CN106727271B - Small volume oral transmucosal dosage form - Google Patents

Abstract

Provides a small volume oral transmucosal dosage form or containing a predetermined amount of a pharmaceutically active agent

Exemplary applications include the use ofThe drug is administered to treat acute pain, post-operative pain, or breakthrough pain.

Description

Small volume oral transmucosal dosage form

This application is a divisional application of the 200780007142.9 chinese patent application entitled "low volume oral transmucosal dosage form" filed on month 01, 08, 2007.

Cross reference to other applications

This application claims priority from U.S. provisional application No. 60/756,937, filed on 6.1.2006, the disclosure of which is incorporated herein by reference in its entirety.

Technical Field

The invention provides what is referred to herein as

Small volume oral transmucosal drug delivery dosage forms of various sizes and features and methods of use thereof.

Background

Currently, the standard therapeutic regimen for oral administration for the treatment of many disease states is significantly limited by both efficacy and toxicity. The route of administration, formulation and dosage control contribute to these limitations, among other factors.

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

The development of drugs and new and improved dosage forms based on various routes of administration for the treatment of many medical conditions such as pain is ongoing. There remains a need to develop safer pharmaceutical dosage forms that do not have the effect level fluctuations seen with drugs in currently commercially available dosage forms. Currently available treatment regimens for pain are often ineffective in providing adequate or stable therapeutic benefit to the patient due to slow onset, instability, and difficulty in controlling the dosage, such that the medical condition is not effectively treated.

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 pharmaceutical combinations of active compounds such as fentanyl and its analogs in combination with a foaming agent that acts as a penetration enhancer to affect the penetration 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 having at least one pharmaceutically active agent adhered to the surface of carrier particles by bioadhesion and/or mucoadhesion promoting agents. U.S. patent No. 6,759,059 discloses compositions and methods for sublingual administration of fentanyl or a pharmaceutically acceptable salt thereof using tablets of about 100mg in size.

U.S. patent nos. 5,800,832 and 6,159,498 (taposky et al) and U.S. patent publication nos. 20030194420 and 20050013845 disclose water-soluble, biodegradable drug delivery devices, such as a two-layer thin film disc having an adhesive layer adhered to a mucosal surface and a backing layer, 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.) disclose the delivery of analgesics via the inhalation route by methods comprising: a) heating a thin layer of analgesic drug on a solid support to form a vapor; and b) flowing air through the heated vapor to produce aerosol particles.

U.S. patent No. 6,252,981 (Zhang et al) discloses oral transmucosal drug delivery as an alternative to systemic drug delivery formulations and methods of oral transmucosal drug delivery. The invention provides pharmaceutical formulations comprising a solid medicament in a solid solution with a co-solvent in solid form, and producing a solid solution. The solid solution formulations may also be combined with buffers and other excipients as needed to aid in the manufacture, storage, administration, and delivery of the drug through the oral mucosal tissues. The formulation can be used with a variety of oral transmucosal delivery dosage forms, such as tablets, lozenges, lollipops, chewing gums, and buccal or mucosal patches. See also Zhang et al,Clin Pharmacokinet.2002；41(9)：661-80。

many transmucosal dosage forms for the treatment of pain are currently in clinical development, examples including buccal morphine and fentanyl sprays (Generex Biotechnology) and oral fast dissolving fentanyl tablets for sublingual administration (Rapinyl)^TM(ii) a Endo Pharmaceuticals). Two of the currently commercially available transmucosal fentanyl formulations are the fentanyl buccal tablets (FENTORA)^TM(ii) a Cephalon) and oral transmucosal form of fentanyl citrate administered as lollipop

(Cephalon), both of which are used only to treat breakthrough cancer pain in patients who are already receiving and are resistant to opioid therapy for the persistent cancer pain they are experiencing.

Although various oral drug delivery systems and dosage forms have been described for the treatment of various medical conditions and disease states, there remains a need for improved dosage forms, formulations, and treatment regimens for the treatment of such medical conditions and disease states, e.g., the treatment of acute and breakthrough pain.

High bioavailability is critical for effective treatment with various drugs, including opioids, because higher doses must be packaged in commercial dosage forms to counter the generally lower bioavailability. For example, oxymorphone

Is 10% and therefore for oral tablets, nine times more drug must be encapsulated than the equivalent IV dosage form. A particular problem is drug systems where a large amount of residual drug remains after complete use of the drug. Examples are low-efficiency drug delivery systems (transdermal) IonSys^TMThis system requires that three times more drug amount be packaged in a transdermal patch than the amount delivered to the patient during routine use at the most. These inefficient systems, whether tablets or patches for oral administration, can be easily abused by intravenous injection of the drug and obtaining full bioavailability of the excess drug. If a given dosage form administered by the intended route of administration provides near complete bioavailability, thatDrug abuse by intravenous injection does not provide increased bioavailability and thus such dosage forms may mitigate drug abuse and migration.

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

Summary of The Invention

The present invention provides oral transmucosal drug delivery dosage forms comprising small volumes or

Compositions and methods of

Contains a predetermined unit dose of a pharmaceutically active amount of a self-administrable drug while providing a therapeutic effect and a predictable and safe pharmacokinetic profile.

The small size of (a) and its placement in the sublingual cavity enable transmucosal absorption of potent lipophilic molecules and minimize salivary responses 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 gastrointestinal route, which is variable and in which significant drug metabolism occurs in the stomach and intestine.

According to the invention

Has bioadhesive properties and is capable of adhering to oral mucosa, such as sublingual and buccal membranes. Such that

May be of the hydrogel-forming or erosion type.

According to the invention

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

According to the invention

May be used for oral transmucosal administration of any drug that can be absorbed via the transmucosal route and that undergoes GI and first pass metabolism and therefore can benefit from such dosage forms.

In one aspect of the inventionComprises 0.25 μ g to 99.9mg, 1 μ g to 50mg, or 1 μ g to 10mg of the drug.

In one aspect, the present 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 compositions comprising opioid drugs

The opioid amount is 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, e.g., about 2.5, 5, 10, or 15 micrograms of sufentanil, about 10mcg to 10mg of alfentanil,about 2 to 1500 meg of fentanyl, about 50 to 1500 meg of fentanyl, about 200 to 1500 meg of fentanyl, about 0.25 to 99.9mg of lofentanyl, about 0.25 to 99.9mg of carfentanyl, about 0.25 to 99.9mg of remifentanil, about 0.25 to 99.9mg of trefentanil, about 0.25 to 99.9mg of mirfentanyl.

Designed to be self-administered by an individual or without a device, wherein

Is selected from the group consisting of a disc shape having a flat, concave or convex surface, an ellipsoid shape, a sphere shape and a polygon shape having three or more edges and a flat, concave or convex surface.

According to the 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.

Oral transmucosal administration of the invention to a subject in a single or repeated doseThe bioavailability of the post-drug is greater than 65%, greater than 75%, greater than 85%, greater than 90%, or greater than 94%.

According to the invention

Also by C after a single oral transmucosal administration to a subject_maxHas a coefficient of variation of less than 30% or 40%, an AUC coefficient of variation of less than 30% or 40%, and T_maxHas a coefficient of variation of less than 40%, a plasma half-life of from about 30 minutes to about 4 hours, and a treatment time ratio of greater than 0.07 or from about 0.5 to about 2.0.

The amount of drug in (a) that is 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 invention also provides methods of treating a subject by administering the compounds described herein

Methods of treating individuals exhibiting symptomatic medical conditions that enable the drug to effectively treat the symptomatic medical condition.

In one embodiment, the symptomatic medical condition is pain, e.g., acute pain, breakthrough pain, or post-operative pain, and

comprising an opioid such as sufentanil or an analog thereof.

Brief Description of Drawings

FIG. 1 is sufentanil for the human clinical study described in example 1

Graphical representation of in vitro dissolution kinetics of formulations #46 to # 48.

Figure 2 is an intravenous administration or sublingual single dose administration of three different strengths of sufentanil in healthy human volunteers (n-12)

Graphical representation of the plasma concentration of postsufentanil.

FIG. 3 is a sublingual administration of sufentanil compared to an intravenous administration of sufentanil (n ═ 3) in a healthy, conscious beagle dog model

Graphical representation of post-sufentanil plasma concentration for formulation #44 (equivalent to human #47 formulation; n-3). Error bars represent Standard Error (SEM) around the mean.

FIG. 4 is a schematic representation of sublingual administration of slowly disintegrating sufentanil in a healthy, conscious beagle model

Graphical representation of sufentanil plasma concentration after formulation #58 (n-3).

Figure 5 is a sublingual administration of a solution of sufentanil (n ═ 6) or oral ingestion of sufentanil in a healthy, conscious beagle dog model compared to intravenous administration of sufentanil (n ═ 3)

Graphical representation of post sufentanil plasma concentrations (n-6). Error bars represent ± Standard Error (SEM) around the mean.

FIG. 6 is a graph of moderately disintegrating fentanyl administered sublingually as compared to intravenous fentanyl (n-3) administration in a healthy, conscious beagle dog model

Formulation #60(n ═ 2) and slowly disintegrating fentanyl

Graphical representation of fentanyl plasma concentration after formulation #62 (n-3). Error bars represent ± Standard Error (SEM) around the mean.

Figure 7 is a sublingual alfentanil administration compared to an intravenous alfentanil administration (n-3) in a healthy, conscious beagle dog model

Graphical representation of post (n-2) alfentanil plasma concentrations. Error bars represent ± Standard Error (SEM) around the mean.

Detailed Description

The present invention provides oral transmucosal dosage forms or

It provides high bioavailability, low T_maxVolatility, low C_maxVolatility and low AUC volatility. According to the invention

Also provides controlled dissolution, solubility and stability, resulting in controlled release of the drug over time, resulting in prolonged plasma levels within the therapeutic window.

The invention is based on small solid oral transmucosal dosage forms or

Certain embodiments thereof adhere to the oral mucosa during drug delivery. Transmucosal dosage forms minimize the salivary response and thus minimize the delivery of the drug to the Gastrointestinal (GI) tract, allowing the majority of the drug to be delivered across the oral mucosa.

The following disclosure describes what constitutes the invention

The preparation is prepared. The invention is not limited to the particular dosage forms and methodologies or medical conditions described herein, as these may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present 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, the meaning of "pharmaceutical formulation (a drug delivery)" includes a plurality of such formulations and "drug delivery device (a drug delivery device)" includes various systems comprising pharmaceutical formulations as well as devices for containing, storing and delivering such formulations.

Unless defined otherwise, 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 the compositions and methodologies that are described in the publications that might be used in connection with the invention. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

Definition of

As used hereinRelates to small volume dosage forms having a volume of about 0 μ l (microliter) to about 100 μ l and a mass of about 0mg (milligram) to about 100 mg. According to the inventionMay or may not have bioadhesive properties and is a dissolvable drug-containing dosage form that may have hydrogel-forming or eroding sheet properties.

The term "formulation" or "pharmaceutical formulation" or "dosage form" as used herein refers to a physical entity (physical entity) containing at least one therapeutic agent or drug for delivery to a subject. The physical entity may 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", "pharmacologically active agent", and the like are used interchangeably herein and generally refer to any substance that alters the physiology of an animal. According to the invention

Can be used to deliver any drug that can be administered via the oral transmucosal route, through small dimensions

I.e., 0.25 μ g to 99.9mg, 1 μ g to 50mg, or 1 μ g to 10mg, the amount administered can vary.

To the invention

The term "drug" as used herein means any "drug", "active", "drug" or "therapeutically active" agent that can be effectively administered via the oral transmucosal route.

The term "drug" as applied to the treatment of pain (analgesia) includes sufentanil, sufentanil analogs such as alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil or mirfentanil, as well as dosage forms containing one or more therapeutic compounds. The use of "drug" or the phrase "sufentanil or congener" is not intended to be limited to the use of, or to dosage forms containing, only one of these selected opioids. Furthermore, reference to sufentanil alone or to a selected sufentanil congener, for example "fentanil", is to be understood as merely an example of a drug suitable for delivery according to the method of the invention and not as a limitation in any way. It is also to be understood that a dosage form of the present invention may comprise more than one therapeutic agent, where exemplary combinations of therapeutic agents include combinations of two or more opioid analogs, for example sufentanil plus an opioid such as alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil or mirfentanil, or an opiate such as morphine and codeine, semi-synthetic opioids such as heroin and oxycodone, or a fully synthetic opioid such as pethidine or methadone whose structure is not related to the opioid base, or any other drug that may be administered in combination.

The term "congener" as used herein refers to one of a plurality of variations or configurations of a common chemical structure.

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

The term "mucosal membrane" generally refers to any mucous-wrapped biological membrane in the body. Absorption via the oral mucosa is of particular concern. Thus, buccal, sublingual, gingival and palatal absorption are especially contemplated by the present invention. In a preferred embodiment, the penetration enhancer of the invention is used to promote absorption through these oral tissues, i.e. the gingiva and the palate, which are most similar to the skin in terms of their cellular structure.

The term "transmucosal" delivery of a drug or the like is meant to encompass all forms of delivery across or through a mucosal membrane. In particular, "oral transmucosal" delivery of a drug includes delivery through any tissue of the mouth, pharynx, larynx, trachea or upper gastrointestinal tract, including especially sublingual, gingival and palatal mucosal tissues.

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

The oral dosage form is typically a "sublingual dosage form", although other oral transmucosal routes may be used in some cases. The present invention relies on such dosage forms for sustained delivery of drugs across the oral mucosa.

The term "oral transmucosal drug delivery" as used herein refers to dosage forms in which drug delivery occurs substantially via a transmucosal route, not via swallowing, and then 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 via placement of the dosage form in the sublingual cavity.

As used herein, "sublingual" means literally "under the tongue," and refers to a method of administering a substance orally in a manner such that the substance is rapidly absorbed through the blood vessels under the tongue, rather than through 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 the therapeutic substance takes place rapidly, allowing direct access to the systemic circulation and thus enabling a rapid onset of action, while avoiding all complications of oral administration.

The term "hydrogel-forming formulation" as used herein means a substantially water-free solid formulation capable of absorbing an aqueous solution such as water when in contact with bodily fluids, particularly in the oral mucosa, in a manner such that it swells while retaining the 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 over time, which occurs primarily by diffusion.

The term "T" as used herein_max"means the point in time at which the maximum plasma concentration is observed.

The term "C" as used herein_max"means the maximum plasma concentration observed.

The term "AUC" as used herein means "area under the curve" in a plot of plasma concentration of a drug versus time. AUC is usually given for zero to infinite time intervals, however, it is clear to the patient that plasma drug concentrations cannot be measured "to infinity", so the AUC is estimated from a limited number of concentration measurements using mathematical approximations. In a practical sense, AUC (from zero to infinity) represents the total amount of drug absorbed by the body, regardless of the rate of absorption. This is useful in attempting to determine whether two formulations of the same dosage will deliver the same dosage to the body. The AUC of the transmucosal dosage form compared to the AUC for the same dose given intravenously was taken as the basis for measuring bioavailability.

The term "F" as used herein means "percent bioavailability" and denotes the fraction of drug absorbed from a test substance as compared to when the same drug is administered intravenously. It is the AUC of the measured substance after delivery via the intended route_∞Relative to AUC after intravenous administration of the same drug_∞And (4) calculating. It is calculated from the following equation: AUC [% ]_∞(test substance)/AUC_∞(intravenous route/substance). This is an important term that establishes the relative fraction of drug absorbed via the measured pathway (or substance) relative to the maximum possible amount available via the intravenous route.

The term "treatment time ratio" or "TTR" means the drug to treatMean time to onset of therapeutic levels, defined as the time at which the drug plasma concentration remains above C corrected for elimination half-life of the drug_maxAnd it is calculated by the following formula: TTR ═ C (over C)_maxTime of 50%/(final intravenous elimination half-life of drug). The latter term is derived from literature data on the drug of interest in the appropriate species.

The term "disintegration" as used herein means the physical process by which a tablet disintegrates 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 eventually into fine and large particles, or erosion from the outside inwards until the tablet disappears.

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

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

Alternatively, such a "swell ratio" may 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 expansion ratio (SR) can be defined based on the specific time of exposure to water and is expressed as a ratio or percentage, e.g., SR expressed as a percentage (volume of tablet after exposure-volume of tablet before exposure)/(volume of tablet before exposure) × 100. When the radial dimensions of such experiments are well controlled, the same expansion ratio can be defined in terms of variable dimensions such as thickness, as SR expressed as a percentage (thickness of tablet after exposure-thickness of tablet before exposure)/(thickness of tablet before exposure) x 100.

The term "bioadhesive" as used herein refers to adhesion to a biological surface, more generally including a mucosal membrane.

The term "therapeutically effective amount" means an amount of a therapeutic agent effective to promote a desired therapeutic effect, such as pain relief, or a rate (e.g., amount over time) at which the therapeutic agent is delivered. 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 tolerance of the individual, the drug and/or pharmaceutical formulation to be administered (e.g., the efficacy of the therapeutic agent (drug), the concentration of the drug in the formulation, etc.), and a variety of other factors as understood by one of ordinary skill in the art.

"sustained drug delivery" refers to the release or administration of a drug from a source (e.g., a pharmaceutical formulation) over an extended period of time, e.g., over 1 minute or more. Continuous drug delivery is in fact opposed to 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 and held on the surface without the application of an external force. Adhesion is not intended to imply a particular degree of adhesion or bonding, nor is it intended to imply any degree of permanence.

The term "active agent" or "activity" may be used interchangeably herein 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 the skin is not blocked or isolated from air contact when using a patch device, a fixed reservoir, an application chamber, a tape, a bandage, adhesive plaster, etc., which remains on the skin at the application site for an extended period of time.

The term "mucosal reservoir" (mucosal-depot) is used herein in its broadest sense to refer to a reservoir or deposit of an active agent in or immediately beneath a mucosal membrane.

The expression "mucoadhesion" as used herein refers to adhesion to mucous-covered mucous membranes, such as the oral mucosa, and is used herein interchangeably with the term "bioadhesive" for adhesion to any biological surface.

The term "drug delivery device" is used herein interchangeably with the term "dispersion device" and refers to a dispersion packageIncluding formulations further described herein, such as those of the present inventionThe device of (1) an oral transmucosal dosage form.

Oral transmucosal drug delivery dosage form

The present invention provides oral transmucosal dosage forms or

Which enables a reduced salivary response compared to other oral dosage forms, thereby increasing the rate of absorption 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 means of drug delivery.

Oral dosage forms or

Typically in a "sublingual dosage form", although other oral transmucosal routes may be used in some cases. The present invention relies on such oral dosage forms for sustained delivery of drugs through the oral mucosa. The dosage form is a substantially homogeneous composition comprising one or more active ingredients and may comprise one or more mucoadhesive agents (also referred to herein as "bioadhesives") that provide adhesion to the oral mucosa of the patient, one or more binders that provide adhesion to 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 sublingual mucosa is more permeable to drugs than other mucosal areas such as the buccal mucosa, making uptake more rapid (Shojaei AH, et al. buccal mucosa as a route of systemic drug delivery: review.) Journal of pharmacy and Pharmaceutical sciences.1: 15-30, 1998).

According to the invention

Allowing a greater percentage (and amount) of the drug to be delivered via the oral mucosa than traditional oral dosage forms or oral transmucosal dosage forms for clinical use, with a corresponding reduction in delivery via the gastrointestinal tract.

The preferred site of oral transmucosal drug delivery is the sublingual area, but in certain embodiments it may be advantageous for the dosage form to be located within the cheek or to adhere to the top of the oral cavity or to the gums.

The dosage forms of the present invention are suitable for oral transmucosal (e.g., sublingual) delivery of drugs and have dissolution times of 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 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 particular therapeutic indication. Examples of uses of the drug delivery dosage forms of the present invention for the treatment of pain are provided herein, however, the present inventionCan be used to treat any of a number of disease states and diseases and is not limited to any particular drug or patient population. Thus, the invention is intended for administration

Can be used for administration to the pediatric and adult populations and for treatment of human and non-human mammals.

When using the invention

To treat pain, the present invention can be used to administer drugs to pediatric and adult populations and to treat human and non-human mammals and humans who are opioid-tolerant and who are first to receive opioidsAnd (4) clustering.

Characteristics of the dosage form

In one embodiment, the dosage form of the invention is either

Are 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 invention is

Has no biological adhesiveness.

The invention

A volume of about 0 μ l (milliliters) to about 100 μ l, a mass of about 0mg (milligrams) to about 100mg, and a thickness of about 0.1mm to about 10.0mm, e.g., about 0.5mm to about 3.0 mm; and a diameter of about 1.0mm to about 30.0mm, about 1.0mm to about 10.0mm, for example about 3.0 mm.

More particularly, the invention

Is selected from the group consisting of less than 100mg, less than 90mg, less than 80mg, less than 70mg, less than 60mg, less than 50mg, less than 40mg, less than 30mg, less than 20mg and less than 10 mg.

According to the invention

The volume of (D) may also be selected from less than 100. mu.l, less than 90. mu.l, less than 80. mu.l, less than 70. mu.l, less than 60. mu.l, less than 50. mu.l, less than 40. mu.l, less than 30. mu.l, less than 20. mu.l and less than 10. mu.l.

Shape of: according to the invention

Dosage formsSubstantially may have a match with the description herein

Any shape of the parameter of the dimension. Exemplary shapes are selected from the group consisting of a disk shape having a flat, concave, or convex surface, an ellipsoid shape, a sphere shape, and a polygon shape having three or more edges and a flat, concave, or convex surface.

The shape may be symmetrical or asymmetrical and have features or geometries that enable controlled, convenient or easy storage, processing, packaging or administration.

Oral and GI intake: in general, the inventionGreater than 30%, greater than 50%, greater than 75%, or greater than 95% to 99% of the drug is taken up via the oral mucosa.

In some embodiments of the present invention, the substrate is,suitable for delivering 30% or more of the total amount of drug contained in a single drug dosage form to a subject via the oral mucosa. In other embodiments the percentage of the total amount of drug contained in a single dosage form delivered mucosally may be greater than 30% to 40%, 40% to 50%, 60% to 70%, 70% to 80%, 80% to 90% and preferably greater than 95%. In exemplary embodiments, at least 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% of the total amount of drug contained in a single pharmaceutical 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 provide a significant improvement over existing methods of drug delivery.

Reduced salivary response: according to the invention

The pharmaceutical dosage form is designed and adapted to reduce salivary response, reduce the amount of drug swallowed, and thereby deliver large amounts of drug to an individual via the oral mucosa. According to the inventionAlso provided are improved dissolution profiles for oral transmucosal dosage forms, efficient drug delivery through the oral mucosa, and stable plasma concentrations within the therapeutic window as compared to the aforementioned oral or oral transmucosal dosage forms.

Time of erosion: the dosage form of the present invention is designed to provide a maximum delivered erosion rate through the oral cavity, typically by placing the dosage form in a sublingual location. According to the invention

The erosion time of sublingual administration of (a) is typically 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 typically designed to achieve drug dissolution times of 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, depending on the patient and the situation of administration and the inherent pharmacokinetics of the drug. It will be appreciated that the composition of the oral transmucosal formulation of the present invention can be adjusted to provide a range of doses and a range of dissolution times to suit a particular clinical situation.

Preparation: the pharmaceutical dosage forms of the invention for oral transmucosal delivery may be solid or non-solid. In a preferred embodiment, the dosage form is in a solid state that converts to 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 form of the present invention is a substantially homogeneous preparation comprising from 0.01% to 99% w/w of the active ingredient (medicament, pharmaceutical product, etc.) and further containing one or more of: mucoadhesives (also referred to herein as "bioadhesives") that provide adhesion to the patient's oral mucosa; one or more binding agents that provide excipient binding 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 modulators; 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.

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

Dosage forms of the invention for oral transmucosal drug delivery may include at least one bioadhesive agent (mucoadhesive agent) or a mixture of bioadhesive agents in order to promote adhesion to the oral mucosa during drug delivery. Furthermore, the bioadhesive or mucoadhesive may also be effective in controlling the erosion time of the dosage form and/or the dissolution kinetics of the drug over time when the dosage form is wetted by saliva. In addition, certain mucoadhesives exemplified herein may also be used as binders in formulations to provide the necessary binding to the dosage form.

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

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

The dosage forms of the present invention for oral transmucosal drug delivery also include a binder or a mixture of two or more binders that facilitate incorporation of the excipients into a single dosage form. Exemplary binders are selected from cellulose derivatives (e.g., methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, etc.), polyacrylates (e.g., carbopol, polycarbophil, etc.), povidone (all grades), Polyox of any molecular weight or grade with or without irradiation, starch, polyvinylpyrrolidone (PVP), Avicel, and the like.

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 also include 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 of ethylene glycol units, block copolymers 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 tradenames of Union Carbide), hydroxypropyl methylcellulose (HPMC) of all molecular weights and grades (e.g., Metolose 90SH50000, Metolose 90SH30000, both tradenames of Shin-Etsu chemicals), poloxamers (e.g., Lutrol F-68, Lutrol F-127, F-105, etc., both tradenames of BASF chemicals, fapol chemicals, Poloxamer (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 crosslinked polyacrylic acid-based polymers and combinations thereof, biodegradable polymers such as polylactic acid, polyglycolic acid, and any combination thereof by physical mixing or crosslinking. In embodiments, the hydrogel component may be crosslinked. The amount of the hydrogel-forming excipient is typically from 0.1% to 70% w/w, preferably from 1% to 50% w/w or most preferably from 1% to 30% w/w.

The dosage form for oral transmucosal drug delivery of the present invention may further comprise at least one controlled release modulator that is a substance that: when the dosage form is hydrated, the substance will preferentially adhere to the drug molecules and thereby reduce the rate of diffusion of the drug from the oral dosage form. Such excipients may also reduce the rate at which the formulation takes up water and thereby enable more prolonged drug dissolution and release from the tablet. In one embodiment, such controlled release modulators are capable of molecularly binding with the active agent via a physical (and thus reversible) interaction, thereby increasing the effective molecular weight of the active agent and thus further modulating its penetration (diffusion) characteristics through the epithelium and basement membrane of the sublingual mucosa. Such binding is practically reversible and does not involve any chemical modification of the active agent and therefore does not have any effect on its pharmacological effect. In another preferred embodiment, such controlled release modulators may form a discontinuous structure upon hydration, which may spontaneously entrap the active agent and thus further prolong its action. Exemplary controlled release modulators are selected from the group consisting of lipids, phospholipids, sterols, surfactants, polymers, and salts. The excipients generally chosen are lipophilic and are capable of forming complexes naturally with hydrophobic or lipophilic drugs. The degree of association of the release modifier and drug can be varied by varying the ratio of modifier to drug in the formulation. Furthermore, such interactions may be suitably enhanced by suitably combining the release modifier with the active agent during the manufacturing process. Alternatively, the controlled release modulator may be a synthetic or biopolymer charged polymer with a net positive or negative charge and which is capable of binding the active agent via electrostatic interaction to modulate its diffusion through the tablet and/or its osmotic kinetics through the mucosal surface. Like the other compounds described above, such interactions are reversible and do not involve permanent chemical bonds with the active agent.

The amount of controlled release regulator may typically be 0 to 80% w/w, preferably 1 to 20% w/w, most preferably 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), calcium hydrogen phosphate dehydrate, sucrose, or mixtures thereof. The amount of filler is generally from 20% to 99% w/w, preferably from 40% to 80% w/w.

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

The formulations may also contain flavoring or sweetening agents 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 against chemical or physical degradation. Such degradation reactions may include oxidation, hydrolysis, aggregation, deamidation, and the like. Suitable excipients that stabilize the drug may include antioxidants, anti-hydrolysis agents, aggregation blockers, and the like. Antioxidants may include BHT, BHA, vitamins, citric acid, EDTA, and the like. Aggregation blockers may include surfactants, amino acids, and the like.

The formulation may also contain surfactants to increase tablet moisture, especially when faster release kinetics are desired, which may result in faster initiation of film adhesion. Such surfactants should be present in an amount of 0.01% to 3% by weight of the composition. Exemplary surfactants are selected from ionic (sodium lauryl sulfate, etc.), nonionic such as polysorbates (tween and span surfactant series), bile salts (such as sodium taurocholate, sodium taurodeoxycholate, sodium deoxycholate, sodium glycocholate, etc.), various alkyl glycosides and mixtures thereof.

The dosage form of the present invention may also contain one or more excipients that may affect tablet disintegration kinetics and drug release from the tablet thereby affecting pharmacokinetics. Such additives are disintegrants, such as those known to those skilled in the art, and may be selected from starches, carboxymethylcellulose-type or crosslinked polyvinylpyrrolidones (e.g. crospovidone, PVP-XL), alginates, cellulose-based disintegrants (e.g. purified cellulose, methylcellulose, croscarmellose sodium (Ac-Di-Sol) and carboxymethylcellulose), microcrystalline celluloses such as (Avicel), ion exchange resins (e.g. ambrellite IPR 88), gums (e.g. agar, locust bean, karaya, pectin and tragacanth), guar gum, karaya, chitin and chitosan, chicina, gellan gum, psyllium ovata husk, polacrilin potassium (tulion), and the like³³⁹) Disintegrants for gas evolution (such as citric and tartaric acid with sodium bicarbonate, sodium carbonate, potassium bicarbonate or calcium carbonate), sodium starch glycolate (such as Explotab and Primogel). The addition of such additives helps the dosage form to rapidly break or disintegrate into smaller particles with a faster dissolution rate than if the disintegrant was not present. An additional benefit of incorporating such bioadhesive containing additives described herein into the dosage forms of the present invention is that the smaller drug-containing particles formed upon disintegration have better bioadhesive properties due to the greatly increased surface area in contact with the oral mucosa. In addition, the increased surface area may further enhance the rapid release of the active substanceThe drug is absorbed quickly and reaches the required therapeutic level in the whole body. However, as mentioned above, such disintegrants are used at low levels in solid dosage forms, typically 1% to 20% w/w of the total weight of the dosage unit.

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 acid, poly (dl-lactide-co-glycolide) (PLGA), poly (lactic acid) (PLA), poly (glycolic acid) (PGA), polyorthoesters, proteins, and polysaccharides.

The dosage forms of the present invention for oromucosal 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 may be chemically modified to significantly improve its pharmacokinetics in plasma. This can be achieved, for example, by conjugation with polyethylene glycol (PEG), including site-specific pegylation. Pegylation can improve drug performance by optimizing pharmacokinetics reducing immunogenicity and dosing frequency.

According to the invention

Provided in a plurality of dosage forms which maintain controlled dissolution of the invention in the oral cavity

According to the nature and quantity of the active ingredient. Thus, 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. According to the invention

Also has high bioavailability and T_maxLow fluctuation of (C)_maxLow fluctuation of AUC, and low fluctuation of AUC.

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

Hydrogel formation in the dosage form of the present invention occurs in the presence of certain excipients capable of forming hydrogels, which are capable of absorbing water and forming gels. Such excipients include all grades of Polyox, polyethylene glycol (all grades), PEG-based copolymers whether homopolymers or heteropolymers (e.g., poloxamers, etc.), dextran, HPMC, starch, and the like, as detailed above. Further, any combination of such excipients may contribute to hydrogel formation upon contact with body fluids. In addition, the combination of such hydrogel-forming excipients with excipients that aid in the non-formation of a gel (i.e., do not have such swelling capacity), such as carbopol, certain celluloses, etc., can result in the formation of a hydrogel structure, albeit with modified properties.

Another aspect of the present invention provides a dosage form referred to herein as an "eroding" dosage form. 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 the gel of the hydrogel-type formulation 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 form is exposed to the moisture in the sublingual cavity, the tablet surface hydrates and erodes; subsequent layers become hydrated and erode, causing a continued reduction in tablet size.

Such erodible dosage forms are generally characterized by the absence of a hydrogel-forming excipient. However, it is understood that the weight to weight percent (w/w) composition of the various components of the dosage form can affect the erosion mechanism. For example, small amounts of particular hydrogel-forming excipients do not cause hydrogel formation, and thus, certain hydrogel-forming excipients can be included in eroding formulations without altering their disintegration mechanism upon erosion. It is the combination of excipients and their weight percentage composition that enables the hydrogel to swell and maintain the structural matrix after contact with an aqueous solution. In other words, in general, inclusion of a hydrogel-forming excipient in a given formulation does not necessarily result in "swelling" of the dosage form, as is typical for hydrogel formulations. The hydrogel-forming dosage form expands to at least 110% of its original volume upon contact with an aqueous fluid.

Pharmacokinetics (PK)

Compared to the oral transmucosal dosage forms currently available, in which most of the drug is taken via the GI routeThe transmucosal drug uptake of (a) allows for more consistent drug delivery between each dosage form and each patient.

The dosage form of the present invention is designed to function effectively in the unique environment of the oral cavity such that limited amounts of fluid, relatively short time for drug dissolution, and pH levels in the oral cavity do not adversely affect absorption of the drug. The formulations are also designed to improve the dissolution, solubility and stability of the pharmaceutical dosage form. Advantages of the present invention include the ability to provide higher levels of drug absorption via the oral transmucosal route and a constant dose-response time, such that the present formulation significantly improves the treatment of acute or breakthrough pain.

The oral transmucosal formulations of the present invention are designed to avoid high peak plasma levels of intravenous dosage forms by utilizing the sublingual mucosa and by independently controlling tablet disintegration (or erosion) as well as 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 of a given amount of active agent, allowing the patient to accurately titrate the amount of drug delivered and appropriately adjust that amount in a safe and effective manner.

The advantage of the controlled release oral transmucosal dosage form of the present invention is that it has a more constant bioavailability and is able to maintain plasma drug concentrations over a targeted therapeutic window for a longer period of time with significantly less variability than currently available dosage forms, whether solid or IV dosage forms. The high peak plasma levels typically observed for IV dosage forms will be in the course of administering the invention

And then attenuated, which can be characterized by controlled release of the drug over a period of 1 to 60 minutes or more. Furthermore, since the drug continues to enter the blood stream orally during the period of tablet dissolution or longer, a rapid drop in plasma levels is avoided, providing plasma pharmacokinetics with a prolonged plateau as compared to the IV route of administration. In addition, the dosage forms of the present invention can improve therapeutic safety by minimizing potentially harmful side effects due to the relative reduction of peaks and troughs in plasma pharmacokinetics that compromise therapeutic safety and are typical of currently available dosage forms.

Advantages of solid sublingual dosage forms over various liquid dosage forms for sublingual or intranasal administration of opioids include the controlled local release of the solid dosage form and the avoidance of swallowing of the liquid drug via the nasal or buccal cavity. Published pharmacokinetic data for human intranasal sufentanil liquid administration (15mcg) indicate a bioavailability of 78% (Helmers et. company of intravenous and intranasal sufentanil absorption and sedation comparison.) Canadian Journal of Anaesthesia 36: 494 497, 1989). Bioavailability was 40% for sublingual sufentanil liquid administration (5mcg) in beagle dogs (see example 4 below). The aforementioned bioavailability data are lower than for sufentanil in human volunteers with the present invention

Is administered sublingually to achieve a mean bioavailability of 91% (see example 1 below).

Due to the small size, can be repeatedly used

Is placed in sublingual cavity for a period of time. The small size minimizes saliva production and physical discomfort, which allows repeated titrations over days to weeks to months. Due to the lipophilic nature of the sublingual cavity, this route also allows for slower release into the plasma for certain drugs, probably because of the use of 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 sublingually comfortably, allowing sufficient and slow disintegration of the drug dosage form to avoid the immediate and subsequent significant decline in peak plasma levels seen in prior art formulations, as described in U.S. patent No. 6,759,059 (Rapinyl), in which fentanyl is administered via a tablet containing 400mcg of fentanyl, which results in a peak plasma level of 2.5ng/ml, followed by an immediate decline in plasma levels. Fentora (fentanyl buccal tablet) also presents no plateau but a steep slope up to C_maxFollowed by a rapid decrease in plasma levels (Fentora package insert).

Evaluation of

Test (2)

Sublingual in humans and animals made in support of the present invention and described in the following description and examples 1 to 6

Prior to human and animal studies, the inventors were unaware 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 body study

Human clinical studies were performed with healthy volunteers. In example 1 belowDetailed description the study was carried out with 12 subjects (6 men and 6 women) using sublingual sufentanil with 2.5. mu.g, 5. mu.g or 10. mu.g sufentanil base (corresponding to 3.7. mu.g, 7.5. mu.g or 15. mu.g sufentanil citrate, respectively)

The process is carried out. All excipients were inactive and had a GRAS ("generally recognized as safe") status.

Sufentanil intended for sublingual useCompared to IV sufentanil administered by continuous infusion through an IV tube over 10 minutes. Plasma samples were drawn from different IV tubes at a remote location. Analysis confirmed good daytime precision and accuracy at high, medium and low quality control sample concentrations.

In all individuals, the study

Erode away over a period of 10 to 30 minutes. Sufentanil was placed sublingually in each sublingual cavity of 12 healthy volunteersAfter that, a very consistent pharmacokinetic profile was obtained (see figure 2 and table 2). The bioavailability for a single administration of all three doses averaged 91% compared to IV administration, which is far superior to the percentage measured by Actiq and fentra for commercially available transmucosal formulations of fentanyl (47% and 65% -fentra package insert, respectively). Although this high bioavailability may be caused by a number of factors, it is likely due to

The lack of saliva due to the small size significantly limits the swallowing of the drug and avoids the low bioavailability often seen with drug absorption via the GI pathway. The packaging instructions of Fentora and Actiq state that, respectively, at least 50% and 75% of the drug dose is swallowed via saliva,and the bioavailability is higher than that of the invention

Low. For clinical trials

Volume was approximately 5 microliters (mass 5.5mg) accounting for only a small fraction of the Actiq and Fentora lozenge sizes. The canine study described in example 4 and those discussed above showed that the GI bioavailability of sufentanil was very low (12%), therefore, if sufentanil were used

Wherein the drug is administered via the oral transmucosal route, this data supports the conclusion that greater than 75% of the drug is absorbed transmucosally. Therefore, the swallowed drug is less than 25%, which is much lower than the proportion of Fentora and Actiq swallowed.

Importantly, this high bioavailability is also associated with a high degree of consistency in the overall drug delivered to the patient. For example, 10mcg sufentanil

The total plasma drug area under the curve (AUC 0-infinity) of 0.0705 ± 0.0194hr ng/ml (mean ± Standard Deviation (SD)). The SD was only 27.5% of the total AUC. Coefficient of Variation (CV) is a term describing the SD percent of the mean. The coefficient of fluctuation for the Fentora AUC was 45% and the ActiqAUC was 41% (Fentora Package insert). Thus, the total dose delivered to the patient/subject is not only for sufentanil

More bioavailable and more consistent from patient to patient.

Sufentanil sublingual on uniformity of initial drug plasma levels after administration

Also has advantages. With 10mcg sufentanil

Obtained C_maxIt was 27.5. + -. 7.7 pg/ml. Thus, C_maxHas a coefficient of variation of only 28%. C of Fentora and Actiq_maxThere is a problem of fluctuation in GI drug intake. Fentora C_max1.02. + -. 0.42ng/ml, so C_maxHas a coefficient of variation of 41%. The coefficient of variation for the various doses of Fentora ranged from 41% to 56% (package insert). C of Actiq_maxThe reported value of the coefficient of variation is 33% (Fentora package insert).

In addition to better bioavailability and consistency of plasma concentration, C is reached_maxTime (also referred to as T)_max) This is important because of the rapid and consistent onset of pain relief in the treatment of acute pain. Sufentanil

10mcg of T_maxIs 40.8 + -13.2 minutes (range 19.8 to 60 minutes). Mean T of Fentora_maxThe reported value was 46.8, ranging from 20 to 240 minutes. T of Actiq_maxIs 90.8 minutes and ranges from 35 to 240 minutes (Fentora package insert). Thus sufentanil

The analgesic effect of (1) has significantly improved consistency of onset compared to Fentora and Actiq, with the slowest onset of T_maxThe reduction is 400%.

In the treatment of acute pain, especially acute breakthrough pain, it is important that the half-life of the drug is consistent and short. 10mcg sufentanil

Has a plasma elimination half-life of 1.71 + -0.4 hours, which makes the drug titratable for various levels of pain. If the breakthrough pain event lasts more than 1.5 hours, the patient may take another doseFor the lowest dose, plasma elimination half-lives of Actiq and fentra were 3.2 hours and 2.63 hours, respectively. For higher doses, the half-life of these drugs is substantially increased, limiting the titratability of these drugs.

While still under development, published data allows us to combine the sufentanil provided herein

The pharmacokinetic data were compared with that of the fentanyl sublingual fast dissolving lozenge, Rapinyl. As previously mentioned, sufentanil according to the invention

The observed bioavailability averages 91%, and the bioavailability of the disclosed Rapinyl is about 70% (Bredenberg, New Concepts in Administration of drugs in Tablet Form, Acta Universal Upsaliensis, Uppsala, 2003). Rapinyl has a coefficient of variation in AUC (0-infinity) ranging from 25% to 42% depending on the dose, for 10mcg of sufentanil

Our value was 27.5%. Our high bioavailability may indicate sufentanil regardless of the dose

There will be consistent AUC low volatility, but not for Rapinyl. In fact, for all three doses of sufentanil

The mean of the AUC fluctuation coefficients we measured was 28.6%, indicating that this low fluctuation is dose independent.

C of Rapinyl_maxThe coefficient of variation is 34% to 58% depending on the dose. As shown by the data presented herein, 10mcg sufentanil

Dosage of C_maxVariation was only 28%, all three dose strengths (2, 5 and 10mcg)

Average C of_maxThe coefficient of variation was 29.4%, indicating the minimum variability in relation to dose. Similarly, T of Rapinyl_maxThe coefficient of variation was 43% to 54% depending on the dose, and for our sufentanil

This T for all three dose intensities_maxThe average value of the coefficient of variation is only 29%. Compared with any one of the three comparative drugs, sufentanil is used

This consistent onset achieved allows for a safer re-dosing window, since elevated plasma levels are contained within a shorter period of time.

In addition, for Fentora and Actiq, Rapinyl bissufentanil

Has a longer plasma elimination half-life (5.4 to 6.3 hours, depending on the dose). Sufentanil after a single oral transmucosal administration in humans

The plasma elimination half-life of (2) was 1.5 to 2 hours (table 2), which allows for more titratability and avoids overdosing. Those skilled in the art will appreciate that the exemplary embodiments described herein

Can be modified to produce a given half-life

The composition and relative amounts of excipients in the formulation of (a). At this pointSublingual sufentanil passage was also tested in a human studyThe ability to titrate to higher plasma levels with repeated doses. Repeated administration of 5mcg every 10 minutes

Up to four doses, a bioavailability of 96% was obtained, indicating that higher plasma levels can be achieved by repeated dosing while still maintaining high bioavailability. Whether for the treatment of post-operative pain or cancer breakthrough pain, it is important to be able to titrate effectively to the level of pain relief to the individual itself.

Plateau plasma levels

Sublingual sufentanilAnother aspect of the PK profile generated is a plateau, which allows for a period of consistent plasma levels, important for both safety and efficacy. Sufentanil, whether administered as a bolus IV infusion (see animal studies of examples 2 to 6) or 10 minutes IV infusion in our human study (example 1 and figure 2)

The PK profile of (a) is significantly safer. Fast and high C_maxPlasma levels are avoided. It is advantageous to avoid these high peaks in the PK profile if the opioid is able to produce respiratory depression.

Confirmation of administration

An important mathematical ratio for the plateau extension of the plasma levels of sufentanil measured afterwards is a Cmax of more than 50%_maxThe time taken divided by the known IV terminal elimination half-life of the drug:

because of the detection limits of the assay at these low doses, the IV elimination half-life of 5mcg sufentanil in our human study is 71.4 minutes, the published IV elimination half-life of sufentanil at much higher doses is 148 minutes due to the rapid α -elimination mechanism and longer β -elimination period of detection of redistribution via metabolism and secretion_maxThe average time spent was 110, 111 and 106 minutes respectively. Thus, these specific sufentanil

The treatment time ratio of (a) is 0.72 to 0.75. Due to the fact that

The formulation of (a) may be varied,

will decrease or increase, the treatment time ratio for sufentanil may be about 0.2 to 2.0. In fact, for sufentanil, the treatment time ratio for any oral transmucosal dosage form of the present invention can be within this range, and we therefore do not limit this scope of sought protection to a specific one

An attribute.

This treatment time rate is a short onset of action by avoiding high peak plasma C_maxHow successfully the concentrations are formulated gives a measure of increased treatment time and increased safety. For example, by comparison, the sufentanil IV arm of the human study showed a treatment time ratio of 10min/148min to 0.067. Thus, this low ratio of IV arms is a measure of the high peak produced by IV infusion of sufentanilAnd that this formulation did not produce a significant plateau. The treatment time ratios listed in table 1 (doses used in human studies) for the sufentanil formulations were 10 times higher than for the IV sufentanil, indicating that these are

The treatment platform curve of the formulation is prolonged.

Animal research

A series of studies were conducted in a conscious, alert Beagle dog (Beagle dog) to more fully administer various drugs and drugs

Formulation elucidationThe performance of (c). Will use the invention

Oral transmucosal drug delivery with liquid sublingual administration and swallowing

Making comparisons for evaluationVarious attributes of (2). The results support our proposition that the small bioadhesive property of the present invention

Compared to other oral transmucosal dosage forms, including instilled liquids, tolerates well under the tongue (as demonstrated by use in conscious dogs) and enables higher bioavailability and more consistent pharmacokinetic data.

As described more fully in example 2 below, a first beagle study was conducted to compare sublingual 5mcg sufentanil

And IV sufentanil. A total of 3 beagle dogs were studied and the results are shown in figure 3 and listed in table 3. Sublingual sufentanil compared to IV

The bioavailability of (a) is 75%. Thus, similar to the human data, this bioavailability data for dogs confirms

Superior properties to larger dosage forms. Furthermore, similar to the human data, the coefficient of fluctuation of AUC was lower than that of other commercial transmucosal dosage forms, 14%. Sublingual sufentanil

The treatment time ratio of (a) was 0.28 and the treatment time ratio of IV sufentanil was 0.05 (139 minutes IV elimination half-life using sufentanil published dogs). Thus, similar to humans, 5mcg in Table 1

The resulting treatment time ratio was much higher (5.6 times) compared to IV sufentanil in dogs.

Additional studies confirmed the changes

Effect of the formulation on the pharmacokinetic profile. Example 3 below explains this study in more detail. By lengthening

Erosion time of (2), plasma half-life disintegration from the medium33 minutes (in example 2) was extended to 205 minutes. Slowly disintegrating

The treatment time ratio of (2) is prolonged from 0.28To 1.13. This study demonstrates that varying drug PK based on selection of excipients

Flexibility of the system. Due to the fact that

Is small so that its contact time with the sublingual mucosa can be shortened or prolonged without dislodging or generating excessive saliva that would continually wash the medication into the GI tract, such flexibility being possible.

Another study was conducted in beagle dogs to evaluate sublingual clearance

The advantages of the dosage form over sublingual liquid administration. Example 4 below describes this study in more detail. The results indicate that delivery of sufentanil (5mcg) into the sublingual space despite instillation in a liquid dosage form results in T_maxVery quickly, but with sublingual sufentanil

(75%) the bioavailability is very low (40%) compared to this administration method. This is possible due to the swallowing of liquid drugs. Furthermore, AUC is extremely variable, as indicated by a high fluctuation coefficient (82%). C with this method of administration_maxThe fluctuation coefficient of (2) was also high, and 72%. The treatment time ratio for sublingual instillation of liquid sufentanil was calculated to be 0.06, very similar to the ratio of 0.03 for the IV sufentanil arm of this study. Thus, the curve of such instilled sublingual liquid is not under the tongue

An advantageous treatment platform was observed. These results support the present applicationThe high sublingual bioavailability observed in the claimed bioadhesive formulations is not inherent to the molecule, but rather it isDirect results of the unique design of dosage forms and their formulations.

The strong adhesion in the sublingual cavity minimizes the variability of surface area available for absorption, as is the case with liquid solutions, thereby improving delivery of molecules to the systemic circulation. In addition, due to its unique design and small size,

does not induce significant saliva production, thereby reducing the likelihood of uptake of the released drug. Both factors contribute to a higher and more uniform absorption of the drug from the sublingual cavity.

An additional part of this study in example 4 was swallowed sufentanilThe bioavailability of (4) is determined. Since there are few to no GI bioavailability data in the literature for sufentanil, it is important to further evaluate the low bioavailability of this route of administration in order to further supportDoes not get swallowed and maintains high bioavailability. As shown by PK analysis data in Table 7, from swallowed

The oral bioavailability of sufentanil is low, about 12%. In addition, these are swallowed as predicted from the known irregular GI uptake of fentanyl homologs

The amount of drug Absorbed (AUC) and the absorption pharmacokinetics (C)_max、T_max) The above all had extremely high volatility as shown in Table 7. The conclusion supported by these data is that the bioadhesive sublingual of the invention

Tightly adhering in the sublingual cavity in a manner that makes it immobile, thereby avoiding oral ingestion and avoiding the high variability of plasma levels that is common when drugs are absorbed via the GI route.

Other drugs were also evaluated in beagle dogs as formulated to

Additional studies of fentanyl and alfentanil are described in more detail in examples 5 and 6 below. These studies support

Conclusion that various drugs with high bioavailability could be effectively sublingually delivered. Fentanyl (fentanyl)

Prepared to moderately and slowly disintegrate

Formulations (see table 8 and table 9). Both formulations gave high bioavailability (95% and 90%, respectively) far higher than any other fentanyl oral transmucosal formulation currently patented. The coefficient of fluctuation of AUC was extremely low (10.5% and 4.5%, respectively). These data support

And that these properties are not limited to a particular drug. Slower disintegrating fentanyl than moderately disintegrating forms

With slower T_max(50 minutes versus 22 minutes) and a longer half-life (154 minutes versus 121 minutes). These data further demonstrate that

The ability to modulate PK based on excipient selection.

Compared to IV alfentanil

The bioavailability obtained was 94%, the coefficient of variation of AUC was 5%, C_maxHas a coefficient of variation of 7%, T_maxHas a coefficient of variation of 28%. The treatment time ratio was calculated to be 0.33, whereas the treatment time ratio for the IV alfentanil arm of this study was 0.04 (calculated with the 104 minute IV elimination half-life of the aphentanil published dog). Thus, alfentanil

The formulation (as described in example 6) produced an improved treatment time ratio of 8 times that of the IV alfentanil arm. The high bioavailability of this formulation is again supported

The use of (a) minimizes the assertion that swallowing of the drug.

In vitro

Test of

Bioadhesive

Mucoadhesive strength was determined by sticking the tablet to the bottom of the hanging platform and measuring the force required to separate the formulation from the porcine buccal mucosal matrix. The mucoadhesion test system consisted of a precision loading unit (GS-500 Tracducertechniques, Temecula, Calif.) and a hook attachment. The loading unit generates an analog signal that is converted to a digital signal by a data acquisition system equipped with an A/D converter (Model 500A, Keithley Metrabyte, Taunton, Mass.) and an IBM computer. Data were analyzed using elassyllx software (Keithley Metrabyte). A suspended platform consisting of a glass plate with a plastic piston (8cm) on top and a round steel projection (0.5cm) with a flat surface on the bottom was adhered to the loading unit. The tablet die of the land surface serves as the lower stationary land. The mucosal tissue is mounted on the lower platform using screw-clamps. For the measurement of the adhesion, the following evaluation was carried outThe optimum level of the variable remains constant. Between each measurement, the mucosal surface was washed with 4mL of purified water. Excess water was wiped off with soft tissue paper and the mucosa was wetted with a known volume of phosphate buffer at pH 6.8. The suspended platform with membrane is lowered and placed over the mucosal surface with known applied forces for the required time. The separating force was measured and converted to N/cm². The study was performed three times at room temperature (23 ℃ to 25 ℃). Adhesion and peak separation can be used to evaluate the bioadhesive strength of dosage forms comprising various formulations of the present invention.

Kinetics of drug dissolution

The kinetics of drug dissolution is determined by standard USP dissolution apparatus, e.g., type I, type II and/or type IV, with appropriate modifications for a given dosage form, e.g., a dosage form containing a very small amount of active agent. Drug release from the dosage form can be performed using one of the standard analytical methods such as UV spectrophotometer, HPLC or LC/MS. The dissolution medium is defined as a physiological buffer such as phosphate, Tris or others at pH 6.5 to 7.8. The dosage form of the present invention may be prepared to have a dissolution time of 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 more.

Kinetics of dosage form erosion

Dosage form erosion can be observed sublingually by visual inspection

The disappearance over time was monitored. Complete dosage form erosion can be evident by visual inspection over 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 more, depending on the patient and environment in which the dosage is taken and 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 doses and a range of erosion times to suit a particular clinical situation.

Pharmaceutical active ingredient

The invention provides a small volume dosage form or

Such that oral transmucosal delivery comprises delivery through the oral transmucosal route and in an amount suitable for small sizeAny of the medicaments of (1). The invention

One example of a use of (a) is pain relief. When the invention is used

When used to treat pain, they will contain drugs such as opioids or opioid antagonists for the treatment of acute or breakthrough pain. Opioids are specific analgesics and are used worldwide to treat moderate to severe intensity of acute and chronic pain. However, they can also have severe respiratory depression if they are improperly used, and they also have the problem of being potentially highly abused. In 1998, a total of 36,848 cases of opioid toxicities (both pure and mixed) were reported to the U.S. drug control center, with 1227 (3.3%) causing severe poisoning and 161 (0.4%) causing death. The primary cause of morbidity and mortality from pure opioid overdose is through respiratory syndrome.

Opioids are still widely used for the treatment of pain and are usually delivered intravenously, orally, epidural, 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 located in the peripheral nerve terminals, presynaptic and postsynaptic in the spinal cord, brainstem, midbrain and cerebral cortex regions involved in perception and pain management.

Such active agents in such formulations may include sufentanil, or sufentanil homologs such as alfentanil, fentanyl, lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil. A preferred embodiment uses sufentanil as the active agent. Another preferred embodiment uses a sufentanil homologue as the active agent. Another preferred embodiment uses sufentanil in combination with at least one additional agent for the treatment of pain as active agents. The active agent may also include any opioid or opioid agonist such as morphine or derivatives thereof.

The dosage form of the present invention may further comprise 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 μ g to 99.9mg, about 1 μ g to 50mg, or about 1 μ g to 10 mg.

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

In alternative embodiments, the formulations of the invention comprise 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. Each opioid drug has a different pharmacokinetic profile and different interaction with mu opioid receptor binding variables and therefore can be used in combination to enhance therapeutic efficacy.

In an alternative embodiment, the pharmaceutical dosage form of the present invention may comprise at least one type of opioid and one or more other drugs, wherein the other drugs may be opioid or non-opioid drugs. Non-opioid drugs may be added to increase analgesic effects or to help deter abuse or avoid opioid-induced side effects.

In certain embodiments, the orally administered formulations of the invention include opioid antagonists such as naloxone. In such embodiments, naloxone is provided at a suitable concentration to inhibit the activity of the opioid component of the formulation upon injection.

The invention can be used to treat patients who first receive opioids and opioid-tolerant patients.

The term "patient who has received an opioid for the first time" as used herein refers to a patient who has not received repeated doses of an opioid over a period of several weeks to several months.

The term "opioid-tolerant patient" as used herein means a physiological state characterized by a reduction in the effects of opioids (e.g., pain loss, nausea or sedation) following sustained administration. Opioids are drugs, hormones or other chemical substances with pain-relieving, sedative and/or nausea effects similar to those of substances containing opioids or their derivatives. If pain deficiency tolerance occurs, the opioid dosage is increased to achieve the same level of pain deficiency. This tolerance may not extend to side effects, and side effects may not be well tolerated with increasing doses.

In certain embodiments, a dose of the 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 active ingredient will vary with the size of the dosage form and the nature of the active ingredient, which is optimized for maximum delivery via the oral mucosal route. In certain aspects of the invention, more than one active ingredient may be included in a single dosage form.

In various embodiments, the formulations of the present invention generally have adequate pain relief in all types of patients including opioid-tolerant or first-received children, adults, and non-human mammals of all ages. The invention can be used for inpatients and outpatients.

Clinical use of sufentanil is primarily limited to IV administration in operating rooms or intensive care units. There have been several studies on the use of liquid sufentanil formulations for low dose intranasal administration (Helmers et al, 1989; Jackson K, et al, J pack Symptom Management 2002: 23 (6): 450-. In most of these studies, the minimum dose of sufentanil in adults was 5mcg in first opioid-receiving 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 liquids) and in the literature (nasal liquid drops) -Helmers et al, 1989). Gardner-Nix describes only the analgesic data (no pharmacokinetic data) generated by liquid sublingual sufentanil and describes the onset of analgesia by liquid sublingual sufentanil occurring within 6 minutes, but the duration of pain relief is maintained for only about 30 minutes. Prior to this patent application, no pharmacokinetic data were disclosed for the use of sublingual sufentanil in any dosage form.

It is known that prolonged use of opioids results in physical dependence, possibly addictive behaviour and tolerance. Cells in contact with opioids are capable of exhibiting mu opioid receptor internalization (rapid endocytosis). In vitro mu-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 indicate that the endocytic potential of the opioid is inversely related to the ability to cause desensitization of the receptor in HEK 293 cells and opioid tolerance, and that an opioid with high endocytic potency may cause decreased opioid tolerance. The results shown in Koch et al, 2005 indicate that sufentanil is an opioid with high endocytic potency and therefore has a low potential to induce opioid tolerance compared to the relevant opioid analogs tested.

Sufentanil (N- [ (4- (methoxymethyl-1- (2- (2-thienyl) ethyl) -4-piperidinyl)]-N-phenylpropionamide) as the main anesthetic agent for epidural administration and delivery during labor in cardiac surgery yielding a smooth general anesthetic effect and has been administered experimentally in intranasal and liquid oral formulations. Sufentanil for IV deliveryIs in the commercial form of SUFENTA

And (4) preparing the preparation. This liquid formulation contained 0.075mg/ml of sufentanil citrate (equivalent to 0.05mg of sufentanil base) and 9.0mg/ml of sodium chloride in water. Its plasma half-life was 148 minutes, with 80% of the administered dose excreted within 24 hours.

Fentanyl (N- (1-phenethyl-4-piperidinyl) -N-phenyl-propionamide) was first synthesized in belgium in the late 50 s of the 20 th century and had an analgesic effect about 80 times that of morphine. Fentanyl and its congeners are mu opioid agonists originally developed as analgesics and are often administered intravenously due to their rapid onset of analgesia. Fentanyl, after intravenous administration, has a faster analgesic effect and a shorter duration than morphine and meperidine. By pastilles (e.g. of the type

) After buccal administration, consumption of the troches is usually complete within 30 minutes, with a bioavailability of 50%, despite the T of the 200mg Actiq dosage form _max20 to 120 minutes, showing unstable GI uptake due to swallowing of 75% of the drug:

package insert). T on Actiq_maxThe more recent publication indicates that these initial times tend to be more rapid onset (Fentora package insert indicates T of Actiq_maxThe range is extended to 240 minutes). The PK profile of fentrora was slightly improved due to swallowing of 50% of the drug, with a bioavailability of 65%. Thus, one major drawback of this therapy is that a large amount of fentanyl administered in the form of a lozenge is swallowed by the patient. Fentanyl and other opioid agonists have potentially harmful side effects including respiratory depression, nausea, vomiting, and constipation. This swallowed drug was able to significantly increase C due to the 30% bioavailability of fentanyl via the GI pathway_maxPlasma levels, such that the C observed with these products_maxAnd T_maxIs unstable.

Albeit relaxedFentanyl and fentanyl share many similarities with potential mu opioid receptor agonists, but have been shown to differ in many key ways. Several studies have shown that sufentanil is 7 to 24 times more potent than fentanyl: (

A package insert; paix A, et al. pain, 63: 263-69, 1995; reynolds L, et al, Pain, 110: 182-188, 2004). Thus, sufentanil can be administered in a smaller dosage form, avoiding the increased salivary response caused by larger dosage forms, thereby minimizing swallowing and minimal, variable GI uptake of the drug associated with the larger dosage forms.

Additionally, sufentanil (1778: 1) has a greater lipid solubility (octanol-water partition coefficient) than fentanyl (816: 1). The protein binding of sufentanil (91% to 93%) was also greater than that of fentanyl (80% to 85%) (see, respectively

And

package insert). Sufentanil has a pKa of 8.01 and fentanyl has a pKa of 8.43 (paramis et al, Therapeutic Drug Monitoring, 24: 768-74, 2002). These differences can affect a variety of pharmacokinetic parameters, for example, sufentanil has shown a more rapid onset of action and a more rapid recovery time than fentanyl (Sanford et al, Anesthesia and Analgesia, 65: 259-66, 1986). This is advantageous for the treatment of acute pain when administered repeatedly, for example in the present invention. The use of sufentanil allows for a faster pain relief due to the ability to titrate the effect and avoids overdosing.

Importantly, sufentanil has been shown to produce 80,000 times more potent mu-opioid receptor endocytosis than fentanil (Koch et al, Molecular Pharmacology, 67: 280-87, 2005). The result of this receptor internalization is that neurons continue to respond more strongly to sufentanil over time than fentanyl, suggesting that sufentanil will be less tolerated than fentanyl upon clinical repeat dosing.

As noted above, sufentanil has been used experimentally in adults in the form of oral liquids (Gardner-Nix J., 2001; Kunz et al, 1993) and as nasal drops (Helmers et al, 1989) and nasal sprays (Jackson et al, 2002). No pharmacokinetic data have been published for sublingual sufentanil for any dosage form.

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

Remifentanil is a potent homolog of fentanyl that metabolizes much faster than fentanyl and sufentanil, but may be suitable for treating acute pain when delivered via a sustained release formulation. According to the invention

Typically containing about 0.25mcg to 99.9mg of remifentanil. The dose range for the remifentanil formulation may include 0.1mcg/kg to 50mcg/kg over a 20 minute period, for example for adult and pediatric patients. These doses may be repeated at appropriate intervals, which may be shorter than fentanyl or sufentanil.

Alfentanil is also a potent fentanyl homologue for rapid metabolism, but may be suitable for use in sustained release formulations. According to the invention

Typically comprising from about 10mcg to about 10mg of alfentanil. A suitable dose of alfentanil may be from 1mcg/kg to 2000mcg/kg in 20 minutes, for example for adult and paediatric patients. These doses may be repeated at appropriate intervals, which may be shorter than fentanyl or sufentanil.

Patients with chronic pain conditions may also experience intermittent exacerbations of their pain, requiring emergency use of a rapidly-acting explosive opioid in addition to their use of a slow-acting timed-release opioid to treat their baseline chronic pain.

Breakthrough pain or surgical pain can be exacerbated on a short term basis, as short as 1 or 2 minutes or as long as 30 minutes or more, thus providing the following opioid formulations with significant advantages: it produces clinically effective, more constant and predictable plasma levels more rapidly, but at the same time has a limited half-life to avoid overdosing of opioid for short-term pain events.

Opioids remain the most effective form of analgesic, however, there is a need for improved forms that minimize side effects and can be provided in a manner that a physician can easily follow the patient's use.

Using current therapeutic approaches, pain management is attempted with a variety of interventional methods, 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 methods have met with varying degrees of success with respect to side effects in terms of duration of control, convenience of treatment and safety.

Acute pain needs to be rapidly treated in a number of different clinical situations including post-operative recovery, rheumatoid arthritis, back injuries, advanced cancer, etc. For example, patients are afflicted with severe pain during the first few days after surgery and with mild to moderate levels of pain during the following days.

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

Treatment of acute pain is also necessary for patients in an outpatient setting. For example, many patients are afflicted with chronic pain and require weekly or daily opioid use to treat their pain. Although they may use long acting oral or transdermal opioids to treat the level of chronic pain they are suffering from, they often require short acting potent opioids to treat their severe breakthrough pain.

Under extremely suboptimal conditions, "on-site" treatment of acute pain is also necessary. Paramedics and military physicians are often required to treat severe acute pain without sterilization, wherein needles used for IV or IM administration can cause undesirable needle stick injuries, 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.

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

The drug delivery dosage forms or formulations of the present invention contain from about 0.25 to about 200mcg of sufentanil per oral transmucosal delivery dosage form. In an exemplary embodiment of the invention, each dosage form contains from about 0.25 to about 200 meg of sufentanil, 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 low end of the range and dosages for adults are at the high end of the range, depending on body weight, particularly when administered chronically to an adult who is opioid tolerant. A small volume oral transmucosal drug delivery dosage form for sufentanil has not been disclosed.

The exemplary formulations of the present invention for pediatric (pediatric patient) administration contain from about 0.25 meg to about 120 meg of sufentanil per dosage form. For example, a formulation of the invention for pediatric administration may contain about 0.25, 0.5, 1, 2.5, 4,5, 6,8, 10, 15, 20, 40, 60, or 120 meg of sufentanil for oral transmucosal delivery. This is also true for pediatric patients, with exemplary dosages ranging from at least about 0.02mcg/kg to about 0.5mcg/kg, and preferably ranging from about 0.05mcg/kg to about 0.3 mcg/kg.

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

In still further embodiments of the invention, each dosage form contains about 2mcg to about 1500mcg of fentanyl, alone or in combination with one or more additional therapeutic agents or drugs. It will be understood by those skilled in the art that dosages for children are at the low end of the range and dosages for adults are at the high end of the range, depending on body weight, particularly when administered chronically to an adult who is opioid tolerant.

The exemplary formulations of the present invention for pediatric (pediatric patient) administration contain about 2mcg to about 900mcg of fentanyl per dosage form. For example, a dosage form of the invention for pediatric administration may 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 invention for adult human administration contain about 18.75mcg/kg to about 1500mcg of fentanyl per dosage form. For example, a dosage form of the invention for administration to an adult human may contain about 18.75, 22.5, 37.5, 56, 75, 112.5, 150, 300, 450, 600, 750, 900, 1050, 1350 or 1500 meg 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 fentanil, from about 20mcg to about 1200mcg of fentanil, or from about 100mcg to about 900mcg of fentanil.

The dosage forms of the invention contain from about 10mcg to about 10000mcg 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 low end of the range and dosages for adults are at the high end of the range, depending on body weight, particularly when administered chronically to an adult who is opioid tolerant.

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

Exemplary dosage forms of the invention for adult human administration contain between about 70mcg and about 10000mcg of alfentanil per dosage form. For example, a dosage form of the invention for administration to an adult human may contain about 70, 140, 160, 210, 280, 310, 420, 600, 780, 1050, 2100, 3000, 6300 or 10000 meg or more of alfentanil for oral transmucosal delivery.

In various exemplary embodiments, a dosage form for treating pain may comprise from about 0.25 meg to about 200 meg of sufentanil in combination with from about 2 meg to about 1500 meg of fentanyl, or from about 0.25 meg to about 200 meg of sufentanil or from about 2 meg to about 1500 meg of fentanyl in combination with one or more additional drugs.

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

Method of delivery of oral transmucosal dosage forms

The device of delivery may use various mechanical or electrochemical methods to deliver

Into the buccal or sublingual space. For example, upon a trigger, the trigger,may be forced out by a spring, compressed air, or other mechanical means.

Process for preparing oral transmucosal dosage forms

The invention also provides medicated oral transmucosal delivery dosage forms such asThe preparation method of (1). For example, the method includes the followingThe method comprises the following steps: the drug and one or more bioadhesives, binders, gel-forming excipients, fillers, lubricants or glidants and factors influencing the dissolution time, possible powder milling, dry powder mixing and direct compression tableting are weighed.

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

In addition, the formulations 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 appreciated that the formulation will be converted into a dosage form for delivery to a subject using procedures commonly used by those skilled in the art. The process of preparation of the dosage form is optimized to achieve high dose content uniformity, which is particularly important for potent compounds that are typically present in a mass ratio of 0.01% to 10% w/w.

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

The inventionIs/are as follows

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

Effect of the Small volume oral transmucosal dosage forms of the invention

The dosage form of the present invention is used to deliver any drug capable of being administered via the oral transmucosal route. Oral transmucosal dosage forms of the invention or

Can provide high bioavailability, T_maxLow fluctuation of (2), C_maxLow volatility and low volatility of AUC. According to the invention

Controlled dissolution, solubility and stability are also provided, allowing for 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 are useful for treating a subject suffering from pain that may be associated with any of a variety of identifiable or unidentifiable etiologies. In such embodiments, the dosage form of the present invention may be used to inhibit or alleviate pain. The terms "treatment" or "treatment" with respect to pain are generally used herein to describe the recovery, suppression or relief of pain to make an individual more comfortable, as determined by, for example, a pain score.

The term "acute pain" as used herein means that pain is generally present for less than 1 month, however, in some cases, the presence of pain for up to 3 months may also be considered "acute".

The term "chronic pain" as used herein refers to pain that is typically present for more than 1 month.

The dosage forms of the invention are particularly useful for treating acute pain or other disease states "on-site", i.e., under extremely poor conditions. Paramedics and military physicians are often required to treat severe acute pain or other wounds or disease states without sterilization, where needles used for IV or IM administration can cause undesirable needle stick injuries, 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 may be used to address this need.

The dosage forms of the invention may also be used in pediatric applications, as the comfort and safety of the dosage forms will allow young children to easily receive this mode of therapy and will reliably deliver the drug transmucosally. Specific examples include, but are not limited to, treatment of pediatric acute pain when IV procedures are not possible or convenient, treatment of pediatric asthma when a child is not able to effectively administer by the inhalation route, treatment of nausea when a child is unable or unwilling to swallow a pill, pre-operative sedation when a child is NPO (unable to take orally) or requires a more rapid onset of action.

The dosage form of the invention may also be used in veterinary applications. Specific examples include, but are not limited to, treatment of any acute disease state where IV administration is not easy or convenient, such as pain relief, anxiety/stress relief, pre-operative sedation, and the like.

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 using solid dosage forms such as lozenges or tablets, but liquids, sprays, gels, chewing gums, powders, films, and the like may also be used.

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

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

Examples

Pharmacokinetics in vivo

As described above

Can be tested in vivo after sublingual administration in humans and suitable animal models. The following examples demonstrate

The ability of the dosage forms to achieve consistent sufentanil citrate absorption profiles after sublingual administration in human volunteers and conscious, alert puppy models.

Example 1.Sublingual sufentanil for sublingual administration in adult human volunteers

TABLE 1 sufentanil used in human clinical studies

Preparation

Human clinical studies were performed with healthy volunteers. The study was conducted with 12 individuals (6 men and 6 women) using sufentanil prepared in a volume of 5 μ l and having a mass of about 5.5mg and all dosage forms tested for strength having a uniform size of about 3mm in diameter and about 0.8mm in thickness

(formulations #46 to #48 shown in Table 1). Sufentanil

Contains 2.5. mu.g, 5. mu.g or 10. mu.g of sufentanil base, corresponding to 3.7. mu.g, 7.5. mu.g or 15. mu.g of sufentanil citrate, respectively. All excipients were inactive and had a GRAS ("generally recognized as safe") status. SufentanilTested for sublingual use. Researchers have placed individual pieces directly on the base of the zonules by placing them with very blunt-tipped forceps

Administering to the individual.

Property (2) of

Bioadhesive

Bioadhesion was measured as described previously with sufentanil clinical test formulations (#46 to #48) without the sufentanil component. Measured and removed

The required bioadhesive force is 0.046 +/-0.01N/cm²。

In vitro dissolution evaluation

Sufentanil citrate self

Dissolution rates of formulations #46, #47 and #48 were evaluated in a type II in vitro dissolution system as previously described and shown in figure 1 below.

For bioavailability calculations, 5 μ g of intravenous sufentanil was diluted to a total volume of 20mL in 0.9% physiological saline and administered as a continuous infusion through an IV tube over 10 minutes. Plasma samples were drawn at the distal location with different IV tubes. This human test is a crossover design with a washout period between the transition from higher to lower doses. The individual is blocked with the opioid antagonist naltrexone on a daily basis to avoid opioid-induced side effects.

● day 0: IV sufentanil infusion

○ collect 17 samples:

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

● day 2: sufentanil 2.5 μ g sublingually

○ 17 parts of sample:

5.0 (administration)

Front), 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 45, 60, 90, 120, 160, 320, 480, and 640 minutes

● day 3: sufentanil 5.0 μ g Sufentanil Sublingual

○ 17 parts of sample:

5.0 (administration)

Front), 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 45, 60, 90, 120, 160, 320, 480, and 640 minutes

● day 4: sufentanil 10.0 μ g sublingually

○ 17 parts of sample:

5.0 (administration)

Front), 2.5, 5, 7.5, 10, 12.5, 15, 20, 30, 45, 60, 90, 120, 160, 320, 480, and 640 minutes

● day 7: sufentanil 5.0 μ g Sufentanil Sublingual

Repeating for 4 times at intervals of 10min

○ 23 samples:

5.0 (first administration)

Before),5. 7.5 minutes

10 (second administration)

First moment), 15, 17.5 minutes

20 (third administration)

First moment), 25, 27.5 minutes

30 (fourth administration)

The first moment), 35, 40, 45, 50, 55, 60, 90, 120, 150, 190, 350, 510, and 670 minutes.

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

The sufentanil concentration in plasma samples was determined using a validated LC-MS/MS sufentanil human plasma assay. This analysis confirmed day precision and accuracy at high, medium and low quality control sample concentrations.

Time of erosion

In all individuals, the study

Erosion takes 10 to 30 minutes. Under the tongue of each sufentanilAfter placement in the sublingual cavity of 12 healthy volunteers, a distinct and consistent pharmacokinetic profile was obtained for the three doses (fig. 2).

TABLE 2 IV (5mcg) and Sublingual sufentanil in human clinical study with three dose strengths

PK analysis of dose arms (2.5mcg ═ 46, 5mcg ═ 47, 10mcg ═ 48)

¹Representing the drug reaching therapeutic levels (above C)_max50%) and is calculated from the following equation: TTR ═ C (over C)_max50% of the time spent)/(IV terminal elimination half-life). The denominator was obtained from the literature and was 148 minutes for sufentanil in humans.

Example 2.Sublingual sufentanil in Canine modelIn vivo evaluation of

The following examples 2 to 5 used a beagle model, and

the preparation (A) was used in a total mass of 5.5mg

Sublingual administration of 5mcg of the above

(canine formulation #44, identical to human formulation # 47) the in vivo Pharmacokinetics (PK) of sufentanil was evaluated in healthy beagle dogs. Briefly, a single 5mcg of the above was placed directly into the sublingual cavity

Sublingual administration was carried out in fully conscious healthy dogs. A total of three dogs were evaluated. After administration, visual observation is carried out every 5 to 15 minutes

In the sublingual cavity. Sublingual sufentanil PK was compared to sufentanil IV-administered PK at the same dose level.

All dogs were catheterized via the cephalic vein for blood collection up to 2 hours after dosing. All dogs were fitted with an elizabeth collar to prevent catheter detachment throughout the 2 hour post-dose blood collection period. The catheter was removed after the 2 hour blood collection was completed. Blood collection at 4, 8 and 24 hours post-dose is collected de novo or other suitable vein. Approximately 2ml of blood was collected into pre-cooling 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 by the appropriate validated LC/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.Sufentanil sublingual compared to intravenous sufentanil in beagle dogs

PK analysis of

¹Representing the drug reaching therapeutic levels (above C)_max50%) and is calculated from the following equation: TTR ═ C (over C)_max50% of the time spent)/(IV terminal elimination half-life). The denominator was obtained from the literature and in beagle dogs for sufentanil was 139 minutes.

Example 3: exemplary sufentanil dosage forms for controlled drug release and in vivo pharmacokinetics

For illustrative purposes, sufentanil citrate was used to prepare formulations of longer duration

Dosage form (formulation #58) was evaluated for the slower release rate of the dosage form and the pharmacokinetics in vivo for the long acting dosage form. This slower disintegrating sufentanil as shown in table 4Prepared by direct compression and tested as described above. The erosion time in dogs ranged from 35 to 120 minutes, and the bioadhesion of placebo formulations was tested as described above and determined to be 0.18 + -0.08N/cm²。

Sample analysis was performed using the validated LC/MS method to analyze sufentanil in canine plasma. Pharmacokinetic analysis was performed using a non-compartmental model of absorption. Sufentanil plasma concentrations are shown in figure 4. The results of the limited PK analysis are shown in table 5.

TABLE 4 Slow disintegrating sufentanilDosage form preparation

TABLE 5 Slow disintegrating Sublingual sufentanil in beagle dogs

PK analysis of

¹Representing the drug reaching therapeutic levels (above C)_max50%) and is calculated from the following equation: TTR ═ C (over C)_max50% of the time spent)/(IV terminal elimination half-life). The denominator was obtained from the literature and in beagle dogs for sufentanil was 139 minutes.

Example 4.Sublingual sufentanil solution and sufentanil in canine modelIn vivo study of swallowing

A.Evaluation of bioavailability of sufentanil following Sublingual administration of solution dosage forms

In the body buildingBioavailability of sufentanil after sublingual and intravenous administration from solutions was evaluated in a healthy, conscious beagle animal model, as shown in table 6. Commercially available formulation using sufentanil citrate in both arms of the study: (

50 μ g/mL) and administered at the same total dose of 5 μ g sufentanil base. Intravenous administration (group 1) single administration by bolus injection into the cephalic vein via a sterile needle and syringe of appropriate size (n ═ 3)

50. mu.g/mL. For sublingual administration (group 2), by appropriate dilution with 0.9% w/w

Test samples were prepared at the same final dose of 50 μ g/mL to 5 μ g sufentanil base and administered sublingually twice (total n ═ 6) with each administration separated by a wash period of at least 2 days. Sublingual administration near the zonule was slow via a sterile syringe. Blood samples were collected via the jugular vein or other suitable vein prior to and approximately 1,3, 5, 10, 15, 30 minutes, 1, 2, 4, 8, and 24 hours after dosing. Approximately 2mL of blood was collected at each time point into pre-cooling tubes containing K2 EDTA. The samples were centrifuged at 3,000Xg for approximately 10 minutes in a refrigerated centrifuge. Plasma was collected within 20 minutes after centrifugation and frozen at approximately-70 ℃ until maintained at the same temperature prior to analysis. Sample analysis was performed using a validated LC/MS method to analyze sufentanil in canine plasma.

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.

B.Oral ingestion Evaluation of bioavailability of post-sufentanil

Uptake of 5mcg sufentanil

(formulation #44, same as formulation #47 used in the above human study) the bioavailability of sufentanil compared to intravenous sufentanil administration was evaluated in a healthy, conscious beagle animal model, as described in the previous examples. Single 5mcg

Two doses were administered orally, each dose being separated by a minimum of 2 days of washout, for a total of n-6 (table 6). Will be provided with

Manually placed as far as possible into the throat and rinsed with water to promote a swallowing response in the animal. 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 test groups

a ═ expressed as the free base

The same animals will be used for groups 1 to 3 with a minimum of 2 days washout between administrations.

Animals of groups 2 and 3 were dosed twice with a minimum of 2 days of washout period, for a total of n 6.

d ═ dilution of test samples with physiological (0.9% w/w) saline: (

50 μ g/mL) to the desired concentration.

TABLE 7 Sufentanil solution and Sufentanil uptake by Sublingual instillation in beagle dogs

PK analysis of comparative intravenously administered sufentanil

¹Representing the drug reaching therapeutic levels (above C)_max50%) and is calculated from the following equation: TTR ═ C (over C)_max50% of the time spent)/(IV terminal elimination half-life). The denominator was obtained from the literature and in beagle dogs for sufentanil was 139 minutes.

Example 5Sublingual fentanyl in canine model

In vivo evaluation of

To prove said

And its superior performance compared to other commercial oral transmucosal fentanyl formulations, the use of fentanyl citrate for the preparation of fentanyl

Dosage forms in order to evaluate the drug release rate and in vivo pharmacokinetics of the various dosage forms. Moderately (formulation #60) and slowly (formulation #62) disintegrating fentanyl

All were evaluated on dosage forms prepared by direct compression as described in table 8. Formulation #60 erodes in dogs from 5 to 20 minutes and the bioadhesion of the placebo formulation was determined to be 0.056 + -0.01N/cm². Formulation #62 erodes in dogs between 35 and 65 minutes and the bioadhesion of the placebo formulation was determined to be 0.18 + -0.08N/cm²。

Commercially available formulations of fentanyl citrate (Sublimaze 50. mu.g/mL) were used and 70. mu.g of fentanyl base was administered IV. Intravenous administration a single administration was given by bolus injection into the cephalic vein via a sterile needle and syringe of appropriate size (n ═ 3)50. mu.g/mL. For sublingual administrationPlacing the sublingual frenulum near the sublingual frenulum with forceps

Sublingual administration (n-3 in each group). These parameters are shown in table 9. The fentanyl plasma concentration is plotted 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 reference was made to the conditions described previously; sample analysis was performed using a validated LC/MS/MS method to analyze fentanyl in canine plasma.

TABLE 8 exemplary fentanyl

Dosage forms

TABLE 9 fentanyl in beagle dogs

Administration parameters of

^aExpressed as the free base.

TABLE 10 moderately disintegrating (formulation #60) and slowly disintegrating (formulation #62) fentanyl compared to intravenous fentanyl administration

PK analysis of

¹Representing the drug reaching therapeutic levels (above C)_max50%) and is calculated from the following equation: TTR ═ C (over C)_max50% of the time spent)/(IV terminal elimination half-life). The denominator was obtained from the literature and for fentanyl was 244 minutes in beagle dogs.

Example 6: sublingual alfentanil hydrochloride in canine models

In vivo evaluation of

For the purpose of explaining other drugs used in

To prepare another with alfentanil hydrochlorideDosage forms in order to demonstrate the ability of the dosage forms described in this application to effectively improve the PK of alfentanil compared to the IV route of administration. Moderate disintegration

The formulation composition of (a) is as 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 + -0.01N/cm²。

The dose parameters for this study are shown in table 12. The 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 were referenced to the conditions described previously; sample analysis was performed using a validated LC/MS method to analyze the plasma of dogs for alfentanil.

TABLE 11 exemplary Acetanide

Dosage forms

TABLE 12 Sublingual Acetanide in beagle dogsAnd the administration parameters of the intravenous solution

a ═ is expressed as the free base.

The same animals were used for groups 1 and 2 with a minimum of 2 days washout between dosing. TABLE 13 Sublingual Acetanide in beagle dogs

PK analysis relative to intravenous alfentanil

¹Representing the drug reaching therapeutic levels (above C)_max50%) and is calculated from the following equation: TTR ═ C (over C)_max50% of the time spent)/(IV terminal elimination half-life). The denominator was obtained from the literature and was 104 minutes in beagle dogs.

Claims (7)

1. A low volume dosage form for oral transmucosal administration to a subject, comprising sufentanil and a bioadhesive material, wherein the dosage form has a mass of less than 30mg and a volume of less than 30 μ Ι, and the sufentanil is from 2.5 micrograms (mcg) to 100 micrograms (mcg).

2. The dosage form according to claim 1, wherein said sufentanil is provided as sufentanil citrate.

3. The dosage form of claim 1, wherein a single oral transmucosal administration of said dosage form to said subject results in T_maxIs less than 40%.

4. The dosage form of claim 1, wherein a single oral transmucosal administration of said dosage form to said subject results in absorption of a drug amount of at least 55% of the total drug amount in said dosage form via the oral transmucosal route.

5. The dosage form of claim 1, wherein a single oral transmucosal administration of said dosage form to said subject results in an erosion time of from 30 seconds to 30 minutes.

6. The dosage form of claim 1, wherein a single oral transmucosal administration of said dosage form to said subject results in absorption of a drug amount of at least 55% of the total drug amount in said dosage form via the oral transmucosal route, and T_maxIs less than 40%.

7. Use of a dosage form according to any of claims 1-6 in the manufacture of a medicament for treating a subject suffering from pain.

Images