HK1238555B - Small-volume oral transmucosal dosage forms - Google Patents

Description

Small volume oral transmucosal dosage form

The present application is a divisional application of Chinese invention patent application No. 200780007142.9 filed on January 8, 2007, entitled “Small Volume Oral Transmucosal Dosage Form”.

Cross-references to other applications

This application claims priority to U.S. Provisional Application No. 60/756,937, filed January 6, 2006, the disclosure of which is incorporated herein by reference in its entirety.

Field of the Invention

The present invention provides small volume oral transmucosal drug delivery dosage forms, referred to herein, having various sizes and features and methods of use thereof.

Background of the Invention

Currently, standard oral treatments for many disease states are significantly limited by both efficacy and toxicity. Among other factors, route of administration, formulation, and dosage control contribute to these limitations.

Reproducible and effective drug delivery technologies are an active area of research, and controlled drug delivery systems offer many advantages over conventional dosage forms, including enhanced efficacy, reduced toxicity, improved patient tolerability, and greater convenience. This is particularly relevant for the treatment of pain, especially acute, intermittent, and breakthrough pain.

The development of new and improved dosage forms and drugs for treating a variety of medical conditions, such as pain, based on various routes of administration is ongoing. There remains a pressing need for safer pharmaceutical dosage forms that do not experience the level of fluctuation seen with currently commercially available dosage forms. Currently available treatment regimens for pain often fail to provide adequate or consistent therapeutic effects to patients due to slow onset, instability, and difficulty regulating dosage, resulting in ineffective treatment of the medical condition.

U.S. Patent Nos. 6,974,590, 6,764,696, 6,641,838, 6,585,997, 6,509,036, 6,391,335, 6,350,470, 6,200,604 and U.S. Patent Publication Nos. 20050176790, 20050142197 and 20050142198 describe drug combinations of active compounds such as fentanyl and its congeners in combination with effervescent agents that act as penetration enhancers to affect the permeability of the active compound through the buccal, sublingual and gingival mucosa.

U.S. Patent Nos. 6,761,910 and 6,759,059 and U.S. Patent Publication No. 20040213855 disclose pharmaceutical compositions for treating acute conditions such as pain by sublingual administration of a substantially anhydrous, ordered mixture of microparticles of at least one pharmaceutically active agent adhered to the surface of carrier particles by a bioadhesion and/or mucoadhesion promoting agent. U.S. Patent No. 6,759,059 discloses compositions and methods for sublingual administration of fentanyl or a pharmaceutically acceptable salt thereof using tablets approximately 100 mg in size.

U.S. Patent Nos. 5,800,832 and 6,159,498 (Tapolsky et al.) and U.S. Patent Publication Nos. 20030194420 and 20050013845 disclose water-soluble, biodegradable drug delivery devices such as bilayer film discs having an adhesive layer and a backing layer that adhere to a mucosal surface, both of which are water-soluble.

U.S. Patent Nos. 6,682,716, 6,855,310, 7,070,762 and 7,070,764 and (Rabinowitz, et al.) disclose delivering analgesics via inhalation using a method comprising: a) heating a thin layer of analgesic drug on a solid support to form a vapor; and b) passing air through the heated vapor to generate aerosol particles.

U.S. Patent No. 6,252,981 (Zhang et al.) discloses oral mucosal drug delivery as an alternative method for systemic drug delivery formulations and methods for oral transmucosal drug delivery. The invention provides a pharmaceutical formulation comprising a solid medicament in a solid solution having a cosolvent in solid form, and producing a solid solution. The solid solution formulation can also be combined with a buffer and other excipients as needed to facilitate the manufacture, storage, administration and delivery of the drug through oral mucosal tissue. The formulation can be used with various oral transmucosal delivery dosage forms, such as tablets, lozenges, lollipops, chewing gum, and buccal or mucosal patches. See also Zhang et al., Clin Pharmacokinet. 2002; 41(9): 661-80.

A number of transmucosal dosage forms for the treatment of pain are currently in clinical development, examples include oral morphine spray and oral fentanyl spray (Generex Biotechnology) and oral fast-dissolving fentanyl tablets for sublingual administration (Rapinyl ^™ ; Endo Pharmaceuticals). Two transmucosal fentanyl formulations currently commercially available are fentanyl buccal tablets (FENTORA ^™ ; Cephalon) and an oral transmucosal form of fentanyl citrate administered as a lollipop (Cephalon), both of which are only used to treat breakthrough cancer pain in patients who are already receiving and tolerant of opioid therapy for their ongoing cancer pain.

While various oral drug delivery systems and dosage forms have been described for treating various medical conditions and disease states, there remains a need for improved dosage forms, formulations, and treatment regimens for treating such medical conditions and disease states, for example, for treating acute and breakthrough pain.

High bioavailability is crucial for effective treatment with various drugs, including opioids, because higher doses must be packaged in commercial dosage forms to counteract the generally low bioavailability. For example, the bioavailability of oxymorphone is 10%, so for an oral tablet, nine times more drug must be packaged than for a comparable IV dosage form. A particular problem is that there is a large amount of residual drug left after the drug is fully used. An example is the inefficient drug delivery system (transdermal) IonSys ^™ , which requires packaging in a transdermal patch three times the amount of drug delivered to the patient during conventional use. These inefficient systems, whether oral tablets or patches, can be easily abused by intravenously injecting the drug and obtaining the full bioavailability of the overdose. If a given dosage form administered by the intended route of administration provides close to complete bioavailability, then drug abuse by intravenous injection will not provide increased bioavailability, and therefore such dosage forms can alleviate drug abuse and deviation.

There remains a need for improved dosage forms for oral drug delivery that provide faster and more consistent onset of action, more consistent plasma concentrations, and higher and more consistent bioavailability than currently available dosage forms. The present invention addresses this need.

SUMMARY OF THE INVENTION

The present invention provides compositions and methods comprising small volume oral transmucosal drug delivery dosage forms or formulations containing a predetermined unit dose of a pharmaceutically active amount of a drug that can be self-administered while providing therapeutic efficacy and a predictable and safe pharmacokinetic profile.

The small size of the drug and its placement in the sublingual cavity enables transmucosal absorption of the active lipophilic molecule and minimizes salivary response and drug swallowing. This avoidance of gastrointestinal (GI) uptake results in a more rapid and stable onset of action, more stable plasma concentrations, and higher bioavailability. This route of administration minimizes drug uptake via the GI route, which is variable and subject to significant drug metabolism in the stomach and intestines.

The invention has bioadhesive properties and can adhere to oral mucosa, such as sublingual membrane and buccal membrane. Such can be hydrogel-forming or erosive.

The mass of the present invention is less than 100 mg and the volume is less than 100 μl. More particularly, the present invention provides a mass selected from the group consisting of less than 100 mg, less than 90 mg, less than 80 mg, less than 70 mg, less than 60 mg, less than 50 mg, less than 40 mg, less than 30 mg, less than 20 mg and less than 10 mg and/or a volume selected from the group consisting of less than 100 μl, less than 90 μl, less than 80 μl, less than 70 μl, less than 60 μl, less than 50 μl, less than 40 μl, less than 30 μl, less than 20 μl and less than 10 μl.

The invention can be used for oral transmucosal administration of any drug that can be absorbed via the transmucosal route and undergoes GI and first-pass metabolism and therefore can benefit from this dosage form.

In one aspect, the invention comprises 0.25 μg to 99.9 mg, 1 μg to 50 mg, or 1 μg to 10 mg of drug.

In one aspect, the invention provides wherein the drug is an opioid selected from the group consisting of sufentanil, alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, and mirfentanil.

The present invention provides for an opioid-containing drug in an amount selected from the group consisting of about 0.25mcg to 200 micrograms (mcg) of sufentanil, about 2.5mcg to 100mcg of sufentanil, about 0.02mcg to 5 micrograms per kilogram (mcg/kg) of sufentanil, such as about 2.5, 5, 10, or 15 micrograms of sufentanil, about 10mcg to 10mg of alfentanil, about 2mcg to 1500mcg of fentanyl, about 50mcg to 1500mcg of fentanyl, about 10 ... g to 1500mcg of fentanyl, about 200mcg to 1500mcg of fentanyl, about 0.25mcg to 99.9mg of lofentanil, about 0.25mcg to 99.9mg of carfentanil, about 0.25mcg to 99.9mg of carfentanil, about 0.25mcg to 99.9mg of remifentanil, about 0.25mcg to 99.9mg of trefentanil, about 0.25mcg to 99.9mg of mirfentanil.

Designed for self-administration by an individual with or without a device, wherein the shape is selected from a disc having a flat, concave or convex surface, an ellipsoid, a sphere and a polygon having three or more edges and a flat, concave or convex surface.

The present invention can be characterized by an erosion time of from 30 seconds up to 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours or more.

The bioavailability of the drug of the present invention after single or repeated oral transmucosal administration to a subject is greater than 65%, greater than 75%, greater than 85%, greater than 90%, or greater than 94%.

The invention is further characterized by a coefficient of fluctuation of _Cmax less than 30% or 40%, a coefficient of fluctuation of AUC less than 30% or 40%, a coefficient of fluctuation of _Tmax less than 40%, a plasma half-life of about 30 minutes to about 4 hours, and a therapeutic time ratio greater than 0.07 or from about 0.5 to about 2.0 following a single oral transmucosal administration to a subject.

The amount of drug absorbed via the oral transmucosal route is at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% of the total amount of drug in the dosage form.

The present invention also provides methods of treating an individual exhibiting a symptomatic medical condition by administering a drug described herein that is effective in treating the symptomatic medical condition.

In one embodiment, the symptomatic medical condition is pain, such as acute pain, breakthrough pain, or post-operative pain, and an opioid such as sufentanil or a congener thereof is included.

BRIEF DESCRIPTION OF THE DRAWINGS

1 is a graphical representation of the in vitro dissolution kinetics of sufentanil formulations #46 through #48 used in the human clinical studies described in Example 1.

Figure 2 is a graphical representation of sufentanil plasma concentrations following intravenous or sublingual single dose administration of three different strengths of sufentanil in healthy human volunteers (n=12).

Figure 3 is a graphical representation of sufentanil plasma concentrations following sublingual administration of sufentanil formulation #44 (equivalent to human formulation #47; n=3) compared to intravenous sufentanil administration (n=3) in a healthy, conscious beagle dog model. Error bars represent standard error of the mean (SEM).

Figure 4 is a graphical representation of sufentanil plasma concentrations following sublingual administration of slowly disintegrating sufentanil Formulation #58 (n=3) in a healthy, conscious beagle dog model.

Figure 5 is a graphical representation of sufentanil plasma concentrations following sublingual administration of sufentanil solution (n=6) or oral ingestion of sufentanil (n=6) compared to intravenous administration of sufentanil (n=3) in a healthy, conscious beagle dog model. Error bars represent ± standard error of the mean (SEM).

Figure 6 is a graphical representation of fentanyl plasma concentrations following sublingual administration of moderately disintegrating fentanyl Formulation #60 (n=2) and slowly disintegrating fentanyl Formulation #62 (n=3) compared to intravenous fentanyl administration (n=3) in a healthy, conscious beagle dog model. Error bars represent ± standard error of the mean (SEM).

Figure 7 is a graphical representation of alfentanil plasma concentrations following sublingual administration of alfentanil (n=2) compared to intravenous alfentanil administration (n=3) in a healthy, conscious beagle dog model. Error bars represent ± standard error of the mean (SEM).

Detailed description

The present invention provides oral transmucosal dosage forms or the like that provide high bioavailability, low _Tmax variability, low _Cmax variability and low AUC variability. The present invention also provides controlled dissolution, solubility and stability, resulting in controlled release of the drug over time, resulting in extended plasma levels within the therapeutic window.

The present invention is based on a small solid oral transmucosal dosage form or certain embodiments thereof that adhere to the oral mucosa during drug delivery. The transmucosal dosage form minimizes salivary response and thus minimizes drug delivery to the gastrointestinal (GI) tract, allowing most of the drug to be delivered through the oral mucosa.

The following disclosure describes the dosage forms that constitute the present invention. The present invention is not limited to the specific dosage forms and methodologies or medical disease states described herein, as these can of course vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the invention.

It must be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a drug formulation" includes a plurality of such formulations, and reference to "a drug delivery device" includes various systems that include drug formulations as well as devices that contain, store, and deliver such formulations.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described.

All publications mentioned herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing compositions and methodologies described in publications that may be used in conjunction with the present invention. The publications discussed herein are provided solely because their disclosure predates the filing date of the present application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention.

definition

As used herein, small volume dosage forms are those having a volume of about 0 μl to about 100 μl and a mass of about 0 mg to about 100 mg. The drug-containing dosage forms of the present invention may or may not have bioadhesive properties and may be dissolvable and have hydrogel-forming or eroding sheet properties.

As used herein, the term "formulation" or "pharmaceutical formulation" or "dosage form" refers to a physical entity containing at least one therapeutic agent or drug for delivery to a subject. The physical entity can be in the form of a lozenge, pill, tablet, capsule, film, strip, liquid, patch, film, gel, spray, chewing gum, or other form.

The terms "drug," "medication," "pharmacologically active agent," and the like are used interchangeably herein and generally refer to any substance that alters the physiology of an animal. The present invention can be used to deliver any drug that can be administered via an oral transmucosal route, and the amount administered can vary, via a small size, i.e., 0.25 μg to 99.9 mg, 1 μg to 50 mg, or 1 μg to 10 mg.

The term "drug" as used in reference to the present invention means any "drug," "active agent," "active," "medication," or "therapeutically active agent" that can be effectively administered via the oral transmucosal route.

The term "drug," as applied to pain treatment (analgesia), includes sufentanil, sufentanil congeners, such as alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil, and dosage forms containing one or more therapeutic compounds. The use of "drug" or the phrase "sufentanil or a congener" is not intended to limit the use of only one of these selected opioid compounds, or to dosage forms containing only one of these selected opioid compounds. Furthermore, references to sufentanil alone or to selected sufentanil congeners alone, such as references to "fentanyl," should be understood as merely examples of drugs suitable for delivery according to the methods of the present invention and are not intended to be limiting. It should also be understood that the dosage forms of the present invention can include more than one therapeutic agent, where exemplary therapeutic agent combinations include a combination of two or more opioid analogs, for example, sufentanil plus an opioid such as alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil, or an opioid such as morphine and codeine, a semi-synthetic opioid such as heroin and oxycodone, or a fully synthetic opioid whose structure is not related to an opioid such as meperidine or methadone, or any other drug that can be administered in combination.

As used herein, the term "congener" refers to one of various variations or configurations of a common chemical structure.

The term "subject" includes any subject, typically a mammal (eg, human, canine, feline, equine, bovine, ungulate, etc.), in whom treatment of a condition is desired, such as management of pain or anesthesia.

The term "mucosal" generally refers to any biological membrane in the body that is covered by mucus. Absorption through the oral mucosa is of particular interest. Thus, the present invention specifically contemplates buccal, sublingual, gingival, and palate absorption. In a preferred embodiment, the penetration enhancers of the present invention are used to promote absorption through these oral tissues, namely the gums and palate, which are most similar to skin in their cellular structure.

The term "transmucosal" delivery of a drug, etc., is intended to encompass all forms of delivery through or via mucosal membranes. In particular, "oral transmucosal" delivery of a drug includes delivery through any tissue of the mouth, pharynx, larynx, trachea, or upper gastrointestinal tract, particularly including sublingual, gingival, and palate mucosal tissues.

The terms "buccal dosage form," "oral transmucosal dosage form," and "oral transmucosal dosage form" are used interchangeably herein to refer to dosage forms used to practice the present invention.

Oral dosage forms are typically "sublingual dosage forms," but other oral transmucosal routes may be used in certain circumstances. The present invention relies on such dosage forms to provide sustained delivery of the drug across the oral mucosa.

As used herein, the term "oral transmucosal drug delivery" refers to dosage forms in which drug delivery occurs substantially via a transmucosal route, rather than via swallowing followed by absorption through the GI. The dosage forms of the present invention are designed to provide a drug dissolution rate that allows for maximum delivery via the oral mucosa, typically by placing the dosage form in the sublingual cavity.

As used herein, "sublingual" literally means "under the tongue" and refers to a method of administering a substance via the mouth in a manner such that the substance is rapidly absorbed via the blood vessels beneath the tongue, rather than via the digestive tract. Due to the highly vascularized nature of the sublingual mucosa and the lower number of epithelial cell layers compared to other mucosa, absorption of therapeutic substances occurs rapidly, allowing direct access to the systemic circulation and thereby enabling rapid onset of action while avoiding all the complications of oral administration.

As used herein, the term "hydrogel-forming formulation" means a substantially water-free solid formulation that, when in contact with body fluids, particularly those in the oral mucosa, is capable of absorbing aqueous solutions such as water in a manner that causes it to swell while maintaining its structural matrix and forming a hydrated gel in situ. The formation of the gel follows unique disintegration (or erosion) kinetics while allowing controlled release of the therapeutic agent over time, primarily by diffusion.

As used herein, the term " _Tmax " means the time point at which maximum plasma concentration is observed.

As used herein, the term " _Cmax " means the maximum observed plasma concentration.

As used herein, the term "AUC" means the "area under the curve" in a plot of plasma concentration of a drug versus time. Typically, the AUC is given for a time interval from zero to infinity; however, it is obvious that plasma drug concentrations cannot be measured "to infinity" for a patient, so mathematical approximations are used to estimate the AUC from a finite number of concentration measurements. In a practical sense, the AUC (from zero to infinity) represents the total amount of drug absorbed by the body, regardless of the rate of absorption. This is useful when trying to determine whether two identical doses of a formulation release the same amount of drug to the body. The AUC of a transmucosal dosage form, compared to the AUC of the same dose administered intravenously, serves as the basis for measuring bioavailability.

As used herein, the term "F" means "percent bioavailability" and represents the fraction of drug absorbed from a test substance compared to the same drug when administered intravenously. It is calculated as the _AUC∞ of the test substance after delivery via the intended route relative to the _AUC∞ of the same drug after intravenous administration. It is calculated using the following equation: F(%) = _AUC∞ (test substance)/ _AUC∞ (intravenous route/substance). This is an important term that establishes the relative fraction of drug absorbed via the test route (or substance) relative to the maximum possible amount that can be obtained via the intravenous route.

The term "therapeutic time ratio" or "TTR" refers to the average time that a drug is present at therapeutic levels and is defined as the time that the drug plasma concentration remains above 50% of the _Cmax corrected for the drug's elimination half-life, and is calculated by the following formula: TTR = (time above 50% of _Cmax ) / (terminal intravenous elimination half-life of the drug). The latter term is derived from literature data for the drug of interest in the appropriate species.

As used herein, the term "disintegration" means the physical process by which a tablet breaks down and relates only to the physical integrity of the tablet. This can occur in a number of different ways, including breaking into smaller pieces and ultimately breaking into fine and large particles, or eroding from the outside inward until the tablet disappears.

As used herein, the term "dissolution" means the process by which the active ingredient dissolves from a tablet in the presence of a solvent in vitro or in the presence of physiological fluids such as saliva in vivo, without regard to the mechanism of release, diffusion or erosion.

As used herein, the term "swelling ratio" means the ratio of the mass of a dosage form after full exposure to water compared to its dry state before exposure. The swelling ratio (SR) can be defined based on a specific time of exposure to water and expressed as a ratio or percentage, such as SR expressed as a percentage = (mass after exposure to water - initial dry mass) / (initial dry mass) x 100.

Alternatively, such a "swelling ratio" can be defined as the ratio of the volume of a dosage form of the present invention after exposure to water to the volume of the same dosage form before exposure to water. The swelling ratio (SR) can be defined based on a specific time of exposure to water and expressed as a ratio or percentage, such as SR expressed as a percentage = (volume of tablet after exposure - volume of tablet before exposure) / (volume of tablet before exposure) × 100. When the radial dimension of such an experiment is well controlled, the same swelling ratio can be defined based on a variable dimension such as thickness, such as SR expressed as a percentage = (thickness of tablet after exposure - thickness of tablet before exposure) / (thickness of tablet before exposure) × 100.

As used herein, the term "bioadhesion" refers to adhesion to biological surfaces, more typically including mucous membranes.

The term "therapeutically effective amount" means an amount of a therapeutic agent that is effective to promote a desired therapeutic effect, such as pain relief, or the rate of delivery of a therapeutic agent (e.g., amount over time). The precise desired therapeutic effect (e.g., the degree of pain relief and the source of the pain being relieved, etc.) will vary depending on the disease state to be treated, the individual's tolerance, the drug to be administered and/or the drug formulation (e.g., the potency of the therapeutic agent (drug), the concentration of the drug in the formulation, etc.), and a variety of other factors that will be understood by those of ordinary skill in the art.

"Sustained drug delivery" involves the release or administration of a drug from a source (eg, a drug formulation) over an extended period of time, for example, over a period of 1 minute or longer. Sustained drug delivery is effectively the opposite of bolus drug delivery.

As used herein, when referring to a pharmaceutical formulation "adhering" to a surface such as a mucosal membrane, it is meant that the formulation is in contact with the surface and remains on the surface without the application of external forces. Adhesion is not intended to imply a specific degree of adhesion or bonding, nor is it intended to imply any degree of permanence.

The term "active agent" or "active" is used herein interchangeably with the term "drug" and is used herein to refer to any therapeutically active agent.

The term "non-occlusive" is used herein in its broadest sense to mean that a patch device, fixed reservoir, application chamber, tape, bandage, adhesive plaster, etc., which remains on the skin at the application site for an extended period of time, does not block or isolate the skin from contact with the air.

The term "mucosal-depot" is used herein in its broadest sense to refer to a reservoir or deposit of active agent in or just beneath the mucosa.

As used herein, the expression "mucoadhesion" refers to adhesion to mucous membranes covered with mucus, such as the oral mucosa, and is used interchangeably herein with the term "bioadhesion," which refers to adhesion to any biological surface.

The term "drug delivery device" is used herein interchangeably with the term "dispensing device" and refers to a device that dispenses an oral transmucosal dosage form, such as that of the present invention, comprising a formulation further described herein.

Oral transmucosal drug delivery dosage forms

The present invention provides oral transmucosal dosage forms or formulations that can reduce salivary response compared to other oral dosage forms, thereby increasing the absorption rate of the pharmaceutically active substance in the dosage form across the oral mucosa, and reducing uptake through the gastrointestinal tract and thus providing a more stable and reproducible drug delivery method.

Oral dosage forms are often referred to as "sublingual dosage forms," but other oral transmucosal routes may be used in certain circumstances. The present invention relies on such oral dosage forms for sustained delivery of drugs through the oral mucosa. The dosage forms are substantially homogeneous compositions comprising one or more active ingredients and may include one or more mucoadhesives (also referred to herein as "bioadhesives") that provide adhesion to the oral mucosa of the patient, one or more binders that provide adhesion to the excipients in a single tablet, one or more hydrogel-forming excipients, one or more fillers, one or more lubricants, one or more absorption enhancers, one or more buffering excipients, as well as coatings and other excipients and factors that regulate and control the dissolution time and kinetics of the drug or prevent degradation of the active ingredient.

Sublingual delivery is preferred because the sublingual mucosa is more permeable to drugs than other mucosal areas such as the buccal mucosa, resulting in more rapid uptake (Shojaei AH, et al. Buccal mucosa as a route for systemic drug delivery: a review. Journal of Pharmacy and Pharmaceutical Sciences. 1: 15-30, 1998).

Compared with traditional oral dosage forms or clinically used oral transmucosal dosage forms, the present invention enables a greater percentage (and amount) of the drug to be delivered via the oral mucosa and correspondingly reduces the delivery via the gastrointestinal tract.

The preferred location for oral transmucosal drug delivery is the sublingual area, but in certain embodiments it may be advantageous for the dosage form to be located in the cheek or adhered to the roof of the mouth or gums.

The dosage forms of the present invention are suitable for oral transmucosal (eg, sublingual) delivery of drugs, and have dissolution times typically up to about 60 minutes, in some cases up to 120 minutes, and in other cases up to several hours.

Typically, more than 30%, more than 50%, more than 75%, or more than 95% to 99% of the drug in the dosage form is absorbed through the oral mucosa.

The use of the drug delivery dosage forms of the present invention is not limited to any specific therapeutic indication. Examples of the use of the drug delivery dosage forms of the present invention for the treatment of pain are provided herein; however, the present invention can be used to treat any of a wide variety of disease states and conditions and is not limited to any specific drug or patient population. Thus, the drug delivery dosage forms of the present invention can be used to administer to both pediatric and adult populations and to treat both human and non-human mammals.

When used to treat pain, the invention can be used for administration to pediatric and adult populations and to treat human and non-human mammals as well as opioid-tolerant and opioid-naive patient populations.

Characteristics of the dosage form

In one embodiment, the dosage form of the present invention is or is generally adapted to adhere to the oral mucosa (i.e., bioadhesive) during drug delivery until most or all of the drug has been delivered from the dosage form to the oral mucosa. In other embodiments, the dosage form of the present invention is or is not bioadhesive.

The volume of the present invention is about 0 μl (milliliter) to about 100 μl, the mass is about 0 mg (milligram) to about 100 mg, the thickness is about 0.1 mm to about 10.0 mm, for example, about 0.5 mm to about 3.0 mm; and the diameter is about 1.0 mm to about 30.0 mm, about 1.0 mm to about 10.0 mm, for example, about 3.0 mm.

More particularly, the mass of the present invention is selected from less than 100 mg, less than 90 mg, less than 80 mg, less than 70 mg, less than 60 mg, less than 50 mg, less than 40 mg, less than 30 mg, less than 20 mg and less than 10 mg.

The volume of the present invention may also be selected from less than 100 μl, less than 90 μl, less than 80 μl, less than 70 μl, less than 60 μl, less than 50 μl, less than 40 μl, less than 30 μl, less than 20 μl and less than 10 μl.

Shape : The dosage forms of the present invention can have essentially any shape that matches the dimensional parameters described herein. Exemplary shapes are selected from a disk having a flat, concave, or convex surface, an ellipsoid, a sphere, and a polygon having three or more edges and a flat, concave, or convex surface. The shape can be symmetrical or asymmetrical and have features or geometries that enable controlled, convenient, or easy storage, handling, packaging, or administration.

Oral and GI Uptake : Typically, greater than 30%, greater than 50%, greater than 75%, or greater than 95% to 99% of the drug of the present invention is taken up via the oral mucosa.

In certain embodiments of the present invention, it is suitable to deliver 30% or more of the total amount of the drug contained in a single drug dosage form to an individual via the oral mucosa. In other embodiments, the percentage of the total amount of the drug contained in a single drug dosage form delivered via the mucosa can be greater than 30% to 40%, 40% to 50%, 60% to 70%, 70% to 80%, 80% to 90% and preferably greater than 95%. In an exemplary embodiment, at least 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% of the total amount of the drug contained in a single drug dosage form is delivered via the oral mucosa.

The delivery of a greater percentage (and amount) of drug via the oral mucosa and the corresponding lack of delivery via the GI tract provides a significant improvement over current methods of drug delivery.

Reduced salivary response : The pharmaceutical dosage forms of the present invention are designed and adapted to reduce the salivary response, reducing the amount of drug swallowed, thereby delivering a larger amount of drug to a subject via the oral mucosa. The present invention also provides oral transmucosal dosage forms with an improved dissolution profile compared to previously described oral or oral transmucosal dosage forms, efficient drug delivery via the oral mucosa, and stable plasma concentrations within the therapeutic window.

Erosion Time : The dosage forms of the present invention are designed to provide an erosion rate that enables maximum delivery through the oral cavity, typically by placing the dosage form sublingually. The erosion time for sublingual administration of the present invention is generally about 30 seconds up to 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours.

Dissolution Time : The oral transmucosal formulations of the present invention are generally designed to achieve drug dissolution times ranging from 30 seconds to as high as 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, or longer, depending on the patient and administration scenario and the inherent pharmacokinetics of the drug. It will be understood that the composition of the oral transmucosal formulations of the present invention can be adjusted to provide a range of doses and a range of dissolution times to suit specific clinical conditions.

Formulation : The pharmaceutical dosage form of the present invention for oral transmucosal delivery can be solid or non-solid. In a preferred embodiment, the dosage form is a solid that transforms into a hydrogel upon contact with saliva. In another preferred embodiment, the dosage form is a solid that erodes upon contact with saliva without forming a hydrogel.

The dosage forms of the present invention are substantially homogeneous preparations comprising 0.01% to 99% w/w of an active ingredient (pharmaceutical, pharmaceutical, etc.) and further containing one or more of: a mucosal adhesive (also referred to herein as a "bioadhesive") that provides adhesion to the patient's oral mucosa; one or more binders that provide binding of excipients in a single tablet; one or more hydrogel-forming excipients; one or more fillers; one or more lubricants; one or more absorption enhancers; one or more buffering excipients; one or more coatings; one or more controlled-release modifiers; and one or more other excipients and factors that regulate and control the dissolution or disintegration time and kinetics of the drug or prevent degradation of the active drug.

Excipients are not limited to the above substances. Many suitable non-toxic pharmaceutically acceptable carriers for oral dosage forms can be found in Remington's Pharmaceutical Sciences, 17th Edition, 1985.

The dosage forms of the present invention for oral transmucosal drug delivery can include at least one bioadhesive (mucoadhesive) or a mixture of multiple bioadhesives to promote adhesion to the oral mucosa during drug delivery. In addition, when the dosage form is moistened by saliva, the bioadhesive or mucoadhesive can also effectively control the erosion time of the dosage form and/or the dissolution kinetics of the drug over time. In addition, certain mucoadhesives listed herein can also be used as binders in the formulation to provide the necessary bonding to the dosage form.

Exemplary mucoadhesive or bioadhesive materials are selected from natural, synthetic or biopolymers, lipids, phospholipids, etc. Examples of natural and/or synthetic polymers include cellulose derivatives (such as methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, etc.), natural gums (such as guar gum, xanthan gum, locust bean gum, karaya gum, veegum, etc.), polyacrylates (such as carbopol, polycarbophil, etc.), alginates, polyethylene oxide, polyethylene glycol (PEG) of all molecular weights (preferably 1000 Da to 40,000 Da, which can be any linear or branched chemical structure), dextran of all molecular weights (preferably 1000 Da to 40,000 Da), polysaccharides of all molecular weights (preferably 1000 Da to 40,000 Da, which can be any linear or branched chemical structure ... 0,000 Da, which can be of any origin), block copolymers, such as those prepared by combining lactic acid and glycolic acid (PLA, PGA, PLGA of various viscosities, molecular weights, and lactic acid to glycolic acid ratios), polyethylene glycol-polypropylene glycol block copolymers with any number and combination of repeating units (such as Pluronics, Tektronix or Genapol copolymers), mixtures of combinations of physically or chemically linked units of the above copolymers (such as PEG-PLA or PEG-PLGA copolymers). Preferably, the bioadhesive excipient is selected from polyethylene glycol, polyethylene oxide, polyacrylic acid polymers such as carbopol (e.g., carbopol 71G, 934P, 971P, 974P) and polycarbophil (e.g., Noveon AA-1, Noveon CA-1, Noveon CA-2), cellulose and derivatives thereof, and most preferably polyethylene glycol, carbopol and/or cellulose derivatives or any combination thereof.

The amount of mucoadhesive/bioadhesive is typically 1% to 50% w/w, preferably 1% to 40% w/w or most preferably 5% to 30% w/w.The formulations of the present invention may contain one or more different bioadhesives in any combination.

The dosage form of the present invention for oral transmucosal drug delivery also includes a binder or a mixture of two or more binders, which helps to incorporate the excipient into a single dosage form. Exemplary binders are selected from cellulose derivatives (such as methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, etc.), polyacrylates (such as carbopol, polycarbophil, etc.), povidone (all grades), irradiated or unirradiated Polyox of any molecular weight or grade, starch, polyvinylpyrrolidone (PVP), Avicel, etc.

The amount of binder is typically from 0.5% to 60% w/w, preferably from 1% to 30% w/w and most preferably from 1.5% to 15% w/w.

The dosage form for oral transmucosal drug delivery of the present invention may further comprise at least one or more hydrogel-forming excipients. Exemplary hydrogel-forming excipients are selected from polyethylene glycol and other polymers having an ethylene glycol backbone, whether homopolymers or cross-linked heteropolymers, block copolymers of ethylene glycol units, such as polyoxyethylene homopolymers (e.g., Polyox N10/MW=100,000; Polyox-80/MW=200,000; Polyox 1105/MW=900,000; Polyox-301/MW=4,000,000; Polyox-303/MW=7,000,000; Polyox WSR-N-60K; all of which are trade names of Union Carbide), hydroxypropyl methylcellulose (HPMC) of all molecular weights and grades (e.g., Metolose 90SH50000, Metolose 90SH30000, all of which are trade names of Shin-Etsu Chemical Co.), poloxamers (e.g., Lutrol F-68, Lutrol F-127, F-105, etc., are all trade names of BASF Chemicals), Genapol, polyethylene glycols (PEG, such as PEG-1500, PEG-3500, PEG-4000, PEG-6000, PEG-8000, PEG-12000, PEG-20,000, etc.), natural gums (xanthan gum, locust bean gum, etc.) and cellulose derivatives (HC, HMC, HMPC, HPC, CP, CMC), free or cross-linked polyacrylic acid-based polymers and combinations thereof, biodegradable polymers such as polylactic acid, polyglycolic acid, and any combination thereof by physical mixing or cross-linking. In an embodiment, the hydrogel component may be cross-linked. The amount of the hydrogel-forming excipient is typically 0.1% to 70% w/w, preferably 1% to 50% w/w, or most preferably 1% to 30% w/w.

The dosage form for oral transmucosal drug delivery of the present invention can also include at least one controlled release modifier, which is such a substance: when the dosage form is hydrated, the substance will preferentially adhere to the drug molecules to reduce the diffusion rate of the drug from the oral dosage form. Such excipients can also reduce the rate at which the preparation absorbs water and thus can achieve more prolonged drug dissolution and release from the tablet. In one embodiment, such controlled release modifiers can be molecularly bound to the active agent via physical (and therefore reversible) interactions, thereby increasing the effective molecular weight of the active agent and therefore further regulating its permeability (diffusion) characteristics through the epithelium and basement membrane of the sublingual mucosa. Such binding is actually reversible and does not involve any chemical modification of the active agent, so its pharmacological action is not affected. In another preferred embodiment, such controlled release modifiers can form discontinuous structures when hydration occurs, which can spontaneously capture the active agent and therefore further prolong its effect. Exemplary controlled release modifiers are selected from lipids, phospholipids, sterols, surfactants, polymers and salts. The excipient selected usually is lipophilic and can naturally form complexes with hydrophobic or lipophilic drugs. The degree of association of the release modifier and the drug can be changed by changing the ratio of the modifier to the drug in the preparation. In addition, such interaction can be appropriately enhanced by appropriately combining the release modifier with the active drug during the manufacturing process. Alternatively, the controlled release modifier can be a synthetic or biopolymerized charged polymer with a positive or negative net charge, and it can be combined with the active agent by electrostatic interaction to regulate its diffusion through the tablet and/or its permeation kinetics through the mucosal surface. Similar to the above-mentioned other compounds, such interaction is reversible and does not involve a permanent chemical bond with the active agent.

The amount of controlled release modifier may generally range from 0 to 80% w/w, preferably from 1% to 20% w/w, most preferably from 1% to 10% w/w.

The dosage forms of the present invention for oral transmucosal drug delivery also typically include at least one filler. Exemplary fillers are selected from lactose USP, starch 1500, mannitol, sorbitol, maltitol, or other non-reducing sugars; microcrystalline cellulose (e.g., Avicel), dehydrated calcium phosphate, sucrose, or mixtures thereof. The amount of filler is typically 20% to 99% w/w, preferably 40% to 80% w/w.

The dosage form for oral transmucosal drug delivery of the present invention may further include at least one lubricant. Exemplary lubricants are selected from magnesium stearate, stearic acid, calcium stearate, talc, stearowet, and terotex. The amount of lubricant is generally 0.01% to 8%, preferably 0.1% to 3%.

The formulations may also contain flavoring or sweetening and coloring agents such as aspartame, mannitol, lactose, sucrose, other artificial sweeteners; iron oxides and FD&C lakes.

The formulation may also contain additives to help stabilize the drug substance from chemical or physical degradation. Such degradation reactions may include oxidation, hydrolysis, aggregation, deamidation, etc. Suitable excipients that can stabilize the drug may include antioxidants, anti-hydrolysis agents, aggregation retardants, etc. Antioxidants may include BHT, BHA, vitamins, citric acid, EDTA, etc. Aggregation retardants may include surfactants, amino acids, etc.

The formulation may also contain a surfactant to increase the moisture content of the tablet, especially when faster release kinetics are desired, which will result in faster initiation of film adhesion. Such surfactants should constitute 0.01% to 3% by weight of the composition. Exemplary surfactants are selected from ionic types (such as sodium lauryl sulfate), non-ionic types such as polysorbates (Tween and Span surfactant series), bile salts (such as sodium taurocholate, sodium taurodeoxycholate, sodium deoxyglycocholate, sodium glycocholate, etc.), various alkyl glycosides, and mixtures thereof.

The dosage form of the present invention may also contain one or more excipients that can affect the disintegration kinetics of the tablet and the release of the drug from the tablet, thereby affecting the pharmacokinetics. Such additives are disintegrants, such as those known to those skilled in the art, and can be selected from starch, carboxymethylcellulose-type or cross-linked polyvinyl pyrrolidone (such as cross-linked polyvinyl pyrrolidone, PVP-XL), alginates, cellulose-based disintegrants (such as purified cellulose, methylcellulose, cross-linked sodium carboxymethylcellulose (Ac-Di-Sol) and carboxymethylcellulose), microcrystalline cellulose such as (Avicel), ion exchange resins (such as Ambrelite IPR 88), gums (such as agar, locust bean, karaya, pectin and tragacanth), guar gum, karaya gum, chitin and chitosan, smectite, gellan gum, plantain husk, polacrilin potassium (Tulsion ³³⁹ ), gas-releasing disintegrants (such as citric acid and tartaric acid with sodium bicarbonate, sodium carbonate, potassium bicarbonate or calcium carbonate), sodium starch glycolate (such as Explotab and Primogel). Compared to dosage forms without disintegrants, the addition of such additives facilitates rapid rupture or disintegration of the dosage form, resulting in smaller particles that dissolve more rapidly. Another benefit of incorporating such additives containing bioadhesive materials as described herein into the dosage forms of the present invention is that the smaller drug-containing particles formed upon disintegration have improved bioadhesive properties due to the greatly increased surface area in contact with the oral mucosa. Furthermore, this increased surface area promotes rapid release of the active substance, further accelerating drug absorption and achieving desired systemic therapeutic levels. However, as noted above, such disintegrants are typically used in solid dosage forms at low levels, typically 1% to 20% w/w of the total dosage unit weight.

In one aspect of the invention, the dosage form comprises at least one biodegradable polymer of any type for increasing drug release. Exemplary polymer compositions include polyanhydrides and copolymers of lactic and glycolic acids, poly(dl-lactide-co-glycolide) (PLGA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyorthoesters, proteins, and polysaccharides.

The dosage form of the present invention for oral mucosal drug delivery may also include one or more absorption enhancers, one or more buffering excipients, and/or one or more coatings to improve, for example, hardness and friability.

In another aspect of the invention, the active ingredient can be chemically modified to significantly improve its pharmacokinetics in plasma. This can be achieved, for example, by combining with polyethylene glycol (PEG), including site-specific PEGylation. PEGylation, which can improve drug performance by optimizing pharmacokinetics, reduces immunogenicity and dosage frequency.

The present invention is provided in a variety of dosage forms, each tailored to the nature and amount of the active ingredient while maintaining the controlled oral dissolution characteristic of the present invention. Consequently, a greater percentage of drug absorption occurs via the oral mucosal route rather than the GI route, resulting in controlled release of the drug over time, thereby extending plasma levels within the therapeutic window. The present invention also offers the advantages of high bioavailability, low _Tmax variability, low _Cmax variability, and low AUC variability.

In one aspect of the present invention, a uniform dosage form comprising a formulation according to the present invention adheres upon contact when placed in the sublingual cavity, preferably beneath the tongue on either side of the frenulum. As the dosage form is exposed to the moisture of the sublingual space, it absorbs water, thereby forming a hydrogel network comprising micropores and macropores (or channels). Hydration of the drug influences dissolution and subsequent diffusion through the porous network of the dosage form. The hydrogel dosage form of the present invention is characterized by swelling to at least 110% of its initial volume upon contact with an aqueous solution.

The hydrogel formation in the dosage form of the present invention occurs in the presence of certain excipients capable of forming a hydrogel, which are capable of absorbing water and forming a gel. Such excipients include all grades of Polyox, polyethylene glycol (all grades), PEG-based copolymers (e.g., poloxamers, etc.), dextran, HPMC, starch, etc., as described in detail above. In addition, any combination of such excipients can contribute to hydrogel formation when in contact with body fluids. In addition, the combination of such hydrogel-forming excipients with excipients such as carbopol, certain celluloses, etc., which contribute to the non-formation of the gel (i.e., do not have such swelling capacity), can result in the formation of a hydrogel structure, although with modified properties.

Another aspect of the present invention provides dosage forms referred to herein as "eroding" dosage forms. Although such "eroding" dosage forms can absorb large amounts of water (depending on their composition), they do not have the same swelling capacity and therefore do not form a gel as the hydrogel-type formulations defined above. These "eroding" formulations adhere to the sublingual cavity upon contact, similar to hydrogel formulations. However, in contrast to hydrogels, they follow a surface erosion mechanism without first forming a hydrogel. As the "eroding" dosage forms are exposed to the moisture of the sublingual cavity, the tablet surface hydrates and erodes; subsequent layers become hydrated and eroded, resulting in a continuous reduction in tablet size.

Such erodible dosage forms are typically characterized by the absence of hydrogel-forming excipients. However, it will be appreciated that the weight-to-weight percentage (w/w) composition of the various ingredients in the dosage form can influence the erosion mechanism. For example, a small amount of a particular hydrogel-forming excipient will not cause hydrogel formation, and thus, certain hydrogel-forming excipients can be included in erodible formulations without altering their erosion-based disintegration mechanism. It is the combination of excipients and their weight percentage composition that enables the hydrogel to swell and maintain its structural matrix upon contact with an aqueous solution. In other words, generally, the inclusion of a hydrogel-forming excipient in a given formulation does not necessarily cause the dosage form to "swell," as is typical with hydrogel formulations. A dosage form that becomes a hydrogel swells to at least 110% of its initial volume upon contact with an aqueous fluid.

Pharmacokinetics (PK)

Transmucosal drug administration via [0014] allows for more consistent drug delivery across dosage forms and across patients compared to currently available oral transmucosal dosage forms, in which the majority of drugs are administered via the GI route.

The dosage form of the present invention is designed to work effectively in the unique environment of the oral cavity so that the limited amount of fluid, the relatively short time for drug dissolution, and the pH level in the oral cavity do not adversely affect the absorption of the drug. The formulation is also designed to improve the dissolution rate, solubility, and stability of the pharmaceutical dosage form. Advantages of the present invention include the ability to provide a higher level of drug absorption via the oral transmucosal route and a constant dose-effect time, making the formulation significantly improved for the treatment of acute or breakthrough pain.

The oral transmucosal formulations of the present invention are designed to avoid the high peak plasma levels of intravenous dosage forms by utilizing the sublingual mucosa and by independently controlling tablet disintegration (or erosion) and drug dissolution and release from the tablet over time to provide a safer delivery profile. The oral transmucosal dosage forms of the present invention provide individual repeat doses containing a given amount of active agent, thereby allowing the patient to accurately titrate the amount of drug delivered and appropriately adjust the amount in a safe and effective manner.

The advantages of the controlled release oral transmucosal dosage form of the present invention are that it has a more constant bioavailability and can maintain plasma drug concentrations in the targeted therapeutic window for a longer time with significantly lower volatility than currently available dosage forms, whether solid dosage forms or IV dosage forms. The high peak plasma levels typically observed for IV dosage forms can be weakened after administration of the present invention, which can be characterized by controlled release of the drug over 1 to 60 minutes or longer. In addition, since the drug continues to enter the bloodstream through the oral cavity during the time period or longer period of tablet dissolution, the rapid decline in plasma levels is avoided, thereby providing plasma pharmacokinetics with an extended plateau phase compared to the IV route of administration. In addition, the dosage form of the present invention can improve treatment safety by minimizing potentially harmful side effects, which are due to the relative reduction of peaks and valleys in plasma pharmacokinetics, which compromise treatment safety and are typical in currently available dosage forms.

Advantages of solid sublingual dosage forms over various liquid dosage forms for sublingual or intranasal administration of opioids include controlled local release from solid dosage forms and the avoidance of swallowing liquid medication via the nose or mouth. Published pharmacokinetic data for intranasal sufentanil liquid administration (15 mcg) in humans indicate a bioavailability of 78% (Helmers et al. Comparison of intravenous and intranasal sufentanil absorption and sedation. Canadian Journal of Anaesthesia 36:494-497, 1989). Sublingual sufentanil liquid administration (5 mcg) in beagle dogs (see Example 4 below) resulted in a bioavailability of 40%. These bioavailability data are lower than the average bioavailability of 91% achieved in human volunteers with sublingual sufentanil administered in the form of the present invention (see Example 1 below).

Due to its small size, it can be repeatedly placed in the sublingual cavity for a sustained period of time. The small size minimizes saliva production and physical discomfort, which allows for repeated titration over days to weeks to months. Due to the lipophilicity of the sublingual cavity, this route also allows for slower release into plasma for some drugs, possibly by utilizing a "depot" effect that further stabilizes plasma levels compared to buccal delivery.

The oral transmucosal dosage form of the present invention is designed to be placed comfortably under the tongue, allowing for thorough and slow disintegration of the drug dosage form to avoid the immediate peak in plasma levels followed by a significant decline seen in prior art formulations, such as described in U.S. Patent No. 6,759,059 (Rapinyl), in which fentanyl was administered via a tablet containing 400 mcg of fentanyl, which resulted in a peak plasma level of 2.5 ng/ml followed by an immediate decline in plasma levels. Fentora (fentanyl buccal tablet) also suffers from the lack of a plateau but a steep slope to _Cmax followed by a rapid decline in plasma levels (Fentora package insert).

evaluate Test

Prior to the sublingual human and animal studies conducted in support of the present invention and described in the following specification and Examples 1 to 6 in humans and animals, the inventors were not aware of any published pharmacokinetic data in animals or humans obtained from the use of sublingual sufentanil in any dosage form or alfentanil in any dosage form.

In vivo evaluation

Human studies

Human clinical studies were conducted using healthy volunteers. The study detailed in Example 1 below was conducted with 12 individuals (6 men and 6 women) using sublingual sufentanil containing 2.5 μg, 5 μg, or 10 μg of sufentanil base (corresponding to 3.7 μg, 7.5 μg, or 15 μg of sufentanil citrate, respectively). All excipients were inactive and had GRAS ("generally recognized as safe") status.

Sufentanil designed for sublingual use was compared to IV sufentanil administered as a continuous infusion over 10 minutes through an IV line. Plasma samples were drawn at distal locations from different IV lines. The analysis demonstrated good inter-day precision and accuracy at high, medium, and low quality control sample concentrations.

In all subjects studied, sufentanil eroded within 10 to 30 minutes. Following sublingual placement of sufentanil in the sublingual cavity of each of 12 healthy volunteers, a remarkably consistent pharmacokinetic profile was obtained (see Figure 2 and Table 2). The average bioavailability for all three single doses compared to IV administration was 91%, which far surpasses the percentages measured for commercially available transmucosal fentanyl formulations, Actiq and Fentora (47% and 65%, respectively, according to the Fentora package insert). While this high bioavailability could be due to a variety of factors, it is likely that the lack of saliva due to the small size significantly limits drug swallowing and avoids the low bioavailability typically associated with drug absorption via the GI route. The package inserts for Fentora and Actiq, respectively, claim that at least 50% and 75% of the drug dose is swallowed via saliva, and both have lower bioavailability than the present invention. The volume used in the clinical trials was approximately 5 microliters (5.5 mg mass), a fraction of the size of the Actiq and Fentora tablets. The canine studies described in Example 4 and those discussed above indicate that sufentanil has a very low GI bioavailability (12%), so if sufentanil bioavailability is high, where the drug is administered via the oral transmucosal route, the data support the conclusion that greater than 75% of the drug is absorbed transmucosally. Thus, less than 25% of the drug is swallowed, which is much lower than the proportion of drug swallowed with Fentora and Actiq.

Importantly, this high bioavailability is also associated with a high degree of consistency in the total drug delivered to the patient. For example, the total plasma drug area under the curve (AUC 0-infinity) for 10 mcg of sufentanil is 0.0705 ± 0.0194 hr*ng/ml (mean ± standard deviation (SD)). This SD is only 27.5% of the total AUC. The coefficient of variation (CV) is a term that describes the percentage SD of the mean. The coefficient of variation for the Fentora AUC is 45%, while the Actiq AUC is 41% (Fentora package insert). Therefore, the total dose delivered to the patient/subject is not only more bioavailable for sufentanil but also more consistent across patients.

Sublingual sufentanil also demonstrates superior consistency in drug plasma levels in the early post-dose period. The _Cmax achieved with 10 mcg of sufentanil was 27.5 ± 7.7 pg/ml. Therefore, the coefficient of variation for _Cmax was only 28%. Fentora and Actiq face the issue of GI drug uptake variability with their _Cmax . Fentora's _Cmax was 1.02 ± 0.42 ng/ml, resulting in a coefficient of variation for _Cmax of 41%. The coefficient of variation for Fentora across various doses ranged from 41% to 56% (package insert). Actiq's _Cmax coefficient of variation is reported as 33% (Fentora package insert).

In addition to superior bioavailability and consistent plasma concentrations, the time to _Cmax (also known as _Tmax ) is crucial because rapid and consistent onset of pain relief is crucial in the treatment of acute pain. The _Tmax of 10mcg of sufentanil is 40.8 ± 13.2 minutes (range, 19.8 to 60 minutes). The reported mean _Tmax for Fentora is 46.8 minutes, with a range of 20 to 240 minutes. The _Tmax for Actiq is 90.8 minutes, with a range of 35 to 240 minutes (Fentora package insert). Thus, sufentanil demonstrates significantly improved consistency of analgesic effect compared to Fentora and Actiq, with the slowest onset _Tmax reduced by 400%.

In the treatment of acute pain, especially acute breakthrough pain, a consistent and short half-life is crucial. The plasma elimination half-life of 10 mcg of sufentanil is 1.71 ± 0.4 hours, making it titratable for various pain levels. If the breakthrough pain event persists for more than 1.5 hours, the patient can take another dose. At the lowest dose, Actiq and Fentora have plasma elimination half-lives of 3.2 hours and 2.63 hours, respectively. At higher doses, the half-lives of these drugs increase substantially, limiting their titratability.

Although still under development, published data allow us to compare the sufentanil pharmacokinetic data presented herein with data for Rapinyl, a sublingual fast-dissolving fentanyl tablet. As previously mentioned, the observed bioavailability of the sufentanil of the present invention averages 91%, while the published bioavailability of Rapinyl is approximately 70% (Bredenberg, New Concepts in Administration of Drugs in Tablet Form, Acta Universitatis Upsaliensis, Uppsala, 2003). The coefficient of variation in the AUC (0-infinity) for Rapinyl ranges from 25% to 42%, depending on dose, while our value for 10 mcg sufentanil is 27.5%. Our high bioavailability might suggest that sufentanil will have consistently low AUC variability regardless of dose, but this is not the case for Rapinyl. In fact, our measured AUC variability averaged 28.6% for all three doses of sufentanil, indicating that this low variability is independent of dose.

Rapinyl's _Cmax coefficient of variation ranged from 34% to 58% depending on dose. As shown in the data presented herein, the _Cmax variation for a 10mcg sufentanil dose was only 28%, and the average _Cmax coefficient of variation across all three dose strengths (2, 5, and 10mcg) was 29.4%, demonstrating minimal dose-related variability. Similarly, rapinyl's _Tmax coefficient of variation ranged from 43% to 54% depending on dose, while this _Tmax coefficient of variation averaged only 29% across all three dose strengths of our sufentanil. This consistent onset of action achieved with sufentanil allows for a safer re-dosing window compared to any of the three comparator drugs, as elevated plasma levels are contained within a shorter time period.

Additionally, for Fentora and Actiq, Rapinyl has a longer plasma elimination half-life than sufentanil (5.4 to 6.3 hours, depending on dose). Following a single oral transmucosal dose in humans, sufentanil has a plasma elimination half-life of 1.5 to 2 hours (Table 2), allowing for greater titratability and avoiding overdosing. Those skilled in the art will appreciate that the exemplary half-lives described herein can be adjusted by varying the composition and relative amounts of excipients used to prepare a given formulation. In this human study, the ability to titrate to higher plasma levels via repeated sublingual sufentanil administration was also tested. Repeated administration of 5 mcg every 10 minutes for up to four doses resulted in a bioavailability of 96%, demonstrating that higher plasma levels can be achieved with repeated dosing while still maintaining high bioavailability. Whether treating postoperative pain or cancer breakthrough pain, the ability to effectively titrate to individual levels of pain relief is crucial.

Plateau plasma levels

Another aspect of the PK profile generated by sublingual sufentanil is the plateau phase, which allows for a period of consistent plasma levels and is important for both safety and efficacy. The PK profile of sufentanil is significantly safer when compared to both IV bolus dosing (see Examples 2 to 6 for animal studies) and the 10-minute IV infusion used in our human studies (Example 1 and Figure 2). Rapid, high _Cmax plasma levels are avoided. If opioids can produce respiratory depression, then avoiding these high peaks in the PK profile is advantageous.

The key mathematical ratio demonstrating a prolonged plateau of measured sufentanil plasma levels following administration is the time taken to exceed 50% of _Cmax divided by the known IV terminal elimination half-life of the drug:

The elimination half-life is an intrinsic property of a molecule and can be most reliably measured using the IV route, avoiding contamination from continued sublingual drug ingestion. Due to the analytical detection limit at these low doses, the IV elimination half-life of 5 mcg of sufentanil in our human studies was 71.4 minutes. Due to the rapid α-elimination mechanism observed through redistribution from metabolism and secretion and the longer β-elimination phase, the published IV elimination half-life of sufentanil at much higher doses is 148 minutes. This published elimination half-life is more accurate and more suitable for use in the above equation. The mean time to 50% of _Cmax in 12 volunteers at the 2.5, 5, and 10 mcg dose strengths was 110, 111, and 106 minutes, respectively. Therefore, the therapeutic time ratios for these specific sufentanils ranged from 0.72 to 0.75. Because the erosion time of sufentanil can decrease or increase with varying formulations, the therapeutic time ratio for sufentanil is likely to be approximately 0.2 to 2.0. In fact, for sufentanil, any oral transmucosal dosage form of the present invention may have a therapeutic time ratio within this range, and therefore we do not limit the scope of this sought protection to a specific attribute.

This therapeutic time ratio is a measure of how successfully a drug with a short onset of action has been formulated to increase therapeutic time and safety by avoiding high peak plasma _Cmax concentrations. For example, in comparison, the IV arm of the sufentanil study demonstrated a therapeutic time ratio of 10 min/148 min = 0.067. Therefore, the low ratio in this IV arm is a measure of the high peak produced by IV infusion of sufentanil and indicates that this formulation does not produce a significant plateau. The therapeutic time ratios for the sufentanil formulations listed in Table 1 (doses used in the human study) are 10-fold higher than those for IV sufentanil, indicating that these formulations have a prolonged therapeutic plateau curve.

Animal studies

A series of studies were conducted in awake, alert Beagle dogs to more fully illustrate the performance of various drugs and formulations. The oral transmucosal drug delivery of the present invention was compared with liquid sublingual administration and swallowing to evaluate various properties. The results support our claim that the small bioadhesive of the present invention is well tolerated sublingually (as demonstrated in awake dogs) compared to other oral transmucosal dosage forms, including instilled liquids, and can obtain higher bioavailability and more consistent pharmacokinetic data.

As described more fully in Example 2 below, a first Beagle dog study was conducted to compare sublingual 5mcg sufentanil with IV sufentanil. A total of three Beagle dogs were studied, and the results are shown in FIG3 and listed in Table 3. Sublingual sufentanil had a bioavailability of 75% compared to IV sufentanil. Thus, similar to the human data, this canine bioavailability data demonstrates superior properties compared to larger dosage forms. Furthermore, similar to the human data, the coefficient of variation in AUC was lower, at 14%, than that observed for other commercial transmucosal dosage forms. The therapeutic time ratio for sublingual sufentanil was 0.28, while the therapeutic time ratio for IV sufentanil was 0.05 (using the published IV elimination half-life of sufentanil in dogs of 139 minutes). Thus, similar to humans, the 5mcg dose in Table 1 resulted in a significantly higher (5.6-fold) therapeutic time ratio compared to IV sufentanil in dogs.

Additional studies determined the effects of varying the formulation on the pharmacokinetic profile. This study is explained in more detail in Example 3 below. By extending the erosion time, the plasma half-life was extended from 33 minutes for the medium-disintegrating formulation (in Example 2) to 205 minutes. The therapeutic time ratio for the slow-disintegrating formulation was extended from 0.28 to 1.13. This study illustrates the flexibility of modifying the PK of a drug based on the choice of excipient. This flexibility is possible due to the small size of the formulation, which allows its contact time with the sublingual mucosa to be shortened or prolonged without dislodging or generating excess saliva that would continuously wash the drug into the GI tract.

Another study was conducted in beagle dogs to evaluate the advantages of a sublingual dosage form over sublingual liquid administration. This study is described in more detail in Example 4 below. The results demonstrate that while delivery of sufentanil (5 mcg) to the sublingual cavity in an instilled liquid dosage form resulted in a rapid _Tmax , this method of administration resulted in very low bioavailability (40%) compared to sublingual sufentanil (75%). This is likely due to swallowing of the liquid medication. Furthermore, the AUC was extremely variable, as indicated by a high coefficient of variation (82%). The _Cmax with this dosing method was also highly variable, with a coefficient of variation of 72%. The therapeutic time ratio for sublingual instilled liquid sufentanil was calculated to be 0.06, very similar to the 0.03 ratio for the IV sufentanil arm of this study. Therefore, this instilled sublingual liquid profile does not exhibit the favorable therapeutic plateau observed with sublingual sufentanil. These results support that the high sublingual bioavailability observed in the bioadhesive formulation claimed in this application is not inherent to the molecule, but a direct result of the unique design of the dosage form and its formulation. The strong adhesion in the sublingual cavity minimizes the fluctuation of the surface area available for absorption, as in the case of liquid solutions, thereby improving the delivery of the molecule to systemic circulation. In addition, due to its unique design and small size, it does not induce significant saliva production, thereby reducing the possibility of the released drug being ingested. Both factors contribute to a higher and more uniform drug absorption from the sublingual cavity.

Another component of this study in Example 4 was the bioavailability of swallowed sufentanil. Given the limited to no GI bioavailability data for sufentanil in the literature, it was important to further evaluate the low bioavailability of this route of administration to further support the conclusion that sublingually administered drug is not swallowed and maintains high bioavailability. As shown by the PK analysis data in Table 7, oral bioavailability of sufentanil from swallowed sufentanil was very low, approximately 12%. Furthermore, as expected from the known irregular GI uptake of fentanyl congeners, these swallowed sufentanil exhibited extremely high variability in both the amount of drug absorbed (AUC) and absorption pharmacokinetics ( _Cmax , _Tmax ), as shown in Table 7. These data support the conclusion that the bioadhesive sublingual formulations of the present invention adhere tightly to the sublingual cavity, immobilizing it, thereby preventing oral uptake and avoiding the high variability in plasma levels typically associated with drug absorption via the GI route.

Additional studies evaluating other drugs, such as formulated fentanyl and alfentanil, were conducted in beagle dogs and are described in more detail in Examples 5 and 6 below. These studies support the conclusion that various drugs with high bioavailability can be effectively delivered sublingually. Fentanyl was formulated into moderately and slowly disintegrating formulations (see Tables 8 and 9). Both formulations achieved high bioavailability (95% and 90%, respectively), significantly higher than any other currently patented oral transmucosal fentanyl formulation. The coefficient of variation in AUC was extremely low (10.5% and 4.5%, respectively). These data support the properties of fentanyl and suggest that these properties are not limited to specific drugs. Compared to the moderately disintegrating form, the slower-disintegrating fentanyl had a slower _Tmax (50 minutes vs. 22 minutes) and a longer half-life (154 minutes vs. 121 minutes). These data further demonstrate the ability to modulate PK based on excipient selection.

Compared to IV alfentanil, alfentanil achieved a bioavailability of 94%, a coefficient of variation in AUC of 5%, a coefficient of variation in _Cmax of 7%, and a coefficient of variation in _Tmax of 28%. The therapeutic time ratio was calculated to be 0.33, compared to a therapeutic time ratio of 0.04 for the IV alfentanil arm of this study (calculated using the published IV elimination half-life of alfentanil in dogs of 104 minutes). Thus, the alfentanil formulation (described in Example 6) yielded an 8-fold improved therapeutic time ratio compared to the IV alfentanil arm. The high bioavailability of this formulation further supports the assertion that its use minimizes drug swallowing.

in vitro test

Bioadhesion

Mucosal adhesion strength is determined by attaching the tablet to the bottom of a hanging platform and measuring the force required to separate the formulation from the porcine buccal mucosal matrix. The mucosal adhesion test system consists of a precision loading unit (GS-500 Tranducertechniques, Temecula, CA) and a hook-shaped attachment. The loading unit generates an analog signal, which is converted into a digital signal by a data acquisition system equipped with an A/D converter (Model 500A, Keithley Metrabyte, Taunton, MA) and an IBM computer. Data are analyzed using ELasyLx software (Keithley Metrabyte). A hanging platform consisting of a glass slide with an 8 cm plastic piston on the top and a circular steel projection (0.5 cm) with a flat surface at the bottom is attached to the loading unit. The tablet mold on the platform surface serves as a lower fixed platform. The mucosal tissue is mounted on the lower platform using screws and clamps. To determine adhesion, the optimal levels of the variables are maintained constant in the subsequent evaluations. Between each measurement, the mucosal surface is cleaned with 4 mL of purified water. Excess water was wiped off with soft tissue and the mucosa was moistened with a known volume of phosphate buffered saline (pH 6.8). The suspended platform with the membrane was lowered and placed over the mucosal surface with a known applied force for the desired time. The detachment force was measured and converted to N/cm ² . The study was performed three times at room temperature (23° C. to 25° C.). The adhesion force and peak detachment force can be used to evaluate the bioadhesive strength of dosage forms containing various formulations of the present invention.

Drug dissolution kinetics

Drug dissolution kinetics is measured by the USP dissolution apparatus of standard, as I type, II type and/or IV type, and for given dosage form, as the dosage form containing very small amounts of active drug, suitable changes are made. Drug release from the dosage form can be carried out using standard analytical methods such as one of UV spectrophotometer, HPLC or LC/MS. Dissolution medium is limited to phosphate, Tris or other with a physiological buffer such as pH of 6.5 to 7.8. Dosage form of the present invention can be prepared to have a dissolution time from 30 seconds to 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours or longer.

Dosage form erosion kinetics

Dosage form erosion can be monitored by visual observation of the disappearance of the dosage form under the tongue over time. Complete dosage form erosion can be evident by visual inspection within a period of about 30 seconds to 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, or longer, depending on the patient and the circumstances in which the dosage is taken, as well as the inherent tablet excipients. It will be appreciated that the composition of the oral transmucosal formulations of the present invention can be adjusted to provide a range of dosages and a range of erosion times to suit specific clinical conditions.

Active pharmaceutical ingredients

The present invention provides small-volume dosage forms or formulations for oral transmucosal delivery containing any drug that can be delivered via the oral transmucosal route and in an amount suitable for a small size. One example of the use of the present invention is an application for pain relief. When the present invention is used to treat pain, they will contain drugs such as opioids or opioid antagonists for the treatment of acute or breakthrough pain. Opioids are effective analgesics and are used worldwide to treat acute and chronic pain of moderate to severe intensity. However, if used improperly, they can also have serious respiratory depressant effects, and they also have the problem of high potential for abuse. In 1998, a total of 36,848 cases of opioid poisoning (pure and mixed preparations) were reported to the U.S. Drug Control Center, of which 1,227 (3.3%) resulted in serious poisoning and 161 (0.4%) resulted in death. The main cause of morbidity and mortality from pure opioid overdose is through respiratory syndrome.

Opioids remain widely used to treat pain and are typically delivered intravenously, orally, epidurally, transdermally, rectally, and intramuscularly.Morphine and its analogs are typically delivered intravenously and are effective for severe, chronic, and acute pain.

Opioids exert their effects through mu opioid receptors, which are located on peripheral nerve terminals, pre- and postsynaptic sites in the spinal cord, brainstem, midbrain, and cerebral cortex in areas involved in perception and pain processing.

The active agents in such formulations may include sufentanil, or a sufentanil congener such as alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil. A preferred embodiment utilizes sufentanil as the active agent. Another preferred embodiment utilizes a sufentanil congener as the active agent. Another preferred embodiment utilizes sufentanil in combination with at least one other agent for treating pain as the active agent. The active agent may also include any opioid or opioid agonist, such as morphine or its derivatives.

The dosage form of the present invention may also contain at least 0.001% by weight of a pharmaceutically active ingredient. The pharmaceutically active drug is typically present in a therapeutically effective amount of about 0.25 μg to 99.9 mg, about 1 μg to 50 mg, or about 1 μg to 10 mg.

Preferably, the dosage form comprises about at least 0.005% to as much as 99.9% by weight, e.g., about 0.25 μg to 99.9 mg, about 1 μg to 50 mg, or about 1 μg to 10 mg, of sufentanil; a sufentanil congener such as alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil.

In alternative embodiments, the formulations of the present invention include a combination of two or more opioid analogs, such as sufentanil plus an opioid such as sufentanil, alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil. Various opioids have different pharmacokinetic profiles and different interactions with μ opioid receptor binding variables and can therefore be used in combination to enhance therapeutic effects.

In an optional embodiment, the pharmaceutical dosage form of the present invention can include at least one opioid drug and one or more other drugs, wherein the other drugs can be opioids or non-opioid drugs. Non-opioid drugs can be added to increase the analgesic effect or help prevent abuse or avoid opioid-induced side effects.

In certain embodiments, the orally administrable formulations of the present invention include an opioid antagonist such as naloxone. In such embodiments, naloxone is provided in an appropriate concentration to inhibit the activity of the opioid component of the formulation upon injection.

The present invention can be used to treat opioid-naive patients and opioid-tolerant patients.

As used herein, the term "opioid naive patient" refers to a patient who has not received repeated administration of an opioid over a period of weeks to months.

As used herein, the term "opioid tolerant patient" refers to a physiological state characterized by a reduction in the effects of opioids (such as analgesia, nausea, or sedation) after continued administration. Opioids are drugs, hormones, or other chemicals that have analgesia, sedation, and/or nausea effects similar to those of substances containing opium or its derivatives. If analgesia tolerance occurs, the dose of the opioid is increased until the same level of analgesia is achieved. This tolerance may not extend to side effects, and side effects may not be well tolerated as the dose is increased.

In certain embodiments, a dosage of the present invention may comprise at least 0.001% by weight of an active ingredient, such as sufentanil, alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil. Preferably, the dosage form comprises from 0.005% to as much as 99.9% by weight of sufentanil, alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil. The percentage of the active ingredient will vary with the size of the dosage form and the properties of the active ingredient, and will be optimized to achieve maximum delivery via the oral mucosal route. In certain aspects of the present invention, more than one active ingredient may be included in a single dosage form.

In various embodiments, the formulations of the present invention generally provide adequate pain relief in all types of patients, including children of all ages, adults, and non-human mammals who are opioid tolerant or naive.The present invention can be used in both inpatient and outpatient settings.

Clinical use of sufentanil is primarily limited to IV administration in the operating room or intensive care unit. There have been some studies on the use of liquid sufentanil formulations for low-dose intranasal administration (Helmers et al., 1989; Jackson K, et al., J Pain Symptom Management 2002: 23(6): 450-452) and case reports of sublingual delivery of liquid sufentanil formulations (Gardner-Nix J., J Pain Symptom Management. 2001 Aug; 22(2): 627-30; Kunz KM, Theisen JA, Schroeder ME, Journal of Pain and Symptom Management, 8: 189-190, 1993). In most of these studies, the minimum dose of sufentanil in adults was 5 mcg in opioid-naive patients. Liquids administered to the oral or nasal mucosa suffer from low bioavailability and potentially short duration of action, as demonstrated in our animal studies (sublingual liquid) and in the literature (Helmers et al., 1989). Gardner-Nix describes only analgesic data (no pharmacokinetic data) produced by liquid sublingual sufentanil and describes analgesic onset of liquid sublingual sufentanil within 6 minutes, but pain relief lasts only about 30 minutes. Prior to this patent application, no pharmacokinetic data were published regarding the use of sublingual sufentanil in any dosage form.

It is known that long-term use of opioids produces physical dependence, potentially addictive behavior, and tolerance. Cells exposed to opioids are capable of internalizing μ-opioid receptors (rapid endocytosis). In vitro μ-opioid receptor endocytosis of a series of clinically used opioids was evaluated in human embryonic kidney (HEK) 293 cells alone or in combination with morphine (Koch et al., MoI Pharmacol. 67(1):12-4, 2005). The results showed that the endocytic potential of opioid drugs was negatively correlated with the ability to cause receptor desensitization and opioid tolerance in HEK 293 cells, and that opioids with high endocytic potency may cause reduced opioid tolerance. The results shown in Koch et al., 2005, indicate that sufentanil is an opioid with high endocytic potency and is therefore less likely to cause opioid tolerance than the related opioid analogs tested.

Sufentanil (N-[(4-(methoxymethyl-1-(2-(2-thienyl)ethyl)-4-piperidinyl)]-N-phenylpropionamide), used as a primary anesthetic to produce smooth general anesthesia during cardiac surgery, epidural administration, and delivery during labor, has been administered experimentally in intranasal and liquid oral formulations. The commercial form of sufentanil for IV delivery is the SUFENTA® formulation. This liquid formulation contains 0.075 mg/ml of sufentanil citrate (equivalent to 0.05 mg of sufentanil base) and 9.0 mg/ml of sodium chloride in water. It has a plasma half-life of 148 minutes, and 80% of an administered dose is excreted within 24 hours.

Fentanyl (N-(1-phenylethyl-4-piperidinyl)-N-phenyl-propionamide) was first synthesized in Belgium in the late 1950s and has an analgesic effect approximately 80 times that of morphine. Fentanyl and its congeners are μ-opioid agonists originally developed as analgesics and are often administered intravenously due to their rapid onset of analgesia. Following intravenous administration, fentanyl's analgesic effect is more rapid and shorter-lasting than that of morphine and meperidine. Following buccal administration via a lozenge (e.g.), lozenge consumption is typically complete within 30 minutes, with a bioavailability of 50%, although the _Tmax of a 200 mg Actiq dosage form is 20 to 120 minutes, indicating erratic GI uptake due to swallowing of 75% of the drug (package insert). More recent publications on Actiq's _Tmax suggest that these initial times favor a more rapid onset of action (the Fenta package insert indicates that Actiq's _Tmax range is extended to 240 minutes). Fentora's PK profile is slightly improved due to 50% drug swallowing, resulting in a bioavailability of 65%. Therefore, a major disadvantage of this therapy is that a significant amount of fentanyl administered in lozenge form is swallowed by the patient. Fentanyl and other opiate agonists have potentially harmful side effects, including respiratory depression, nausea, vomiting, and constipation. Since fentanyl has a GI bioavailability of 30%, this swallowed drug can significantly increase _Cmax plasma levels, destabilizing the _Cmax and _Tmax observed with these products.

Although sufentanil and fentanyl share many similarities as potential μ-opioid receptor agonists, they have been shown to differ in several key ways. Sufentanil has been shown in multiple studies to be 7 to 24 times more potent than fentanyl (package insert; Paix A, et al. Pain, 63:263-69, 1995; Reynolds L, et al., Pain, 110:182-188, 2004). Therefore, sufentanil can be administered in smaller dosage forms, avoiding the increased salivary response associated with larger dosage forms, thereby minimizing swallowing and minimal, variable GI uptake of the drug associated with larger dosage forms.

Additionally, sufentanil has a greater lipid solubility (octanol-water partition coefficient) (1778:1) than fentanyl (816:1). Sufentanil also has greater protein binding (91% to 93%) than fentanyl (80% to 85%) (see the and package insert, respectively). The pKa of sufentanil is 8.01, while that of fentanyl is 8.43 (Paradis et al., Therapeutic Drug Monitoring, 24:768-74, 2002). These differences can affect various pharmacokinetic parameters. For example, sufentanil has been shown to have a more rapid onset of action and a faster recovery time than fentanyl (Sanford et al., Anesthesia and Analgesia, 65:259-66, 1986). This is advantageous for the treatment of acute pain when repeated dosing is possible, such as in the present invention. The use of sufentanil can provide more rapid pain relief due to the ability to titrate the effect and avoid overdosing.

Importantly, sufentanil has been shown to produce an 80,000-fold more potent endocytosis of μ-opioid receptors than fentanyl (Koch et al., Molecular Pharmacology, 67:280-87, 2005). As a result of this receptor internalization, neurons continue to respond more strongly to sufentanil than to fentanyl over time, suggesting that sufentanil may produce less tolerance than fentanyl upon repeated dosing in the clinic.

As mentioned above, sufentanil has been used experimentally in adults in the form of an oral solution (Gardner-Nix J., 2001; Kunz et al., 1993) and as nasal drops (Helmers et al., 1989) and nasal spray (Jackson et al., 2002). Pharmacokinetic data for sublingual sufentanil in any dosage form have not been published.

Sufentanil and congeners of fentanyl may be used in the compositions and methods of the present invention, examples of which include remifentanil and alfentanil.

Remifentanil is a potent fentanyl congener that is metabolized much faster than fentanyl and sufentanil, but may be suitable for treating acute pain when delivered via a sustained-release formulation. The present invention generally contains about 0.25 mcg to 99.9 mg of remifentanil. Dosages for remifentanil formulations may range from 0.1 mcg/kg to 50 mcg/kg over a 20-minute period, for example, for adult and pediatric patients. These doses can be repeated at appropriate intervals, which may be shorter than for fentanyl or sufentanil.

Alfentanil is also a rapidly metabolized, potent fentanyl congener, but may be suitable for use in a sustained-release formulation. The present invention typically contains from about 10 mcg to about 10 mg of alfentanil. Suitable doses of alfentanil can range from 1 mcg/kg to 2000 mcg/kg over 20 minutes, for example, for adults and pediatric patients. These doses can be repeated at appropriate intervals, which can be shorter than those for fentanyl or sufentanil.

Patients with chronic pain conditions who may also experience intermittent exacerbations of pain require urgent use of a rapid-acting burst opioid in addition to their use of a slow-acting, timed-release opioid to treat their baseline chronic pain.

Breakthrough or surgical pain can be exacerbated for short periods of time, as short as 1 or 2 minutes or as long as 30 minutes or longer, so it would be a significant advantage to have an opioid formulation that produces clinically effective plasma levels more rapidly, with a more constant and predictable duration of action, but which also has a limited half-life to avoid opioid overdose for short-duration pain episodes.

Opioids remain the most effective form of analgesia, however, there is a need for improved forms that have minimal side effects and can be delivered in a way that doctors can easily track patient use.

Using current treatment approaches, attempts to control pain are made with a variety of interventions, which generally include: intravenous patient-controlled analgesia (PCA), continuous epidural infusion (CEI), other types of acute pain control, palliative care pain control, and home health patient pain control. These approaches have had varying degrees of success in terms of duration of control, convenience of treatment, and safety with respect to side effects.

Rapid treatment of acute pain is necessary in many different clinical situations, including post-operative recovery, rheumatoid arthritis, back injuries, advanced cancer, etc. For example, patients may suffer from severe pain in the first few days after surgery, followed by mild to moderate pain in the following days.

The most common analgesic used to treat moderate to severe postoperative pain is IV morphine. This is either given to the patient by a nurse on an "as needed" basis via IV injection, or a morphine syringe is typically placed in a PCA pump, and the patient self-administers the opioid by pressing a button with a locking feature. Other opioids, such as hydromorphone and fentanyl, can also be used in this manner.

Treatment of acute pain is also necessary for patients in an outpatient setting. For example, many patients suffer from chronic pain and require weekly or daily opioids to manage their pain. Although they can use long-acting oral or transdermal opioids to treat the level of chronic pain they are experiencing, they often require short-acting, high-strength opioids to treat their severe breakthrough pain.

In extremely suboptimal conditions, "on-site" treatment of acute pain is also necessary. Paramedics and military physicians are often asked to treat severe acute pain in non-sterile conditions, where needles used for IV or IM administration can cause unwanted needle sticks, infection risks, etc. Oral opioid tablets typically require 60 minutes to provide relief, which is too long for some people with severe pain.

In many clinical situations, there is a clear need for formulations that effectively relieve pain in a titratable manner, can be used safely and conveniently, and provide relief for both severe breakthrough pain and intermittent pain for an appropriately long period of time.

The drug delivery dosage forms or formulations of the present invention contain from about 0.25 to about 200 mcg of sufentanil per oral transmucosal delivery dosage form. In an exemplary embodiment of the present invention, each dosage form contains from about 0.25 to about 200 mcg of sufentanil, alone or in combination with one or more other therapeutic agents or drugs.

Those skilled in the art will appreciate that pediatric dosages are at the lower end of the range and adult dosages are at the higher end of the range, depending on body weight, particularly for chronic administration to opioid-tolerant adults. Small-volume oral transmucosal drug delivery dosage forms of sufentanil have not been disclosed.

Exemplary formulations of the present invention for administration to children (pediatric patients) contain from about 0.25 mcg to about 120 mcg of sufentanil per dosage form. For example, formulations of the present invention for administration to children can contain about 0.25, 0.5, 1, 2.5, 4, 5, 6, 8, 10, 15, 20, 40, 60, or 120 mcg of sufentanil for oral transmucosal delivery. Similarly for pediatric patients, exemplary dosage ranges are from at least about 0.02 mcg/kg to about 0.5 mcg/kg, with a preferred range of about 0.05 mcg/kg to about 0.3 mcg/kg.

Exemplary formulations of the present invention for administration to adults contain from about 2.5 mcg/kg to about 200 mcg/kg per dosage form. For example, formulations of the present invention for administration to adults can contain about 2.5, 3, 5, 7.5, 10, 15, 20, 40, 60, 80, 100, 120, 140, 180, or 200 mcg or more of sufentanil per dosage form for oral transmucosal delivery.

In yet another embodiment of the present invention, each dosage form contains from about 2 mcg to about 1500 mcg of fentanyl, alone or in combination with one or more other therapeutic agents or drugs. It will be understood by those skilled in the art that dosages for children are at the lower end of the range and dosages for adults are at the higher end of the range, depending on body weight, particularly for long-term administration to adults who are tolerant to opioids.

Exemplary formulations of the present invention for administration to children (pediatric patients) contain from about 2mcg to about 900mcg of fentanyl per dosage form. For example, dosage forms of the present invention for administration to children can contain about 2, 3.75, 7.5, 18.75, 30, 37.5, 45, 60, 75, 112.5, 150, 300, 450, or 900mcg of fentanyl for oral transmucosal delivery.

Exemplary dosage forms of the present invention for administration to adults contain from about 18.75 mcg/kg to about 1500 mcg of fentanyl per dosage form. For example, dosage forms of the present invention for administration to adults can contain about 18.75, 22.5, 37.5, 56, 75, 112.5, 150, 300, 450, 600, 750, 900, 1050, 1350, or 1500 mcg or more of fentanyl for oral transmucosal delivery.

In an exemplary embodiment, a dosage form for treating pain can contain from about 0.25mcg to about 200mcg of sufentanil, from about 0.5mcg to about 120mcg of sufentanil, from about 2.5mcg to about 40mcg of sufentanil, from about 2.5mcg to about 15.0mcg of sufentanil, from about 2.0mcg to about 1500mcg of fentanyl, from about 20mcg to about 1200mcg of fentanyl, or from about 100mcg to about 900mcg of fentanyl.

The dosage forms of the present invention contain from about 10 mcg to about 10,000 mcg of alfentanil per dosage form for oral transmucosal delivery. It will be understood by those skilled in the art that dosages for children are at the lower end of the range and dosages for adults are at the higher end of the range, depending on body weight, particularly for long-term administration in adults who are tolerant to opioids.

Exemplary dosage forms of the invention for administration to children (pediatric patients) contain from about 10 mcg to about 6300 mcg of alfentanil per dosage form. For example, dosage forms of the invention for administration to children can contain about 10, 25, 50, 130, 210, 280, 310, 420, 600, 780, 1050, 2100, 3000, or 6300 mcg of alfentanil for oral transmucosal delivery.

Exemplary dosage forms of the present invention for administration to adults contain from about 70mcg to about 10,000mcg of alfentanil per dosage form. For example, dosage forms of the present invention for administration to adults can contain about 70, 140, 160, 210, 280, 310, 420, 600, 780, 1050, 2100, 3000, 6300, or 10,000mcg or more of alfentanil for oral transmucosal delivery.

In various exemplary embodiments, dosage forms for treating pain may comprise about 0.25mcg to about 200mcg of sufentanil in combination with about 2mcg to about 1500mcg of fentanyl, or about 0.25mcg to about 200mcg of sufentanil or about 2mcg to about 1500mcg of fentanyl in combination with one or more other drugs.

Following delivery of a sufentanil, alfentanil, or fentanyl-containing dosage form of the present invention to a human subject, plasma levels of sufentanil, alfentanil, or fentanyl reach a maximum between 0 and 60 minutes, 5 and 50 minutes, or 10 and 40 minutes after administration.

Methods for delivering oral transmucosal dosage forms

The delivery device can use various mechanical or electrochemical methods to drive the drug into the oral cavity or sublingual space. For example, once triggered, it can be forced out by a spring, compressed air or other mechanical device.

Method for preparing oral transmucosal dosage form

The present invention also provides a method for preparing a drug-containing oral transmucosal delivery dosage form, such as For example, the method comprises the steps of weighing the drug and one or more bioadhesives, binders, gel-forming excipients, fillers, lubricants or glidants, and factors affecting dissolution time, optionally grinding the powder, dry powder mixing, and tableting by direct compression.

Alternatively, a wet granulation method can be used. Such methods (such as high shear granulation methods) involve mixing the active ingredient and possibly certain excipients in a mixer. The binder can be one of the excipients added in the dry mixed state or dissolved in the fluid used for granulation. The granulation solution or suspension is added to the dry powder in the mixer and mixed until the desired properties are achieved. The granules thus produced will generally have properties suitable for producing a dosage form with sufficient hardness, solubility, content uniformity and other physical characteristics. After the wet granulation step, the product is most often dried and/or ground after drying to bring the majority of the product within the desired size range. Sometimes, the product is dried after wet screening using a device such as a vibrating granulator or grinder. Dry granulation can then be performed to obtain an acceptable size range, first screening with a screening device and then grinding oversized particles. In some cases, a suitable glidant is added to improve the flow properties of the granules; suitable glidants include silicates (such as SILOID and SILOX silicas - trademarks of Grace Davison Products, Aerosil - trademark of Degussa Pharma).

Furthermore, the preparations can be produced by all alternative granulation methods known to the person skilled in the art, such as spray fluidized bed granulation, extrusion and spheronization or fluidized bed rotary granulation.

It will be understood that the formulation will be converted into a dosage form for delivery to an individual using procedures commonly employed by those skilled in the art. The preparation method of the dosage form is optimized to achieve high dosage content uniformity, which is particularly important for potent compounds typically present in a mass ratio of 0.01% to 10% w/w.

Many methods for preparing dosage forms of the present invention are known in the art and can be used to practice the present invention, such as direct compression, wet granulation, and the like.

The dosage form of the present invention may or may not have a coating film on the outer surface of the dosage form.

Utility of the small volume oral transmucosal dosage form of the present invention

The dosage forms of the present invention are used to deliver any drug that can be administered via an oral transmucosal route. The small volume of the oral transmucosal dosage forms of the present invention can provide high bioavailability, low volatility of _Tmax , low volatility of _Cmax , and low volatility of AUC. The present invention also provides controlled dissolution, solubility, and stability, allowing controlled release of the drug over time, thereby extending plasma levels within the therapeutic window.

In an exemplary embodiment described in detail herein, the dosage forms of the present invention can be used to treat individuals suffering from pain, which pain can be associated with any of a variety of identifiable or unidentifiable etiologies. In such embodiments, the dosage forms of the present invention can be used to suppress or alleviate pain. The terms "treatment" or "management" with respect to pain are generally used herein to describe the restoration, suppression, or alleviation of pain to make the individual more comfortable, as determined by, for example, a pain score.

As used herein, the term "acute pain" refers to pain that is typically present for less than 1 month, however, in some cases, pain that is present for up to 3 months may be considered "acute."

As used herein, the term "chronic pain" refers to pain that typically exists for more than one month.

The dosage forms of the present invention are particularly useful for treating acute pain or other conditions "in the field," i.e., under extremely suboptimal conditions. Nursing staff and military physicians are often asked to treat severe acute pain or other wounds or conditions in non-sterile conditions, where needles used for IV or IM administration can introduce unwanted needle sticks, infection risks, and the like. Oral opioid tablets typically require 60 minutes to provide relief, which is too long for some people with severe pain. The dosage forms of the present invention can be used to address this need.

The dosage form of the present invention can also be used in pediatric applications because the comfort and safety of the dosage form will allow young children to easily accept this mode of therapy and will reliably deliver the drug through the mucosa. Specific examples include, but are not limited to, treating acute pain in children when IV methods are not possible or convenient, treating pediatric asthma when children cannot effectively administer the drug by inhalation, treating nausea when children are unable or unwilling to swallow pills, and preoperative sedation when the child is NPO (cannot take orally) or requires a faster onset of action.

The dosage forms of the present invention can also be used in veterinary applications. Specific examples include, but are not limited to, treatment of any acute disease state where IV administration is difficult or inconvenient, such as pain relief, anxiety/tension relief, preoperative sedation, etc.

Oral transmucosal delivery is simple, non-invasive, and can be administered by a caregiver or patient with minimal discomfort. Typically, oral transmucosal delivery of drugs is accomplished with solid dosage forms such as lozenges or tablets, but liquids, sprays, gels, chewing gums, powders, films, etc. may also be used.

For certain drugs, such as those with low bioavailability through the GI tract, such as many lipophilic opioids, oral transmucosal delivery can provide a better delivery route than GI delivery. For drugs such as lipophilic opioids, oral transmucosal delivery has a shorter onset time (i.e., the time from administration to therapeutic effect) than oral GI delivery, and there is a significant improvement in bioavailability.

The following examples are provided to illustrate the invention and are not intended to limit any aspect of the invention as described above or in the claims below.

Example

In vivo pharmacokinetics

The above-described dosage form enables testing of in vivo pharmacokinetics in humans and appropriate animal models following sublingual administration. The following examples demonstrate the ability of the dosage form to achieve consistent absorption profiles of sufentanil citrate following sublingual administration in human volunteers and in awake, alert beagle dogs.

Example 1. Sublingual Sufentanil Administered Sublingually in Adult Human Volunteers

Table 1. Sufentanil formulations used in human clinical studies

A human clinical study was conducted in healthy volunteers. The study involved 12 individuals (6 men and 6 women) using sufentanil (formulations #46 to #48 shown in Table 1) formulated to a volume of 5 μl, a mass of approximately 5.5 mg, and uniformly sized to approximately 3 mm in diameter and 0.8 mm in thickness across all dosage strengths. The sufentanil contained 2.5 μg, 5 μg, or 10 μg of sufentanil base, corresponding to 3.7 μg, 7.5 μg, or 15 μg of sufentanil citrate, respectively. All excipients were inactive and had GRAS ("generally recognized as safe") status. Sufentanil was tested for sublingual use. Researchers administered individual doses directly to the base of the frenulum using blunt-tipped forceps.

Attributes

Bioadhesion

Bioadhesion was measured as previously described using sufentanil clinical trial formulations (#46 to #48) that did not contain the sufentanil component. The bioadhesive force required for removal was measured to be 0.046 ± 0.01 N/ ^cm2 .

In vitro dissolution evaluation

The dissolution of sufentanil citrate from formulations #46, #47, and #48 was evaluated in a Type II in vitro dissolution system as described previously and is shown in Figure 1 below.

For bioavailability calculations, 5 μg of intravenous sufentanil was diluted in 0.9% saline to a total volume of 20 mL and administered as a continuous infusion over 10 minutes via an IV line. Plasma samples were drawn at distal sites using a different IV line. This human trial had a crossover design with a washout period between transitions from higher to lower doses. Subjects took the opioid antagonist naltrexone daily for blockade to avoid opioid-induced side effects.

Day 0: IV sufentanil infusion

○ 17 samples collected:

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

Day 2: 2.5 μg sufentanil sublingually

○ 17 samples:

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

Day 3: 5.0 μg sufentanil sublingually

○ 17 samples:

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

Day 4: 10.0 μg sufentanil sublingually

○ 17 samples:

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

Day 7: Sublingual sufentanil 5.0 μg repeated 4 times at 10-minute intervals

○ 23 samples:

-5.0 (before first administration), 5, 7.5 minutes

10 (immediately before the second dose), 15, 17.5 minutes

20 (immediately before the third dose), 25, 27.5 minutes

30 (immediately before the fourth administration), 35, 40, 45, 50, 55, 60, 90, 120, 150, 190, 350, 510 and 670 minutes.

The total blood volume required for pharmacokinetic sampling is approximately 455 mL.

Sufentanil concentrations in plasma samples were determined using a validated LC-MS/MS sufentanil human plasma assay. This assay demonstrated inter-day precision and accuracy at high, medium, and low quality control sample concentrations.

Erosion time

In all subjects studied, erosion occurred within 10 to 30 minutes. After sublingual placement of each sufentanil dose in the sublingual cavity of 12 healthy volunteers, remarkably consistent pharmacokinetic profiles were obtained for the three doses (Figure 2).

Table 2. PK Analysis of Sublingual Sufentanil Dose Arms (2.5 mcg = #46, 5 mcg = #47, 10 mcg = #48) Using Three Dose Strengths in IV (5 mcg) and Human Clinical Studies

¹ represents the relative time for the drug to reach therapeutic levels (more than 50% of _Cmax ) and is calculated by the following formula: TTR = (time spent exceeding 50% of _Cmax )/(IV terminal elimination half-life). The denominator was obtained from the literature and is 148 minutes for sufentanil in humans.

Example 2. In vivo evaluation of sublingual sufentanil in a canine model

The following Examples 2 to 5 utilize a beagle dog model, and all formulations are evaluated in healthy beagle dogs using a total mass of 5.5 mg of 5 mcg (canine formulation #44, identical to human formulation #47) administered sublingually. Briefly, a single 5 mcg dose was administered sublingually to fully conscious, healthy dogs by direct placement in the sublingual cavity. A total of three dogs were evaluated. Sublingual sufentanil location was visually observed every 5 to 15 minutes after dosing. The PK of sublingual sufentanil was compared with that of IV-administered sufentanil at the same dose level.

All dogs were catheterized via the cephalic vein for blood collection up to 2 hours after dosing. During the entire 2-hour post-dose blood collection period, all dogs were fitted with Elizabethan collars to prevent catheter dislodgement. The catheters were removed after the 2-hour blood collection period. Blood was collected 4, 8, and 24 hours post-dose from the cephalic or other appropriate vein. Approximately 2 ml of blood was collected into pre-chilled tubes containing potassium EDTA at the following time points: pre-dose and approximately 1, 3, 5, 10, 15, 30 minutes, 1, 2, 4, 8, and 24 hours post-dose. Samples were analyzed using an appropriate validated LC/MS/MS method to determine sufentanil citrate in canine plasma. Sufentanil plasma concentrations and pharmacokinetic results are shown in Figure 3 and Table 3.

Table 3. PK Analysis of Sublingual Sufentanil Compared to Intravenous Sufentanil in Beagle Dogs

¹ represents the relative time for the drug to reach therapeutic levels (more than 50% of _Cmax ) and is calculated by the following formula: TTR = (time spent exceeding 50% of _Cmax )/(IV terminal elimination half-life). The denominator was obtained from the literature and is 139 minutes for sufentanil in beagle dogs.

Example 3 : Exemplary Sufentanil Dosage Forms for Controlled Drug Release and In Vivo Pharmacokinetics

For illustrative purposes, a longer-lasting dosage form (Formulation #58) was prepared with sufentanil citrate to evaluate the slower release rate and in vivo pharmacokinetics of the long-acting dosage form. This slower-disintegrating sufentanil, as shown in Table 4, was prepared using direct compression and tested as described above. Erosion times in dogs ranged from 35 to 120 minutes. The bioadhesion of the placebo formulation was tested as described above and was determined to be 0.18 ± 0.08 N/cm ² .

Samples were analyzed for sufentanil in canine plasma using a validated LC/MS/MS method. Pharmacokinetic analysis was performed using a non-compartmental model of absorption. Sufentanil plasma concentrations are shown in Figure 4. Results of the limited PK analysis are shown in Table 5.

Table 4. Slowly disintegrating sufentanil dosage form formulations

Table 5. PK Analysis of Slowly Disintegrating Sublingual Sufentanil in Beagle Dogs

¹ represents the relative time for the drug to reach therapeutic levels (more than 50% of _Cmax ) and is calculated by the following formula: TTR = (time spent exceeding 50% of _Cmax )/(IV terminal elimination half-life). The denominator was obtained from the literature and is 139 minutes for sufentanil in beagle dogs.

Example 4. In vivo study of sublingual sufentanil solution and sufentanil swallowing in a canine model

A. Evaluation of the bioavailability of sufentanil following sublingual administration of a solution dosage form

The bioavailability of sufentanil following sublingual and intravenous administration of a solution was evaluated in a healthy, conscious beagle dog animal model, as shown in Table 6. A commercially available formulation of sufentanil citrate (50 μg/mL) was used in both arms of the study and administered at the same total dose of 5 μg sufentanil base. Intravenous administration (Group 1) was performed by bolus injection (n=3) of 50 μg/mL into the cephalic vein via a sterile needle and syringe of appropriate size. For sublingual administration (Group 2), the test sample was prepared by appropriately diluting 50 μg/mL with 0.9% w/w to the same final dose of 5 μg sufentanil base and administered sublingually twice (n=6 total), with each dose separated by a washout period of at least 2 days. The dose was administered slowly under the tongue near the frenulum via a sterile syringe. Blood samples were collected via the jugular vein or other appropriate vein before and approximately 1, 3, 5, 10, 15, 30 minutes, 1, 2, 4, 8, and 24 hours after administration. At each time point, approximately 2 mL of blood was collected into pre-chilled tubes containing K2EDTA. Samples were centrifuged at 3,000 x g for approximately 10 minutes in a refrigerated centrifuge. Plasma was collected within 20 minutes of centrifugation and frozen at approximately -70°C until analysis. Samples were analyzed using a validated LC/MS/MS method for sufentanil in canine plasma.

Pharmacokinetic analysis was performed using a non-compartmental absorption model. Sufentanil plasma concentrations are shown in Figure 5. The results of the PK analysis are shown in Table 7.

B. Evaluation of Sufentanil Bioavailability Following Oral Ingestion

Following ingestion of 5 mcg of sufentanil (Formulation #44, the same Formulation #47 used in the human studies above), the bioavailability of sufentanil compared to intravenous sufentanil administration was evaluated in a healthy, conscious beagle dog animal model, as described in the previous examples. A single 5 mcg oral dose was administered twice, with each dose separated by a minimum 2-day washout period, for a total of n = 6 (Table 6). A handpiece was placed as far down the throat as possible and rinsed with water to facilitate the swallowing response in the animals. Pharmacokinetic analysis was performed using a non-compartmental model of absorption. Sufentanil plasma concentrations are shown in Figure 5 . The results of the PK analysis are shown in Table 7 .

Table 6. Organization of the test group

a = expressed as free base

b = Groups 1 to 3 will use the same animals with a minimum 2-day washout period between dosing.

c = Animals in Groups 2 and 3 were dosed twice with a minimum washout period of 2 days, total n = 6.

d = Test sample (50 μg/mL) was diluted with normal (0.9% w/w) saline to the desired concentration.

Table 7. PK Analysis of Intravenously Administered Sufentanil Compared to Sublingual Sufentanil Solution and Ingested Sufentanil in Beagle Dogs

¹ represents the relative time for the drug to reach therapeutic levels (more than 50% of _Cmax ) and is calculated by the following formula: TTR = (time spent exceeding 50% of _Cmax )/(IV terminal elimination half-life). The denominator was obtained from the literature and is 139 minutes for sufentanil in beagle dogs.

Example 5. In vivo evaluation of sublingual fentanyl in a canine model

To demonstrate the superiority of the described formulation and its performance compared to other commercial oral transmucosal fentanyl formulations, fentanyl dosage forms were prepared using citrate fentanyl to evaluate the drug release rate and in vivo pharmacokinetics of the various formulations. Moderately disintegrating fentanyl (Formulation #60) and slowly disintegrating fentanyl (Formulation #62), as described in Table 8, were evaluated using formulations prepared by direct compression. Formulation #60 had an erosion time in dogs of 5 to 20 minutes, and the bioadhesion of the placebo formulation was measured to be 0.056 ± 0.01 N/ ^cm² . Formulation #62 had an erosion time in dogs of 35 to 65 minutes, and the bioadhesion of the placebo formulation was measured to be 0.18 ± 0.08 N/ ^cm² .

A commercially available formulation of fentanyl citrate (Sublimaze 50 μg/mL) was used and 70 μg of fentanyl base was administered IV. Intravenous administration was performed by bolus injection of a single dose (n=3) of 50 μg/mL into the cephalic vein via a sterile needle and syringe of appropriate size. For sublingual administration, the drug was administered sublingually (n=3 in each group) by placing it near the frenulum of the tongue with forceps. These parameters are shown in Table 9. Fentanyl plasma concentrations are graphically shown in Figure 6. PK analysis was performed using a non-compartmental absorption model. The results of the PK analysis are shown in Table 10. Blood sampling and storage were performed according to the conditions described previously; sample analysis was performed using a validated LC/MS/MS method for analyzing fentanyl in canine plasma.

Table 8. Exemplary Fentanyl Dosage Forms

Table 9. Fentanyl administration parameters in beagle dogs

^a is expressed as the free base.

Table 10. PK Analysis of Moderately Disintegrating (Formulation #60) and Slowly Disintegrating (Formulation #62) Fentanyl Compared to Intravenous Fentanyl Administration

¹ represents the relative time for the drug to reach therapeutic levels (more than 50% of _Cmax ) and is calculated by the following formula: TTR = (time spent exceeding 50% of _Cmax )/(IV terminal elimination half-life). The denominator was obtained from the literature and is 244 minutes for fentanyl in beagle dogs.

Example 6 : In vivo evaluation of sublingual alfentanil hydrochloride in a canine model

For purposes of illustration of other drug applications, another dosage form was prepared with alfentanil hydrochloride to demonstrate the ability of the dosage forms described herein to effectively improve the PK of alfentanil compared to the IV route of administration. The composition of the moderately disintegrating formulation is described in Table 11. The erosion time of Formulation #63 in dogs was 20 minutes, and the bioadhesion of the placebo formulation was determined to be 0.056 ± 0.01 N/cm ² .

The dosing parameters for this study are shown in Table 12. Alfentanil plasma concentrations are shown in Figure 7. PK analysis was performed using a non-compartmental absorption model. The results of the PK analysis are shown in Table 13. Plasma sampling and storage followed the conditions described previously; samples were analyzed using a validated LC/MS/MS method for alfentanil in canine plasma.

Table 11. Exemplary Alfentanil Dosage Forms

Table 12. Dosing parameters of sublingual alfentanil and intravenous solution in beagle dogs

a = expressed as free base.

b = Groups 1 and 2 used the same animals with a minimum 2-day washout period between dosing. Table 13. PK analysis of sublingual alfentanil versus intravenous alfentanil in beagle dogs

¹ represents the relative time for the drug to reach therapeutic levels (more than 50% of _Cmax ) and is calculated by the following formula: TTR = (time spent exceeding 50% of _Cmax )/(IV terminal elimination half-life). The denominator was obtained from the literature and is 104 minutes in beagle dogs.

Claims (7)

1. A small-volume dosage form for oral mucosal administration to an individual, comprising sufentanil and a bioadhesive material, wherein the dosage form has a mass of less than 30 mg and a volume of less than 30 μl, and wherein the sufentanil is 2.5 micrograms (mcg) to 100 micrograms (mcg). 2. The dosage form of claim 1, wherein the sufentanil is provided in the form of sufentanil citrate. 3. The dosage form of claim 1, wherein a single oral transmucosa administration of the dosage form to the individual results in a fluctuation coefficient of less than 40% for _Tmax . 4. The dosage form of claim 1, wherein a single oral transmucosal administration of the dosage form to the individual results in the absorption of at least 55% of the total amount of drug in the dosage form via the oral transmucosal route. 5. The dosage form of claim 1, wherein a single oral transmucosa administration of the dosage form to the individual results in an erosion time ranging from 30 seconds to 30 minutes. 6. The dosage form of claim 1, wherein a single oral transmucosal administration of the dosage form to the individual results in the absorption of at least 55% of the total amount of drug in the dosage form via the oral transmucosal route, and the fluctuation coefficient of _Tmax is less than 40%. 7. Use of the dosage form according to any one of claims 1-6 in the preparation of a medicament for treating an individual suffering from pain.