing couplers and pH adjusting agents have also been found to provide even better and very unexpected results.

Determining whether a particular formulation is capable of achieving the results described herein requires only routine human clinical studies of the formulation in at least 10 patients. Any conventional model can be used for appropriate clinical studies. Examples of appropriate research are as follows: Clinical Study Design and Implementation This study and informed consent (ICF) were approved by the Institutional Review Board (IRB). All subjects read and signed the IRB approved ICF prior to the start of the study. The signed and witnessed ICF is on record.

During the first two periods, the study utilized a single-dose, randomized, open-label, two-way crossover design of the designated test and reference products, and the subjects randomly received one of three additional test formulations during the third period. All subjects were randomly selected and were fasted overnight after 10 hours of fasting overnight. There is a 7-day elution interval between the three doses. Subjects were confined to the clinic within 36 hours of the administration of fentanyl.

The subjects were reviewed for 21 days prior to participating in the study. The review process includes medical history, physical examination (height, weight, physical size, vital signs and ECG) and clinical laboratory tests (hematology, serum chemistry, urinalysis, HIV antibody screening, hepatitis B surface antigen screening, hepatitis C antibody) Screening, serum pregnancy [female only]) and examination of cannabinoids and opioids.

All subjects enrolled in the study met the inclusion/exclusion criteria listed in the protocol. A total of 42 subjects participated in the study, 17 males and 25 literate, and 39 subjects completed the study, 17 males and 22 females.

Subjects were reported to the clinic prior to each dose in the morning and received lunch 19 hours prior to dosing, dinner 14 hours prior to dosing, and snacks 11 hours prior to dosing. The subjects then followed a 10-hour fast overnight. On the first day, a standardized meal schedule was started, 4.5 hours after dosing, 9.5 hours after dosing, and 13 hours after dosing. On the second day, breakfast was provided 24.5 hours after dosing, 28.5 hours after dosing and 33 hours after dosing.

Subjects do not consume any food or beverages containing alcohol, broccoli, citrus, caffeine or jaundice during the 48 hours prior to the confinement period and during the confinement period. Subjects quit nicotine and tobacco for at least 6 months prior to participation in the study. In addition, the counter medication was banned within 7 days prior to dosing and during the study period. Prescription medications (excluding female hormonal contraceptives) are not allowed for 14 days prior to dosing and during the study period.

During the study, the subjects remained on hold for 4 hours after administration of fentanyl citrate. Water is limited from 0 hours up to 4 hours after administration. The food was limited 10 hours before administration until 4 hours after administration. During the study, the subjects were not allowed to engage in any vigorous activities.

Subjects received naltrexone at various times, as described in detail below: Adm 1: 50 mg ReVia (Naltrexone hydrochloride) produced by Bristol-Myers Squibb Company Lot number: 5C269A Validity: April 2004 Lot number: TB1798 Validity: March 2005

Subjects assigned to therapies A, B, C, and D took a 50 mg oral dose of naltrexone tablet at 240 mL of water 15 hours before and 3 hours before and after 12 months of fentanyl administration.

Subjects assigned to Treatment E took a 50 mg oral dose of naltrexone tablet at 240 mL of water 15 hours before and 3 hours prior to phenanodamine administration.

Subjects received one of the following fentanyl treatments in each of three periods: A: OraVescent Bentani citrate tablet 1080μg (as phenanthrene base) produced by CIMA LABS INC Lot number: 930502

Subjects randomized to treatment A received a single oral dose of 1080 μg of phenanodized tablet placed between the gums above the molars and the cheeks and allowed to disintegrate for 10 minutes. Should pay attention to "OraVescent "Disclosure of formulations and dosage forms in accordance with the present invention.

B: Actiq equivalent to 1600μg (Oral transmucosal fentanyl citrate) manufactured by Cephalon, Inc. or Anesta Lot number: 02 689 W3

Subjects randomized to treatment B received a single oral dose of 1600 μg of Actiq The unit is placed between the cheek and the lower gum. The unit was moved from one side to the other using a handle and allowed to dissolve for 15 minutes.

C: 1300μg OraVescent Bentani citrate tablet (in the form of fentanyl base) produced by CIMA LABS INC Lot number: 930503

Subjects randomized to Treatment C received a single oral dose of 1300 μg of phenanodized lozenge placed between the upper gums and the cheeks and allowed to disintegrate for 10 minutes.

D: 810 μg OraVescent Bentani citrate tablet (in the form of fentanyl base) produced by CIMA LABS INC Lot number: 930501

Subjects randomized to treatment D received a 810 [mu]g single oral dose of phenanthrene lozenge placed between the upper gums and the cheeks and allowed to disintegrate for 10 minutes.

E: 270 μg OraVescent Bentani citrate tablet (in the form of fentanyl base) produced by CIMA LABS INC Lot number: 930500

Subjects randomized to treatment E received a 270 [mu]g single oral dose of phenanthrene lozenge placed between the upper gums and the cheeks and allowed to disintegrate for 10 minutes.

Each of these fentanyl citrate tablets is described in Examples 1-4.

Every morning before administration (0 hours) and after administration 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, At 8th, 10th, 24th and 36th hours, the signs of sitting posture (blood pressure, pulse and breathing) were assessed. Continuous pulse oximetry was performed 8 hours after administration. At the completion of the study, a 12-lead ECG, clinical laboratory assessment (hematology, serum chemistry, and urinalysis) and a complete vital sign examination were performed. Oral stimulation assessment was performed 4 hours after dosing. The subject is instructed to inform the research physician and/or nurse of any adverse events that occurred during the course of the study.

Blood samples (7 mL) of subjects assigned to therapies A-D were collected at the following times: before administration (0 hours) and at 10, 20, 30 and 45 minutes; and after administration 1, 2, 4, 6 8, 10, 12, 16, 20, 24, 28, 32 and 36 hours. Blood samples (7 mL) of subjects assigned to Treatment E were collected at the following times: before administration (0 hours) and at 10, 20, 30, and 45 minutes; and after administration 1, 2, 4, 6, and 8 9, 10, 11, 12, 14, 16, 20 and 24 hours. A total of 54 blood samples (378 mL) were taken during the study for drug analysis. Samples were collected and processed at room temperature under fluorescent lighting. Serum samples were coagulated, centrifuged, frozen at -20 °C, and kept frozen until assayed.

Analytical Methods LC-MS/MS (Liquid Chromatography-Mass Spectrometry/Mass Spectrometry) in Human Serum Pharmacokinetics and Statistical Methods Pharmacokinetics and Statistical Analysis are based on the Food and Drug Administration (Food and Drug Administration) Drug Administration), Center for Drug Evaluation and Research (CDER), an industrial guide issued in January 2001 and named "Statistical Approaches to Establishing Bioequivalence" and promulgated in March 2003 and named " Bioavailability and Bioequivalence studies for Orally Administered Drug Products-General Considerations.

The following undivided pharmacokinetic parameters were calculated using WinNonlin Standard Edition version 2.1 from the phenanthrene concentration-time data for each treatment. The actual (rather than nominal) sampling time is used in this analysis.

AUC(0-t) uses the linear trapezoidal sum from time zero to time t to calculate the area under the phenanthrene concentration-time curve, where t is the time (Ct) at which the last measurable concentration is.

AUC(0-inf) The area under the phenanthrene concentration-time curve from time zero to infinity, AUC(0-inf)=AUC(0-t)+Ct/Kel, where Kel is the final elimination rate constant.

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

AUC(0-tmax) Calculates the area of the median value from time 0 to the T _{m a x} of the reference formulation calculated using the linear trapezoidal sum.

Kel calculates the final elimination rate constant by linear regression of the logarithmic concentration versus the final linear portion of the time curve, where Kel = - slope. The final linear fraction was determined by visual inspection.

T1/2 is calculated by ln(2)/Kel to eliminate the half-life.

The maximum phenanthrene concentration observed for C _{m a x} .

The time at which T _{m a x is the} maximum phenanthrene concentration (obtained without interpolation).

This study is a two-way crossover study of single-dose, randomized, open-labeling of designated test and reference products. (Therapeutic A and Treatment B, Periods 1 and 2) In Phase 3, subjects were randomly selected to receive one of three additional test formulations (Therapeutic C, Treatment D, or Treatment E). Due to the large number of subjects, the study was divided into two groups. The primary comparison for this study was treatment A versus treatment B. For the analysis of variance of the two treatments, only two sequences (AB, BA), two periods (1, 2), and two treatments (A, B) were considered. A one-parameter (standard theory) approximate linear model was applied to the log-transformed AUC (0-inf), AUC (0-t), and _{Cm a x} values from therapies A and B. ^{The 5 - 7} Complete Variance Analysis (ANOVA) model examines the subject group in the model and includes the following factors: subject group, intra-group period, treatment, sequence, grouping order, subjects within the grouping order, and group therapy . Since the interaction of the grouped therapeutics is not significant, the model is reduced to the subject, period, and treatment within the sequence, sequence. All other major effects were tested using the mean square test sequence effect of the subjects in the sequence and using residual error (error mean square). By constructing a 90% confidence interval for the ratio of this test to the reference mean (therapeutic A versus treatment B), two of AUC (0-t), AUC (0-inf) and C _{m a x} at 5% level were tested. One-sided assumption.

The _{Tm a x} difference between Treatment A and Treatment B was assessed using the Wilcoxon Signed Ranks Test (α=0.05).

Serum phenanthrene concentration and pharmacokinetic parameters were also determined according to Treatment C, Treatment D, and Treatment E (1300 μg, 810 μg, and 270 μg of OraVescent, respectively). Phentani citrate lozenges). To evaluate OraVescent Dosage proportionality of the phenanthrene citrate formulation, a mixed linear model was used for dose normalized _{Cm a x} and AUC parameters from therapies A, C, D, and E. ^{5 - 7} This complete model examines the subject group and includes the following terms: subject group, intra-group period, treatment, sequence, grouping order, subjects within the grouping order, and grouped treatments. The interaction between the 2 [C _{m a x} and AUC(0-t)] grouped therapeutics of the 3 parameters was not significant and the model was reduced to one-way ANOVA with therapeutic factors. If an overall therapeutic effect is established, a pairwise comparison is performed using Treatment A as a reference.

The residence time value (the length of time the formulation is present in the oral cavity) is calculated from the perceived and recorded disappearance time of the formulation minus the time of administration of the therapeutic agent. The values are tabulated and show summary statistics.

Results Demographics and Arrangements of Subjects A total of 42 subjects participated in the study, 17 males and 25 females, and 39 subjects completed the study, 17 males and 22 females.

Three subjects discontinued/exited the study. One subject stopped before period 2 because the subject did not want to continue the study. The second subject stopped before period 3 because the subject did not want to continue the study. The third subject stopped before period 2 because the subject took antibiotics.

The mean age of the subjects was 27 years (range 19-55 years), the average height of the subjects was 68吋 (within the range of 62-74吋), and the average weight of the subjects was 152.1 pounds (109.0-197.0). Within the range of pounds).

Experimental Protocol Deviations and Adverse Events The following experimental protocol deviations occurred during the performance of this study.

According to this protocol, the subject's breathing will be recorded at the 3.5 hour vital signing time point. In Period 2, one subject's breath was not recorded at the 3.5 hour vital signing time point. Two subjects were not re-examined for vital signs at the 3 hour time point of the period. A subject was not re-examined at time 2.25 hours of period 3. Blood samples from the two patients were not properly labeled at the 33 hour time point of Period 1 (Therapeutic A). These samples were not analyzed. According to this protocol, the subject's pulse will be recorded at the 3.5 hour vital signing time point. The pulse of one subject was not recorded at the time of the 3.5-hour life sign at period 1. None of the subjects received more than one of the aforementioned deviations. No serious adverse events were recorded.

A total of 15 batches were required to process the clinical samples of this study. Of the 15 batches, 14 batches were acceptable. The inverse calculated standard concentrations of the 14 acceptable batches of human serum used in this study ranged from 50.0 to 5000.0 pg/mL (picks per milliliter) with a limit of quantitation of 50.0 pg/mL. The quality control sample analyzed with each acceptable batch has a coefficient of variance of less than or equal to 7.89%.

Residence time These residence time data are summarized in the table below.

Summary of residence time of tablets/tablets Therapeutic substance A = 1 x 1080 mcg Oravescent phenanthrene citrate lozenge: test therapeutic substance B = 1 x 1600 mcg oral transmucosal citrate citrate (Actiq): reference therapeutic substance C = 1 x 1300 mcg OraVescent phenantani citrate Salt Lozenges: Test Therapeutics D = 1x810 mcg OraVescent Stentini Citrate Lozenges: Test Therapeutics E = 1 x 270 mcg OraVescent Stentini Citrate Lozenges: Test SD = standard deviation; CV = variance coefficient; SEM = standard error of the mean; number of N = (observed data)

One subject reported a mild oral stimulation of treatment C (2 on a scale of 1 to 10). The allergy occurred on the right side of the mouth after administration of the test product in period 3. After treatment E, the researchers reported redness in the area. The redness was placed on the upper right cheek after the test product was administered in period 3.

Of the 42 subjects enrolled, 40 subjects completed periods 1 and 2 and were included in the summary statistics, ANOVA analysis, and the mean number of Treatment A and Treatment B. 39 subjects completed periods 1, 2, and 3 and were included in the statistical analysis of dose balance.

The statistical mean of the mathematical mean and serum phenanthrene pharmacokinetic parameters and the statistical comparison of Treatment A and Treatment B are summarized in the table below.

Summary of pharmacokinetic parameters of serum phenanthrene of therapeutic A and therapeutic B ^* = Based on the LS average in Table 13. Therapeutic substance A=1x1080 mcg OraVescent phenanthrene citrate lozenge: test therapeutic substance B=1x1600 mcg oral transmucosal citrate citrate (Actiq): reference substance

The results of the Wilcerson rank sum test showed that the T _{m a x} median (0.998 hours) of Treatment A was significantly earlier (P < 0.0001) than Treatment B (1.999 hours).

Individual and mean serum fentanyl pharmacokinetic parameters of treatments C, D, and E were calculated. Five subjects in Treatment E were unable to calculate their Kel. 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 table below.

Summary of serum phenanthrene pharmacokinetic parameters of therapeutic agents C, D and E Therapeutic substance C=1x1300 mcg OraVescent phenanthrene citrate lozenge treatment D=1x810 mcg OraVescent phenanthrene citrate tablet treatment E=1x270 mcg OraVescent phenanthrene citrate tablet AUCR is AUC _{o - t} /AUC _{o -} ratio of _∞

The dose proportional assessment (including p-values) for therapeutics A, C, D, and E is summarized in the table below.

Summary of dose parameterization parameters of serum phenanthrene of therapeutic agents A, C, D and E Therapeutic substance A=1x1080 mcg OraVescent phenanthrene citrate lozenge treatment C=1x1300 mcg OraVescent phenanthrene citrate lozenge treatment D=1x810 mcg OraVescent phenanthrene citrate lozenge treatment E=1x270 Mcg OraVescent phenanthrene citrate lozenge

The time interval over the Kel value is determined.

The primary objective of this study was to evaluate the commercial and commercial 1600 μg oral transmucosal citrate citrate Actiq under fasted conditions. (Therapeutic substance B, reference substance) compared to the 1080 μg dose of CIMA LABS INC OraVescent Bioequivalence of fentanyl citrate tablets (Therapeutics A, tested). This study is a two-way crossover design of single dose, random, open markers for period 1 and period 2. All subjects also returned 3 times for the purpose of voting for three OraVescent One of the fentanyl citrate test formulations: 1300 [mu]g (therapeutic C), 810 [mu]g (therapeutic D) or 270 [mu]g (therapeutic E). Rate OraVescent Dosage proportionality of the fentanyl citrate tablet formulation (therapeutics A, C, D, and E).

A total of 42 healthy subjects were initially enrolled in the study. Thirty-nine subjects completed all three period studies and 40 subjects completed both treatments A and B (periods 1 and 2). Data from 40 subjects who completed treatments A and B were included in pharmacokinetics and statistical analysis.

For Treatment A vs. Treatment B, the geometric mean mean ratio (test/reference) of phenanthrene C _{m a x} , AUC (0-t), and AUC (0-inf) was 123.4%, 101.4%, and 101.1%. These data indicate that the average fentanyl exposure is similar but the therapeutic A has a higher exposure peak than Treatment B. The T _{m a x} (0.998 hours) of Treatment A occurred one hour earlier than Treatment B (2.00 hours) and C _{m a x was} 23% higher, indicating that the phenanodane absorption rate of Treatment A was significantly higher than that of Treatment B. fast.

The 90% confidence interval is located at 111.82%-136.20% for C _{m a x} , 94.42%-108.86% for AUC (0-t), and 93.60%-109.23% for AUC (0-inf), indicating therapeutic A Subject to treatment B for bioequivalence requirements for AUC but not for C _{m a x} . In fact, the C _{m a x of} therapeutic A is illustrated with 1600 μg of Actiq Compared to the formulation, the example used in Example 1 is more than OraVescent Formulations least about 30-35% by weight to provide a dose of fentanyl of statistically significant higher C _{m a x.} In order to obtain _a bioequivalence result for C _{m a x} , in fact to obtain a comparison result, it will be necessary to use the inclusion ratio in the comparison product Actiq OraVescent of at least about 45%, more preferably about 47.5%, and even more preferably about 50% of the phenanodene found in the tablet, by weight of the phenanthrene (in the form of free phenanthrene) Phentani formula. In this example, approximately 800-880 micrograms were compared to 1600 micrograms of ACTIQ.

It has thus been found that using the present invention and a dose of 1 mg or less, C _{m a x} can be obtained compared to the envisioned or even less fentanyl. Quickly achieve T _{m a x} . This allows for a further reduction in dosage while being expected to have the advantage from the dose reduction rate described herein and to add reduced efficacy.

Investing in OraVescent The phenanthrene AUC (as defined herein as linear) increases proportionally to the dose in the range of 270 to 1300 μg after the phenanoate citrate tablet formulation. In the 4 OraVescent There was no significant difference in dose-normalized AUC (0-t) or AUC (0-inf) between doses. Comparison of dose-normalized C _{m a x} found a significant overall therapeutic effect. Because all subjects received Treatment A, pairwise comparisons were performed using Treatment A as a reference. No patterns were observed in the pairwise comparison. Significant differences were found between Treatment D (810 [mu]g) and Treatment A (1080 [mu]g).

1080μg OraVescent The average residence time of the citrate citrate tablet (21 minutes) is better than Actiq (34 minutes) Short 13 minutes. 3 other doses of OraVescent The average residence time of the fentanyl citrate tablets (19, 25 and 22 minutes) is similar to 1080μg OraVescent Formulation.

OraVessent One subject reported a slight irritation of the oral mucosa after administration of the citrate citrate tablet and one subject experienced redness. Actiq No stimulation or redness was reported after administration.

Compare with 1080μg OraVescent Bentani citrate lozenges with 1600 μg oral mucosal fentanyl citrate (Actiq The subsequent serum phenanthrene pharmacokinetics showed that the average phenanthrene exposure of the two products was similar but the absorption rate was different. The geometric least squares ("LS") average ratio of AUC(0-t) to AUC(0-inf) is close to 100%, and the 90% confidence interval is within 80% to 125%. 1080μg OraVescent The geometric mean C _{m a x of the} citrate citrate is 23% higher, and the 90% confidence interval upper limit of the therapeutic/reference ratio is greater than 125%, indicating that this parameter does not meet the bioequivalence criteria. Therefore, a further dose reduction rate can be achieved. OraVescent The T _{m a x of the} fentanyl citrate tablet was significantly earlier (1 hour earlier).

Phentani AUC increases proportionally with dose, but for OraVescent The fentanyl citrate formulation is not completely linear over the entire dose range of 270 to 1300 μg.

1080μg OraVescent The average residence time of the citrate citrate tablet (21 minutes) is better than Actiq The average residence time (34 minutes) is 13 minutes short. The "residence time" according to the present invention is the amount of time between the start of use of the dosage form (in the insertion port) to the disappearance of all visually identifiable dosage forms.

There were no serious or unexpected adverse events during the course of the study. The oral mucosa is well tolerated for both formulations.

references

1. Physician's Desk Reference. 56th Print, Montvale, NJ: Medical Economics Company, Inc.; 2002. Actiq ; pp. 405-409.

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

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

4. Naltrexone. Micromedex [online] Vol. 107: Health Series Integrated Index; 2002 [Visit Date: 2003/JunI6]. http://www.tomescps.com .

5. SAS Institute, Inc., SAS /STAT User's guide, 6th edition, 4th print, volume 1 Cary, NC: SAS Institute; 1989.

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

7. SAS Institute, Inc., SAS Procedures guide, 6th edition, 3rd edition, Cary, NC: SAS Institute; 1990.

A second study was also conducted. This study demonstrates _a roughly linear relationship between dose and _{Cm a x} over _a dose range of 100-800 micrograms.

The study was performed to evaluate the formulation to the lozenge of the invention (herein referred to as OraVescent) The dose proportionality (AUC and C _{m a x} ) within the therapeutically usable range of the phenantiric citrate in the lozenge), and confirms the C _{m a x} observation data of the study just discussed.

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

Subjects were reviewed for 21 days prior to entering the study. The review process includes medical history, physical examination (height, weight, physical size, vital signs and electrocardiogram [ECG]) and clinical laboratory tests (hematology, serum chemistry, urinalysis, HIV antibody screening, hepatitis A antibody screening, type B) Hepatitis surface antigen screening, hepatitis C antibody screening, serum pregnancy [female only]) and selection of cannabinoids and opioids.

All subjects enrolled in the study met the inclusion/exclusion criteria listed in the protocol and the primary investigator reviewed the medical history, clinical laboratory evaluation, and performed the physical examination before the subject entered the study. A total of 28 subjects participated in the study, 16 males and 12 females, and 25 subjects completed the study, 14 males and 11 females.

Subjects report to the clinic in the afternoon before dosing and receive lunch at 14:00, dinner at 19:00, and snacks at 22:00. The subjects then followed a 10-hour fast overnight. On the first day, the standard meal schedule begins with lunch at 13:30, dinner at 18:30 and snacks at 22:00. On the second day, start the standard meal schedule (including breakfast).

Subjects do not consume any food or beverages containing alcohol, broccoli, caffeine or jaundice during the 48 hours prior to the incontinence period and during the confinement period. Grapefruit was eaten 10 days before the administration and during the middle of the study period. Subjects should quit nicotine and tobacco at least 6 months prior to participation in the study and until completion of the study. In addition, the counter medications (including herbal supplements) were banned 7 days prior to dosing and during the study period. Prescription medications (excluding monoamine oxidase (MAO) inhibitors) were not allowed for 14 days prior to dosing and during the study period.

During the study, subjects were placed in an upright position for 4 hours after administration of fentanyl citrate. Water is limited from the time of administration until 4 hours after administration. The food was limited 10 hours before administration until 4 hours after administration. During the study, subjects were not allowed to engage in any vigorous activities.

Subjects were randomized to receive the following treatments: Adml: ReVia (Naltrexone Hydrochloride Lozenge) 50 mg by Duramed Pharmaceuticals, Inc. Lot Number: 402753001T Validity Period: June 2006

Subjects of Treatment A took an oral dose of ReVia at 240 mL of water 15 hours before and 3 hours prior to dosing. 50 mg lozenge.

Subjects of therapeutics B, C, and D took an oral dose of ReVia at 240 mL of water 15 hours before and 3 hours before dosing and 12.17 hours after dosing. 50 mg lozenge.

A: 200μg OraVescent Bentani citrate lozenge produced by CIMA LABS INC Lot number: 930859

Subjects randomized to treatment A received a single oral dose of OraVescent Bentani citrate 200 μg lozenge placed between the upper gums and the cheeks on a molar and allowed to disintegrate for 10 minutes.

B: OraVescent Benzene citrate 500μg tablet produced by CIMA LABS INC Lot number: 930860

Subjects randomized to Treatment B received a single oral dose of OraVescent Bentani citrate 500 μg lozenge placed between the upper gums and the cheeks on a molar and allowed to disintegrate for 10 minutes.

C: OraVescent Benzene citrate 810μg lozenge produced by CIMA LABS INC Lot number: 930501

Subjects randomized to treatment substance C received a single oral dose of OraVescent Bentoni citrate 810 μg lozenge placed between the upper gums and the cheeks on a molar and allowed to disintegrate for 10 minutes.

D: OraVescent Bentani citrate 1080μg lozenge produced by CIMA LABS INC Lot number: 930502

Subjects randomized to treatment dose D received a single oral dose of OraVescent Bentani citrate 1080 μg lozenge placed between the gums and the cheeks over a molar and allowed to disintegrate for 10 minutes.

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, each morning before administration and after administration Sitting postures (blood pressure, pulse rate, and respiratory rate) were assessed at 24 and 36 hours. Each patient was attempted to sleep at any time during the first 8 hours after dosing and during the first 12 hours after dosing to perform continuous pulse oximetry. 12-lead ECG, clinical laboratory evaluation (hematology, serum chemistry, and urinalysis) and a brief physical examination with complete vital signs performed at the completion of the study. Oral stimulation assessment was performed 4 hours after dosing. At each registration, the oral cavity was tested to ensure that the subject had no mouth ulcers in the area of administration of the drug. The subject is instructed to inform the research physician or nurse of any adverse events that occurred during the course of the study.

Blood samples (7 mL) of subjects assigned to Treatment A were collected at the following times: before administration (0 hours) and at 10, 20, 30, and 45 minutes; and after administration, 1, 2, 4, 6, and 8, 9, 10, 11, 12, 14, 16, 20 and 24 hours. Blood samples (7 mL) of subjects assigned to Treatments B, C, and D were collected at the following times: before administration (0 hours) and at 10, 20, 30, and 45 minutes; and after administration 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32 and 36 hours.

The phenanthrene concentration of human serum samples was analyzed by a sensitive and specific LC-MS/MS program.

The following undivided pharmacokinetic parameters were calculated from the phenanthrene concentration-time data for each treatment using WinNonlin Standard Edition version 2.1. The actual (rather than nominal) sampling time is used in this analysis.

Descriptive statistics (mean, standard deviation [SD], coefficient of variance [CV], mean standard error [SEM], sample size, minimum, maximum, and median) are listed by treatment and time points and are summarized. Tenny plasma concentration value. ^{The value of 9 - 1 1} below the quantization low limit (LOQ) is set to zero. Show average and individual concentration-time curves. The phenanthrene pharmacokinetic parameters and dose-normalized pharmacokinetic parameters are listed according to the treatment and the summary statistics are calculated.

Dosage ratios from 200 μg to 1080 μg were evaluated using the method described by Smith et al. ⁸ First, the parameters of the logarithmic transformation are analyzed using a mixed effect model (including dose logarithmic transformation and fixed and random effects of the intercept). The model was fitted using SAS Proc Mixed. ^{9 - 1 1}

The 90% confidence interval (CI) for the slope (β ₁ ) fit effect was calculated and compared to the critical range (0.8677, 1.1323) for which the dose range for the study was given.

Based on the following conclusions: 1) If 90% CI of β ₁ is completely contained in this range (0.8677, 1.1323), it can be summarized as dose proportionality.

2) If 90% CI of β ₁ is completely outside this range, it can be summarized as lack of dose proportionality.

3) If the 90% CI portion of β ₁ is within the range and the portion is outside the range, the result is considered to be "indeterminate". In this case, the β ₁ value is used as the best estimate of the ideal proportional deviation, and the lower and upper limits of 90% CI can be considered to be in the range of drug safety, efficacy or pharmacological effect data. ⁸

In the event of an indeterminate outcome, the maximum dose ratio that would allow 90% CI of β _{1 to} be completely within the critical range and the dose ratio that would cause 90% CI of β _{1 to} fall completely outside the critical range were calculated. Smith et al. refer to these equal dose ratios as ρ1 and ρ2, respectively.

ρ ₁ = θ _{H ^} [1/max(1-L, U-1)], where θ _H = 1.25, L = 90% CI, the lower limit, U = 90% CI upper limit.

ρ ₂ = θ _{H ^} [1/max(L-1, 1-U)], θ _H , L and U are as defined above.

A secondary analysis was performed to detect the difference between the dose normalized C _{m a x} of the three lowest dose levels (200 μg, 500 μg, and 810 μg). The parameters (standard theory) GLM were applied to dose normalized _{Cm a x} values from therapeutics A, B and C after logarithmic transformation. The analysis of variance (ANOVA) model includes the following factors: treatment, sequence, sequence, subject and period of time. A p value of less than 0.05 is considered to be statistically significant.

The residence time value (the length of time the formulation is present in the oral cavity) is calculated by subtracting the medical administration time from the time of disappearance of the perceived and recorded formulation. The values are tabulated and the summary statistics are displayed.

Three subjects discontinued/exited the study. Two subjects stopped before period 3 because they did not want to continue the study. One subject stopped after an adverse event in the period 2 administration. The average age of the subjects was 33 years (range 19-55 years), the average height of the subjects was 68.6 吋 (within the range of 60-76 )), and the average weight of the subjects was 160.9 lbs (110-215). Within the range of pounds).

The following experimental protocol deviations occurred during the performance of this study. One subject was not re-examined for life at 0.5 hours of period 2. One subject was not re-examined for life at 2.5 hours of period 3. One subject did not provide a serum pregnancy test result prior to naltrexone administration for a period of 15 hours. The results were obtained before 3 hours of naltrexone administration. One subject was misplaced with ECG at 36 hours of period 4. One subject did not complete the early termination procedure. The subject was considered to have lost the tracking process. All subjects who also had period 3 were scheduled for oral stimulation assessment at 3.83 hours after dosing. The nurse responsible for the incident recalled the implementation of the assessment but stated that the oral stimulation assessment form was not completed at the time of the incident. Therefore, the evaluation information cannot be confirmed and should not be considered.

The residence time data is summarized in the table below.

Therapeutic A=200 μg of therapeutic B=500 μg of therapeutic C=810 μg of therapeutic D=1080 μg

During the registration of the oral assessment, it was noted that one subject had a mouth ulcer at the inner right cheek at the beginning of period 4, whereas the test product administration occurred during the period 3 at the upper right cheek. The planner identified that the ulcer was not an apthous ulcer and approved the subject to receive dosing at period 4.

Two subjects reported mild oral irritation (2 and 3 on grades 1 to 10) after receiving treatment A. Stimulation occurred on the left side of the mouth after two subjects were dosed with the test product in period 2; one subject also showed redness when visually inspected by the subject. Another subject reported pain in the upper left oral region of the gingival line 11 minutes after receiving treatment C. No serious or unexpected adverse events were reported.

Of the 28 subjects enrolled, 25 completed Treatment A, 26 completed Treatment B and 27 completed Treatments C and D. Statistical analysis was performed on pharmacokinetic data for all subjects. One subject in Treatment A was unable to calculate its elimination rate constant because there was a restricted data point at the end. Therefore, AUC (0-inf), AUCR, and T1/2 cannot be calculated for this subject.

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

Summary of serum phenanthrene pharmacokinetic parameters Therapeutic substance A=1x200 mcg OraVescent phenanodamine citrate lozenge treatment B=1x500 mcg OraVescent phenanthrene citrate lozenge treatment C=1x810 mcg OraVescent phenanthrene citrate lozenge treatment D=1x1080 Mcg OraVescent phenanthrene citrate lozenge

The slopes of ln[AUC(0-t)] versus ln (dose) and ln[AUC(0-inf)] versus ln (dose) are at 1.0574 and 0.9983, respectively, close to 1, and 90% CI of each parameter is completely contained. Within the critical range required for the proportionality of the dose of 200 μg to 1080 μg. The slope of ln(C _{m a x} ) versus ln (dose) is 0.8746 less than 1 and 90% CI (0.8145-0.9347) is not fully contained within the critical range required to achieve dose proportionality. The maximum dose ratio that causes 90% CI of β _{1 to} be completely within the critical range is 3.33. The maximum dose ratio that causes 90% CI of β _{1 to} fall completely outside the critical range is 30.48. ANOVA results for dose normalization _{Cm a x} of therapeutics A, B and C indicate that there is no statistically significant difference in dose normalized C _{m a x} over the dose range of 200 μg to 810 μg (p=0.13).

The main purpose of this study was to evaluate the investment in OraVescent 200 μg (therapeutic A), 500 μg (therapeutic substance B), 810 μg (therapeutic substance C) and 1080 μg (therapeutic D) phenanodamine doses of phenanthrene citrate tablets after fentanyl AUC and C _{m a x} The extent to which the dose is proportional. In addition, this study was performed to confirm that OraVescent was previously administered at doses of 810 μg and 1080 μg. Observations on C _{m a x} after fentanyl citrate tablets. This study was a single-dose, randomized, open-label, 4-period crossover design.

Of the 28 subjects enrolled in the study, 25 completed Treatment A, 26 completed Treatment B, and 27 completed Treatments C and D. Statistical analysis was performed on data on pharmacokinetics of all subjects.

The slopes of ln[AUC(0-t)] versus ln (dose) and ln[AUC(0-inf)] versus ln (dose) are at 1.0574 and 0.9983, respectively, close to 1, and 90% CI of each parameter is completely contained. Within the critical range required for dose proportionality. These results indicate that between the study doses of 200 μg to 1080 μg, with OraVescent The dose level of the phenanthrene citrate lozenge increased and the fentanyl AUC increased proportionally.

The slope of ln(C _{m a x} ) versus ln (dose) is 0.8746 less than 1, indicating that the phenanthrene C _{m a x} increases proportionally with the dose. 90% CI (0.8145-0.9347) is not completely contained within the critical range. A less than proportional increase was observed at the highest dose (1080 [mu]g) and a smaller increase was observed at the second high dose (810 [mu]g) (±11% confidence interval). C _{m a x} increased from 200 μg to 500 μg. The ρ ₁ value (the maximum dose ratio such that 90% CI of β ₁ is completely within the critical range) was 3.33, and the ratio of 810 μg: 200 μg was 4.05. This illustration is a linearity of the formulation according to the invention at doses up to about 800 micrograms.

Comparison of the dose normalized C _{m a x} using the ANOVA secondary analysis to compare doses of 200 μg, 500 μg, and 810 μg indicated no statistically significant difference between the dose levels (p=0.13). The LS mean of ln(C _{m a x} /dose) was 1.06 (200 μg), 1.06 (500 μg), and 0.94 (810 μg), indicating no difference between the 200 and 500 μg doses, and the 810 μg dose was the smallest compared to the lower dose ( Less than 15%) difference. There was no significant difference in ANOVA results and a small difference between the combination of the 810 μg dose and the lower 2 doses showed no clinically significant bias in the ratio of C _{m a x} doses from 200 μg to 810 μg. Therefore, it is "linear" as defined herein.

OraVescent of 200μg, 500μg, 810μg and 1080μg The mean residence times of the citrate citrate tablets were similar, 14 minutes, 14 minutes, 17 minutes, and 15 minutes, respectively.

OraVescent After administration of the citrate citrate tablet, two subjects reported mild irritation to the oral mucosa and one subject had redness.

The fentanyl AUC will increase proportionally with increasing doses ranging from 200 μg to 1080 μg. At the two highest dose levels, the increase in phenanthrene C _{m a x} was lower than the proportional increase in dose. However, this increase is linear as defined herein in all doses except greater than 1 mg. The average ln (C _{m a x} /dose) of 810 μg is 10% to 11% lower than the 200 μg and 500 μg doses. The average ln (C _{m a x} /dose) of the 1080 μg dose is 20% to 21% lower than the 200 μg and 500 μg doses. There is no clinically significant deviation in dose proportionality between 200 μg and 810 μg of C _{m a x} . OraVescent of 200μg, 500μg, 810μg and 1080μg The mean residence times of the citrate citrate tablets were similar, 14 minutes, 14 minutes, 17 minutes, and 15 minutes, respectively.

There were no serious or unexpected adverse events during the course of the study. Oral mucosa for each OraVescent The formulations are well tolerated.

references

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

9. SAS Institute, Inc., SAS /STAT User's guide, 6th edition, 4th edition, Vol. 1, Cary, NC: SAS Institute; 1989.

10. SAS Institute, Inc., SAS /STAT Users guide, 6th edition, 4th print, Volume 2, Cary, NC: SAS Institute; 1989.

11. SAS Institute, Inc., SAS Procedures guide, 6th edition, 3rd edition, Cary, NC: SAS Institute; 1990.

12. Summary Basis of Approval NDA 20-747 (Actiq ). Approval date November 4, 1998, Clinical Pharmacology and Biopharmaceutics Review, page 6.

Any formulation containing sufficient sudsing material and pH adjusting agent, preferably with a suitable disintegrant, can be used which provides a dosage form for oral, gingival or sublingual administration at the dosage levels contemplated herein. And the dose reduction rate and/or dose shown herein is provided in relation to _{Cm a x} . Most preferably, for dosage forms containing from about 100 to 800 micrograms of phenanthrene (calculated as the free base), any foaming coupler and/or pH adjusting agent can be used in an amount that produces a T _{m a of} 1.5 hours or less. A dosage form of _x and/or _a C _{m a x} to dose ratio of from about 2.0 to about 4.0 picograms per milliliter per microgram, more preferably from about 2.5 to about 3.5, and even more preferably from about 2.7 to about 3.5 picograms per milliliter per microgram. . Preferably, such dosage forms should also exhibit _a linear relationship between C _{m a x} and dose as described herein. This means that the ratio of C _{m a x} to dose will be along a line produced by a series of at least three different doses (100 to 800 micrograms of the present invention, phenanthrene) having the same composition except for the amount of fentanyl ( p 0.15) down.

Likewise, any amount of foaming coupler and pH adjusting agent are contemplated that provide a dosage form having a comparable _{Cm a x} as compared to an ACTIQ formulation having at least about 80% phenanthrene. Having the meaning C _{m a x} for at least 75% to 125% C _m ACTIQ formulation of _{a x,} and more preferably from about 80% to about 125% (p less than or equal to 0.15) and most of the ACTIQ formulation It is from about 85% to about 115%, although it has at least 45% less phenanthrene (calculated as the free base). In a particularly preferred embodiment, the formulations should not include any significant amount of disintegrant or combination of excipients or excipients that interfere with the performance profile. Spray-dried mannitol is a preferred filler. Another preferred excipient is a disintegrant which is a glycolic acid starch salt and especially sodium starch glycolate. The former is usually characterized by a filler and the latter is a disintegrant. However, these features are not controllable.

It is believed that the formulation of the '604 patent includes lactose monohydrate in an amount greater than 20% and/or microcrystalline cellulose in an amount of at least about 20% and crosslinked PVP in an amount of 5% or more, which is not provided Formulations having the desired linear behavior of the dosages discussed herein and C _{m a x} , despite the presence of pH adjusting agents and foaming couplers. The formulation of the '604 patent also has more than 880 μg of fentanyl.

A preferred foaming orally disintegrating dosage form according to one of the present invention is a dosage form comprising a pharmaceutically acceptable salt of from about 100 to 800 micrograms of phenanthrene (90 to 880) or a proportional weight based on the weight of the free base material. . Moreover, such numbers are intended to include normal processing variability, such as content uniformity and the like. Particularly preferred dosages are about 100 micrograms, about 200 micrograms, about 300 micrograms, about 400 micrograms, about 600 micrograms, and about 800 micrograms, respectively.

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

As the foaming agent or foaming coupling agent, any known combination can be used. Such combinations include the combinations described in U.S. Patent No. 5, 178, 878, and U.S. Patent No. 5,503, 846, the disclosure of each of which is incorporated herein by reference in its entirety. Foaming couplers are generally water or saliva activated materials which are typically maintained in a dry state with little or no absorption of water or in a stable hydrated form. Typically such materials comprise at least one acid source and at least one reaction source, typically a carbonate or bicarbonate. The components of the foaming coupler can be any safe for human consumption.

Such acids generally include edible acids, anhydrides, and acid salts. Edible acids include citric acid, tartaric acid, malic acid, maleic acid, adipic acid, ascorbic acid, and succinic acid. An acid anhydride or a salt of such an acid can be used. Salts in this context may include any of the known salts but are especially sodium dihydrogen phosphate, disodium hydrogen phosphate, acid citrate and sodium acid sulphate. Bases useful in accordance with the invention typically include sodium bicarbonate, potassium bicarbonate, and the like. Sodium carbonate, potassium carbonate, magnesium carbonate, and the like can also be used as part of the foaming coupler. However, it is more preferably used as a pH adjuster. It is preferred to use a stoichiometric equivalent of an acid, an acid anhydride or an acid salt and a base. However, it is also possible to use an excess of acid or base. However, care should be taken when formulating such a formulation, especially considering the overall pH adjustment effect of the components, if any. Excessive amounts can affect absorption.

The foaming mass that can be used in accordance with the present invention is an effective amount and is determined based on other properties than those necessary to achieve the disintegration of the tablet in the mouth. In contrast, foaming agents act as a matrix for enhancing the transport of phenanthrene in the oral cavity through the oral cavity, gums or sublingual administration through the mucosa. Accordingly, the amount of foaming coupler should be from about 5% to about 85%, more preferably from about 15% to 60%, even more preferably from 30% to 45%, and most preferably from about 35 to about 40%, based on the total weight of the formulation. Within the scope. Of course, the relative proportion of acid and alkali should be determined by the specific component (for example, whether the acid is a single proton, a diproton or a three proton) relative to the molar weight. However, it is preferred to provide a stoichiometric amount of each component, although of course an excess is acceptable.

Preferably, the formulation according to the invention comprises at least one pH adjusting agent. Without wishing to be bound by any particular theory, this allows for the appropriate conditions for the drug to be affected by changes in ionization state to be transmitted by ensuring its dissolution and passage through one or more of the oral lining or tissue (eg, through the oral mucosa) Come to the medicine. If the ideal conditions for the delivery of a particular drug are basic, it does not mean that a sufficient excess of a suitable strong acid is added as part of the manufacture of the foaming coupler or as a pH adjuster. Preferably, another pH adjusting agent, such as anhydrous sodium carbonate, is selected which acts alone and is separated from the blowing agent.

The pH adjusting agent according to the present invention can be used to further enhance the permeability. The selection of a suitable pH adjusting agent should be based on the drug to be administered and, in particular, the pH value of its ionization or non-ionization, and whether the ionized or non-ionized form promotes transmission through the oral mucosa. For phenanthrene and its salts, it is preferred to use a basic substance for the delivery of phenanthrene. The pH adjusting agent according to the present invention may include, without limitation, any substance capable of adjusting the local pH to facilitate transport across the oral membrane in an amount such that the pH is generally in the range of from about 3 to 10 and more preferably from about 4 to about 9. Within the scope. The pH is the "local pH" in the microenvironment of the surface contact area of the oral mucosa and the dosage form or any portion thereof (e.g., when it disintegrates) in the patient's mouth. For the purposes of the present invention, the local pH can be determined as follows: to characterize the dynamic pH change exhibited by the tablet in question, using an in vitro pH measurement. The method comprises the use of 0.5-10 mL of phosphate buffered saline in a suitably sized tube or similar container. The amount of media is determined by the size and dosage of the tablet. For example, when the pH distribution of the phenanthrene tablet is equivalently measured, a tablet weighing 100 mg is used in a volume of 1 mL. Immediately after the tablet contacted the medium, the pH profile of the solution was monitored as a function of time using a microcomposite pH electrode. Substances which are preferably used as the pH adjuster of the present invention include carbonates such as sodium carbonate, potassium carbonate or calcium carbonate, or phosphates such as calcium phosphate or sodium phosphate. The best is sodium carbonate. The pH adjusting dose usable in accordance with the present invention may vary depending on the type of pH adjusting agent used, the amount of any excess acid or base from the foaming coupler, the nature of the remaining ingredients, and (of course) the drug (in this case, phenanthrene). And change.

The amount of optimal pH adjusting agent should be from about 0.5 to about 25%, more preferably from about 2 to about 20%, even more preferably from about 5 to about 15%, and most preferably from about 7 to about, based on the weight of the total formulation. Within 12%. The preferred pH adjusting agent is a carbonate, bicarbonate or phosphate. Also preferred are their pH adjusting agents which, when provided in suitable amounts, provide at least 0.5 pH units, more preferably about 1.0 pH units, and even more preferably about 2.0 pH, as compared to the same formulation without the pH adjusting agent. The local pH of the unit changes.

Any filler or any amount of filler may be used as long as the resulting dosage form achieves the results described herein. Among the fillers, sugars and sugar alcohols are preferred and such materials may include indirect compression and direct compression of the filler. Indirect compression fillers generally have flow and/or compression characteristics at least during formulation which are not useful for high speed compression features without being added or adjusted. For example, the formulation may not flow sufficiently enough and thus it may be desirable to add a glidant such as cerium oxide.

In contrast, direct compression of the filler does not require similar tolerances. It generally has compressibility and flow characteristics that make it directly usable. It should be noted that depending on the method of preparing the formulation, the properties of the non-direct compression filler directly compressing the filler can be imparted. The opposite is also true. In general, indirect compression fillers tend to have relatively small particle sizes compared to direct compression fillers. However, certain fillers such as spray-dried mannitol have a relatively small particle size and are still often directly compressed depending on how they are further processed. There are also relatively large non-direct compression fillers.

The extent to which preferred fillers in accordance with the present invention are useful for providing the results described herein include mannitol, lactose, sorbitol, dextrose, sucrose, xylitol, and glucose. More preferably, the filler according to the present invention is not lactose monohydrate used in an amount of 20% by weight or more based on the weight of the formulation and even more preferably no lactose monohydrate is used. Spray-dried mannitol is preferably used in accordance with the present invention. The amount of filler may range from 10 to about 80% and even more preferably from about 25 to about 80%, most preferably from 35 to about 60%, by weight of the formulation.

Disintegrants may also be used in accordance with the present invention as long as they permit or even facilitate the reduction in dosage, _{Cm a x} and linearity and/or ratio of the dosages described herein. These disintegrants may also include a binder having disintegration properties. The disintegrant according to the present invention may comprise microcrystalline cellulose, crosslinked polyvinylpyrrolidone (PVP-XL), sodium starch glycolate, croscarmellose sodium, crosslinked hydroxypropylcellulose and analog. Of course, the choice of disintegrant depends on whether the results described herein can be obtained in a given system. More preferably, the formulation should contain no more than about 20% microcrystalline cellulose and about 5% or more cross-linked polyvinylpyrrolidone, especially in formulations comprising an additional 20% lactose monohydrate. The most preferred disintegrant is glycolic acid starch salt and especially sodium starch glycolate. It has in fact been found that the use of glycolic acid starch salts in the formulations of the present invention provides significant improvements in dose reduction compared to foaming formulations including pH adjusting agents and other disintegrants, while still providing a comparison C _{m a x} . A particularly useful sodium starch glycolate is GLYCOLYS available from Roquette of Lestrem France. (Standard level). In fact, even better, the formulation does not include microcrystalline cellulose or crosslinked PVP.

The amount of disintegrant should vary with known factors such as the size of the dosage form, the nature and amount of other ingredients used, and the like. Generally, however, the amount should range from about 0.25% to about 20% by weight of the final formulation, more preferably from about 0.5 to about 15% by weight, even more preferably from 0.5 to about 10% by weight and even more preferably about 1 to about 8 wt%. This is also based on the weight of the final formulation.

It is also generally possible to use a tablet or a release lubricant in accordance with the present invention. The most commonly known lubricant is magnesium stearate and magnesium stearate is preferred. In general, the lesser the knowledge behind the pressing of the lubricant, the better. In most cases it is preferred to use less than about 1% of the tablet lubricant. Usually the amount should be 0.5% or less. However, the amount of magnesium stearate used may be greater than 1.0%. In practice, it is preferably greater than about 1.5% and most preferably from about 1.5% to about 3%. The best use is about 2% magnesium stearate. Other conventional tableting lubricants such as stearic acid, calcium stearate and the like may be used in place of some or all of the magnesium stearate.

The foaming lozenge according to the present invention may be relatively soft or relatively strong. It can be prepared, for example, according to the method described in U.S. Patent No. 5,178,878 and should have a hardness generally less than about 15 Newtons. Unlike the formulations described in the '878 patent, the active ingredients herein need not be coated with a protective material. In fact, the preferred fentanyl active is uncoated. When a lozenge which is as soft and flexible/brittle as such is produced, it is preferably packaged in a foamed package as found in U.S. Patent No. 6,155,423. It may also have a hardness of greater than about 15 Newtons and is very strong, made according to the procedure set forth in U.S. Patent No. 6,024,981. In a preferred embodiment, the phenentramine dosage form of the present invention is provided in a foamed package that is protected from children. See, for example, U.S. Patent No. 6,155,423, issued toK. The package is optimally up to the standards set forth in 16 U.S.C. §1700.15 and .20 (2003). Also preferred packages include those commonly referred to in the industry as so-called "F1" and "F2" packages. The "F1" package is best.

The lozenges according to the invention may be designed differently for oral, gingival or sublingual administration. However, in each case, the disintegration time/dissolution (residence time) in the mouth reached by the formulation is preferably less than about 30 minutes and most preferably about 20 minutes or less. It is usually greater than 5 minutes, most often 10 minutes or more. This is based on subjective determination of patient response.

According to a particularly preferred embodiment of the present invention, there is provided a foaming orally disintegrating lozenge designed to administer oral, gingival or sublingual administration of phenentrid or a pharmaceutically acceptable salt thereof, comprising from about 100 to about 800 Microgram of phenanthrene (based on the weight of the free base), an effective amount of a foaming coupler, and an effective amount of a pH adjusting agent and a glycolic acid starch salt. The formulation may further comprise mannitol.

In a particularly preferred aspect of this embodiment of the invention, the formulation described above does not include making it incapable of obtaining relative to ACTIQ At least about 45% by weight of the phenanthrene dose reduction rate of lactose monohydrate and/or crosslinked PVP. In particular, preferably no more than about 10% by weight of the formulation is lactose monohydrate or microcrystalline cellulose and no more than about 4% is crosslinked PVP. More preferably, the formulation does not contain all of these materials except for the accompanying amounts of such excipients. According to the present invention, sodium starch glycolate is preferably used as a disintegrant and mannitol is used as a filler. Optimal fillers include spray dried mannitol.

The formulations according to the present invention may not detract from the advantages described herein, including other conventionally known amounts of other conventional excipients. Such materials may include, without limitation, binders, sweeteners, coloring components, perfumes, glidants, lubricants, preservatives, disintegrants, and the like.

Lozenges as a preferred dosage form of the invention can be made by any known tableting technique. Preferably, however, the materials used are dry blended and compressed directly. Although tablets can be obtained from granulation, this method is not good. Of course, the particular excipients and materials used in the formulations according to the invention may be wet granulated or dry granulated. For example, granulated mannitol can be used as a filler. It may also be desirable to partially granulate or premix one of the formulations prior to final blending and compression. The substance in question was selected to provide a suitable pre-dose and content uniformity and the dose reduction rate described herein, C _{m a x} / dose ratio and / or dose linearity. Accordingly, a suitable amount of a foaming coupler, a suitable and suitable pH adjusting agent, and a suitable disintegrant are provided in a predetermined amount and formulated into a dosage form which is preferably a tablet.

Preferably, the pH adjusting agent is a carbonate, a hydrogencarbonate or a phosphate. Preferably, the disintegrant is a glycolic acid starch salt. The amount of each substance used is otherwise described herein. However, preferred disintegrants are selected and have an amount that allows for a further dose reduction in the amount of phenanthrene used compared to other equivalent formulations containing a foaming coupler and a pH adjusting agent without a disintegrant. The pH adjusting agent is preferably selected and has an amount that provides a local pH change of at least 0.5 pH units, more preferably about 1.0 pH units, and most preferably about 2.0 pH units. Although the tablet can be compressed to any hardness and/or friability, its completion must not adversely affect residence time and drug release and transmission through the oral mucosa. Where possible, it is desirable to provide a phenentramine 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 form according to the invention can be used to treat any type of pain and in particular for the treatment of general anesthetic pain. As with all anesthetics, the fentanyl product, and in particular the fentanyl product of the present invention, should always be taken at the discretion of a physician or under the strict supervision and supervision of a physician. A general description of the ACTIQ product and its precautions and contraindications found in the previously mentioned physician's handbook are widely applicable to the use of the dosage form of the present invention. This generally includes titrating the patient at a lower dose prior to the dose increase.

The dosage form according to the invention is administered by placing it in the patient's mouth, preferably under the tongue or between the cheeks and the gums, wherein the drug stays until it substantially completes dissolution/disintegration and it is no longer identifiable as a dosage form. Preferably, swallowing should be minimized to help promote the maximum transfer of fentanyl through the adjacent oral mucosa.

Take additional doses as needed. As noted previously, a dose such as 800 micrograms of phenanthrene may be administered in a single dosage form or in multiple dosage forms in accordance with the present invention, such as two dosage forms of the invention, each containing 400 micrograms of fentanyl or four dosage forms according to the invention. Each contains approximately 200 micrograms of fentanyl. Preferably, the multi-dose administration should involve all dosage forms administered within one hour, and more preferably, if not simultaneously administered, the administration is about simultaneous.

In particular, a method of making a tablet of the present invention for oral, gingival or sublingual administration comprises providing phenanthrene or a salt thereof (measured as a phenanthrene base) in an amount of from about 100 to about 800 micrograms per dose. , or its equivalent salt. Also provided is from 5% to about 85% by weight of the dosage form of a foaming coupling agent, from 5% to about 25% by weight of the dosage form of at least one pH adjusting agent and from 0.25% to about the weight of the dosage form. 20% of at least one disintegrant, preferably glycolic acid starch salt. The materials are blended and compressed into a tablet. In a preferred embodiment, a filler is also used. In a particularly preferred embodiment, a portion of the filler can be pre-blended with phenanthrene or another excipient such as a color former.

Further, one of the excipients frequently used in accordance with the present invention is a lubricant such as magnesium stearate. This material is typically added at the end of the blending period. The blending is often interrupted and then magnesium stearate is added and mixing is continued for a few minutes.

In a preferred embodiment, the foamed package containing the dosage form from and according to the present invention should be opened directly prior to use of the product. The patient should place the dosage form in his or her mouth, preferably between the cheeks and the upper or lower gums. The dosage form should not be sucked or chewed. Bentani is the same as many anesthetics, preferably titrated at a relatively low dose for the initial dose. The initial dose of the phenentrant formulation according to the invention, especially for those dosage forms for the treatment of sudden onset of cancer pain, should be 100 micrograms. The patient should be provided with a limited initial titration supply of 100 micrograms of dosage form, thus limiting the number of units in the home during titration. The dose can then be increased by the physician.

EXAMPLES Manufacturing Methods In each of Examples 1-7 and 9-11, the materials were screened prior to use, fed to a V-blender, or blended into any other suitable low shear blender. Medium and blended when appropriate. After discharge from the blender, the materials were compressed on a standard rotary tablet press to a target hardness of 13 Newtons and a target weight of 100 or 200 mg in each example.

Example 1 - Formulation A OraVescent Stetani, 1080 mcg, 5/16" lozenge, red

Example 2 - Formulation C OraVescent Stetani, 1300 mcg, 5/16" lozenge, red

Example 3 - Formulation D OraVescent Bentham, 810 mcg, 5/16" lozenge, yellow

Example 4 - Formulation E OraVescent Stetani, 270 mcg, 5/16" lozenge, white

Example 5 OraVescent Stetani, 500 mcg, 5/16" lozenge, orange

Example 6 OraVescent Stetani, 200 mcg, 5/16" lozenge, white

Example 7 OraVescent Stetani, 100mcg, 1/4" lozenge, white

Example 8 These materials can be screened prior to use, fed into a V-blender or other suitable low shear blender and blended for the appropriate period of time. After discharge from the blender, the material was compressed to a target hardness of 13 Newtons and a target weight of 200 mg/tablet on a standard rotary tablet press.

OraVescent Stetani, 300 mcg, 5/16" lozenge, light yellow

Example 9 OraVescent Stetani, 400 mcg, 5/16" lozenge, pink

Example 10 OraVescent Stetani, 600 mcg, 5/16" lozenge, orange

Example 11 OraVescent Stetani, 800 mcg, 5/16" lozenge, yellow

Example 12 The following materials were weighed and screened.

Mannitol EZ (2a.) and yellow 10 iron oxide were transferred to a V-blender and blended for 30 minutes. The pre-blending is discharged and ground. The entire amount of the preblend, phenanthrene citrate, sodium bicarbonate, citric acid, sodium carbonate sodium starch glycolate was added to the V-blender and blended for 30 minutes. Mannitol (2b) was fed into a V-blender and blended for 13 minutes. Magnesium stearate was fed into a V-blender and blended for 5 minutes. The tablet is compressed from the final blend. The tablets were 1/4" round, flat surface, white with beveled edges. They were compressed to an average hardness of 13 Newtons on a fully processed 36 Fette press.

Claims (46)

A dosage form comprising: from about 100 to about 800 micrograms of fentanyl or an equivalent salt thereof, in the form of a phenanthroline free base, from about 5 to about 85%, by weight of the dosage form, of a foaming agent, The dosage form is from about 0.5 to about 25% by weight of the pH adjusting substance and from about 0.25 to about 20% by weight of the dosage form of glycolic acid starch salt, which is suitable for delivery through the oral mucosa of the patient by oral, gingival or sublingual administration. The phenanthrene. The dosage form of claim 1, wherein the pH adjusting substance is selected and provided to provide a local pH change of at least 0.5 pH units. The dosage form of claim 2, wherein the pH adjusting substance is a carbonate or a hydrogencarbonate. The dosage form of claim 1, which further comprises a filler. The dosage form of claim 4, wherein the filler is present in an amount between about 10 and about 80% by weight. The dosage form of claim 4, wherein the filler is mannitol. A dosage form according to claim 1 which is a compressed tablet. The dosage form of claim 1, wherein the ratio of _Cmax to dose is between about 2.0 and about 4.0 pg/ml/μg. The dosage form of claim 8, wherein the ratio of _Cmax to dose is between about 2.5 and about 3.5 picograms per milliliter per microgram. The dosage form of claim 9, wherein the ratio of _Cmax to dose is between about 2.7 and about 3.5 picograms per milliliter per microgram. A dosage form comprising: from about 100 to about 800 micrograms of phenanthrene or an equivalent salt thereof, a foaming agent, a pH adjusting substance, in the form of a phenanthroline free base, the pH adjusting substance being selected and providing a content energy Providing a local pH change of at least 0.5 pH units, and glycolic acid starch salt, the dosage form being adapted to deliver the phenanthrene through the oral mucosa of the patient by oral, gingival or sublingual administration, and providing a _Cmax to dose ratio of about 2.0 to about 4.0 pg / ml / microgram. A dosage form according to claim 11 which provides a _Cmax to dose ratio of between about 2.7 and about 3.5 picograms per milliliter per microgram. The dosage form of claim 11, wherein the foaming agent is present in an amount of from about 5 to about 85% by weight of the dosage form, and the pH adjusting substance is present in an amount of from about 0.5 to about 25% by weight of the dosage form, the glycolic acid starch salt being present The amount is from about 0.25 to about 20% by weight of the dosage form. The dosage form of claim 13, wherein the foaming agent is present in an amount of from about 15 to about 60% by weight of the dosage form, and the pH adjusting substance is present in an amount of from about 2 to about 20% by weight of the dosage form, the glycolic acid starch salt being present The amount is from about 0.5 to about 15% by weight of the dosage form. The dosage form of claim 13, which further comprises a filler. The dosage form of claim 15, wherein the filler is present in an amount from about 10 to about 80% by weight. The dosage form of claim 16, wherein the filler is mannitol. The dosage form of any one of claims 1 to 12, wherein the dosage form contains no more than 10% by weight of lactose monohydrate. The dosage form of any one of claims 1 to 12, wherein the dosage form contains no more than 10% by weight of microcrystalline cellulose. The dosage form of any one of claims 1 to 12, wherein the dosage form contains less 4% by weight of crosslinked polyvinylpyrrolidone. The dosage form of any one of claims 1 to 12, wherein the dosage form does not contain all of the substances except for the accompanying amounts of lactose monohydrate, microcrystalline cellulose, and crosslinked polyvinylpyrrolidone. Use of a dosage form for the manufacture of a medicament for the treatment of pain in a patient in need thereof, wherein the dosage form comprises from about 100 to about 800 micrograms of phenanthrene or its equivalent salt, foaming agent, pH adjustment in the form of a phenanthroline free base. The substance (the selected conditioning substance and the amount provided provides a local pH change of at least 0.5 pH units) and the glycolic acid starch salt, the dosage form being adapted to deliver the phenanthrene through the oral mucosa of the patient by oral, gingival or sublingual administration And the ratio of _Cmax to dose is between about 2.0 and about 4.0 picograms per milliliter per microgram, the relationship between dose and _Cmax is linear, and the drug is placed in the patient's mouth to remain tight with the oral mucosa of the patient. Contact for a period of time sufficient to deliver a therapeutically effective amount of the fentanyl through the oral mucosa. The use of claim 22, wherein the drug is maintained in contact with the oral mucosa for a period of between about 10 and about 30 minutes. The use of claim 22, wherein the drug is maintained in contact with the oral mucosa for a period of time sufficient to provide at least about 75% of the fentanyl dose absorbed into the bloodstream of the patient. The use of claim 22, wherein the pain is selected from the group consisting of sudden cancer pain, back pain, neuralgia, surgical pain, or post-operative pain. Use of a dosage form for the manufacture of a medicament for the treatment of a sudden onset of cancer pain, wherein the dosage form comprises an initial dose of about 100 micrograms of phenanodamine or an equivalent salt thereof calculated as the phenanthrene free base, by weight of the dosage form About 5 to About 85% of a foaming agent, from about 0.5 to about 25% by weight of the dosage form of a pH adjusting substance and from 0.25 to about 20% by weight of the dosage form of glycolic acid starch salt, the dosage form being adapted to be delivered through the oral mucosa of the patient Stetani, and the drug is placed between the cheek and the upper or lower gums of the patient's mouth for a period of time sufficient to deliver a therapeutically effective amount of the fentanyl through the oral mucosa. A method of making a tablet for oral, gingival or sublingual administration of phenanthrene comprising the steps of providing a fentanyl or between about 100 to about 800 micrograms per dose as measured by phenanthrene base a salt thereof, or an equivalent salt thereof, providing from about 5 to about 85% by weight of the dosage form of a foaming agent, providing from about 0.5 to about 25% by weight of the dosage form of the pH adjusting substance and about 0.25 by weight of the dosage form. Up to about 20% of the glycolic acid starch salt, blending the phenanthrene, a foaming agent, a pH adjusting substance with the glycolic acid starch salt, and compressing the resulting blend into at least one tablet. The method of claim 27, further comprising providing from about 10 to about 80% by weight of the dosage form of the filler, and first incorporating the phenanthrene, the foaming agent, the pH adjusting substance, and the glycolic acid starch salt After the combination, the resulting blend is further compressed into at least one tablet. The method of claim 28, wherein the filler is mannitol. The method of claim 29, wherein the mannitol is spray dried mannitol. The method of claim 28, further comprising the step of first adding a lubricant to the blend and then compressing it into at least one tablet. The method of claim 31, further comprising first applying the lubricant to the phenanthrene, a foaming agent, a pH adjusting substance, a glycolic acid starch salt, and the filler After blending, the resulting blend is further compressed into at least one tablet. The method of claim 32, wherein the tablet is compressed to a hardness of between about 5 and about 100 Newtons. The method of claim 27, wherein the tablet is compressed to a hardness of between about 15 and about 100 Newtons. A method of making a tablet for oral, gingival or sublingual administration of phenanthrene comprising the steps of: providing from about 100 to about 800 micrograms of phenanthrene or an equivalent thereof in the form of a phenanthroline free base a salt, a foaming agent, a pH adjusting substance (the selected pH adjusting substance and a content provided to provide a local pH change of at least 0.5 pH units) and a glycolic acid starch salt, blending the phenanthrene, foaming The agent, the pH adjusting substance and the glycolic acid starch salt, and the resulting blend is compressed into at least one lozenge suitable for delivering the fentanyl through the oral cavity, gums or sublingual administration through the oral mucosa of the patient. The method of claim 35, further comprising the steps of providing from about 10 to about 80% filler by weight of the dosage form, and reacting the same with the phenanthrene, a foaming agent, a pH adjusting substance, and the glycolic acid The starch salt is blended and the resulting blend is compressed into at least one tablet. The method of claim 36, wherein the filler is mannitol. The method of claim 37, wherein the mannitol is spray dried mannitol. The method of claim 36, further comprising the step of compressing the blend into at least one tablet after adding the lubricant to the blend. The method of claim 39, further comprising mixing the lubricant with the phenanthrene, a foaming agent, a pH adjusting substance, a glycolic acid starch salt, and the filler After the combination, the resulting blend is further compressed into at least one tablet. The method of claim 40, wherein the tablet is compressed to a hardness of between about 5 and about 100 Newtons. The method of claim 35, wherein the tablet is compressed to a hardness of between about 5 and about 100 Newtons. The method of any one of claims 37 to 42, wherein the tablet contains no more than 10% by weight of lactose monohydrate. The method of any one of claims 37 to 42, wherein the tablet contains no more than 10% by weight of microcrystalline cellulose. The method of any one of claims 37 to 42, wherein the tablet contains no more than 4% by weight of crosslinked polyvinylpyrrolidone. The method of any one of claims 37 to 42, wherein the tablet contains no such substances except for the accompanying amounts of lactose monohydrate, microcrystalline cellulose, and crosslinked polyvinylpyrrolidone.