EA040771B1 - FILM COMPOSITIONS CONTAINING DEXMEDETOMIDINE AND METHODS FOR THEIR PRODUCTION - Google Patents

Description

Cross-references to related applications

This application claims priority over U.S. Provisional Applications No. 62/690407, filed June 27, 2018; 62/693726, filed July 3, 2018; 62/767422, filed November 14, 2018; 62/787649, filed January 2, 2019; 62/798842, filed January 30, 2019; and 62/849747, filed May 17, 2019, each of which is incorporated herein by reference in its entirety.

The field of technology to which the invention belongs

This document discloses a self-supporting soluble film containing dexmedetomidine or a pharmaceutically acceptable salt thereof. The film is administered orally to treat various conditions, in particular agitation, by transmucosal delivery of the active agent. The film is formulated into a medicament to obtain a rapid onset of action without the significant sedation typically associated with dexmedetomidine administration.

State of the art

On December 17, 1999, the US Food and Drug Administration approved a formulation of dexmedetomidine, PRECEDEX®, formulated as an intravenous solution for continuous infusion, and specified its use as a sedative agent for initially intubated and mechanically ventilated patients, during intensive care treatment. PRECEDEX® was later approved as a sedative agent for non-intubated patients before and/or during surgical and other procedures.

In addition to its use as a sedative, dexmedetomidine also has analgesic and antiarrhythmic properties. However, to date it has not been possible to develop a formulation containing dexmedetomidine for use as an antiarrhythmic agent. For example, PRECEDEX® is not a suitable antiarrhythmic agent for the following reasons: it can currently only be administered to institutionalized patients; difficult is the ability to titrate the dose to the appropriate for a particular patient; self-administration is generally impractical since PRECEDEX® is administered as an injection; and its pronounced sedative properties may be undesirable in many circumstances in the treatment of restless patients.

There continues to be an unmet need for non-addictive antiarrhythmic drugs. A dexmedetomidine-based drug that can be administered alone, eg orally, to provide rapid relief from agitation without significant sedation would be a very valuable addition to agitation treatment options. However, oral administration of dexmedetomidine to provide rapid relief from agitation is challenging. For example, sublingual tablets tend to be swallowed prior to complete dissolution and transmucosal delivery, resulting in wastage of the active substance due to first pass metabolism in the liver. As a result, when using sublingual tablets, therapeutic plasma levels of dexmedetomidine may not be reached. Oral sprays, in particular for sublingual delivery, also have disadvantages such as dose inaccuracy, ingestion of the drug, the need for frequent dosing, non-compliance by the patient with the treatment regimen, and the cost of finished products. In addition, significant cardiovascular side effects have been found to occur in humans treated with dexmedetomidine hydrochloride when administered as a sublingual spray (see International Patent Application Publication No. WO 2010/132882). WO 2010/132882 states that when dexmedetomidine hydrochloride was administered sublingually or administered intravenously, a significant number of subjects experienced post-administration hypotension along with an undesirable high level of sedation. Hypotension was observed with the sublingual dose of 100 µg of dexmedetomidine and to a lesser extent with the 50 µg dose. These and other limitations placed on existing formulations of dexmedetomidine have put a stop to the development of an oral formulation of dexmedetomidine for the treatment of agitation. However, the authors of this application have now unexpectedly found a new oral film composition that can be entered for the treatment of agitation without the above restrictions.

The essence of the invention

Provided herein is a self-supporting dissolving film comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more water soluble polymers, and optionally one or more pharmaceutically acceptable carriers, the film is formulated to release dexmedetomidine, allowing for mucosal absorption of dexmedetomidine to provide effective antiarrhythmic relief to patients. within minutes without concomitant significant sedation.

In one embodiment, the invention provides a pharmaceutical film composition suitable for sublingual administration, comprising or consisting essentially of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, a polymeric component consisting of one or more water-soluble polymers; and optional

- 1 040771 but one or more pharmaceutically acceptable carriers.

In one embodiment, the invention provides film formulations comprising a polymer-based film support (eg, a drug-free polymer matrix film) containing dexmedetomidine or a pharmaceutically acceptable salt thereof on the surface of the support. Dexmedetomidine or a pharmaceutically acceptable salt thereof may be conventionally applied to the surface of a film support as part of a composition also containing a liquid carrier and optionally a polymeric component and/or one or more additional pharmaceutically acceptable carriers (hereinafter referred to as the dexmedetomidine composition).

The dexmedetomidine composition in one aspect of this invention may be applied to the film support as a single drop or multiple drops at one or more specific locations on the support, or alternatively by discontinuous placement (e.g., micro-placement) of the dexmedetomidine composition at discrete locations on a conventional placebo film.

In another embodiment, the invention provides film formulations comprising a polymer-based film substrate (e.g., a drug-free polymer matrix film) on the surface of which the dexmedetomidine composition is stencilled at one or more discrete locations.

In another aspect, the dexmedetomidine composition may be present on the surface of the film substrate after drying as one or more discrete lines. The line(s) may be applied using either a direct placement method or screen application.

In some embodiments, the support is formed into a continuous web of film that can be cut into smaller individual films after placing individual units of the dexmedetomidine composition and drying.

One advantage of such films is the ability to place a high concentration of dexmedetomidine on the surface of a placebo support for rapid transmucosal delivery of dexmedetomidine. Another advantage is that the use of individually shaped doses limits variations in the amount of active ingredient between dosage units. In particular, in the case where the dexmedetomidine composition is screen-printed onto the surface of the film substrate, the advantages include the ability to easily form the dexmedetomidine composition of appropriate thickness on the surface of the film. Another advantage of the placement method includes the ability to include the combination of dexmedetomidine, or a pharmaceutically acceptable salt thereof, and one or more additional active ingredients in a single unit dose, even if the active ingredients would not otherwise be incompatible with each other, by separately placing these active ingredients in separate places on the substrate. Another benefit is the avoidance of production losses associated with traditional dissolving film manufacturing processes. Because the formulations used to make the film typically contain relatively expensive pharmaceuticals, these production losses represent a significant cost.

In a further embodiment, the invention provides film formulations containing dexmedetomidine or a pharmaceutically acceptable salt thereof, located within a polymeric matrix, for example, in which dexmedetomidine or a pharmaceutically acceptable salt thereof is substantially evenly distributed throughout the film.

This invention also provides methods for producing films according to the present invention. In one method, a film is prepared in which dexmedetomidine or a pharmaceutically acceptable salt thereof is applied (eg, substantially evenly distributed) in a polymer film. In another method, a film is prepared in which dexmedetomidine or a pharmaceutically acceptable salt thereof is present on the surface of a polymer-based film substrate.

This document also describes as embodiments of the invention solutions or suspensions containing dexmedetomidine or a pharmaceutically acceptable salt thereof, suitable for placement on the surface of a polymer-based film substrate (ie dexmedetomidine compositions).

The invention also provides methods for treating agitation in humans by administering the films disclosed herein. Various conditions requiring antiagitation therapy can be treated with sublingual administration of the film disclosed herein, including agitation associated with neurodegenerative and neuropsychiatric diseases, particularly in non-hospitalized patients. The treatment provides an effective non-compulsory antiarrhythmic therapy with an adequate safety profile and favorable tolerability, thus reducing the risk of high blood pressure/respiratory depression.

Administration of the film composition of the present invention to a patient suffering from agitation substantially reduces the risk of coercion and injury to the patient and others by preventing worsening and/or limiting the duration and severity of agitation flares. The film compositions of the present invention are particularly useful in the management of cases of acute agitation. They can also be safely administered either in a clinical setting or outside a clinical setting.

- 2 040771

These and other features, advantages and objects of various embodiments will be better understood with reference to the following description of the present invention.

Brief description of graphic materials

In FIG. 1 is a cross-sectional (side) and surface (top) view of an exemplary drug-containing matrix monolithic film disclosed herein.

In FIG. 2 is a cross-sectional (side) and surface (top) view of an exemplary microarray array film disclosed herein.

In FIG. 3 compares the diffusion of the dexmedetomidine film formulations described herein (represented by formulations 1 to 7 and formulation 11 of Example 1 hereinafter) across an oral cell culture membrane compared to the diffusion of PRECEDEX®.

In FIG. 4 shows the mean logarithm of plasma dexmedetomidine concentration versus time for the 10, 20, and 40 μg sublingual film dose levels of dexmedetomidine (semi-log scale). Error bars represent 1 standard deviation.

In FIG. 5A depicts individual dexmedetomidine concentration versus time profiles for all subjects by dose after administration of dexmedetomidine sublingual film (10 μg) on a semi-log scale. Dexmedetomidine sublingual film is shown in example 1, composition 12.

In FIG. 5B depicts individual dexmedetomidine concentration versus time profiles for all subjects by dose after administration of dexmedetomidine sublingual film (20 μg) on a semi-log scale. Dexmedetomidine sublingual film is shown in example 1, composition 12.

In FIG. 5C depicts individual dexmedetomidine concentration versus time profiles for all subjects by dose after administration of dexmedetomidine sublingual film (40 μg) on a semi-log scale. Dexmedetomidine sublingual film is shown in example 1, composition 12.

In FIG. 6 depicts the mean VAS/S versus nominal time after administration of dexmedetomidine sublingual film (10, 20, 40 μg) and placebo. Dexmedetomidine sublingual film is shown in example 1, composition 12.

In FIG. 7 shows standing systolic BP versus nominal time after administration of dexmedetomidine sublingual film (10, 20, 40 μg) and placebo. Dexmedetomidine sublingual film is shown in example 1, composition 12.

In FIG. 8 shows supine systolic BP versus nominal time after administration of dexmedetomidine sublingual film (10, 20, 40 μg) and placebo. Dexmedetomidine sublingual film is shown in example 1, composition 12.

In FIG. 9 depicts standing diastolic BP versus nominal time following administration of 10, 20, and 40 μg dexmedetomidine sublingual film and placebo. Dexmedetomidine sublingual film is shown in example 1, composition 12.

In FIG. 10 depicts supine diastolic BP versus nominal time following administration of 10, 20, and 40 μg dexmedetomidine sublingual film and placebo. Dexmedetomidine sublingual film is shown in example 1, composition 12.

In FIG. 11 depicts pulse rate versus nominal time after administration of 10, 20, and 40 μg dexmedetomidine sublingual film and placebo. Dexmedetomidine sublingual film is shown in example 1, composition 12.

In FIG. 12 depicts the percentage of patients with schizophrenia who achieved RASS-1 in the treatment group (the group receiving intravenous dexmedetomidine hydrochloride treatment) compared to the placebo group.

In FIG. 13 shows the decrease in REC score over time in patients with schizophrenia in the treatment group (the group treated with IV dexmedetomidine hydrochloride) compared to the placebo group.

In FIG. 14 depicts the maximum doses of IV dexmedetomidine hydrochloride received by patients with schizophrenia for the treatment of agitation.

In FIG. 15 depicts the total intravenous dose of dexmedetomidine hydrochloride given to patients with schizophrenia for the treatment of agitation.

In FIG. 16 depicts mean plasma concentration (pg/mL) versus actual time in schizophrenic patients treated with dexmedetomidine hydrochloride.

In FIG. 17 shows the mean plasma concentration (±SD) of dexmedetomidine over time sorted by dose level (linear scale).

In FIG. 18 depicts the mean plasma concentration (±SD) of dexmedetomidine over time, sorted by dose level (semilogarithmic scale).

In FIG. 19 shows the mean change (±SD) in RES score from baseline in patients with schizophrenia treated with dexmedetomidine hydrochloride (120 μg) compared with a pooled placebo group.

- 3 040771

In FIG. 20 shows the mean percent change (±SD) in RES from baseline in patients with schizophrenia treated with dexmedetomidine hydrochloride (120 μg) compared with a pooled placebo group.

Detailed Description of the Invention

Abbreviations.

AD: Alzheimer's disease;

AUC: area under the curve;

AUC _last : area under the curve calculated up to the last observed time point;

C _max : maximum plasma concentration;

CT: computed tomography;

DPBS: Dulbecco's phosphate buffered saline;

DLB: dementia with Lewy bodies;

FTD: frontotemporal disease;

HPC: hydroxypropyl cellulose;

IPD: inpatient departments;

MM: molecular weight;

TLS _last : average hold time calculated up to the last observed point in time;

MRI: magnetic resonance imaging;

mcg: microgram;

µm: micrometer;

mm: millimeter;

OPD: outpatient departments;

PANSS: Positive and Negative Syndrome Scale;

RES: PANSS excitation component;

PEO: polyethylene glycol;

PD: Parkinson's disease;

PTSD: post-traumatic stress disorder;

RASS: Richmond Agitation-Sedation Scale;

TEER: trans-epithelial electrical resistance;

T _max : time to reach maximum plasma concentration;

mass%: mass percentage.

Definitions.

As used herein, the term film is to be understood to include thin films, sheets, and wafers in any shape, including rectangular, square, or other desired shape. The film may be of any desired thickness and size such that it can be conveniently placed sublingually on a patient. For example, the film may be a relatively thin film having a thickness of about 20 to about 200 microns, or may be a slightly thicker film having a thickness of about 20 to about 1000 microns. In certain embodiments, the film may be an even thicker film, such as having a thickness greater than about 30 mm.

As used herein, the phrase water-soluble polymer refers to (i) a polymer that is at least partially soluble in water and desirably completely or predominantly soluble in water; and/or (ii) a polymer that absorbs water.

Polymers that absorb water are referred to herein as water-swellable polymers. Suitable polymers include polymers that are water soluble at room temperature and other temperatures, such as temperatures above room temperature. In addition, suitable polymers include polymers that are water soluble at subatmospheric pressures. Desirably, the water-swellable polymers have a water absorption of at least 20% by weight, such as a water absorption of 25 percent or more. In one embodiment, the film formulations contain one or more water-soluble polymers that aid in dissolving the film upon contact with oral fluids.

The terms composition and composition are used interchangeably, except where it is clearly implied that they have different meanings.

The term pharmaceutically acceptable carrier refers to a pharmacologically inert substance that can be used as a carrier. As used herein, the expression carrier and excipients are used interchangeably except where clearly implied different meanings.

As used herein, the term monolithic in the context of a film composition refers to a single layer polymeric film in the form of a placebo film matrix or drug-containing film matrix. In some aspects, a monolithic film is used in the preparation of a microarranged drug matrix film composition as

- 4 040771 drug-free matrix film intermediate.

As used herein, the term dosage form refers to a film composition in the portion that delivers a single dose in a single administration to a subject.

The term self-supporting means that the films herein maintain structural integrity when handled without the need for a protective layer. Some film flexibility is expected and may be desirable.

The term dissolving means that the films, as used herein, readily disintegrate, for example, within at least about 20 minutes after application to the oral mucosa. Disintegration is achieved with saliva and/or other aqueous media on the mucosal surface.

A term without significant sedation, etc. means that the patient is experiencing a level of sedation not exceeding level 3 on the Ramsey Sedation Scale. Level 3 means the patient is sedated but responds to commands. In some aspects, dexmedetomidine may be dosed to achieve a score of -1 (mild sedation) on the Richmond Agitation-Sedation Scale (RASS).

Used in this document, the term about means plus or minus 10% of the specified numerical value.

As used herein, the phrase "located in a polymer matrix" means that dexmedetomidine, or a pharmaceutically acceptable salt thereof, is incorporated directly into the polymer solution prior to forming the solid polymer matrix film composition.

As used herein, the phrase placed on the surface of a polymer matrix means that dexmedetomidine or a pharmaceutically acceptable salt thereof is formulated as a liquid composition, separate from the preparation of a solid polymer matrix, and it is placed on a solid polymer, for example, in the form of one or more microarrangements, where it dries up. The dried preparation is sometimes referred to herein as a microarray film. The drug liquid composition may be in any form, including such as a solution, emulsion, suspension or dispersion.

Film compositions.

The present invention relates to pharmaceutical film compositions containing or consisting essentially of dexmedetomidine, or a pharmaceutically acceptable salt thereof, as the active agent, a polymeric component, and optionally one or more pharmaceutically acceptable carriers. The film compositions described have desirable functional attributes for sublingual administration. In particular, the disintegration time of the film compositions is such that oromucosal delivery of dexmedetomidine or a pharmaceutically acceptable salt thereof is effective in rapidly treating agitation in a subject. For example, the film compositions may conventionally disintegrate completely sublingually within from about 15 seconds to about 180 seconds, for example from about 30 seconds to about 180 seconds, including about 120 seconds. A disintegration time of approximately this time interval promotes optimal sublingual drug delivery and optimal onset of drug action.

active agent.

Dexmedetomidine has the IUPAC name (+) 4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. Because the monohydrochloride salt is predominantly used as a drug for sedating patients during treatment in an intensive care setting or for sedating patients before and/or during surgical and other procedures. Such a medicinal product is currently marketed under the registered trade name PRECEDEX.

The pharmaceutically acceptable salts of dexmedetomidine that may be used in the film compositions disclosed herein include basically any suitable salt that has been or may be approved by the US FDA or other suitable foreign or local agency for human administration. Non-limiting examples of suitable pharmaceutically acceptable salts include inorganic acid salts such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrophosphoric, dihydrophosphoric, sulfuric, hydrosulfuric, and hydroiodic acid. Other examples include salts derived from non-toxic organic acids, including acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthaleic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids, or combinations salts of these acids. Примеры солей включают дексмедетомидина гидрохлорид, дексмедетомидина гидробромид, дексмедетомидина сульфат, дексмедетомидина сульфонат, дексмедетомидина фосфат, дексмедетомидина нитрат, дексмедетомидина формиат, дексмедетомидина цитрат, дексмедетомидина тартрат, дексмедетомидина малат, дексмедетомидина бензоат, дексмедетомидина салицилат, дексмедетомидина аскорбат или т.п. In other embodiments, deuterated forms of dexmedetomidine or a pharmaceutically acceptable salt thereof may be included in the film composition.

Dexmedetomidine, or a pharmaceutically acceptable salt thereof, may conventionally contain from about 0.01% to about 50%, such as from about 0.05% to about 30%, such as from about 0.05% to about 20%, such as from about 0.05% % to about 3% wt./wt. (wt./wt.) in terms of the total weight of the film

- 5 040771 compositions by dry weight. However, it should be understood that when the film composition is a film with a microarranged matrix, % wt./wt. dexmedetomidine or a pharmaceutically acceptable salt may vary from the percentages mentioned above depending on the overall dimensions (and hence total weight) of each film unit.

In one aspect, dexmedetomidine, or a pharmaceutically acceptable salt thereof, may be present in an amount of from about 0.05 micrograms to about 3 micrograms for every 100 micrograms of the total unit dose weight of the film composition.

The film formulations described herein contain dexmedetomidine or a pharmaceutically acceptable salt thereof, either (i) located within a polymer matrix or (ii) placed on the surface of a polymer matrix, such as on the surface of a placebo film.

In addition, dexmedetomidine or a pharmaceutically acceptable salt thereof may be included as part of a film composition in a taste masking form. In this embodiment, the drug particles may be coated or granulated with a flavoring agent such as a polymer, oil or wax.

polymer component.

The polymeric component consists of one or more water-soluble polymers. The polymeric component is present in the film composition in a sufficient amount to cause the subsequently formed film matrix to disintegrate on the oral mucosa within a suitable time frame, such as allowing the film matrix to completely disintegrate after about 15 seconds to about 180 seconds, such as about 30 seconds. up to about 180 s, including about 120 s. The present invention relates to film compositions containing at least one water-soluble polymer that produces films with sufficient film strength (ie, self-supporting) and fast disintegration profiles. In one aspect of the present invention, the polymeric component consists of a single water-soluble polymer. In another aspect, the polymeric component is comprised of two or more water soluble polymers, including two or more identical water soluble polymers having different molecular weights.

When present in one or more droplets of a dexmedetomidine composition that is placed on the surface of a polymeric substrate, the polymeric component may, for example, consist of a water-soluble hydroxypropyl cellulose polymer, although various water-soluble polymers are also contemplated, as described hereinafter in the definition of the first water-soluble polymer and the second water soluble polymer. For example, the polymeric component may consist of one, two or three hydroxypropylcelluloses having different molecular weights. The molecular weights of the various hydroxypropylcelluloses can typically range from (i) less than about 60,000 daltons (eg, about 5,000 daltons to about 49,000 daltons);

(ii) from about 90,000 daltons to about 200,000 daltons; and (iii) from about 200,000 daltons to about 500,000 daltons.

The two or more hydroxypropyl celluloses may be mixed in any suitable ratio to achieve the desired drip viscosity. The viscosity of a solution or suspension of the dexmedetomidine composition can be measured using a Brookfield viscometer with a small sample adapter at 25° C. and can range from about 5 centipoise to about 3700 centipoise. For example, the viscosity may range from about 5 centipoise to about 500 centipoise, from about 6 centipoise to about 200 centipoise, from about 6 centipoise to about 100 centipoise, or from about 6 centipoise to about 50 centipoise. In one aspect of the present invention, the viscosity of the solution or suspension of the dexmedetomidine composition is from about 6 centipoise to about 20 centipoise at 25 and the shear rate is about 7 (1/s).

When present in a monolithic (ie, placebo or drug-containing) film, the polymeric component may, for example, consist of one water-soluble polymer or two different water-soluble polymers. When two different water soluble polymers are present, one of the water soluble polymers may include the same polymer but present in the polymer component as a combination of different molecular weights. For example, the polymeric component may be composed of one, two, or three hydroxypropylcelluloses having different molecular weights, although various water-soluble polymers are also contemplated, as described herein below, as defined by a first water-soluble polymer and a second water-soluble polymer, such as polyethylene oxide. The molecular weights of the various hydroxypropylcelluloses can typically range from (i) about 5,000 daltons to about 49,000 daltons;

(ii) from about 90,000 daltons to about 200,000 daltons; and (iii) from about 200,000 Daltons to about 500,000 Daltons (eg, from about 300,000 Daltons to about 450,000 Daltons).

Two or more hydroxypropyl celluloses (eg, low and high molecular weight hydroxypropyl celluloses) can be mixed in any suitable ratio to achieve the desired film properties.

When present in a monolithic (i.e. placebo or drug-containing) formulation

- 6 040771 agent) film or micro-arranged film matrix, the polymeric component may conventionally consist of one or more water-soluble polymers having a molecular weight of less than about 60,000 daltons (for example, from about 5000 daltons to about 49,000 daltons), and/or from about 90,000 Daltons to about 200,000 Daltons, and/or from about 200,000 Daltons to about 500,000 Daltons (eg, from about 300,000 Daltons to about 450,000 Daltons). When a structurally different water-soluble polymer is also present, it can typically have a higher molecular weight, such as a molecular weight in excess of about 500,000 daltons.

In a related aspect, the invention relates to pharmaceutical film compositions containing (i) dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) a polymer component consisting of a first water-soluble polymer having a molecular weight of less than about 60,000 daltons (eg, from about 5,000 daltons to about 49,000 daltons) and one or more second water-soluble polymers having a molecular weight of more than about 60,000 daltons; and optionally (iii) one or more pharmaceutically acceptable carriers.

In another related aspect, the invention relates to pharmaceutical film compositions consisting essentially of (i) dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) a polymer component consisting of a first water-soluble polymer having a molecular weight of less than about 60,000 daltons (eg, from about 5,000 daltons to about 49,000 daltons) and one or more second water-soluble polymers having a molecular weight of more than about 60,000 daltons; and optionally (iii) one or more pharmaceutically acceptable carriers.

In yet another aspect, the invention relates to pharmaceutical film compositions consisting of (i) dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) a polymer component consisting of a first water-soluble polymer having a molecular weight of less than about 60,000 daltons (eg, from about 5,000 daltons to about 49,000 daltons) and one or more second water-soluble polymers having a molecular weight of more than about 60,000 daltons; and optionally (iii) one or more pharmaceutically acceptable carriers.

Examples of the one or more first water-soluble polymers are selected from the group consisting of hydroxypropylcellulose (HPC), hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose, methylcellulose and mixtures thereof, including mixtures of the same polymer having different molecular weights.

Examples of the one or more second water soluble polymers are selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose and mixtures thereof, including mixtures of the same polymer having different molecular weights. Polyethylene oxide (PEO) may also be present herein as the second water-soluble polymer, or it may be described separately below in pharmaceutical film compositions as an example of a pharmaceutically acceptable carrier, or more particularly as a mucoadhesive agent.

In one embodiment, the weight ratio of said first water-soluble polymer to said second water-soluble polymer(s) (including PEO, if present in the film) in the entire film composition is from about 2:1 to about 1 :50, for example from about 1:1 to about 1:40, including about 1:1, 1:2, 1:3, 1:5, 1:5, 1:6, 1:7, 1:8, 1 :9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21 , 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1 :34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40.

In a further embodiment, the weight ratio of said first water-soluble polymer to said second water-soluble polymer(s) (including PEO, if present in the film) in the entire film composition is from about 1:10 to about 1 :30, from about 1:15 to about 1:25, or from about 1:15 to about 1:20. In certain aspects, a ratio of about 1:15 to about 1:20 provides beneficial functional effects.

Examples of other water soluble polymers that can be incorporated into the film with the first water soluble polymer/second water soluble polymer or replace such polymer(s) include povidone (polyvinylpyrrolidone), copovidone (copolymers of N-vinyl-2-pyrrolidone and vinyl acetate), polyvinyl alcohol, polyethylene glycol, polyacrylic acid, methyl methacrylate copolymers, carboxyvinyl copolymers, polydextrose, pullulan, carboxymethylcellulose, sodium alginate, chitosan, xanthan gum, tragacanth gum, guar gum, gum arabic, gum arabic, starch, carrageenan, gelatin, and mixtures thereof.

The water-soluble polymer component, including water-soluble polymer carriers, when they may conventionally comprise from about 40% to about 99.8%, from about 50% to about 99.7%, from about

- 7 040771

60% to about 99.6% of the film composition, based on the dry weight of the film, by dry weight.

In one aspect, the polymer component for the film composition comprises a first water-soluble polymer present in an amount of from about 2% to about 15%, based on the dry weight of the polymer component (e.g., from about 3% to about 8% w/w of the total weight films). This water-soluble polymer may conventionally have a molecular weight of from about 5,000 daltons to about 49,000 daltons. Examples of such suitable water-soluble polymers include those selected from the group consisting of hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, and mixtures thereof.

In a further aspect, low molecular weight hydroxypropyl cellulose may be present in the film in an amount of from about 3% to about 8% w/w. from the total weight of the film.

In a further aspect, the one or more second water soluble polymers (including water soluble polymer carriers such as polyethylene oxide) may, for example, be present in an amount of from about 50 to about 98 wt % based on the dry weight of the polymer component. Each of the one or more second water-soluble polymers has a molecular weight greater than 60,000 daltons; for example, from about 90,000 Daltons to about 1,500,000 Daltons, especially when the polymer is selected from the group consisting of polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, and mixtures thereof.

In one aspect, one or more second water-soluble polymers may be present together in the film in an amount of from about 25% to about 40% w/w. based on the total weight of the film, when the one or more second water-soluble polymers each have a molecular weight of from about 90,000 Daltons to about 200,000 Daltons and/or from about 200,000 Daltons to about 500,000 Daltons, and the polymer is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose and mixtures thereof.

In another aspect, the polyethylene oxide may be present in the film in an amount of from about 50% to about 60% w/w. from the total weight of the film.

In one embodiment, the polymeric component for the film composition is comprised of a low molecular weight, water soluble polymer (e.g., having a molecular weight of less than 60,000 daltons) and one or more high molecular weight polymers (e.g., having a molecular weight greater than 60,000, up to about 1,500,000 daltons when polyethylene oxide is included in the polymer blend). , or up to about 500,000 daltons when polyethylene oxide is not included in the polymer blend). This polymer combination, especially when the polymers are a combination of hydroxypropyl cellulose and polyethylene oxide, offers certain advantages in terms of tensile strength and pharmacokinetic parameters of the film composition.

In one aspect, the present invention provides a thin film composition comprising, for example, consisting essentially of (i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) a polymeric component consisting of one or more water-soluble polymers; and (iii) one or more pharmaceutically acceptable carriers.

In one embodiment, the present invention provides a thin film composition comprising, for example, consisting essentially of (i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) a polymeric component consisting of (a) one or more first water-soluble polymers (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, and mixtures thereof) having a molecular weight of from about 5,000 daltons to about 49,000 daltons, for example, in an amount of from about 2 wt.% to about 15 wt.% in terms of dry weight of the entire polymer component; and (b) one or more second water-soluble polymers (e.g., polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, and mixtures thereof) having a molecular weight greater than 60,000 daltons, such as greater than 100,000 daltons, such as in an amount of from about 50 wt. .% to about 98 wt.% in terms of dry weight of the entire polymer component; and (iii) one or more pharmaceutically acceptable carriers.

The molecular weight of hydroxypropyl cellulose, when present in the film of the present invention, may vary and may be present as either a low molecular weight water soluble polymer or one or more high molecular weight water soluble polymers. In some embodiments, the molecular weight may be less than about 60,000 daltons (eg, from about 5,000 daltons to about 49,000 daltons). In other embodiments, the molecular weight may range from about 90,000 Daltons to about 200,000 Daltons. In still other embodiments of the invention, the molecule

- 8 040771 The lar mass can range from about 200,000 Daltons to about 500,000 Daltons.

Hydroxypropyl cellulose, when part of the film composition contains polyethylene oxide, can typically be present in the range of from about 10% to about 90%, based on the dry weight of the polymer component, for example, from about 20% to about 80 wt.%, based on the dry weight of the polymer component, for example from about 20% to about 50 wt.%, based on the dry weight of the polymer component, for example, from about 25% to about 45 wt.%, based on the dry weight of the polymer component.

The molecular weight of polyethylene oxide, when present in the film of the present invention, may also vary. In some embodiments of the invention, a water-soluble high molecular weight polyethylene oxide can be used, for example, to increase the mucoadhesiveness of the film. In some embodiments, the molecular weight may range from about 100,000 Daltons to about 1,500,000 Daltons, including about 100,000, 200,000, 300,000, 600,000, 900,000, or 1,000,000 Daltons. In some embodiments, it may be desirable to use a combination of a polyethylene oxide having a molecular weight of from about 600,000 Daltons to about 900,000 Daltons with a polyethylene oxide having a molecular weight of about 100,000 Daltons to about 300,000 Daltons in the polymer component.

The polyethylene oxide, when forming part of the film composition, can typically be present in the range of from about 30 wt.% to about 90 wt.%, based on the dry weight of the entire polymer component, for example, from about 40 wt.% to about 85 wt.%, based on on dry weight of the polymer component, for example from about 55 wt.% to about 80 wt.% in terms of dry weight of the polymer component.

Such film compositions may contain the drug dispersed in the film or micro-arranged on the surface of the film. When microplating on the surface of the placebo film, the drug can conventionally be added as part of the dexmedetomidine composition as one or more drops in a liquid carrier such as a solvent (e.g. an alcohol such as ethanol), optionally together with one or more (e.g. two) water-soluble polymers and/or pharmaceutically acceptable carriers. Suitable water-soluble polymers include (1) a low molecular weight water-soluble polymer, such as a low molecular weight water-soluble polymer with a molecular weight of less than about 60,000 daltons (eg, a molecular weight of about 5,000 daltons to about 49,000 daltons); and optionally (2) one or more (e.g., one or two) high molecular weight water-soluble polymers, e.g., a high molecular weight water-soluble polymer with a molecular weight greater than about 60,000 daltons (e.g., a molecular weight from about 60,000 daltons to about 150,000 daltons, such as hydroxypropyl cellulose (MW 77,000 ), hydroxypropyl cellulose (MM 80,000), hydroxypropyl cellulose (MM 90,000), or hydroxypropyl cellulose (MM 140,000)), and/or a high molecular weight, water-soluble polymer with a molecular weight greater than about 60,000 daltons (e.g., molecular weight from about 200,000 daltons to about 900,000 daltons, such as hydroxypropyl cellulose (MM 340,000), hydroxypropyl cellulose (MM 370,000), polyethylene oxide (MM 200,000) or polyethylene oxide (MM 600,000)). Each water-soluble polymer can be independently selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene oxide, and methyl cellulose, such as hydroxypropyl cellulose and/or polyethylene oxide.

In one aspect, the dexmedetomidine composition comprises dexmedetomidine hydrochloride, a low molecular weight polymer that is hydroxypropyl cellulose, and one or two high molecular weight polymers, each of which is hydroxypropyl cellulose in an ethanol solvent.

In one aspect, the dexmedetomidine composition comprises hydroxypropyl cellulose (MM 40,000) and one or both of hydroxypropyl cellulose (MM 140,000) and hydroxypropyl cellulose (MM 370,000).

In one aspect, the dexmedetomidine composition contains only two hydroxypropyl celluloses, namely hydroxypropyl cellulose (MM 40,000) and hydroxypropyl cellulose (MM 140,000).

In other aspects, the dexmedetomidine composition may be added as one or more drops in an ethanol based solution optionally containing a pH neutralizing agent such as sodium hydroxide.

The viscosity of the placement solution/slurry can range from about 6 centipoise to about 3700 centipoise measured at 25° C. using a Brookfield viscometer with a small sample adapter. By way of example, the viscosity may range from about 5 centipoise to about 500 centipoise, from about 6 centipoise to about 200 centipoise, from about 6 centipoise to about 100 centipoise, or from about 6 centipoise to about 50 centipoise. In one aspect of the present invention, the viscosity of the dexmedetomidine composition is from about 6 centipoise to about 20 centipoise at 25° C. and a shear rate of about 7 (1/s). The placement composition may be in any form, including such as a solution, emulsion, suspension, or dispersion.

After drying to remove the solvent, the film contains a film support (for example, place

- 9 040771 bo) with dexmedetomidine composition, as described previously, but without the placed solvent (for example, micro-placed) on the surface of the film substrate. The dried composition may cover the entire surface of the film substrate or only a portion of the surface of the film substrate. In one aspect, the composition is presented as one or more discrete drug-containing droplets on the surface of a film substrate. Alternatively, screen printing can be used to achieve one or more defined and discrete regions of the drug-containing composition on the surface of the film substrate.

In one aspect, the present invention provides a dry film formulation comprising a film support with one or more discrete drug-containing drops on the surface of the film support, each such drug-containing drop containing dexmedetomidine or a pharmaceutically acceptable salt thereof and two hydroxypropylcelluloses. molecular weights: hydroxypropyl cellulose (MM 40000), available as HPC-SSL, and hydroxypropyl cellulose (MM 140000), sold under the trade name Klucel™ type JF NF, and wherein the film substrate contains hydroxypropyl cellulose of three molecular weights: hydroxypropyl cellulose (MM 40000), hydroxypropyl cellulose (MM 140000) and hydroxypropyl cellulose (MM 370000) marketed under the trade name Klucel™ type GF NF. In one aspect, the film substrate also contains polyethylene oxide (MW 600,000) available under the name Sentry Polyox WSR 205 LEO NF.

In one aspect, the film contains a placement composition (also referred to herein as a dexmedetomidine composition) comprising (i) dexmedetomidine hydrochloride present in an amount of from about 9% w/w. up to about 50% wt./wt. composition for placement, for example from about 15% wt./wt. up to about 25% wt./wt. composition for placement;

(ii) hydroxypropyl cellulose (MM 40,000) present in an amount of from about 5% to about 85% by weight of the placement composition;

(iii) hydroxypropyl cellulose (MM 140,000) present in an amount of about 5% to 85% w/w of the placement composition; and (iv) hydroxypropylcellulose (MM 370,000) present in an amount of from about 0% wt./wt. up to about 65% wt./wt. compositions for placement.

The film also contains a polymer matrix, and the polymer matrix contains (i) hydroxypropyl cellulose (MM 40000) present in an amount of from about 3% wt./wt. up to about 40% w/w polymer matrix;

(ii) hydroxypropyl cellulose (MW 140,000) present in an amount of from about 3% to about 40% by weight of the polymer matrix;

(iii) hydroxypropyl cellulose (MM 370,000) present in an amount of from about 0% to about 30% by weight of the polymer matrix; and (iv) polyethylene oxide (MW 600,000) present in an amount of from about 55% to about 75% w/w of the polymer matrix.

The present invention also provides a monolithic film formulation for sublingual administration. The film contains a composition for placement containing (i) dexmedetomidine hydrochloride, present in an amount of from about 1% to about 50 wt.%, of the entire composition;

(ii) hydroxypropyl cellulose (MM 40,000) present in an amount of from about 2% to about 30% by weight of the total composition;

(iii) hydroxypropyl cellulose (MM 140,000) present in an amount of from about 2% to about 30% by weight of the total composition;

(iv) hydroxypropyl cellulose (MM 370,000) present in an amount of from about 10% to about 50% by weight of the total composition;

(v) polyethylene oxide (MW 600,000) present in an amount of from about 40% to about 75% by weight of the total composition; and (vi) optionally other pharmaceutically acceptable carriers.

In certain aspects, the films disclosed herein combine several types of hydroxypropyl cellulose (HPC) to provide a film with advantageous properties. For example, the film composition may contain two or three of hydroxypropyl cellulose (MW 40,000), hydroxypropyl cellulose (MW 140,000), and hydroxypropyl cellulose (MW 370,000) in combination. In some embodiments, polyethylene oxide (MW 600,000) is formulated with these types of HPCs when it forms part of a monolithic film.

In some film compositions, low molecular weight hydroxypropyl cellulose (eg, MM 40,000) is present in an amount of about 3% to about 8% (eg, about 5%) w/w. based on the total weight of the film, high molecular weight hydroxypropylcellulose (eg, MM 140,000) is present in an amount of from about 3% to about 8% (eg, about 5%) wt./wt. from the total mass of the film, you

- 10 040771 molecular weight hydroxypropyl cellulose (for example, MM 370000) is present in an amount of from about 20% to about 40% w/w, based on the total weight of the film, and polyethylene oxide (for example, MM 600000) is present in an amount of from about 40% to about 70% w/w (eg, from about 50% to about 60% w/w) based on the total weight of the film. In one aspect, the two high molecular weight water-soluble polymers are present together in an amount of from about 25% to about 40% w/w. from the total weight of the film.

The choice and ratio of water-soluble polymers can be adjusted to effect complete dissolution of the film composition in oral mucosal fluid within seconds to minutes, such as from about 0.25 minutes to about 15 minutes, thereby delivering a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable thereof. salt through the oral mucosa. For example, the film compositions may be present in the sublingual region of the mouth for up to about 15 minutes, up to about 10 minutes, or up to about 5 minutes, including a period of time from about 30 seconds to about 15 minutes, from about 1 minute to about 10 minutes, or from about 1 minute. up to about 5 min.

The standard basket or paddle apparatus described in any pharmacopoeia can be used for in vitro dissolution studies. The choice of dissolution medium will essentially depend on both the conditions of immersion and the highest dose of drug. The temperature of the dissolution medium must be maintained at 37±0.5° C. and at 50 rpm (see Bala et al., in Int. J. Pharm. Investigation, vol. 3(2), p. 67-76).

The films disclosed herein have several functional advantages for facilitating a rapid onset of drug action. In some aspects, the thin film compositions of the invention have a disintegration time (DT) from about 15 seconds to about 180 seconds, from about 15 seconds to about 160 seconds, from about 25 seconds to about 150 seconds, from about 15 seconds to about 140 seconds. , from about 15 seconds to about 120 seconds, from about 40 seconds to about 120 seconds, from about 50 seconds to about 120 seconds, for example, about 120 seconds for sublingual application. The disintegration time in this time interval provides the optimal onset of drug action.

In certain other aspects, the thin film compositions of the present invention have mucoadhesion properties that provide practical advantages for localizing the film to the sublingual site and reducing or preventing effective removal prior to dissolution. This quality provides an exceptional advantage in the clinical setting in an agitated subject. Thus, in some aspects, the thin film compositions have a mucoadhesion strength (mucoadhesion force or shear force) of about 50 g or more, about 100 g or more, about 200 g or more, about 300 g or more, about 400 g or more, about 500 g or more, about 600 g or more, about 700 g or more, about 800 g or more, about 900 g or more, about 1000 g or more. In certain aspects, the mucoadhesion strength is in the range of about 300 g to about 4000 g, about 500 g to about 3000 g, or about 1000 g to about 2000 g.

Drug delivery is also aided by tensile strength. Some thin film compositions of the present invention have a tensile strength equal to or greater than 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, 3500, 4000, 4.500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000 or 15000 g. about 200 g to about 15,000 g, from about 300 g to about 10,000 g, or from 400 g to about 5,000 g.

Pharmaceutically acceptable carriers.

The film compositions may additionally contain one or more pharmaceutically acceptable carriers, which include, but are not limited to, liquid carriers, flavors, sweeteners, refreshing agents, antioxidants, pH adjusting agents, penetration enhancers, mucoadhesive agents, plasticizers, bulking agents, surfactants. agents/nonionic solubilizers, stabilizers, defoamers, colorants or the like. In some embodiments, the film compositions are substantially free of acidic buffer or other acidic agents.

Liquid carriers.

In one aspect, the pharmaceutically acceptable carrier comprises a liquid carrier. The liquid carrier contains one or more solvents useful in the preparation of the polymer matrix (containing the drug or placebo) and the composition for placement in the film composition. In some embodiments, the solvent may be water. In some embodiments, the solvent may be a polar organic solvent, including, but not limited to, ethanol, isopropanol, acetone, butanol, benzyl alcohol, and mixtures thereof. In some embodiments, the solvent may be a non-polar organic solvent such as methylene chloride, toluene, ethyl acetate, and mixtures thereof. Some solvents are alcohols, especially ethanol, water, and mixtures thereof.

Desirably, the solvent content of the wet polymer matrix is at least about 30% by weight of the total liquid weight of the entire film composition prior to drying. The subsequent dried film preferably contains less than about 10 wt % solvent, more desirably less than about 8 wt % solvent, even more desirably less than about

- 11 040771

6% by weight solvent, and most desirably less than about 2% by weight solvent.

Flavors/sweeteners/refreshing agents.

It may be useful to add a sweetener, flavoring agent, refreshing agent, taste masking agent, or a combination thereof to the film compositions to improve the taste of the film composition.

Flavors can be selected from natural and synthetic flavor liquids. An illustrative list of such agents includes volatile oils, synthetic fragrance oils, fragrances, oils, liquids, natural gums or extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof.

A non-limiting representative list of examples includes peppermint oils, cocoa and citrus oils such as lemon, orange, grape, lime and grapefruit, and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, or other fruit flavors.

Some flavors or flavoring agents include natural and artificial flavors. These flavors can be selected from synthetic flavor oils and flavoring flavors and/or oils, natural resins and extracts derived from plants, leaves, flowers, fruits, and the like. and their combinations. Non-limiting aromatic oils include spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, and bitter almond oil. Artificial, natural, or synthetic fruit flavors are also suitable, such as vanilla, chocolate, coffee, cocoa and citrus oils, including lemon, orange, grape, lime, and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry. , plum, pineapple, apricot, etc. These flavors can be used alone or in combination. Commonly used flavors include mints such as peppermint, artificial vanilla, cinnamon derivatives, and various fruit flavors, whether used alone or in combination. Flavoring agents such as aldehydes and esters may also be used, including cinnamyl acetate, cinnamaldehyde, citral, diethyl acetal, dihydrocarvyl acetate, eugenyl formate, p-methyl anisole, or the like. Additional examples of aldehyde flavors include, but are not limited to, acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamaldehyde (cinnamon); citral, i.e. alpha citral (lemon, lime); neral, i.e. beta-citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream); heliotropin, i.e. piperonal (vanilla, cream); vanillin (vanilla, cream); alpha-amyl cinnamaldehyde (spicy fruit flavors); butyraldehyde (butter, cheese); valeraldehyde (butter, cheese); citronellals (modifiers, many species); decanal (citrus); aldehyde C-8 (citrus); aldehyde C-9 (citrus); aldehyde C-12 (citrus); 2-ethylbutyraldehyde (fruit and berry); hexenal, i.e. trans-2 (fruit and berry); tolylaldehyde (cherry, almond); veratraldehyde (vanilla); 12,6-dimethyl-5-heptenal, i.e. melon (melon); 2dimethyloctanal (green fruits) and 2-dodecenal (citrus, tangerine); cherry flavors; grapes and their mixtures. In one embodiment, the flavor is a peppermint oil flavor, available as peppermint oil, NF.

The amount of flavoring agent used, usually a substance of preference, is subject to factors such as flavor type, flavor profile, and desired dosage. The amount can be varied to obtain the result desired in the final preparation. Such variations are within the ability of those skilled in the art without the need for undue experimentation. In general, flavoring levels of from about 0.1% to about 30% by weight can be used in films.

Suitable sweeteners include both natural and artificial sweeteners. Non-limiting examples of suitable sweeteners include, for example, water soluble sweeteners such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), high fructose corn syrup , maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, dry corn syrup and dihydrocalcones; water-soluble artificial sweeteners such as soluble saccharin salts, i.e. sodium or calcium salts of saccharin, cyclamate salts, sodium, ammonium or calcium salt of 3,4-dihydro-6-methyl1,2,3-oxathiazin-4-one-2,2-dioxide, potassium salt of 3,4-dihydro-6 -methyl-1,2,3-oxathiazine-4-one-2,2 dioxide (acesulfame-K), free acid form of saccharin, etc.; dipeptide-based sweeteners such as those derived from L-aspartic acid such as L-aspartyl-L-phenylalanine methyl ester (aspartame), L-alpha-aspartyl-N-(2,2,4,4-tetramethyl- 3thietanyl)-D-alanineamide hydrate, methyl esters of L-aspartyl-L-phenylglycerol and Laspartyl-L-2,5-dihydrophenylglycine, L-aspartyl-2,5-dihydro-L-phenylalanine, L-aspartyl-L-( 1cyclohexien)-alanine and the like; water-soluble sweeteners derived from natural water-soluble sweeteners such as chlorinated derivatives of common sugar (sucrose), known for example as sucralose, and protein-based sweeteners such as from thaurnatoccous daniellii (taurna

- 12 040771 tin I and II), high intensity natural sweeteners such as Lo Han Kuo, stevia, steviosides, monellin and glycyrrhizin. In one embodiment, the sweetener is sucralose.

Refreshing agents, also called cooling agents, are chemicals that activate cold sensory receptors, creating a feeling of cold. Refreshing agents that may be added to the film composition include menthol, thymol, camphor and eucalyptol. In one embodiment, the refreshing agent is menthol.

Flavorings, sweeteners, and refreshing agents may be added in conventional amounts, typically from about 0.01% to about 10% by weight of the film on a dry weight basis, for example, from about 0.1% to about 7% by weight of the film. films on a dry weight basis, for example from about 0.1% to about 5% by weight of the film on a dry weight basis.

Other taste-masking agents include, for example, polymers, oils, or waxes. In one embodiment, dexmedetomidine, or a pharmaceutically acceptable salt thereof, is coated with a taste-masking agent prior to formulation into film compositions.

In some embodiments, if a taste-masking agent is used to coat the active ingredient, it may be present in an amount of from about 5% to about 80% by weight of the particle or granule containing the active ingredient. In another embodiment, the taste-masking agent is present in an amount of from about 25% to about 35% by weight of the particle or granule containing the active ingredient. The exact content of the active ingredient in a taste-masked particle or bead depends on many parameters, including the particular form of the active ingredient (i.e., the free base or salt thereof) used, the coating, and any flavorings present in the particle or bead or in the film-forming polymeric matrix. .

Dexmedetomidine, or a pharmaceutically acceptable salt thereof, can be taste-masked by the above-described taste-masking agents using a variety of techniques. Suitable coating methods include, but are not limited to, fluid bed coating, curing spray coating, agglomeration or granulation coating, entrapment coating, coacervation coating, infusion coating, spin coating, ion exchange coating, or the like.

Antioxidants.

Film compositions may advantageously use an antioxidant or oxygen scavenger to prevent or reduce oxidative degradation of dexmedetomidine or a pharmaceutically acceptable salt thereof prior to use. Examples of oxygen scavengers or antioxidants that substantially improve the long-term stability of the film composition against oxidative degradation include sulfite salts such as sodium sulfite, sodium bisulfite, sodium metabisulfite, and similar potassium and calcium salts.

A suitable amount of sulfite salt (eg sodium sulfite) is up to about 5%, eg from about 0.001% to about 2% by weight, of the film composition on a dry weight basis.

pH adjusting agents/pH neutralizing agents.

Oral mucosal absorption of dexmedetomidine or a pharmaceutically acceptable salt thereof may be increased in an alkaline microenvironment. By way of example, this can be achieved when the film compositions are maintained at a pH above 6, about 6 to about 9, or about 6.5 to about 8. In some embodiments, the film may contain an alkaline substance that increases the pH of the film preparation. Non-limiting examples of pH adjusting/neutralizing agents include bicarbonates (eg sodium bicarbonate), citrates (eg potassium citrate), carbonates (eg calcium carbonate), lactates (eg sodium lactate), acetates (eg calcium acetate), alkaline a buffering agent (eg, glycine), sodium hydroxide, sodium chloride, or the like.

An alkaline buffer such as glycine is one example of a pH neutralizing agent.

pH adjusting agents/pH neutralizing agents may be added to the film composition in amounts effective to stabilize the pH in the desired pH range. A suitable amount of pH adjusting/pH neutralizing agent present in the film composition includes, for example, up to about 10% by weight, eg from about 1% to about 5% by weight, of the film composition on a dry weight basis.

Conversely, it has been shown (Table 24 in Example 2 herein below; comparative formulation 11) that the addition of an acidic buffer (e.g. lactate buffer) and/or an acidic agent (e.g. lactic acid) to the film composition has a negative effect on permeability/diffusion of the active ingredient through the oral mucosa.

Penetration enhancing agents.

In order to further stimulate the absorption of dexmedetomidine or its pharmaceutical salt through the oral mucosa and reduce the amount of dexmedetomidine that enters the gastrointestinal tract, it may be advantageous to add an agent to the film composition.

- 13 040771 penetration enhancer (i.e. penetration enhancer). Some effective penetration enhancers that promote absorption of dexmedetomidine or a pharmaceutically acceptable salt thereof through the oral mucosa include alcohols. An alcohol penetration enhancer in alcohol, such as butanol, can conventionally be added to the film composition in an amount of up to about 10%, such as about 0.1% to about 5%, such as about 1% to about 3%, based on the weight of the film composition. in the form of a dry mass.

mucoadhesive agents.

To promote adhesion of the film formulation through the oral mucosa, it may be advantageous to add a mucoadhesive agent to the film formulation. Examples of mucoadhesive agents that can be added to the film include, but are not limited to, sodium alginate, sodium carboxymethylcellulose, guar gum, polyethylene oxide, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, karaya gum, methylcellulose, rethene, tragacanth, and the like. One mucoadhesive agent is polyethylene oxide, which can typically be added to the film composition in an amount of from about 20% to about 90%, such as from about 40% to about 70%, based on the total dry weight of the film composition. It should be understood that water-soluble mucoadhesive agents that are polymers, such as polyethylene oxide, are also within the scope of the second water-soluble polymer, as previously described under the term polymer component.

plasticizers.

Plasticizers can advantageously be used in film compositions, if necessary, to appropriately modify the flexibility of the film to facilitate manufacture and allow the film to easily adapt to the shape of the portion of the mouth in which the film is applied. Plasticizers that can be effectively used herein include polyethylene glycol, propylene glycol, tributyl citrate, triethyl citrate, and glycerin. Depending on the chosen film-forming polymer(s) and other components of the film composition, a suitable amount of plasticizer included in the film composition can typically be up to about 10%, such as from about 0.1% to about 5%, such as from about 0.5 % to about 5%, based on the dry weight of the film. For certain applications, higher molecular weight polyethylene glycols, including polyethylene oxide, can be used.

bulking agents.

Bulking agents (ie, fillers) may be added as desired to increase the size of the finished film formulation for ease of manufacture and manufacture, or to modify properties (eg, increase or decrease residence time or increase stiffness) of the film formulation. Suitable excipients that can be added to the film composition include starch, calcium salts such as calcium carbonate, and sugars such as lactose, glucose, sucrose, mannose, sorbitol, mannitol, galactitol, sucralose, trehalose, and combinations thereof. The amount of filler that can conventionally be added to the film formulation is typically up to about 25%, such as about 0.5% to about 20%, such as about 1% to about 15%, such as about 2% to about 10%. %, by weight of the film composition in terms of dry weight.

Surfactants/nonionic solubilizers.

The film typically includes at least one surfactant/nonionic solubilizer including, for example, but not limited to, poloxamer, polyoxyhydrogenated castor oil, glyceryl-polyethylene glycol oxystearates, glyceryl-polyglyceryl fatty acid esters, and combinations thereof. The amount of surfactant(s) that(s) may be added to the film composition is typically up to about 5%, such as from about 0.5% to about 3%, such as from about 1% to about 3 wt.% film composition in terms of dry weight.

antifoam components.

Defoamers and/or defoamers may also be used in the film composition. These components aid in the removal of air, such as entrapped air, from the film compositions. Such entrapped air can lead to inhomogeneous films. An example of a suitable antifoam and/or antifoam agent is simethicone, although other antifoam and/or antifoam agents may be used. An antifoam and/or defoamer, such as simethicone, may be added to the film composition in an amount of from about 0.01% to about 5.0%, more desirably from about 0.05% to about 2.5%, and most desirably from about 0.1% to about 1.0% by weight of the film composition, based on dry weight.

Dyes.

Color additives that may be included in the film composition include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or topical drug and cosmetic colors (Ext. D&C). These dyes are colorants, their respective pigments, and certain natural and derived colorants. Pigments are dyes absorbed on aluminum hydroxide

- 14 040771 Other examples of coloring additives include known azo dyes, organic or inorganic pigments or coloring agents of natural origin. Some examples of color additives are inorganic pigments, such as iron or titanium oxides, added at a concentration in the range of about 0.001% to about 10%, such as about 0.01% to about 3%, by weight of the film composition on a dry basis, based on dry weight. In one embodiment, the dye used for the dexmedetomidine composition (ie, the placement composition) is different from the dye used for the film support (eg, the placebo film).

One monolithic film and micro-arrangement film substrate dye is emerald green and is available as Fast Emerald Green Shade (06507). One dye of the dexmedetomidine composition (ie, the placement composition) is a color other than the color of the film substrate, such as blue (available as FD&C Blue No. 1).

Production of film compositions.

Film compositions can be prepared as described herein.

In general, one method for producing monolithic thin film formulations involves casting the liquid formulation as a continuous web in the form of a wide and long roll on a continuous support (e.g., paper or polyester tapes, which may or may not contain protective coatings) to form a so-called ( in some cases) of the main roll. The manufacturing process involves drying the liquid formulation to remove solvents (aqueous and/or non-aqueous) to form a thin film on the substrate. The base rolls thus obtained are then converted into smaller unit doses by cutting the roll and stamping individual unit doses. The unit doses are then transferred from the production carrier to the primary packaging of the formulation.

As an example, solvent dip casting can be traditionally used to form a polymer film matrix. If the active ingredient is part of a polymer film matrix, the active ingredient, polymer(s) and other ingredients (eg, carriers) are mixed in a solvent prior to preparing the polymer film matrix. Generally, a low shear agitator can be used for bulk mixing and efficient heat transfer, while an in-line homogenizer can be used to produce a high shear dispersion. During manufacture, the mixer is able to use vacuum to eliminate the entrapment of air bubbles in the mixture, which show up as film defects during the subsequent coating process. The ingredients may be added to the mixer in any order and therefore the process is not limited to the order in which each ingredient was added.

During the coating process, the mixture is delivered to the coating head by means of a controlled metering pump to ensure continuous liquid delivery. Coating can be done with a knife-over-roll coater, a back-roll coater, or a slit coater that works best with respect to the rheology of the fluids and the substrate to be coated. Those skilled in the art of coating processes are aware of various techniques and are able to determine the appropriate coating technique based on the desired film parameters. During the coating process, the liquid is placed on a protective tape and then transported through a drying tunnel.

During the drying process, forced hot air is applied to the top side of the coating, the bottom side of the coating, or any combination of the top and bottom sides to produce a film that contains less than or equal to the specified residual solvent level. Drying ovens can be of any length, but are typically between 2 and 10 meters in length. drying temperatures at different air pressures. During the drying process, the coater may operate at a line speed between 0.25-5 m/min, and the line speed is determined by the efficiency of the drying process and the set residual solvent level required for the particular film preparation. After removing the film coating from the oven, it is wound on the core.

In addition to solvent dip casting, other examples of preparing a resin film matrix include a semi-solid casting method, a solid dispersion extrusion method, a roll method, a hot melt extrusion method, and a combination thereof.

Casting refers to a process in which polymers and additional ingredients (including the active agent) can be dissolved or suspended in a suitable solvent, any entrapped air is removed, the resulting mixture is poured onto a suitable support, and dried to remove the solvent to form a film (e.g., a thin film ). The film is then cut into any desired shape and size.

In one embodiment of the solvent dipping method, a solution containing one or more polymers (and optionally one or more suitable pharmaceutically acceptable carriers) is mixed with a solution of the active ingredient (and any other pharmaceutically acceptable

- 15 040771 my carriers), remove any entrapped air (eg under vacuum) and the resulting mixture is poured onto a suitable substrate and dried to remove the solvent to form a film (eg thin film).

In another embodiment of the solvent dipped casting process, all the ingredients of the film composition are mixed together in a solvent to form a solution or slurry, any entrapped air is removed (e.g. under vacuum) and the resulting mixture is poured onto a suitable substrate and dried to remove the solvent to form a film ( e.g. thin film).

In a further embodiment, when the active ingredient is dispersed within the polymer matrix film (as opposed to being placed on the surface of the placebo polymer matrix), the active ingredient can be substantially evenly distributed throughout the polymer matrix.

If, alternatively, the active ingredient is present on the surface of the polymer film matrix, the placebo polymer film matrix (i.e. drug-free) is initially prepared as a continuous polymer film matrix and the active ingredient as part of a suitable formulation (dexmedetomidine formulation) directly applied to the surface with a dried continuous matrix of polymer film. In another embodiment, the placebo polymer matrix is formed as a continuous web that is cut into individual blocks prior to placing the dexmedetomidine composition on the surface of the placebo polymer matrix. One advantage of microarrayed matrix formulations and the method used to prepare them is that the final unit doses are less susceptible to variation in the amount of dexmedetomidine present than may occur during the production of conventional drug-containing monolithic films. The micro-placement helps ensure that a relatively more precise and consistent volume of formulation and dexmedetomidine is applied. Another advantage of microarrayed matrix compositions and the method used to prepare them is that different doses can be obtained from the same roll of film substrate. The dose either depends on the number of drops that are applied to a certain area of the substrate, or on the method of cutting the film after applying the drops, placed in an ordered pattern. Conversely, in drug-containing monolithic films, the process provides only the possibility of obtaining units containing the same dose of drug.

In a detailed embodiment of the solvent dip casting process, a solution containing one or more polymers (and optionally any suitable pharmaceutically acceptable carriers) is prepared, any entrapped air is removed (e.g. under vacuum) and the resulting mixture is poured onto a suitable support and dried to remove the solvent. with the formation of a film (for example, a thin film). Separately, the active ingredient and any other necessary ingredients, eg the pharmaceutically acceptable carrier(s) and/or polymeric component, are dissolved/dispersed in the liquid carrier to form a solution or suspension containing the active agent. The resulting solution or suspension of the active agent is then applied to a preformed film (ie, placebo polymer matrix).

In some exemplary embodiments, the method of depositing a solution or suspension of an active agent onto a placebo polymer matrix is by direct distribution, as described in more detail below. In some alternative examples of embodiments of the invention, direct distribution can also be carried out using a needle or an array of needles.

Broadly, methods for placing an active ingredient on a placebo polymer matrix according to exemplary embodiments utilize a small volume distribution of the active ingredient, typically in the range of 1 µl to about 5000 µl, 1 µl to about 100 µl, 1 µl to about 500 µl, 250 µl to about 750 µl, alternatively in the range of 500 µl to about 1000 µl, alternatively in the range of 1 µl to about 1000 µl, alternatively in the range of 500 µl to about 1500 µl, alternatively in the range of 1000 µl to about 2000 µl, alternatively in the range of 1500 µl to about 2500 µl, alternatively in the range of 2000 µl to about 3000 µl, alternatively in the range of about 2500 µl to about 3500 µl, alternatively in the range of 3000 µl to about 4000 µl , alternatively ranging from 3500 µl to about 4500 µl, alternatively ranging from about 4000 µl to about 5000 µl directly onto the surface of the placebo polymer matrix. In some embodiments, the entire volume is dispensed in one step, although for total volumes greater than 10 µl, it may be desirable to serially distribute smaller volumes adjacent and/or contiguous (e.g., in a linear fashion) over multiple cycles to form a microarranged matrix composition. .

Dexmedetomidine can be dispensed from the dosing head using a force that moves liquid from, or connected to, a reservoir in the dosing head onto the surface of the placebo polymer matrix. This can be achieved by progressive displacement pumping through a dosing head positioned above the surface of the placebo polymer matrix. The placebo polymer matrix can be a continuous sheet of polymer film or a single block of polymer. The dispenser head is usually, but not necessarily, a needle, such as a needle

- 16 040771 shaped tip of the type used in the above micro-placement processes.

The placement geometry of dexmedetomidine formed by direct distribution in accordance with exemplary embodiments of the invention may be of any type. In some embodiments of the invention, the active composition may be distributed in an annular form, as would be achieved by release of the composition from a cylindrical tip, in which the surface energy on the surface of the substrate is uniform. In accordance with other embodiments of the invention, a square, a rectangle, or even more complex polygonal shapes may be used. This can be achieved by providing a dispenser head in which the dexmedetomidine solution or suspension exits through the head and is pinpointed out of the head onto the target surface to form the desired shape. Thus, if the surface geometry of the dispenser head that is closest to the placebo polymer matrix is rectangular, then a rectangular placement is created.

Alternatively, a single dose may be obtained by repeated smaller dosing cycles from one or more dispensers. Each dispenser head can be attached to a robotic arm that controls where the liquid formulation of dexmedetomidine is applied on the placebo polymer matrix. Alternatively, the platform on which the placebo polymer matrix is mounted can be motorized to move the placebo polymer matrix so that a liquid-accommodating formulation is dispensed from a fixed dispenser head. These configurations allow the size and shape of the dose to be varied as needed.

It should be understood that other methods for distributing the liquid formulation of dexmedetomidine may also use different geometries. For example, the surface energy of the placebo polymer matrix can be modified to provide better wetting with the liquid formulation of dexmedetomidine. In one embodiment, a well-defined area on the surface of the placebo polymer matrix of increased surface energy is provided that facilitates fluid migration to cover the treated area by corona or plasma treatment using a mask with apertures of the resulting geometry. In another embodiment of the invention, the surface energy can be modified or specifically changed to achieve the desired flow characteristics during and after spreading. In yet another embodiment of the invention, a barrier or frame with the desired geometry is provided on a placebo polymer matrix, followed by distribution of the dexmedetomidine liquid from the dosing head over a defined area to create a placement with a specific geometry and uniformity. The dexmedetomidine composition is applied to the surfaces of the placebo polymer matrix within the boxed area in sufficient volume to fill the boxed area to the desired depth. This screen-printing technique allows the placebo polymer matrix to provide a peripheral seal around the active layer when the film is applied to the mucosa. This can prevent leakage of the active ingredient from the periphery of the active layer into the oral cavity and further helps to ensure that all of the drug is delivered via the desired mucosal pathway.

It should be understood that the liquid characteristics of the dispensed liquid dexmedetomidine formulation (dexmedetomidine composition) may affect the ability to consistently obtain a uniform distribution on the film. For progressive displacement pumping, the viscosity of the dexmedetomidine formulation fluid is, for example, in the range of 1 to 5000 cps as measured at 25 using a Brookfield viscometer with small sample adapter. However, the specific viscosity of the dexmedetomidine formulation in this range may vary depending on a variety of factors depending on the placement characteristics created, including how the liquid formulation is desired to behave after spreading on the substrate, which itself may be a function of the resulting geometry on the film. . For example, spotting a liquid film formulation so that it does not spread beyond the intended area can be affected by the viscosity of the liquid as well as its surface tension and the surface energy of the placebo polymer matrix.

Typically, the solvent dip casting process results in a film having a thickness of about 20 microns to about 1200 microns, such as about 50 microns to about 1000 microns, such as about 70 microns to about 200 microns. The dry film may be cut into appropriate sizes, typically about 1 cm ² to about 15 cm ² (e.g., about 1 cm ² to about 3 cm ² ), to provide a suitable dose of dexmedetomidine or a pharmaceutically acceptable salt thereof, for example, for a length of about 5 mm to about 15 mm (eg, 8.8±0.5 mm) and a width of about 10 mm to about 30 mm (eg, 22±1.5 mm).

In one embodiment of the invention, the film composition is prepared by a placement method that results in a placebo film having a substantially non-uniform distribution of dexmedetomidine or a pharmaceutically acceptable salt thereof on its surface. In some aspects, when the placement process requires or benefits from drying after

- 17 040771 rooms may use drying ovens and/or forced hot air supply. The drying temperature may vary from about 40°C to about 80°C. By adjusting the temperature so that the moisture content of the film is approximately <5%. The drying time may vary from about 5 minutes to about 180 minutes, such as from about 5 minutes to about 60 minutes. In some embodiments, the drying time may be about at least 30 minutes. Optionally, gentle air flow and low temperatures (~40-50°C) can be used in drying ovens. The rheology of a fluid of a particular composition for placement will determine the specific drying parameters required. In some embodiments, drying conditions may include heating at 70°C for 5-10 minutes. Each unit contains at least one patch of micro-placement composition. The viscosity of the microarrangement solution/suspension (dexmedetomidine composition) can range from about 6 cps to about 3700 cps when measured at 25° C. using a Brookfield viscometer with small sample adapter. For example, the viscosity is about 6 centipoise to about 500 centipoise, about 6 centipoise to about 200 centipoise, about 6 centipoise to about 100 centipoise, about 6 centipoise to about 50 centipoise, or about 6 centipoise to about 20 centipoise at 25 °C and the shear rate is about 7 (1/s).

If the placement does not require a drying step, then the process can continue after the initial drying of the substrate and during cutting of the main rolls. Since the film is a wide web, it is possible for a plurality of placement strips to be performed at the same time. It is also contemplated that the placement process can be carried out using a single track.

In addition, if the placement does not require drying after placement, the packaging machine can be equipped with a slitting station to control the width of the produced film. This is an independent station that can function in the production line during the manufacture of finished units. The composition can be applied to the surfaces of the placebo cut roll by using a single layer placement device in the production line at the cutting station. An in-line air knife and PC heater for gentle blowing of air over the film after placement ensured a slight drying of the placement despite application that did not require drying. This reduces the amount of solvent left in the placement, if necessary. After placement, the film is punched and packaged in single doses.

In other embodiments of the invention, any suitable drying process can be used, such as a thermal drying process. Other methods include forced gas air drying, in which hot air is blown at high speed from above onto the housing to minimize the boundary layer and promote mass transfer, dead-end oven drying, and IR drying, as examples.

Packaged films must be stored at a controlled temperature, for example about 15-30°C.

Another effect of the direct distribution of single unit doses is the possibility of vacuum drying the dispensed dexmedetomidine composition on the polymer matrix film. The use of vacuum drying provides faster drying times at lower temperatures, which in turn results in improved productivity, lower energy consumption (less heat) and improved film and drug stability as a result of lower temperatures. Vacuum drying can also give better content and dosage uniformity to patients with a reduced chance of defects from trapped air or bubbles. Improved productivity can be achieved by drying faster at lower pressures as well as allowing integration of other product conversion steps as part of the overall process sequence in the process line.

One example of a placement method includes the following steps:

(i) obtaining a first composition containing a polymeric component and one or more pharmaceutically acceptable carriers, including a liquid carrier, and optionally other pharmaceutically acceptable carriers;

(ii) solvent dipping casting the product of step (i) to obtain a polymer matrix (placebo polymer matrix);

(iii) transporting said polymer matrix through a dryer to form a dried polymer matrix;

(iv) obtaining a second composition containing dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable carriers, including a liquid carrier, and optionally other pharmaceutically acceptable carrier(s) and a polymeric component;

(v) placing the dexmedetomidine composition on the dried polymer matrix of step (iii) as one or more drops; and (vi) drying, including the possibility of drying without using a drying process, to remove at least a portion of the liquid carrier from the product of step (v) to obtain the final product.

Additional ingredients may also be applied to the dried film, for example by printing, spraying, spraying or vapor adsorption processes, among others.

- 18 040771

The film preparation may be processed into unit doses by any suitable method, including, for example, stamping or cutting across the width of a single narrow roll to prepare unit doses of any desired geometric dimensions or shapes. The unit doses can then be conventionally packaged with various suitable materials known in the art to prevent degradation and protect the active ingredient from deterioration.

It is desirable that a series of such single doses be packaged together according to the prescribed regimen or treatment, eg for 10-90 days delivery depending on the particular therapy. Individual films may also contain a base material that can be removed prior to use.

The present invention also provides film compositions of dexmedetomidine or pharmaceutically acceptable salts thereof, wherein the film has a thickness of from about 0.02 mm (20 µm) to about 0.2 mm (200 µm) to provide a weight in the range of about 0.5 mg up to about 200 mg. Thus, in some aspects, the film compositions comprise a polymeric matrix monolayer having a limited thickness allowing it to rapidly disintegrate in the oral environment and release dexmedetomidine or a pharmaceutically acceptable salt thereof without undue oral mucosal discomfort. Such a composition may be a placebo layer with a drug placed on the surface, or may contain the active ingredient in the polymer matrix itself.

In a further embodiment, we provided for the co-administration of the film of this disclosure along with a long acting dexmedetomidine formulation. Examples of long acting dexmedetomidine formulations include transdermal patches and depot formulations such as depot injections (eg IV or IM) or implantable devices. Examples of transdermal plasters include patching stages described in published patents/patent applications of the United States No. US 2015/0098980, US 2015/0098997, US 2015/0098983, US 2015/0098982, US 2015/0098981, US 2018/0117012, US 20140328898, USE, 2014032898, US , US 5817332, US 5217718, US 5820875 and US 9974754 and related patents/patent applications.

A specific embodiment of the invention provides a method for treating agitation in a subject, comprising administering to the subject a film of the present invention and simultaneously or sequentially administering a long acting dexmedetomidine transdermal patch composition, optionally followed by additional administration of a film of the present invention.

A further embodiment of the invention provides a method for treating agitation in a subject comprising administering to the subject a film of the present invention and simultaneously or sequentially administering a long acting dexmedetomidine depot injectable composition, optionally followed by administering a film of the present invention.

Therapeutic application of film compositions.

The film compositions described herein may be used to treat a variety of disorders/conditions, including agitation associated with neurodegenerative conditions selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), dementia, Lewy body dementia (DLB ), post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy; senile dementia in Alzheimer's disease (SDAT);

agitation associated with neuropsychiatric conditions selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium, and depression, including dementia or mood disorders in subjects with major depression (eg, stress-related major depression);

agitation associated with other conditions such as OPD/IPD procedures (eg, MPT, CT, or CAT scans, lumbar puncture, bone marrow aspiration/biosia, tooth extractions, and other dental procedures);

alcohol-related agitation, opioid use disorder, opioid withdrawal, and withdrawal of an addictive substance;

delirium;

traumatic brain injury (TBI), including TBI subjects with alcohol or other substance disorder (ASUD);

post-traumatic stress disorder (PTSD), including PTSD subjects with alcohol or other substance disorder (ASUD);

tardive dyskinesia.

The film compositions disclosed herein find particular use in the treatment of acute agitation associated with the disorders/conditions described above.

The film compositions disclosed herein also find particular use in the treatment of hyperarousal associated with acute agitation in patients with schizophrenia, bipolar disorder.

- 19 040771 disorder and dementia.

The film compositions disclosed herein also find particular utility in the treatment of acute agitation without causing significant sedation.

The film compositions disclosed herein also find particular utility in the treatment of chronic agitation without causing significant sedation.

The film compositions disclosed herein may also be used as adjunct therapeutic agents for exposure therapy for the treatment of post-traumatic stress disorder (PTSD).

The film compositions disclosed herein may also be used to treat PTSD with or without standard PTSD treatment.

The film compositions disclosed herein also find particular use in the treatment of post-traumatic stress disorder (PTSD) associated with alcohol or other substance use disorder (ASUD).

The film compositions disclosed herein can also be used as an adjuvant therapeutic agent before, during, or after exposure therapy (ET) for ASUD patients with concomitant PTSD or traumatic brain injury.

In one aspect, the film compositions disclosed herein may be used to treat PTSD patients who are suffering from alcohol and/or substance abuse, for example, in the treatment of PTSD patients who are trying to overcome alcohol and/or drug addiction and are sensitive to withdrawal symptoms from alcohol and/or addictive substance.

In another aspect, the film compositions disclosed herein may be used to treat TBI patients who suffer from alcohol and/or substance abuse, for example, in the treatment of TBI patients who are trying to overcome alcohol and/or drug addiction and are sensitive to withdrawal symptoms from alcohol and/or addictive substance.

Patients, also referred to as subjects, are typically human subjects. In aspects of the invention, the human is at least 55 years old, at least 60 years old, at least 65 years old, or at least 75 years old. Thus, the methods and compositions described herein find use, for example, in people aged 55 to 75 years.

In one aspect, the invention provides methods for treating or alleviating agitation associated with neurodegenerative conditions by administering to such patients in need of treatment a dexmedetomidine film formulation as described herein.

In another aspect, the present invention provides methods for treating or alleviating agitation associated with neuropsychiatric conditions by administering to such patients in need of treatment a dexmedetomidine film formulation as described herein.

In a further aspect, the present invention provides methods for treating or alleviating agitation associated with other conditions, such as OPD/IPD procedures (e.g., MPT, CT or CAT, lumbar puncture, bone marrow aspiration/biopsy, tooth extraction, or other dental procedures) by administering to such patients in need of treatment a dexmedetomidine film formulation as described herein.

In a further aspect, the present invention provides methods for treating or alleviating agitation associated with alcohol or addictive substance withdrawal by administering to such patients in need of treatment a dexmedetomidine film formulation as described herein.

The dosage forms described herein dissolve or disintegrate rapidly in the patient's mouth without chewing or the need for water.

Because of their ease of administration, such compositions are particularly suited to the specific needs of patients with impaired motor skills.

A typical unit dose of dexmedetomidine or a pharmaceutically acceptable salt thereof includes about 0.5 µg to about 200 µg, about 0.5 to 150 µg, about 1 to 100 µg, about 3 to 90 µg, about 3 to 80 µg , about 3 to 70 micrograms, about 3 to 60 micrograms, about 3 to 50 micrograms, about 3 to 40 micrograms, about 3 to 35 micrograms, about 5 to 35 micrograms, about 10 to 50 micrograms, about 10 to 40 micrograms, about 10 to 35 micrograms, about 15 to 35 micrograms, or about 15 to 35 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. In certain embodiments, the unit dose is about 10 micrograms, about 15 micrograms, about 20 micrograms, about 25 micrograms, about 30 micrograms, about 35 micrograms, about 40 micrograms, about 45 micrograms, about 50 micrograms, about 55 micrograms, about 60 micrograms. , about 65 micrograms, about 70 micrograms, about 75 micrograms, about 80 micrograms, about 85 micrograms, about 90 micrograms, about 95 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, about 130 micrograms, about 140 micrograms or about 150 mcg. Each unit dose may be administered to a subject multiple times per day, including twice, three times, four times, five times, or six times per day.

Exemplary dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof, administered

- 20 040771 my particular patient will depend on the type and extent of the condition, the general health of the particular patient, the particular form of dexmedetomidine or its pharmaceutically acceptable salt administered, and the particular film formulation used to treat the patient.

Combined therapy.

In one embodiment, the invention provides a film as described herein, wherein the film contains dexmedetomidine or a pharmaceutically acceptable salt thereof, together with one or more additional therapeutic agents. Such combination therapy may be particularly useful in the treatment of agitation of conditions caused or exacerbated by alcohol or other substance abuse, including post-traumatic stress disorder and traumatic brain injury (TBI).

Examples of suitable additional therapeutic agents include opioid antagonists (eg, naltrexone or naloxone), partial opioid agonists (eg, buprenorphine, butorphanol, pentazocycin, or tramadol), and antidepressants such as serotonin-norepinephrine reuptake inhibitors (eg, amitriptyline, atomoxetine, desipramine, duloxetine, maprotiline, mefazodone, milnacipan, nefazodone, protriptyline, trimipramine, reboxetine, venlafaxine, or viloxazine) or selective serotonin inhibitors, reuptake inhibitors (eg, citalopram, fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, or escitalopram). For example, a film containing dexmedetomidine or a pharmaceutically acceptable salt thereof disclosed herein may improve response to currently used treatments in subjects with PTSD, such as serotonin-norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, for example, by achieving faster response or enhanced response before initial use and after use of a serotonin-norepinephrine reuptake inhibitor or a selective serotonin reuptake inhibitor. Dexmedetomidine, or a pharmaceutically acceptable salt thereof, may also be used in combination with an NMDA receptor antagonist such as ketamine to treat major depression, such as agitation in subjects with dementia or stress-mediated major depression mood disorders.

In one embodiment, the present invention provides a film as described herein, wherein the film contains dexmedetomidine or a pharmaceutically acceptable salt thereof together with an opioid antagonist or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention provides a film as described herein, wherein the film comprises dexmedetomidine, or a pharmaceutically acceptable salt thereof, together with an effective amount of an opioid antagonist, or a pharmaceutically acceptable salt thereof, to treat agitation without causing excessive sedation.

In a further embodiment, the present invention provides a film as described herein, wherein the film comprises dexmedetomidine, or a pharmaceutically acceptable salt thereof, together with an effective amount of an opioid antagonist, or a pharmaceutically acceptable salt thereof, for the treatment of agitation associated with opioid or other substance withdrawal.

In a specific embodiment, the present invention provides a film as described herein, wherein the film contains dexmedetomidine or a pharmaceutically acceptable salt thereof together with naltrexone or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a film as described herein, wherein the film comprises dexmedetomidine or a pharmaceutically acceptable salt thereof together with a partial opioid agonist or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention provides a film as described herein, wherein the film comprises dexmedetomidine, or a pharmaceutically acceptable salt thereof, together with an effective amount of a partial agonist, or a pharmaceutically acceptable salt thereof, to treat agitation without causing excessive sedation.

In a further embodiment, the present invention provides a film as described herein, wherein the film comprises dexmedetomidine, or a pharmaceutically acceptable salt thereof, together with an effective amount of a partial agonist, or a pharmaceutically acceptable salt thereof, for the treatment of opioid withdrawal agitation.

In a specific embodiment, the present invention provides a film as described herein, wherein the film contains dexmedetomidine or a pharmaceutically acceptable salt thereof together with buprenorphine or a pharmaceutically acceptable salt thereof.

An effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and an opioid antagonist or partial agonist may be included in the film of the present invention to provide the desired effect.

In one embodiment, the film contains from about 5 to 150 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and from about 2 mg to about 16 mg of a partial agonist per unit. More desirably, the film contains from about 5 to 150 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and from about 4 mg to about 12 mg of a partial agonist per unit.

In another embodiment, the film contains from about 5 to 150 micrograms of dexmedeto

- 21 040771 midin or its pharmaceutically acceptable salt and from about 0.5 mg to about 5 mg of the opioid antagonist per unit. More desirably, the film contains about 5 to 150 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 1 mg to about 3 mg of an opioid antagonist per unit.

In one specific embodiment, the film contains about 10 to 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 0.5 mg of naltrexone, or about 10 to 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 1 mg of naltrexone, or from about 10 to 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 2 mg of naltrexone, or about 10 to 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 3 mg of naltrexone, or about 10 to 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, and about 4 mg naltrexone or any equivalent amount.

In another specific embodiment, the film contains about 10 to 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 2 mg of buprenorphine, or about 10 to 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 4 mg of buprenorphine, or from about 10 to 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 6 mg of buprenorphine, or about 10 to 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 8 mg of buprenorphine, or about 10 to 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 10 mg buprenorphine, or about 10 to 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 12 mg of buprenorphine, or about 10 to 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and about 16 mg of buprenorphine or any similar amounts.

The drug combinations above can be included in the monolithic film of the present invention or the microarrangement film of the present invention. If in a monolithic film, the present invention proposes the presence of all drugs in one layer of the matrix film. Drugs may also be present in separate monolithic films, which are then combined to form a multilayer film.

In one embodiment (and more conveniently), the drugs are included in a microarrangement film according to this disclosure. Thus, for example, individual drug compositions can be added as discrete droplets to the surface of a film support (i.e., placebo film) in accordance with the general process used and described herein for adding a dexmedetomidine composition to a film support. Drops can be added in any pattern to meet the required requirements for a single dose. Each drop may contain a dye, which may be the same or different for each drug composition. It may be convenient to use different dyes to distinguish different drugs on the surface of the film substrate.

In one embodiment, we provide a method for treating agitation in a subject, comprising administering to the subject a film of the present invention with concomitant exposure therapy.

In another embodiment, examples of suitable therapeutic agents to be combined with dexmedetomidine in a film composition include selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, sertraline, serotonin, and norepinephrine (SNRI) inhibitors, such as desipramine. In one embodiment, the present invention provides a film as described herein, wherein the film comprises dexmedetomidine or a pharmaceutically acceptable salt thereof together with a selective serotonin reuptake inhibitor or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a film as described herein, wherein the film comprises dexmedetomidine or a pharmaceutically acceptable salt thereof together with a serotonin norepinephrine reuptake inhibitor or a pharmaceutically acceptable salt thereof.

In a specific embodiment, the present invention provides a film as described herein, wherein the film contains dexmedetomidine or a pharmaceutically acceptable salt thereof together with desipramine or a pharmaceutically acceptable salt thereof.

An effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and ketamine or a pharmaceutically acceptable salt thereof may be included in the film of the present invention to provide the desired effect.

Specific Embodiments

Embodiment 1. A pharmaceutical film composition suitable for sublingual administration, comprising (i) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof;

(ii) a polymeric component consisting of one or more water-soluble polymers; and (iii) one or more pharmaceutically acceptable carriers.

Embodiment 2. A pharmaceutical film composition suitable for sublingual administration, consisting essentially of (i) a therapeutically effective amount of dexmedetomidine or a pharmaceutical formulation thereof

- 22 040771 Lemoy salt;

(ii) a polymeric component consisting of one or more water-soluble polymers; and (iii) one or more pharmaceutically acceptable carriers.

Embodiment 3. The pharmaceutical film composition of Embodiment 1 or Embodiment 2, wherein said polymeric component consists of at least two different water-soluble polymers.

Embodiment 4. The pharmaceutical film composition of Embodiment 3, wherein the first water-soluble polymer has a molecular weight of from about 5,000 Daltons to about 49,000 Daltons and the one or more second water-soluble polymers have a molecular weight of greater than about 60,000 Daltons.

Embodiment 5. The pharmaceutical film composition of Embodiment 3 or Embodiment 4, wherein the ratio of the first water-soluble polymer to the second water-soluble polymer(s) (including PEO if present in the film) in the entire film composition is from about 1:10 to about 1:30, from about 1:15 to about 1:25, or from about 1:15 to about 1:20.

Embodiment 6. The pharmaceutical film composition of Embodiment 4 wherein the first water soluble polymer is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose and mixtures thereof.

Embodiment 7 The pharmaceutical film composition of Embodiment 6 wherein the first water soluble polymer is composed of hydroxypropyl cellulose and hydroxyethyl cellulose.

Embodiment 8. The pharmaceutical film composition of Embodiment 4 wherein the one or more second water soluble polymers are/are selected from the group consisting of polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose and mixtures thereof.

Embodiment 9. The pharmaceutical film composition of Embodiment 7 wherein the second water soluble polymer(s) is(are) selected from hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide and mixtures thereof.

Embodiment 10. The pharmaceutical film composition of any one of Embodiments 1-9, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

Embodiment 11. The pharmaceutical film composition of any one of Embodiments 1-10 in the form of a dosage unit, wherein the amount of dexmedetomidine or a pharmaceutically acceptable salt thereof present per unit is from about 0.5 µg to about 150 µg, from about 1 µg to about 100 µg, from about 3 µg to about 90 µg, from about 3 µg to about 80 µg, from about 3 µg to 70 µg, from about 3 µg to about 60 µg, from about 3 µg to 50 µg, from about 3 µg to about 35 µg, about 3 µg to about 50 µg, about 5 µg to about 50 µg, about 5 µg to about 45 µg, about 3 µg to about 40 µg, about 5 µg to about 35 µg, about 10 µg to about 50 µg, about 10 µg to about 40 µg, about 10 µg to about 35 µg, about 15 µg to about 35 µg, or about 15 µg to about 35 µg of dexmedetomidine or a pharmaceutical thereof acceptable salt.

Embodiment 12. The pharmaceutical film composition of any one of Embodiments 1-11, wherein the dexmedetomidine hydrochloride is present in an amount of from about 0.01 wt% to about 50 wt% of the film on a dry weight basis, such as from about 0.05 wt.% to about 30 wt.% film in terms of dry weight, for example from about 0.05 wt.% to about 20 wt.% film in terms of dry weight.

Embodiment 13. The pharmaceutical film composition of any one of Embodiments 1-12, wherein the pharmaceutically acceptable carrier includes, but is not limited to, one or more liquid carriers, flavoring agents, sweeteners, refreshing agents, pH adjusting agents, penetration enhancers, mucoadhesive agents. , plasticizers, bulking agents, surfactants, antifoam agents, colorants, or the like.

Embodiment 14. The pharmaceutical film composition of any one of Embodiments 1-13, wherein the film has a thickness of about 20 microns to about 1200 microns.

Embodiment 15. The pharmaceutical film composition of any one of embodiments 1-14 wherein the film, when placed sublingually, will dissolve within about 10 seconds to about 180 seconds, such as about 60 seconds to about 180 seconds.

Embodiment 16 The pharmaceutical film composition of any one of Embodiments 1-15, wherein the film is mucoadhesive in nature.

Embodiment 17. The pharmaceutical film composition of any one of Embodiments 1-16, wherein the disintegration time of the film composition when brought into contact with simulated liquids is from about 10 seconds to about 180 seconds, from about 15 seconds to about 180 seconds, from about 30 s to about 180 s, about 45 s to about 180 s, about 60 s to about 180 s, or about 60 s to about

- 23 040771

140 s; or the disintegration time of the film composition upon contact with the simulated liquids is from about 15 seconds to about 180 seconds, from about 15 seconds to about 160 seconds, from about 25 seconds to about 150 seconds, from about 15 seconds to about 140 seconds, from about 15 s to about 120 s, from about 40 s to about 120 s, from about 50 s to about 120 s, for example about 120 s.

Embodiment 18. A process for preparing a pharmaceutical film composition comprising the steps of (i) preparing a mixture containing dexmedetomidine or a pharmaceutically acceptable salt thereof, polymeric component(s), and one or more pharmaceutically acceptable carriers, including a liquid carrier and optionally one or more other pharmaceutically acceptable carriers;

(ii) dispersing or casting the mixture onto a support to form a drug-containing polymer matrix; and (iii) drying the drug-containing polymer matrix to remove at least a portion of the carrier liquid to form a drug-containing matrix monolithic film composition.

Embodiment 19. A method for preparing a pharmaceutical composition of a film composition, comprising the steps of (i) obtaining a monolithic film matrix composition according to Embodiment 18, except that the composition does not contain dexmedetomidine or a pharmaceutically acceptable salt thereof (i.e., a placebo film composition);

(ii) obtaining a second composition containing dexmedetomidine or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers, including a liquid carrier, and optionally one or more other pharmaceutically acceptable carriers and/or a polymeric component;

(iii) placing the product of step (ii) on the surface of the film composition of the placebo of step (i), for example, in the form of one or more drops; and (iv) drying the product of step (iii) to remove at least a portion of the liquid carrier to form a matrix film composition containing the drug on the surface of the film.

Embodiment 20. The method of Embodiment 19 wherein the second composition contains a polymeric component.

Embodiment 21. A method of treating agitation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical film composition of any one of Embodiments 1-15.

Embodiment 22. The method of Embodiment 21 wherein the pharmaceutical film composition is placed in the oral cavity of the subject under the tongue.

Embodiment 23. The method of embodiment 21 or 22 wherein the agitation is associated with neurodegenerative diseases selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), dementia, Lewy body dementia (DLB), post-traumatic stress disorder (PTSD), Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy.

Embodiment 24. The method of embodiment 21 or 22 wherein the agitation is associated with neuropsychiatric conditions selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium, and depression.

Embodiment 25. The method of embodiment 21 or 22 wherein the agitation is associated with circumstances such as OPD/IPD procedures (e.g., MPT, CT, or CAT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extraction, or other dental procedures ).

Embodiment 26. The method of embodiment 21 or 22 wherein the agitation is associated with alcohol withdrawal, opioid use disorder, opioid withdrawal, and withdrawal of the addictive substance.

Embodiment 27. The pharmaceutical film composition obtained according to Embodiment 18 or Embodiment 19, wherein said polymeric component consists of at least two different water-soluble polymers.

Embodiment 28 The pharmaceutical film composition of Embodiment 27, wherein the first water-soluble polymer has a molecular weight of about 5,000 Daltons to about 49,000 Daltons and each of the one or more second water-soluble polymers has a molecular weight of greater than 60,000 Daltons.

Embodiment 29. The pharmaceutical film composition of Embodiment 18 or Embodiment 28, wherein the ratio of the first water-soluble polymer to the second water-soluble polymer(s) (including PEO, if present in the film) in the entire film composition is from about 1:10 to 1:30, from about 1:15 to about 1:25, or from about 1:15 to about 1:20.

Embodiment 30. The pharmaceutical film composition of Embodiment 19 or Embodiment 28, wherein the ratio of the first water-soluble polymer to the second

- 24 040771 mu(th) water-soluble(th) polymer(s) (including PEO, if present in the film) in the polymer matrix composition (placebo) is from about 1:10 to 1:30, from about 1:15 to about 1 :25 or from about 1:15 to about 1:20.

Embodiment 31. A method of treating opioid withdrawal agitation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical film composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and an effective amount of an opioid antagonist.

Embodiment 32. A method of treating opioid withdrawal agitation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical film composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and an effective amount of a partial agonist.

Embodiment 33. A method of treating PTSD-related agitation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical film composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof as an exposure therapy adjuvant.

Embodiment 34. A method of treating post-traumatic stress disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical film composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof as an exposure therapy adjuvant.

Embodiment 35. A method of treating opioid withdrawal post-traumatic stress disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical film composition comprising an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 36. A method of treating a traumatic brain injury in a subject in need thereof, the method comprising administering to the subject a pharmaceutical film composition containing an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Examples

Example 1 Thin Film Formulations.

Composition 1.

Table 1

Dexmedetomidine hydrochloride dispersed in a polymer matrix film composition

Ingredients Concentration g/100 g Function Dexmedetomidine hydrochloride 3.60 Active substance Hydroxypropylcellulose (MM = 40,000) 4.82 film former Hydroxypropylcellulose (MM = 140,000) 4.82 film former Hydroxypropylcellulose (MM = 370,000) 28.94 film former polyethylene oxide (MM = 600,000) 57.84 Film-forming and mucoadhesive agent Purified water* in enough. quantity Solvent (or liquid carrier)

* Essentially removed from the final composition by drying.

Process. All ingredients listed in Table. 1 was dissolved in water with stirring, poured through a fixed gap onto a protective tape support to form a film, and then dried in a laboratory oven at 70° C. for 30 minutes to obtain a thin film preparation.

Composition 2.

table 2

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Film Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.48 Active substance Ethanol* enough. quantity Solvent Composition with polymer matrix Hydroxypropylcellulose (MM = 40,000) 4.98 film former Hydroxypropylcellulose (MM = 140,000) 4.98 film former Hydroxypropylcellulose (MM = 370,000) 29.86 film former polyethylene oxide (MM = 600,000) 59.70 Film-forming and mucoadhesive agent Purified water* enough. quantity Solvent (or liquid carrier)

* Essentially removed from the final composition by drying.

Process. All polymers of the polymer matrix composition were dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70°C for 30 min. Separately, dexmedetomidine hydrochloride was dissolved in ethanol on a vortex mixer and then applied (as drops) with a volumetric pipette onto the film. Placed drug composition was dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

- 26 040771

Composition 3.

Table 3

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine 0.34 Active substance Sodium chloride 0.10 pH neutralizing agent Sodium hydroxide 0.65 pH neutralizing agent Ethanol* enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Hydroxypropylcellulose (MM = 40,000) 4.74 film former Hydroxypropylcellulose (MM = 140,000) 4.74 film former Hydroxypropylcellulose (MM = 370,000) 28.44 film former Polyethylene oxide (MM = 600,000) 56.86 Film-forming and mucoadhesive agent Glycine 3.80 Alkaline buffer Sodium hydroxide 0.33 Alkaline buffer Purified water* enough. quantity Solvent (or liquid carrier)

* Essentially removed from the final composition by drying.

Process. All polymers and alkaline buffers of the polymer matrix composition were dissolved in water with stirring, poured through a fixed gap onto a protective tape substrate to form a film, and then dried in a laboratory oven at 70°C for 30 min. Separately, dexmedetomidine hydrochloride was dissolved in ethanol on a vortex mixer, neutralized with an excess of sodium hydroxide and sodium chloride, and then applied (in the form of drops) using a volumetric pipette on the film. Placed drug composition was dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 4.

Table 4

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.48 Active substance Hydroxypropylcellulose (MM = 40,000) 2.08 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Hydroxypropylcellulose (MM = 40,000) 4.87 film former Hydroxypropylcellulose (MM = 140,000) 4.87 film former Hydroxypropylcellulose (MM = 370,000) 29.23 film former Polyethylene oxide (MM = 600,000) 58.47 Film-forming and mucoadhesive agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers of the polymer matrix composition were dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70°C for 30 min. Separately, dexmedetomidine hydrochloride and hydroxypropyl cellulose (MM 40000) were dissolved in ethanol on a vortex mixer and then applied (dropwise) with a volumetric pipette onto the film. Placed drug composition was dried in a laboratory oven at 70°C for 5 minutes to obtain a thin film preparation.

- 27 040771

Composition 5.

Table 5

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.47 Active substance Hydroxypropylcellulose (MM = 40,000) 0.28 film former Hydroxypropylcellulose (MM = 140,000) 0.28 film former Hydroxypropylcellulose (MM = 370,000) 1.54 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Hydroxypropylcellulose (MM = 40,000) 4.87 film former Hydroxypropylcellulose (MM = 140,000) 4.87 film former Hydroxypropylcellulose (MM = 370,000) 29.23 film former Polyethylene oxide (MM = 600,000) 58.46 Film-forming and mucoadhesive agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers of the polymer matrix composition were dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70°C for 30 min. Separately, the dexmedetomidine hydrochloride and hydroxypropyl cellulose drug-containing composition were dissolved in ethanol on a vortex mixer and then applied (dropwise) with a volumetric pipette onto the film. Placed drug composition was dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 6.

Table 6

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.48 Active substance Hydroxypropylcellulose 0.26 Film-forming (MM = 40,000) substance Hydroxypropylcellulose (MM = 140,000) 0.26 film former Hydroxypropylcellulose (MM = 370,000) 1.57 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Peppermint Oil 2.06 flavoring Sucralose 0.97 Sweetener Durable emerald green 0.13 Dye Hydroxypropylcellulose (MM = 40,000) 4.7 film former Hydroxypropylcellulose (MM = 140,000) 4.7 film former

- 28 040771

Hydroxypropylcellulose (MM = 370,000) 28.29 film former Polyethylene oxide (MM = 600,000) 56.58 Film-forming and mucoadhesive agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers and other ingredients of the polymer matrix composition were dissolved in water with stirring, poured through a fixed gap onto a protective tape substrate to form a film, and then dried in a laboratory oven at 70°C for 30 min. Separately, the dexmedetomidine hydrochloride and hydroxypropyl cellulose drug-containing composition were dissolved in ethanol on a vortex mixer and then applied (dropwise) with a volumetric pipette onto the film. Placed drug composition was dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 7.

Table 7

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.48 Active substance Hydroxypropylcellulose oh and Film-forming (MM = 40,000) substance Hydroxypropylcellulose (MM = 140,000) oh and film former Hydroxypropylcellulose (MM = 370,000) 0.63 film former Polyethylene oxide (MM = 600,000) 1.25 film former ethanol enough. quantity Solvent (or liquid carrier) Purified water enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Hydroxypropylcellulose (MM = 40,000) 4.87 film former Hydroxypropylcellulose (MM = 140,000) 4.87 film former Hydroxypropylcellulose (MM = 370,000) 29.23 film former Polyethylene oxide (MM = 600,000) 58.45 Film-forming and mucoadhesive agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers of the polymer matrix composition were dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70°C for 30 min. Separately, dexmedetomidine hydrochloride and the polymers of the drug-containing composition were dissolved in a mixture of ethanol and water on a vortex mixer, and then applied (as drops) using a volumetric pipette onto the film. Placed drug composition was dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 8.

Table 8

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.49 Active substance Butanol enough. quantity Solvent (or

- 29 040771

| liquid carrier) Composition with polymer matrix Hydroxypropylcellulose (MM = 40,000) 4.98 film former Hydroxypropylcellulose (MM = 140,000) 4.98 film former Hydroxypropylcellulose (MM = 370,000) 29.85 film former Polyethylene oxide (MM = 600,000) 59.70 Film-forming and mucoadhesive agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers of the polymer matrix composition were dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70°C for 30 min. Separately, dexmedetomidine hydrochloride was dissolved in n-butanol on a vortex mixer and then applied (as drops) with a volumetric pipette onto the film. Placed drug composition was dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 9.

Table 9

Dexmedetomidine placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine 0.41 Active substance Sodium chloride 0.12 Neutralizing pH agent Hydroxypropylcellulose (MM = 40,000) 0.26 film former Hydroxypropylcellulose (MM = 140,000) 0.26 film former Hydroxypropylcellulose (MM = 370,000) 1.57 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Peppermint Oil 2.06 flavoring Sucralose 0.97 Sweetener Durable emerald green 0.13 Dye Hydroxypropylcellulose (MM = 40,000) 4.70 film former Hydroxypropylcellulose (MM = 140,000) 4.70 film former Hydroxypropylcellulose (MM = 370,000) 28.27 film former Polyethylene oxide (MM = 600,000) 56.55 Film-forming and mucoadhesive agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers and other ingredients of the polymer matrix composition were dissolved in water with stirring, poured through a fixed gap onto a protective tape substrate to form a film, and then dried in a laboratory oven at 70°C for 30 min. Separately, the dexmedetomidine, sodium chloride, and hydroxypropyl cellulose drug-containing composition were dissolved in ethanol on a vortex mixer and then applied (dropwise) with a volumetric pipette onto the film. Placed drug composition was dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

- 30 040771

Composition 10.

Table 10

Dexmedetomidine placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine 0.34 Active substance Sodium chloride 0.10 pH neutralizing agent Hydroxypropylcellulose (MM = 40,000) 0.22 film former Hydroxypropylcellulose (MM = 140,000) 0.22 film former Hydroxypropylcellulose (MM = 370,000) 1.31 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Peppermint Oil 2.07 flavoring Sucralose 0.98 Sweetener Durable emerald green 0.13 Dye Hydroxypropylcellulose (MM = 40,000) 4.53 film former Hydroxypropylcellulose (MM = 140,000) 4.53 film former Hydroxypropylcellulose (MM = 370,000) 27.16 film former Polyethylene oxide (MM = 600,000) 54.33 Film-forming and mucoadhesive agent Glycine 3.76 Alkaline buffer Sodium hydroxide 0.32 pH neutralizing agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers and other ingredients of the polymer matrix composition were dissolved in water with stirring, poured through a fixed gap onto a protective tape substrate to form a film, and then dried in a laboratory oven at 70°C for 30 min. Separately, the dexmedetomidine, sodium chloride, and hydroxypropyl cellulose drug-containing composition were dissolved in ethanol on a vortex mixer and then applied (dropwise) with a volumetric pipette onto the film. Placed drug composition was dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 11.

Table 11

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.38 Active substance ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Hydroxypropylcellulose (MM = 40,000) 4.47 film former Hydroxypropylcellulose 4.47 Film-forming (MM = 140,000) substance Hydroxypropylcellulose (MM = 370,000) 26.83 film former Polyethylene oxide (MM = 600,000) 53.61 Film-forming and mucoadhesive agent sodium lactate 6.52 acid buffer Lactic acid 3.72 acid buffer Purified water enough. quantity Solvent (or liquid carrier)

- 31 040771

Process. All polymers and the acid buffer system of the polymer matrix composition were dissolved in water with stirring, poured through a fixed gap onto a protective tape substrate to form a film, and then dried in a laboratory oven at 70°C for 30 min. Separately, dexmedetomidine hydrochloride was dissolved in ethanol on a vortex mixer and then applied (as drops) with a volumetric pipette onto the film. Placed drug composition was dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 12.

Table 12

Dexmedetomidine placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g (10 µg film) Concentration g/100 g (20 µg film) Function Medicinal composition Dexmedetomidine hydrochloride 0.136 0.267 active agent Hydroxypropylcellulose, HPC-SSL (MM = 40,000) 0.301 0.593 film former Hydroxypropylcellulose (MM = 140,000) 0.301 0.593 film former Blue No. 1 FD&C, granulated 0.002 0.004 Dye Ethyl alcohol as a solvent DOST, quantity DOST, quantity Solvent Composition with polymer matrix Hydroxypropylcellulose (MM = 140,000) 4,803 4.768 film former Hydroxypropylcellulose, HPC-SSL (MM = 40,000) 4,803 4.768 film former Hydroxypropylcellulose (MM = 370,000) 28.809 28.601 film former Hue durable emerald green (No. 06507) 0.129 0.128 Dye Sucralose, USPNF quality 0.993 0.985 Sweetener Peppermint Oil, NF 2.104 2.089 flavoring Polyethylene oxide (Sentry Poly ox WSR 205 LEO NF) (MM = 600,000) 57.618 57.202 Film-forming and mucoadhesive agent Water as solvent DOST, quantity DOST, quantity Solvent

(A) The process of preparing the polymer matrix.

polymer blend. The polyethylene oxide and the strong emerald green were mixed in water for at least 180 minutes at about 1400 rpm to about 2000 rpm. Sucralose, hydroxypropyl cellulose (molecular weight 140 K), hydroxypropyl cellulose, HPC-SSL (molecular weight 40 K) and hydroxypropyl cellulose (molecular weight 370 K) were added and mixed for at least 120 minutes at about 1600 rpm to 2000 rpm. min. Peppermint oil was added to the water and the resulting dispersion was then added to the polymer mixture and mixed for at least 30 minutes. The resulting mixture was further stirred under vacuum (248 Torr) for at least 30 minutes at 350 rpm and at a temperature of 22.9°C.

Coating station. A roll was mounted on an unwind stand and the leading edge passed through the guide rods and the coating rods. The protective tape was placed with the silicone coated side up. A gap of 40 mm was maintained between the coating rods. The oven temperature was adjusted to 70°C and the final drying temperature was adjusted to 85°C.

Coating/drying process. The polymer mixture was poured onto the belt between the guide rods and the coating rods. The tape was slowly pulled through the coating rods at a constant speed by hand until no liquid remained on the coating rods. The tape was cut approximately into sheets about 12 inches long using

- 32 040771 safety knife. Each sheet was placed on a dryer plate and attached at the corners to prevent curling during drying. The sheets were dried in an oven until the moisture content was less than 5% (approximately 30 minutes) and then removed from the dryer plate. The coating weight was checked against acceptance criteria and, if met, the sheets were then stacked and placed in a 34x40 inch foil envelope that was secured with PET security tape.

(B) The process of preparing the placement solution.

Dissolve blue FDC in ethanol for at least 180 minutes. Dexmedetomidine hydrochloride was added to the ethanol solution with continuous stirring for 10 minutes at about 400 rpm to about 800 rpm. Hydroxypropyl cellulose (40 K) and hydroxypropyl cellulose (140 K) were added to the mixture and stirred for at least 30 minutes until all substances were dissolved.

(C) The process of obtaining a micro-placed matrix.

The placement solution obtained in step (B) above was pipetted to the required volume (determined according to the specific dosage of the end product drug). Place an appropriate amount (1.5 μl=approximately 5 μg) of the placement solution (e.g. droplets) onto the polymer matrix obtained in step (A) and repeat up to a total of 10 times (i.e. 10 placements/ drops) with a gap between each placement to prevent the combination of placements/drops and allow further cutting of the film into individual units containing the drug. The film was initially cut into individual 22x8.8 mm units containing one placement of the drug containing composition. The punch-cut microarranged matrices were then dried in a 70° C. oven for 10 minutes and further punch-cut into 10 units, each unit containing one placement of the drug-containing composition.

(D) Packaging.

Each defect-free unit was sealed individually in a foil bag, which was then sealed. If heat sealing was acceptable, then the package was considered an acceptable unit for commercial use.

Similarly, other dosage units (eg, 40, 60, and 80 μg films) were prepared by varying the concentrations of drug, polymers, and dye in the drug-containing composition. For example, 40, 60, and 80 μg films were prepared from drug-containing compositions containing, respectively, approximately 2x, 3x, and 4x the amounts of drug, polymers, and dye found in the 20 μg drug composition described in Table 1. 12 above.

Composition 13

Table 13

Dexmedetomidine placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine HCL 0.33 Active substance ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Hydroxypropylcellulose (MM = 40,000) 4.99 film former Hydroxypropylcellulose (MM = 140,000) 4.99 film former Hydroxypropylcellulose (MM = 370,000) 29.90 film former Polyethylene oxide (MM = 600,000) 59.79 Film-forming and mucoadhesive agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers of the polymer matrix composition were dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70°C for 30 min. Separately, dexmedetomidine hydrochloride was dissolved in ethanol on a vortex mixer and then applied (as drops) with a volumetric pipette onto the film. Placed drug composition was dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

- 33 040771

Composition 14.

Table 14

Dexmedetomidine placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine 0.34 Active substance Sodium chloride 0.10 Neutralizing pH agent Hydroxypropylcellulose (MM = 140,000) 0.44 film former Hydroxypropylcellulose (MM = 370,000) 1.31 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Peppermint Oil 2.07 flavoring Sucralose 0.98 Sweetener Durable emerald green 0.13 Dye Hydroxypropylcellulose (MM = 40,000) 4.53 film former Hydroxypropylcellulose (MM = 140,000) 4.53 film former Hydroxypropylcellulose (MM = 370,000) 27.16 film former Polyethylene oxide (MM = 600,000) 54.33 Film-forming and mucoadhesive agent Glycine 3.76 Alkaline buffer Sodium hydroxide 0.32 Neutralizing pH agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers and other ingredients of the polymer matrix composition are dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70°C for 30 minutes. Separately dissolve the dexmedetomidine, sodium chloride and hydroxypropylcellulose drug-containing composition in ethanol on a vortex mixer and then apply (dropwise) with a volumetric pipette onto the film. Placed drug composition is dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

- 34 040771

Composition 15.

Table 15

Dexmedetomidine placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine 0.34 Active substance Sodium chloride 0.10 pH neutralizing agent Hydroxypropylcellulose (MM = 140,000) 1.75 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Peppermint Oil 2.07 flavoring Sucralose 0.98 Sweetener Durable emerald green 0.13 Dye Hydroxypropylcellulose (MM = 40,000) 4.53 film former Hydroxypropylcellulose (MM = 140,000) 4.53 film former Hydroxypropylcellulose (MM = 370,000) 27.16 film former Polyethylene oxide (MM = 600,000) 54.33 Film-forming and mucoadhesive agent Glycine 3.76 Alkaline buffer Sodium hydroxide 0.32 pH neutralizing agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers and other ingredients of the polymer matrix composition are dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70°C for 30 minutes. Separately dissolve the dexmedetomidine, sodium chloride and hydroxypropyl cellulose (MW 140000) of the drug-containing composition in ethanol on a vortex mixer and then apply (dropwise) with a volumetric pipette onto the film. Placed drug composition is dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 16.

The composition was prepared as described in table. 16.

Table 16

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.48 Active substance Hydroxypropylcellulose (MM = 140,000) 2.09 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Peppermint Oil 2.06 flavoring Sucralose 0.97 Sweetener Durable emerald green 0.13 Dye Hydroxypropylcellulose (MM = 40,000) 4.7 film former Hydroxypropylcellulose (MM = 140,000) 4.7 film former Hydroxypropylcellulose (MM = 370,000) 28.29 film former Polyethylene oxide (MM = 600,000) 56.58 Film-forming and mucoadhesive agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers and other ingredients of the polymer matrix composition are dissolved in water with stirring, poured through a fixed gap onto a backing tape for

- 35 040771 film formation, and then dry it in a laboratory oven at 70°C for 30 minutes. Separately dissolve the dexmedetomidine hydrochloride and hydroxypropyl cellulose containing the drug composition in ethanol on a vortex mixer, and then apply (in the form of drops) using a volumetric pipette on the film. Placed drug composition is dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 17.

Table 17

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.48 Active substance Hydroxypropylcellulose (MM = 140,000) 0.52 film former Hydroxypropylcellulose (MM = 370,000) 1.57 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Peppermint Oil 2.06 flavoring Sucralose 0.97 Sweetener Durable emerald green 0.13 Dye Hydroxypropylcellulose (MM = 40,000) 4.7 film former Hydroxypropylcellulose (MM = 140,000) 4.7 film former Hydroxypropylcellulose (MM = 370,000) 28.29 film former Polyethylene oxide (MM = 600,000) 56.58 Film-forming and mucoadhesive agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers and other ingredients of the polymer matrix composition are dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70°C for 30 minutes. Separately dissolve the dexmedetomidine hydrochloride and hydroxypropylcellulose drug-containing composition in ethanol on a vortex mixer and then apply (dropwise) with a volumetric pipette onto the film. Placed drug composition is dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

- 36 040771

Composition 18.

Table 18

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.48 Active substance Hydroxypropylcellulose (MM = 40,000) 0.26 film former Hydroxypropylcellulose (MM = 140,000) 0.26 film former Hydroxypropylcellulose (MM = 370,000) 1.57 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Peppermint Oil 2.06 flavoring Sucralose 0.97 Sweetener Durable emerald green 0.13 Dye Hydroxypropylcellulose (MM = 40,000) 18.845 film former Hydroxypropylcellulose (MM = 140,000) 18.845 film former Polyethylene oxide (MM = 600,000) 56.58 Film-forming and mucoadhesive agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers and other ingredients of the polymer matrix composition are dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70°C for 30 minutes. Separately dissolve the dexmedetomidine hydrochloride and hydroxypropylcellulose drug-containing composition in ethanol on a vortex mixer and then apply (dropwise) with a volumetric pipette onto the film. Placed drug composition is dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 19.

Table 19

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.48 Active substance Hydroxypropylcellulose (MM = 40,000) 2.09 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Peppermint Oil 2.06 flavoring Sucralose 0.97 Sweetener Durable emerald green 0.13 Dye Hydroxypropylcellulose (MM = 40,000) 18.845 film former Hydroxypropylcellulose (MM = 140,000) 18.845 film former Polyethylene oxide (MM = 600,000) 56.58 Film-forming and mucoadhesive agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers and other ingredients of the polymer matrix composition are dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70°C for 30 minutes. Separately

- 37 040771 Dissolve the dexmedetomidine hydrochloride and hydroxypropyl cellulose of the drug-containing composition in ethanol on a vortex mixer and then apply (dropwise) with a volumetric pipette onto the film. Placed drug composition is dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 20.

Table 20

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.48 Active substance Hydroxypropylcellulose (MM = 40,000) 2.09 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Peppermint Oil 2.06 flavoring Sucralose 0.97 Sweetener Durable emerald green 0.13 Dye Hydroxypropylcellulose (MM = 40,000) 19.27 film former Polyethylene oxide (MM = 600,000) 75.00 Film-forming and mucoadhesive agent Purified water enough. quantity Solvent (or liquid carrier)

Process. All polymers and other ingredients of the polymer matrix composition are dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70°C for 30 minutes. Separately dissolve the dexmedetomidine hydrochloride and hydroxypropyl cellulose containing the drug composition in ethanol on a vortex mixer, and then apply (in the form of drops) using a volumetric pipette on the film. Placed drug composition is dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 21.

Table 21

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.48 Active substance Hydroxypropylcellulose (MM = 40,000) 0.26 film former Hydroxypropylcellulose (MM = 140,000) 0.26 film former Hydroxypropylcellulose (MM = 370,000) 1.57 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Peppermint Oil 2.06 flavoring Sucralose 0.97 Sweetener Durable emerald green 0.13 Dye Polyethylene oxide (MM = 600,000) 94.27 Film-forming and mucoadhesive agent Purified water enough. quantity Solvent (or liquid carrier)

Process. The polyethylene oxide and other ingredients of the polymer matrix composition are dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70°C for 30 minutes. Separately dissolve the dexmedetomidine hydrochloride and hydroxypropylcellulose drug-containing composition in ethanol on a vortex mixer and then apply (dropwise) by vol.

- 38 040771 metric pipettes on film. Placed drug composition is dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 22.

Table 22

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine hydrochloride 0.48 Active substance Hydroxypropylcellulose (MM = 40,000) 0.26 film former Hydroxypropylcellulose (MM = 140,000) 0.26 film former Hydroxypropylcellulose (MM = 370,000) 1.57 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Peppermint Oil 2.06 flavoring Sucralose 0.97 Sweetener Durable emerald green 0.13 Dye Hydroxypropylcellulose (MM = 370,000) 94.27 film former Purified water enough. quantity Solvent (or liquid carrier)

Process. Hydroxypropyl cellulose and other ingredients of the polymer matrix composition are dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70° C. for 30 minutes. Separately dissolve the dexmedetomidine hydrochloride and hydroxypropyl cellulose of the drug-containing composition in ethanol on a vortex mixer and then apply (dropwise) with a volumetric pipette onto the film. Placed drug composition is dried in a laboratory oven at 70°C for 5 min to obtain a thin film preparation.

Composition 23.

Table 23

Dexmedetomidine hydrochloride placed on the surface of a film composition with a polymer matrix

Ingredients Concentration g/100 g Function Medicinal composition Dexmedetomidine 0.48 Active substance hydrochloride Hydroxypropylcellulose (MM = 40,000) 0.26 film former Hydroxypropylcellulose (MM = 140,000) 0.26 film former Hydroxypropylcellulose (MM = 370,000) 1.57 film former ethanol enough. quantity Solvent (or liquid carrier) Composition with polymer matrix Peppermint Oil 2.06 flavoring Sucralose 0.97 Sweetener Durable emerald green 0.13 Dye Hydroxypropylcellulose (MM = 140,000) 94.27 film former Purified water enough. quantity Solvent (or liquid carrier)

Process. Hydroxypropyl cellulose and other ingredients of the polymer matrix composition are dissolved in water with stirring, poured through a fixed gap onto a backing tape to form a film, and then dried in a laboratory oven at 70° C. for 30 minutes. Separately dissolve the dexmedetomidine hydrochloride and hydroxypropylcellulose drug-containing composition in ethanol on a vortex mixer and then apply (dropwise) with a volumetric pipette onto the film. Placed drug composition is dried in the laboratory

- 39 040771 Torque oven at 70°C for 5 minutes to obtain a thin film preparation.

Example 2 Ex-vivo penetration of formulations 1-13 of Example 1 compared to PRECEDEX®.

Formulations 1-13 were evaluated in an oromucosal cell model as a mediator for drug absorption (EpiOral™; MatTek Corp., Ashland, MA, USA) into tissues to determine the rate and degree of diffusion.

ORL-200 24-well plates (MatTek Corp) containing tissue cultures of oral cells were used for 1 day after preparation followed by overnight equilibration in a 5% CO2 chamber set at 37°C and 95% relative humidity. 300 μl of TEER buffer (DPBS containing Ca2+ and Mg2+ and 3.6 mg/ml glucose) was added to each well in a 24-well plate and placed in the CO2 chamber overnight. The next morning, the tissue inserts were removed from the TEER buffer and placed in a new 24-well plate containing 300 µl of DPBS host medium. Prior to dosing with Formulations 1-13 and Precedex® preparation, TEER was measured for each tissue insert to ensure viability after equilibration.

Each insert was pre-moistened with 25 µl DPBS prior to applying Formulations 1-13 and Precedex® formulation to the donor side of the tissue insert, followed by applying an additional 25 µl DPBS to the top of each formulation. Before compositions 1-13 were applied to the fabric inserts, compositions 2-13 were die cut to 52.65 mm ² and composition 1 was die cut to 13.125 mm ² . Units were punched out to deliver the intended dose as indicated below.

The 24-well plate containing each tissue insert was returned to the incubator for a specified time and then removed from the incubator after the specified time had elapsed. Tissue inserts were transferred to a fresh 24-well plate containing 300 μl of host media and returned to the incubator for an additional specified time. Transfer 300 μl of receiving medium from each well of a 24-well plate to HPLC vials and store in the refrigerator (1 day) until analysis by HPLC/MS. This experimental sequence was repeated for all time points.

Results. In table. 24 illustrates the assay values and estimated PICs (in nanograms) of formulations 1-13 and the Precedex® formulation. In table. 24 additionally illustrates the disintegration time of compositions 1, 2, 3, 7 and 13. In table. 25 highlights the diffusion of Formulations 1-13 and Precedex® formulation and FIG. 3 shows diffusion data visually for formulations 1-7, 11 and Precedex®. Formulations 1-10 and 12 each performed better than Precedex®. For example, the rate and rate of permeation of dexmedetomidine through oral tissue culture of Formulations 1-10 and 12 ranged from 1.5 to 4.5 times that of dexmedetomidine from Precedex®.

Table 24

Assay values, disintegration times and estimated AUCs of formulations 1-13 and Precedex® are illustrated.

Composition No. Analysis (micrograms) Decay time (s) Average normalization. intake (ng / cm ² ) Estimated AUC (ng) Average SO 1 10.16 0.27 13 46 402 10 277 2 6.718 0.58 59 43 491 5673 3 8.975 0.86 83 61 954 8274 4 6.63 1.01 — 5936 5 6.51 1.75 — 5886 6 10.58 N/A — 8209 7 6.84 1.14 64 Average admission103,319 5077 8 P,9 37.5 — 10 116 9 9.37 N/A — 9171 10 9.74 N/A — 8356 12 Film analysis at 20 µg 20.432 1.54 Average normalization. intake from film per 10 µg 46.644 Alleged AUC (ng) 10 µg film 9061 13 2.725 1.37 35 43 FROM 2718 Precedex (100mcg/ml) - - N/A 4894 Comparative composition 11 8.402 1.20 — 1924

- 40 040771

Table 25

Diffusion of formulations 1-13 (mean cumulative amount) and Precedex® across oral cell culture membrane is shown.

Time (h) 0 0.08 0.25 0.5 0.75 1 Average cumulative amount (ig) Composition 1 (10 mcg) 0 1378 3355 5019 6245 7137 Composition 2 (10 mcg) 0 405 1402 2435 3262 3890 Composition 3 (10 mcg) 0 132 1123 2615 3916 5197 Formulation 4 (10 mcg) 0 384 1383 2481 3384 4044 Composition 5 (10 mcg) 0 279 1196 2340 3272 3971 Composition 6 (10 mcg) 0 721 1759 3586 5197 5810 Composition 7 (10 mcg) 0 348 1186 2120 2734 3354 Composition 8 (10 mcg) 0 611 2122 3838 5439 6690 Composition 9 (10 mcg) 0 801 1737 3207 4976 6120 Composition 10 (10 mcg) 0 530 1091 2364 4226 5408 Precedex® (100 µl, 10 µg) 0 159 727 1353 2200 2893 Formulation 11 (10 mcg) 0 27.9 40 409 698 1035 Formula 12 (10 mcg) 0 426.5 1968.5 3679.7 5088.7 6210.5 Composition 13 (10 mcg) 0 183.7 657.7 1087.8 1476.8 1809

Assumed PPC. Estimated area under the arrival/time curve from the data obtained using the trapezoidal rule, which corresponds to the total amount of diffused drug.

Example 3

Pharmacokinetics in rabbits (study 1).

Description of the studied animals.

Species: Oryctolagus cuniculus;

initial age: correspondence with weight;

gender: male;

breed: New Zealand white;

initial body weight: ~1.5-4 kg;

repeats per treatment: N=5 per dosing group, total 30 rabbits (non-crossover study);

washout interval: minimum 3 day washout.

The design of the study was as follows: for a minimum of 12 hours before the start of the study and four hours after receiving doses, animals were deprived of food. Animals were weighed prior to dosing and assigned to experimental groups stratified according to body weight. Individual doses were calculated based on body weights recorded on the day of dosing. Animals were anesthetized with isoflurane. Formulations 1, 2, 3, 7 and 13 were administered to the animals sublingually (s/l). Precedex® was administered through a butterfly needle, followed by a flush with 1 ml of saline, or by direct ear vein injection. Blood samples were collected pre-dose and 10, 20, 30 min, 1, 2, 4 and 8 hours post-dose. Blood samples were stabilized and kept cold until analysis. Bioassays were performed using C18RP-HPLC-MS. Concentrations were measured in plasma samples using a standard LC/MS/MS method against six point minima calibration curves (N=1).

The study design and PK parameters for various formulations are presented in Table 1. 26 and 27 respectively.

- 41 040771

Table 26

Non-crossover study design depicted

Group number Test item Dose route Animals N= Dose Conc, input. DOZ. Volume input, doses Carrier 1 Precedex® i/v 5 1.5 µg/kg 4.0 µg/ml 0.375 ml/kg 0.9%NaCl 2 Composition 1 s/l 5 10 mcg 10 mcg - - 3 Composition 2 s/l 5 10 mcg 10 mcg - - 4 Composition 7 s/l 5 10 mcg 10 mcg - - 5 Composition 3 s/l 5 10 mcg 10 mcg - - 6 Composition 13 s/l 5 10 mcg 10 mcg - -

In table. 27 summarizes the mean pharmacokinetic parameters for dexmedetomidine hydrochloride after intravenous and sublingual administration in male New Zealand white rabbits with a mean body weight ranging from 2.96 to 3.34 kg.

Table 27

Devmedetemidi Group 1 Group .2 Group 3 Group 4 Pears. 5 Group 6 on: shfohlprn ι PrecedexS Composition 1 Compound! Composition 7 Composition 3 Composition 13 Path .rapeseed her Sublmmgwal yuye Sublanguagegvm yie ί wow.sh gave NOE Su&iigwal iiie 1 \ 5. shyu ba.1vy1 m Dose U mshlg 10 mcg 10 mcg 10 .mcg 10 mcg 10 µt Experience (pgAi) 738 220 1.12 235 88,A 75.2. Those? (h) 0.00 0.767' 0,"0 0.9" 0.567 1.13 SVU _{No. a} . H 0.325 1.14 1.16 1.46 1.51 1.06 PPKiv. (h-pgAil) 161 3® 1® 4M 151 92.6

Cmax: maximum plasma concentration;

T _max : time to reach maximum plasma concentration;

TLS _last : average hold time calculated up to the last observed point in time;

AUC _last : area under the curve calculated up to the last observed time point.

Summary of results: The sublingual film preparations (Formulations 1, 2 and 7) provided exposure levels for dexmedetomidine hydrochloride in rabbits that are similar to the IV route when normalized for dose. Based on an average animal weight of 3.34 kg in Group 1, the IV bolus dose administered was about 5 µg. The intravenous AUC was 161 h-pg-mL in a rabbit study, while sublingual film preparations administered twice at a dose (10 µg) gave a two-fold increase in AUC (range 359-426 h-pg-mL) over compared with the intravenous drug. Therefore, delivery of dexmedetomidine hydrochloride via films provides an exposure equivalent to an IV dose.

Example 4

Pharmacokinetics in rabbits (study 2).

Description of the studied animals.

Species: Oryctolagus cuniculus;

initial age: correspondence with weight;

gender: male;

breed: New Zealand white;

initial body weight: ~2.9-3.9 kg;

repeats per treatment: N=8 per dosing group, total 64 rabbits (non-crossover study);

washout interval: at least 7 days of washout;

time points for blood sampling: pre-dose, 5, 10, 20, 30 min, 1, 2, 4 and 8 hours post-dose.

The design of the study was as follows: Animals were anesthetized with isoflurane prior to dosing. Dosing formulations were administered sublingually (s/l) using Precedex® film or drops placed in the sublingual space (under the bottom of the animal's tongue). The micro-placed films in the dosing groups were applied sublingually with the letter P facing upwards (outside the mucosal tissue). Animals in the Precedex® injection dose group were anesthetized with isoflurane and Precedex with 0.9% NaCl was administered via syringe and 25 gauge needle into the extreme ear vein. To determine the dependence on time began with the placement of the study drug (T0).

- 42 040771

Animals were left anesthetized and in the sternal position with their heads supported for 30 minutes to ensure that the TA dose would not shift (T0-T30). After the dosing period, the sublingual space was not cleared and the animals were released (T30).

Blood samples were collected from rabbits through the ear vessels, jugular vein, or other suitable vessels by direct vein puncture and then placed into chilled polypropylene tubes containing K2EDTA as an anticoagulant. The samples were kept under refrigeration throughout the processing. Blood samples were centrifuged at 4°C and 3000xg for 5 min. The plasma was then transferred to a chilled labeled polypropylene tube, placed on dry ice and stored in a freezer maintained at -60 to -80°C.

Plasma samples.

Whole blood samples (˜2.0 ml) were collected from rabbits via the jugular vein or other suitable vessel at appropriate time points and placed in tubes containing K2EDTA as an anticoagulant and inverted several times to mix. Blood samples were centrifuged at 4°C at 3000xg for 5 min. All samples were kept chilled throughout processing. The resulting plasma samples were transferred to polypropylene tubes and placed in a freezer mold to maintain -60 to -80°C until transport to the sponsor's bioanalytical laboratories for analysis.

The study design and PK parameters for various formulations are presented in Table 1. 28 and 29 respectively.

Table 28

Non-crossover study design depicted

Investigational drug Film type composition number Description micro-hosted -1 micro-hosted Identical composition 12 in composition S/L film containing 1.47 µg dexmedetomidine micro-hosted -2 micro-hosted Identical composition 12 in composition S/L film containing 2.94 µg dexmedetomidine micro-hosted -3 micro-hosted Identical composition 12 in composition S/L film containing 5.88 µg dexmedetomidine micro-hosted -4 micro-hosted Identical composition 12 in composition S/L film containing 8.82 µg dexmedetomidine Monolithic 1 monolithic Identical composition 1 in composition S/L film containing 5.88 µg dexmedetomidine Monolithic 2 monolithic Identical composition 1 in composition S/L film containing 8.82 µg dexmedetomidine Precedex (100mcg/ml) Solution for s / l drops Reference s/l drops S/l solution containing 100 mcg/ml dexmedetomidine Precedex (4 µg/ml) Solution for intravenous injection Reference Injection 4 µg/ml dexmedetomidine solution for intravenous injection Period 2 results (minimum 7-day washout) Precedex (4 µg/ml) Solution for intravenous injection Reference Injection 4 µg/ml dexmedetomidine solution for intravenous injection Precedex (4 µg/ml) Solution for intravenous injection Reference Injection 4 µg/ml dexmedetomidine solution for intravenous injection Precedex (4 µg/ml) Solution for intravenous injection Reference Injection 4 µg/ml dexmedetomidine solution for intravenous injection

- 43 040771

Table 29

The arithmetic mean values of the results of pharmacokinetic studies from s/l administration of dexmedetomidine films or Precedex® are shown.

Ilapastei ri Mkkrvraz target spitting 1 C / l film. content m 1.47 mcg dexmede! omidina Mpcrorapm still film 2 S/L film. contain aya 2.94 mcg dexmedeto midina mp crore »1 extra film 3 S/L film. contain 5.88 mcg dexmedea midina Microframed shii 4 C/l film containing 8.82 µg dexmedea mi psha Movolit us film 1 S/l film containing mi dexmede yumndia MONYLITE prison 2 S/l n. screw. containing taya X.K2 mcg dexme ie yum go on Proceedings dex s/l Dose ί MK1 /κι) 0.471 0.939 1.79 2.65 1.83 2.70 2.71 Stakh (iAv) 0.157 0.112 0.119 0.315 0.142 0.205 <290 Ttzhk (h) 1.06 1.56 0.833 1.25 0.667 0.688 0.396 111 Idyus l. Tsgshly) 0.145 0.094 0.206 OD 18 0.224 0.344 <335 Merging / dm "zu 0.333 0.119 0.066 0.119 0.078 0.076 0.107 PPKps lUdazu 0.30S 0.100 0.115 0.233 0.122 0.127 0.124 F% 110% 52.2% 70.5% 83.4% 63 45.6% 44.2%

* F% was calculated using individual iv animal data as a crossover study.

Results. Systemic exposure of dexmedetomidine after sublingual dosing showed a numerical trend for higher exposures at higher doses from micro-array matrix films 2, 3 and 4. Micro-array matrix film 1 showed higher values than proportional to C _max and AUC _after . compared to microarranged matrix films 2-4. Monolithic films 1 and 2 showed an approximately dose-proportional increase in _Cmax and AUC _after . Systemic exposure to dexmedetomidine after sublingual dosing showed a numerical trend for higher exposures at higher doses from micro-arrayed matrix films 2, 3 and 4.

The microarranged matrix film 1 showed higher values than the proportional C _max and AUC _pos . compared to microarranged matrix films 2-4. Monolithic films 1 and 2 showed an approximately dose-proportional increase in C _max and AUC _sec . Microarranged matrix films 1 and 4, which showed 2.5 and 1.9 times higher F% compared to s/l Precedex dosing, which may be due to the lack of cross-sectional data on IV administration for animals in these groups.

- 44 040771

Example 5 Evaluation of films.

Table 30

12 formulations evaluated on various parameters including stability studies and results

Options Description Composition 12 Composition 12 Dose (mcg) 10 mcg 20 mcg Appearance Green rectangular thin film with one blue spot Corresponds Corresponds Size (mm) Width: 22mm±1.5mm Length: 8.8mm±0.5mm Width - 22.3 mm Length - 9.2 mm Width - 22.2 mm Length -9.1 mm Analysis (%) 90%-110% 105.3% 101.0% Dosage Uniformity (%) (average) USP<905> Stage 1-10 out of 10 AV samples <15 Stage 2 (when necessary) - 30 of 30 samples AV < 25 Average (10) : 105.8% AV:10 Average (10) : 99.4% AV:7 Related impurities Hydroxymedetomidine (1-(2,3dimethylaminophenyl)-1 (III-imide azol-5-yl) ethanol) < 1.0% BUT BUT N- Benzylhydroxymedetomidine (1-(1-benzyl-1nimidazol-5-yl)-1-(2,3d imethyl phenyl)ethanol) <1.0% But BUT Ethylmedetomidine (5-[1- BUT But (2,3- dimethylaminophenyl)ethyl]-1-ethyl-1H- imidazole) < 1.0% N-Benzylmedetomidine (1-benzyl-5-[1-(2,3d imethyl phenyl)ethyl] 1H-imidazole) <1.0% But But N-Benzylvinyl analogue (1-benzyl-5-[1(2,3dimethylphenyl)vinyl]1H-imidazole) <1.0% But But Any unspecified degradation product <1.0% But But General content degradation products <5.0% 0.0% But Dissolution (Q>80% in 15 minutes) 104.2% 102.3% Decay time (USP<701> no more than 3 minutes) Corresponds Corresponds Tensile strength (g) — Average (n=3): 605.891 g Average (n=3): 503.286 g Mucoadhesion (g) (average peak force) — Average peak force (n=3): 436.011 g Average peak force (n=3): 105.937 g Mucoadhesion (g*s) (average AUC) — Average AUC (n=3): 21.739 g*sec Average AUC (n=3): 4.702 g*s water activity <0.75A _w Mean (n=3): 0.44 Mean (n=3): 0.37 Microbiological purity Total microorganisms <200 cfu/film <200 cfu/film (10 films) <200 cfu/film (10 films) Total total number of yeasts and molds. mushrooms <20 cfu/film <20 cfu/film (10 films) <20 cfu/film (10 films) Pseudomonas aeruginosa Missing / 10 units BUT BUT Staphylococcus aureus Missing / 10 units BUT BUT

- 45 040771

stability data. Formulation 1 (monolithic film) and composition 12 (micro spaced matrix film (60 μg)) were individually packaged in foil pouches. The films were tested for stability by exposing the packaged films to temperatures of 25 and 40°C. After 6 months, the films were evaluated for various parameters. The results are presented in table. 31 and 32.

Table 31

Stability data for micro-arranged matrix film (composition 12) are presented.

Options Waiting (.\‘iyai UaJt'IJU II aUlKJ ε M' 4SKJ KklMl JelnWi pin Mirrprp1.is|sch.»1st jlilkkj. xp-shinshazhya iri 25HZhZhSV Mic | and * ra1MsSh1 .:shay m.iciikj. chraiiiim-sya at WSMOB 4 months ! m "yatsev 1 month 6 months 0 months 1 month .month Bmvyaiv Vveshmai Viya garyashugsshsho skewers with one piece Syotetsgv Cwaercr zuet Reply there is guuet Answering uet Saotvetsta uet Reply 1-weT Appropriate etauet- Avadiz 90%-110% them, in % LJ I2, F 99.4% mzhv" 102.2% 98.8% 94.3% Happy .ψίηαχ" Hmdroyasiyeyaomyadi" <1% nude But But NUDE NUDE NUDE BUT NUDE N- Bekjlgyarox i-jezhgoidv <1% But iu But NUDE NUDE BUT NUDE But Etu- adetomad nude nude But nude nude nude nude But Y-Beyuyumedetomidia < AND nude WO But nude nude nude nude nude N- Beiiiishvo y: aiayaog < m nude nude But BUT NUDE nude BUT But Yumy jeueengvpvii y irschschgkt Chv-rdaiik < 1% nude nude But nude nude nude But nude General the content of the pronoun. cefamsci < 5% "4 "4 0% Wb* and. I4 f> "4 AND MIN 97.134 E%0% mzh 99.6% 97.1% 95.2% 93.0% 96.1% Decay WSP <701> no More than 3 min Z-b-l "s 59-she 24-" with »€ Μ-li® with 20-107 p. 26-107 s 4-31 e

- 46 040771

P | "wow. ia ryazriv — 476D" _G 526.415 g 343 D96 32OD74 g 476D30g SD66 i 92.133 g 57D35 g Muvzhagez." Peak 510.,.173 g SUBSUG ID® g 76.815 g 510.173 g 198.586 g 234.896 g 64zh g shzh 31D07A 4.839 g*s 3.583 g*s 4D24L 31 BEFORE? L 10.158 L 13.046 g*s 2.D24 g*s Ao' msst yudi <0.75^ 0.44 0.41 0.41 0.44 ODO adv 0.43 Mshfobaalogi cheskazh cleanliness Longevity aero&their Mitspwpiasim MOB <200 YuIiev Sodaets» uet VD VD hell Corresponding vuet n/a n/a hell The total total vdoteo» of yeast and fungi <20 KOIPzhizhu Sviveteta. yw ShchD VD hell Burntweetet voer n/a hell n/a PseiKiomom & zhgajoi. SUJUVRYALO one IC Corresponds to VD hell hell Corresponds n/a hell n/a Stephylscaccas willow Fired® uet hell, hell n/a Smtvetet- auet n/a hell hell

Table 32

Stability data for a monolithic film are presented (similar to composition 1, different in dose)

Options Description Sublingual film with 60 mcg dexmedetomidine Monolithic film, stored at 25°C/60% RH Monolithic film stored at 40°C/75% RH 0 month in 1 month in 2 months 6 months 0 month in 1 month in 2 months 6 months Appearance I'm green, I'm straight naked, I'm a thin film I'm green, I'm straight naked, I'm a thin film I'm green, I'm straight naked, I'm a thin film I'm green, I'm straight naked, I'm a thin film I'm green, I'm straight naked, I'm a thin film I'm green, I'm straight naked, I'm a thin film I'm green, I'm straight naked, I'm a thin film I'm green, I'm straight naked, I'm a thin film

- 47 040771

Analysis 89.4 Not carried out 88.0 85.6 89.4 77.0 71.8 71.9 Related impurities Hydroxime detomidine BUT Not carried out BUT oh, s BUT 0.7 0.5 oh, s Nbenzylhydr oxymedetomidi and But Not carried out But BUT But BUT BUT BUT Ethylmedeto mussels BUT Not carried out But But But But But But N- Benzylmede tomidine But Not carried out But But But But But But N- Benzylvinyl analogue But Not carried out But But But But But But Unidentified impurity A (vinylmede tomidine) But Not carried out But But But But 0.2 0.8 total impurities 0.0 Not carried out But 0.3 But 0.7 0.7 0.8 Dissolves after 15 minutes 87.1 Not carried out But 64.7 87.1 71.1 n/a 79.4 Disintegration (s) 35.00 24.33 19.00 17.00 35.00 8.33 10.00 11.30 Tensile strength (g) 482.27 472.37 662.84 428.79 482.27 18.3 14.22 14.46 Mucoadhesion (g) 1646.8 5 1004.6 7 1228.7 2 882.54 1646.8 5 836.64 791.90 762.82

Conclusion. Micro-spaced matrix films, as confirmed by composition example 12, are more stable than monolithic films, as confirmed by composition example 1, when stored at 25 and 40°C for 6 months.

Example 6 Randomized, Single-Blind, Placebo-Controlled, Phase 1 Single Escalating Dose Study to Determine the Pharmacokinetics, Safety, and Tolerability of Dexmedetomidine Sublingual Film (Formulation 12) in Healthy Adult Volunteers.

This was a randomized, single-blind, placebo-controlled, single-dose escalating pharmacokinetic, safety, and tolerability study with 4 dosing groups in healthy adult (18-65 year old) males and females. The study protocol was reviewed and approved by the institutional review board of the study center(s). This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practices (GCP) ICH.

Four (4) doses were evaluated from three doses of 10, 40 and 60 µg films: 10, 20 µg (2 10 µg films), 40 and 60 µg in cohorts 1, 2, 3 and 4, respectively. All eligible participants who had previously been screened arrived at the Clinical Research Unit (CRU) the day before admission and baseline evaluation. They were housed in CRU for 4 days (day -1, 1, 2 and 3) and discharged on day 4, during which time they were under medical observation. Pre-dose assessment of all participants was performed between approximately 07:00 and 09:00 hours after an overnight fast of at least 8 hours. Participants were given free access to drinking water until at least one hour prior to dosing. A venous catheter was inserted to allow sampling for FC. IN

- 48 040771 At the beginning of each study session, a single dose of dexmedetomidine sublingual film (formulation 12) was administered sublingually by authorized personnel. The dexmedetomidine sublingual film was held in the sublingual cavity until dissolved. Evaluations were made every 5 minutes for the first 15 minutes and then every 15 minutes to determine the dissolution time of the film. ECG, BP and oxygen saturation were monitored according to the graph. Participants were allowed to drink water as desired for at least 1 hour after drug administration. Standard meals were offered approximately 4, 8 and 12 hours after dosing with dexmedetomidine sublingual film. After plasma sampling within 24 hours post-dose of dexmedetomidine sublingual film, safety and tolerability assessments continued until the morning of day 4 (day of discharge), and repeated again on day 5, day 7 ± 1, and day 14 ± 2. Blood samples were taken immediately before dosing (baseline) and after 5, 10, 20, 30, 60, 90, 120, 180, 240 min. Additional blood samples were taken at 5, 6, 8, 10, 12 and 24 hours post-dose to obtain a total of 16 PK sampling times.

Number of participants.

The study evaluated dose escalation of dexmedetomidine sublingual film (Formulation 12) in 4 cohorts of healthy adult participants. The first two cohorts (cohort 1 and cohort 2), included twelve (12) new participants per cohort, were randomized in a 2:1 ratio, ie. 8 people received dexmedetomidine film and 4 received placebo film.

Participants who were on active treatment and completed treatment in cohort 1, ie. did not interrupt or stop were on active treatment in cohort 3. In addition to participants who switched from cohort 1 to cohort 3, six new participants were included in cohort 3. Similarly, participants who were on active treatment and completed treatment in cohort 3 2, i.e. did not interrupt or stop were on active treatment in cohort 4. In addition to participants who switched from cohort 2 to cohort 4, six new participants were included in cohort 4.

Participants who discontinued placebo in cohorts 1 and 2 were switched to receive placebo after they switched, ie. where placebo participants dropped out from cohort 1 to cohort 3 or from cohort 2 to cohort 4, additional new participants were added to increase the total number of participants to four (4) participants in the cohort 3 and cohort 4 placebo groups.

Inclusion Criteria.

1. Healthy males and non-pregnant/non-breastfeeding female patients aged 18 to 65, including both.

2. Participants who were able to give written informed consent to participate in the study.

3. Participants who weighed >50 kg with a body mass index (BMI) in the range of 19-30 kg/m ² , including both categories.

4. Participants who have undergone a physical examination and a vital signs test determined to be within normal limits by the PI or an authorized officer.

5. Participants whose clinical laboratory test results (CBC, CBC, and urinalysis) were normal or clinically acceptable to the PI or designee.

6. Participants who were physically healthy enough to receive an s/l dose of dexmedetomidine sublingual film and tolerate drowsiness as judged by the PI or designee.

7. Participants who spoke English fluently and were able to understand written and verbal protocol requirements in English.

8. Participants who were willing and able to stay in restricted conditions in CRU for approximately 4-5 days per dosing cohort and are in compliance with the study design and study requirements.

9. Participants who received a reliable intravascular access from which blood samples were taken.

10. Men, unless vasectomized, must consent to the use of a spermicide condom or to abstain from sexual intercourse during the study and for 3 months after discontinuing the drug.

11. The male participant must be a non-sperm donor from screening and throughout the study period, and for 90 days after the last study drug administration.

12. For female participants of childbearing potential, the participant must agree to practice a clinically accepted birth control method for at least 30 days prior to the first study drug administration, during the study, and for at least 30 days after the last study drug dose.

- 49 040771

13. For women of no childbearing potential, the participant was surgically neutered (i.e. underwent a hysterectomy, bilateral oophorectomy, or tubal ligation) or menopausal (at least 1 year without a period) as evidenced by FSH levels.

exclusion criteria.

1. Participants with a history of an allergic reaction or intolerance to an investigational drug or related contaminants and additives.

2. Participants with a history of surgery within 4 weeks of screening.

3. Participants with a history of significant traumatic brain injury.

4. Participants with a history of alcohol or drug dependence as defined by the Diagnostic and Statistical Manual of Mental Disorders IV within the 6-month period prior to enrollment in the study.

5. Participants with a history of clinically significant mental illness with mental retardation, borderline personality disorder, anxiety disorder, or organic brain syndrome.

6. Participants with a history of orthostatic hypotension (i.e. sustained reduction in systolic BP (SBP) of at least 20 mmHg, or diastolic BP (DBP) of 10 mmHg, or both for 3 minutes of standing or head up position to at least 60° in on an inclined stand) and high vagal tone.

7. Participants who regularly consume high amounts of xanthine-containing substances (i.e. more than 5 cups of coffee or xanthine equivalents per day).

8. Participants who were on maintenance drugs that can inhibit or induce the CYP2A6 enzyme and other drugs as listed in Appendix 15.1.

9. Participants who received dexmedetomidine or other alpha-2 agonists within 1 week of study date.

10. Participants with a history of clinically significant sleep apnea or chronic obstructive pulmonary disease or asthma.

11. Suicidal Participants as determined by the PI or designee.

12. Participants with abnormal clinical laboratory results (including positive for hepatitis B, hepatitis C, HIV) unless they are cured to remission.

13. Participants with abnormal vital signs as determined by the PI or designee unless they are cured to remission.

14. Participants were enrolled in another clinical study (eg, laboratory or clinical evaluation) or received investigational drug in the last 30 days (or within 5 half-lives of investigational drug if >30 days have elapsed).

15. Participants who had a resting heart rate <65 beats per minute or SBP <110 mmHg or >140 mmHg or DBP <70 mmHg or >100 mmHg .st. at screening and prior to dosing. There is evidence of a clinically significant 12-lead ECG abnormality. Subjects who previously did not meet study inclusion criteria at the screening visit or 1 day before dosing due to exclusion 15 for resting heart rate <70 beats per minute but not <65 beats per minute may be selected by screening again.

16. Participants with abnormal oral/cheek anatomy, inflammation, or pathology that, in the opinion of the PI, may interfere with s/l drug administration and absorption.

17. Participants with hepatic insufficiency or who have hepatic dysfunction, defined as a history of hepatic dysfunction and alanine aminotransferase (ALT) and aspartate aminotransferase (ACT) activity levels greater than 2 times normal in the past 6 months prior to study drug administration.

18. Participants who donated blood within 30 days prior to screening or who donated plasma within 7 days prior to screening.

19. A participant who was part of the study staff or was a family member of the study staff.

Study duration: 39-42 days.

Dosing.

Cohort 1, Cohort 2, Cohort 3, and Cohort 4 received 10, 20 μg (2 films of 10 μg), 40, and 60 μg doses of dexmedetomidine sublingual films (formulation 12) and accompanying placebo films, respectively. With the exception of the first dosing cohort (10 µg dose), each subsequent dose level was approved after reviewing the safety of the previous dosing cohort. Dosing for each cohort was performed only once. The appearance of dexmedetomidine sublingual film (the presence of a dot) was different from placebo.

endpoints.

1. Area under the curve (AUC0-12, AUC0-24, AUC0-^) for 0 to 12 hours and 0 to 24 hours post-dose for plasma dexmedetomidine concentration, peak dexmedetomidine concentration in

- 50 040771 plasma (C _max ), time to peak dexmedetomidine concentration T _max ), terminal half-life (t1/2) of dexmedetomidine, volume of distribution of dexmedetomidine, and clearance of dexmedetomidine (CL).

Results.

Table 33

Pharmacokinetic parameters of sublingual film with 10 µg dexmedetomidine in healthy volunteers are summarized.

Sublingual film with 10 micrograms of dexmedetomidine Subject ID Stax (ng/l) Tmax (h) ti/2 (h) PPK _last . (h*ng/l) PPKO-besk. (h*ng/l) 1001 37.94 1.5 2.06 179.19 201.32 1002 18.27 1.00 1.17 49.45 58.27 1005 33.28 2.00 1.86 116.63 140.07 1007 35.74 2.00 2.95 142.22 168.59 1009 24.15 3.02 2.70 102.76 147.74 1011 30.87 1.00 2.75 114.35 138.82 1012 24.53 1.50 2.58 98.28 132.11 1016 35.19 2.00 1.24 119.28 129.17 N 8 8 8 8 8 Average 29.996 1.752 2.163 115.271 139.512 SO 6,930 0.659 0.693 37.049 40.525 sq% 23.1 37.6 32.0 32.1 29.0 Min. 18.27 1.00 1.17 49.45 58.27 Median 32.08 1.75 2.32 115.49 139.45 Max. 37.94 3.02 2.95 179.19 201.32 Geometric mean 29.214 1.648 2.051 109.219 132.838 Geometric CV% 25.79 39.08 37.61 38.59 37.6

Table 34

Pharmacokinetic parameters of sublingual film with 20 µg dexmedetomidine in healthy volunteers are summarized.

Sublingual film with 20 micrograms of dexmedetomidine Subject ID Stax (ng/l) Tmax (h) ti/2 (h) IIK ate. (h*ng/l) IIKO-besk. (h*ng/l) 2001 0.00 0.00 0.00 2003 83.08 1.00 2.2 359.59 389.48 2004 65.17 2.00 1.72 259.5 279.49 2007 84.90 1.50 1.60 401.79 416.92 2011 70.76 2.00 1.85 309.75 337.01 2013 85.92 1.00 1.85 307.97 330.48 2016 42.34 3.00 1.97 198.79 225.81 2106 66.75 1.50 1.57 283.34 301.60 N 8 7 7 8 8 Average 62.365 1.714 1.824 265.092 285.099 SO 28.982 0.699 0.221 123.337 129.906 sq% 46.5 40.8 12.1 46.5 45.6 Min. 0.00 1.00 1.57 0.00 0.00 Median 68.76 1.50 1.85 295.66 316.04 Max. 85.92 3.00 2.20 401.79 416.92 geometric mean 1.601 1.813 Geometric CV% 41.30 11.95

- 51 040771

Table 35

Pharmacokinetic parameters of sublingual film with 40 µg dexmedetomidine in healthy volunteers are summarized.

Sublingual film with 40 micrograms of dexmedetomidine Subject ID Stax (ng/l) Tmax (h) tl/2 IIK _ON sl. (h*ng/l) IIKO-besk. (h*ng/l) DOE 140.25 1.00 1.78 685.15 709.61 3012 78.69 2.00 2.00 427.97 461.18 3013 97.01 1.07 1.76 292.84 310.29 3023 126.60 1.00 1.86 493.89 508.98 3026 135.02 1.50 1.38 482.44 499.41 3032 78.06 2.00 3.38 378.67 439.85 3114 167.99 1.00 2.05 777.66 806.08 3131 123.52 2.02 2.42 600.88 627.60 4001 109.62 1.00 1.82 419.51 446.40 4022 204.03 1.00 1.82 664.47 704.50 4026 123.68 2.00 1.83 507.83 534.00 4130 143.95 2.00 1.97 772.97 798.78 N 12 12 12 12 12 Average 127.368 1.465 2.007 542.024 570.557 SO 35.794 0.495 0.496 157.144 156.810 sq% 28.1 33.8 24.7 29.0 27.5 Min. 78.06 1.00 1.38 292.84 310.29 Median 125.14 1.28 1.85 500.86 521.49 Max. 204.03 2.02 3.38 777.66 806.08 geometric mean 122.839 1.389 1.961 520.580 550.254 Geometric CV% 28.87 35.22 21.81 30.84 29.15

Table 36

Assessment of indicators on the RASS scale in the first 2 hours. Pharmacodynamic population

Options 10 mcg 20 mcg 40 mcg placebo Evaluated patients by RASS 8 8 12 14 Number of patients who achieved at least a RASS-1 score at any point during the first 2 hours 2 4 4 3 Number of patients who achieved a RASS-2 score at any point during the first 2 hours 1 0 0 1

Results.

The data given in table. 33-35 reflect dose-proportional pharmacokinetics. These data clearly show that the pharmacodynamic effects last for 4 to 6 hours, which is consistent with the optimal treatment window. Plasma concentrations of dexmedetomidine increase rapidly after placement of the film formulation and reach the plasma exposure levels necessary to obtain a pharmacodynamic effect. The half-life of formulation 12 dexmedetomidine sublingual film is comparable to intravenous dexmedetomidine. In FIG. 4 shows the mean logarithmic plasma concentration of dexmedetomidine versus time for the sublingual film with 10, 20 and 40 µg dexmedetomidine (semi-log scale) and clearly demonstrates that 70-80% of mean concentrations were reached within up to 1 hour after administration of the dexmedetomidine film. Additional data showed that sublingual thin film with dexmedetomidine (Formulation 12) was safe and well tolerated with no serious adverse events. All adverse events were transient and mild (below severity 2), except for moderate headache (2 in the placebo group), moderate decrease in systolic/diastolic pressure (1 in the placebo group).

- 52 040771 placebo group) and moderate dizziness (2 subjects in the 40 μg dose group with orthostatic changes). Only drowsiness and dizziness were observed with an incidence of more than 1-2 subjects per group, thus no apparent sedative effect was found compared to placebo. The most common adverse event was drowsiness, observed at a frequency similar to placebo. Lower incidences of dizziness were reported in all groups, and the incidence was greater than placebo for the 40 mcg dose group. The study demonstrated that the mean values of cardiovascular changes were not clinically significant, and the maximum tolerated dose was not reached. The data is further shown in Fig. 5-11.

Example 7 A multicenter, randomized, double-blind, placebo-controlled, multiple escalating-dose, phase Ib study to determine the efficacy, pharmacokinetics, and safety of dexmedetomidine sublingual film against schizophrenia-associated agitation.

At the first stage, an adaptive evaluation of the escalating dose regimens of 20, 60, and 120 µg was performed, with the option to test a different dose, a signal of safety or tolerability should be observed. Adult males and females with acute agitation associated with schizophrenia, schizoaffective disorder, or schizophreniform disorder were included in each cohort. The investigators chose to repeat the 20 mcg dose 1 hour after the initial application.

Table 37

Groups and interventions

Groups Intervention Placebo comparator: placebo Sublingual film without active drug; single injection Medicine: placebo film placebo film for dexmedetomidine hydrochloride Experimental dose: 20 micrograms Sublingual film containing 20 micrograms of dexmedetomidine; single dose with repeat dose 1 hour later Medicine: sublingual film containing dexmedetomidine hydrochloride Introduction: sublingual film containing dexmedetomidine for the treatment of agitation associated with schizophrenia Experimental dose: 60 micrograms Sublingual film containing 60 Medicine: sublingual film containing micrograms of dexmedetomidine; single injection dexmedetomidine hydrochloride Introduction: sublingual film containing dexmedetomidine for the treatment of agitation associated with schizophrenia Experimental dose: 120 micrograms 2 sublingual films, each containing 60 micrograms dexmedetomidine; single injection of 2 films Medicine: sublingual film containing dexmedetomidine hydrochloride Introduction: sublingual film containing dexmedetomidine for the treatment of agitation associated with schizophrenia

Blinded periodic reviews of safety data were performed on an ongoing basis to review all assigned subjects who were dosed and as available data became available. Dose escalation was allowed only if a safety or tolerability issue did not become apparent at the periodic regular safety review. Each study center was assigned a small amount from each dosing cohort in a scaling up but blind method, so that this cohort was balanced between cents to account for subject-center effects and inter-evaluator variability. Patients in the center were assigned to the lowest dose cohort with subsequent appointments of patients assigned to increasing doses. This incremental boost with adaptive engagement provides security for the subjects; the lowest dosing cohort completes enrollment first, the higher dosing cohorts complete recruitment last. If the subject does not respond to treatment, the investigator may repeat the dose so that the subject receives a second administration (and no additional) of the same randomized dose, thereby testing the safety/effectiveness of taking two doses separated by 1 hour, which approximately corresponds to dosing before start cohort participation at the next dose level. Sequential inclusion of subjects in the high dose cohort allows faster discontinuation of dosing, affecting only a minimum number of subjects, which should ensure safety or tolerability under dose-limiting conditions. In addition, based on blinded analyzes combining PK, exposure and safety/tolerance data,

- 53 040771 all subjects and doses, the dosing regimen may be changed (for example, repeated dosing may be stopped or allowed only after the elapsed time) or a different dose may be chosen to test the hypothesis that the (usually lower) dosing regimen is better tolerated.

Eligible patients were randomized to receive dexmedetomidine sublingual film (Formulation 12) or placebo. At the beginning of each study session, a single dose of dexmedetomidine sublingual film (Formulation 12) was self-applied sublingually by the patient after training with the placebo film and under the supervision of qualified personnel who were involved in the safety or efficacy evaluation.

Dexmedetomidine sublingual film (Formulation 12) was held in the sublingual cavity until dissolved. Participants were assessed for local irritation around the area in which the film was placed. Efficacy and safety evaluations were performed periodically before and after dosing. If the decrease in RES was less than or equal to 40% within 1 hour after the first dose, the investigator could suggest a second dose of dexmedetomidine sublingual film (same randomized dose) with an additional REC assessment performed within 1.5 hours after the dose. Could initiate standard supportive care if the patient's condition requires it, eg 4 hours after completion of assessments.

Stage 1. Twenty-seven (27) new participants were included in each cohort, randomized 2:1 dexmedetomidine sublingual film: placebo film, ie. 18 received dexmedetomidine sublingual film and 9 received placebo film. Three doses were originally planned (total 81 subjects). May have tested a different or additional dose based on the results of current safety reviews. At the conclusion of Stage 1, two doses that describe a safe and effective range (high and low) will be selected based on a blind review of the overall clinical safety, tolerability, adverse effects, and PK observed during dosing.

Step 2: In order to more accurately assess the range of safe tolerability and sedative effects observed when exposed to larger numbers of subjects, enroll an additional 120 subjects in a double-blind, placebo-controlled, parallel-group study with a sequential 3-arm design of each of the two identified effective doses. or placebo (randomized 1:1:1, high:low:placebo with 40 subjects per group; total 120 subjects in stage 2; total study about 201 subjects).

Vital signs and ECG with rhythm line are measured according to the assessment schedule, prior to any PK assessment. Participants were allowed to drink water as desired 30 minutes after completion of the dose. Standard meals could be offered starting 1 hour after dosing with dexmedetomidine sublingual film. Safety and tolerability assessments continue until the morning of day 3 (day of discharge) and will be repeated again on day 7(+2).

Approximately 4 ml of venous blood (to obtain a minimum of 1.2 ml of plasma) will be drawn into K2-EDTA tubes at specified time intervals to determine plasma concentrations of study drug (or placebo). Plasma samples for PK must be collected within 5 minutes of the scheduled sampling time on Day 1. Blood samples will be collected according to Table 1. 3-1 schedule of procedures.

Number of subjects (planned). The 201 assessed subjects (81 in stage 1 and 120 in stage 2) are included in approximately 12-20 research centers in the United States.

Diagnostics and main criteria of compliance.

Inclusion Criteria.

1. Men and women aged 18 to 65 inclusive.

2. Patients who met DSM-5 criteria for schizophrenia, schizoaffective disorder, or schizophreniform disorder.

3. Patients defined as clinically agitated at baseline with an overall score of >14 in 5 categories (impaired impulsivity control, tenseness, hostility, non-contact, and arousal) including the PANSS arousal component (PEC).

4. Patients who have a score of >4 on at least 1 of 5 RES scores.

5. Patients who read, understand and give written informed consent.

6. Patients who are in good general health prior to participation in the study, as determined by a detailed review of the medical history, physical examination, 12-lead ECG with rhythm line, blood chemistry profile, hematology results, urinalysis, and the opinion of the Principal researcher.

7. Female participants, if fertile and sexually active, and male participants, if sexually active with a fertile partner, who agree to use a medically acceptable and effective method of birth control throughout the study and for one weeks after the end of the study. The participant and/or her/his partner may use medically acceptable methods of contraception, which include abstinence, pills or patches to control RO

- 54 040771 spermicide diaphragms, intrauterine device (IUD), condom with foaming agent or spermicide, vaginal spermicidal suppository, surgical sterilization and progestin implant or injection. Prohibited methods include the cycling method, interrupted intercourse, condoms only, or diaphragm only.

exclusion criteria.

1. Patients with agitation due to acute intoxication, including positive identification of alcohol by breath analyzer or non-prescribed drugs (excluding THC) during urine screening.

2. Patients treated within 4 hours prior to study drug administration with benzodiazepines, other hypnotics, or short-acting oral or intramuscular antipsychotics.

3. Treatment with alpha-1 noradrenoblockers (terazosin, doxazosin, tamsulosin and alfuzosin and prazocin) or other illegal drugs.

4. Patients at significant risk of suicide or homicide as assessed by the investigator or any suicidal behavior in the last 6 months prior to screening.

5. Female patients who have a positive pregnancy test at screening or who are breastfeeding.

6. Patients who have hydrocephalus, epilepsy, or a history of significant head trauma, stroke, transient ischemic attack, subarachnoid hemorrhage, brain tumor, encephalopathy, meningitis, Parkinson's disease, or focal lesions on neurological examination.

7. History of syncope or other syncope, current evidence of hypovolemia, orthostatic hypotension seen at screening heart rate <55 beats per minute or systolic blood pressure <110 mmHg. or diastolic BP <70 mmHg.

8. Patients with laboratory or ECG abnormalities that are considered clinically relevant by the investigator or qualified designee (progressive heart block (second-degree or higher atrioventricular block without a pacemaker), diagnosis of sinus node dysfunction syndrome) who will have clinical manifestations for patient participation in the study.

9. Patients with serious or unstable medical conditions. They include modern diseases of the liver (moderate and severe liver failure), kidney, gastroenterological diseases, diseases of the respiratory, cardiovascular system (including coronary heart disease, congestive heart failure), endocrinological or hematological disease.

10. Patients treated with study drug within 30 days prior to current episode of agitation.

11. Patients who are unable to use sublingual film or who are considered by the investigator, for whatever reason, to be ineligible candidates for dexmedetomidine; for example, patients with a history of allergic reactions to dexmedetomidine.

Investigational drug, dose and mode of administration.

Dexmedetomidine sublingual film (formulation 12) is tested as a small single dose film formulation approximately 193.6 mm in area and 0.7 mm thick, designed to dissolve completely in the s/l space within 2-3 minutes.

Reference therapeutic agent, dosage and route of administration.

Matching placebo films should be administered sublingually as described above.

Duration of treatment: 1 day.

Criteria for evaluation.

Efficacy evaluation: assessment of the effect of the drug on acute agitation, performed on a scale of positive and negative syndromes - arousal component (PEC). The PEC contains 5 categories associated with agitation: impaired control of impulsivity, tension, hostility, non-contact, and arousal; each is rated from 1 (minimum) to 7 (maximum). RES, the sum of these 5 subscales, therefore, ranges from 5 to 35.

General agitation and sedation will be assessed using the agitation-calmness rating scale (ACES), where it indicates marked agitation;

- moderate agitation;

- weak agitation;

- normal behavior;

- easy calmness;

- moderate calmness;

- noticeable calmness;

- 55 040771

- deep dream; And

- unawakened state.

The change in agitation in response to treatment will also be measured by the overall clinical impression of improvement (CGI-I). CGI-I scores range from 1 to 7:0=not assessed (measurement), 1=much improved, 2=very improved, 3=minimally improved, 4=no change, 5=minimally worsened, 6=much worsened, 7=much worse.

To assess tolerability, safety and tolerability assessments are monitored: AEs, clinical laboratory tests, ECG with a rhythm line, and vital signs. All observed and reported AEs are recorded. Interactions of AEs with investigational medicinal products are classified by investigators as unrelated, unlikely/remotely related, possibly related, probably related, or definitely related. Prior to blood sampling for PK, vital signs are measured, including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate. Check the site of application of the s / l of the drug (cheek mucosa) for any signs of local irritation.

Additional ratings:

demographic data;

medical history;

the preceding and concomitant medicinal product;

physical examination;

pregnancy.

Efficacy Analyzes: The primary efficacy endpoint for Stage 1 is the proportion of subjects at each dose that provides a 40% reduction in RES within 2 hours. The primary efficacy endpoint for Stage 2 is the absolute change from baseline in total RES at Time 2 h.

Sample Size Determination: The study is not designed to detect statistically significant differences in performance measures. However, cohorts of up to 27 subjects (2:1 ratio of dexmedetomidine sublingual film:placebo) are sufficient to characterize safety, tolerability, and PK profile in stage 1. Cohorts of 40 subjects are included in stage 2 (40 for high dose dexmedetomidine sublingual film , 40 for low dose dexmedetomidine sublingual film, 40 for placebo).

- 56 040771

Stage 1 results.

Table 38

Summary statistics of estimates of FC parameters

Koiupia House (M Pzhirvav dose Oaiyachey le le Tizh W Stakh (J1) tlfi Shishk 1. (h*shi) PPK6esk._ embankment 1. 1 h*ng/.n 1 20 No N 10 10 9 10 9 Average 1.895 39.898 3.313 171.639 246.444 SO 0.813 15.019 1.021 57.654 63.994 sq% 42.9 37J 30.8 33.6 26.0 Min. 1.00 14.07 2.12 57.43 145.57 Median 1.74 37 TO 3.17 1LIC 241 74 me. 4.02 vade 5.3v 264.45 332.10 Geometric 1.778 37.157 3.183 160.056 238.688 skoeaverage Geometry*k skin KV% 3<99 43.89 30.51 45.41 27.86 1 20 Yes N 8 8 7 8 7 1 medium 2,:935 96.589 2.946 586.103 499.866 co 2D77 36.954' 0.857 556.166 226.187 kn% MS 38.3 29.1 94.9 45.2 Min. 1.0 49.87 1.81 230.06 294.47 Median 2.31 104.54 3.01 444.23 520.36 Poppy. 8.03 138.69 4.02 1912.52 939.05 Gamerine 2.578 89.711 2.833 453.552 461.828 average Geomsgriche skin KV% 50.30 44.50 31.46 78.77 44.05 2 60 No N 18 18 17 18 17 Average 1.528 139.589 2,861 681.542 792.552 co 0.689 47.223 1.381 482.593 525,000 sq% 45.1 33.8 48.3 MD 66.2 Mia. 0.98 73.42 1.48 265.85 293.67 Median 1.50 131.78 2.36 503.20 616.68 Miss. 3.95 253.14 6.98 2072.02 2195.38 Geometric 1.429 132.558 2,640 576 084 673.986 What is the average Geomegreen skin KV% WbDO 33.88 40.27 60.19 60.92

- 57 040771

Table 39

Individual and generalized statistical data on the assessment of parameters of the PK parameters of dexmedetomidine in plasma

Whom ri J (mp) Pzhushya doi ©p Tyazh " This (Yi) ID m PPKiya. (Arfa} 1ShK0 "k._1np; |. (h" and l) 1 20 No 01-001 1.50 35.54 4.10 224.01 326.88 01-002 1.50 38.55 3.68 182.58 241.74 01-010 1.00 59.82 2.12 104.40 145.57 01-0M 4.02 14.07 57.43 07-015 1.53 33.41 5.36 177.60 299.81 07-030 2.00 34.31 2.29 176.11 203.81 1MY7 2.00 35.38 3.64 184.37 255.41 23-016 1," 69.05 2.95 26445 332.10 23-018 1.97 40.37 3.17 154.62 186.40 23-020 1.95 38.49 2.51 190.81 226.26 N 10 10 9 10 9 Average 1.895 39.898 3.313 171.639 246.444 SO 0.813 15.019 1.021 57.654 63.994 kvs. 42.9 37.6 30.8 33.6 26.0 Min. 1.00 14.07 2.12 57.43 145.57 Media. 1.74 37.02 3.17 1S0.09 241.74 Mike. 4.02 69.05 5.36 264.45 332.10 geometries eskie 1.778 37.157 3.183 160.056 238.688 average GeoEtrich essky 36.99 43.89 30.51 45.41 27.86 KV" 1 20 Yes 01-009 2.00 130.44 3.94 662.46 939.05 01-013 2.00 122.23 2.73 486.82 563.33 05-007 2.50 49.87 4.02 230.06 334.28 05-008 2.12 66.64 2G 27247 304.52 05-021 2.50 86.86 3.10 410.74 543.04 05-023 2.50 52.29 3.01 236.04 294.47

- 58 040771

05-024 S.03 138.69 1912.52 07-02S 1.83 125.70 1.81 477.73 520.36 N 8 8 7 8 7 With relay 2.935 96.589 2.946 5S6.103 499.866 SO 2.077 36.954 0.857 556.166 226.187 sq% 70.S 38.3 29.1 94.9 45.2 Min. 1.83 49.87 1.81 230.06 294.47 Median 2.31 104.54 3.01 444.23 520.36 Max. 8.03 138.69 4.02 1912.52 939.05 geomefich escos 2.578 89.711 2.833 453.552 461.S2S average Geometric her cue 50.30 44.50 31.46 78.77 44.05 sq% 2" No 01-044 1.00 93.67 3.10 442.23 558.81 01-047 1.00 73.42 2.23 265.S5 293.67 01-055 1.50 113.35 2.S7 474.46 562.60 01-056 1.50 154.79 1.4S 413.53 42S.64 03-036 1.55 S3.52 1.62 347.11 369.07 05-050 1.00 121.52 1.S6 352.24 377.98 05-052 1.45 105.84 2.36 330.30 369.14 06-033 1.45 253.14 737.S7 834.44 06-034 1.53 206.42 2.35 887.27 1007.71 06-041 2.07 144.27 6.9S 1714.29 1882.10 06-043 1.02 186.40 2.53 7-4S.96 877.63 07-048 0.98 201.12 2.91 S74.S5 1064.08 0S-046 2.00 93.22 346.61 09-042 3.95 146.17 5.43 2072.02 2195.3S 10-032 1.50 136.25 3.40 650.22 807.14 10-035 1.50 127.27 2.78 519.54 616.68

- 59 040771

1M39 10-045 1.00 1.50 144.93 127.30 2.27 2.19 "3.55 486.85 691.00 537.29 N 1S 18 17 18 17 Average 1.528 139.5S9 2,861 6S 1.542 792.552 SO 0.6S9 47.223 1.381 482.593 525.000 KV ⁰ ., 45.1 33.S 48.3 70.S 66.2 0.98 3.42 1.48 265.85 293.67 Media™ 1.50 131.7S 2.36 503.20 616.6S Make. 3.95 253.14 08 2072.02 219538 Geometric ecwe 1.429 132.558 2.640 576.084 673.986 average 1eoietric ecwl J00 33.88 40.27 60.19 60.92 kitty,

In table. 38 and 39 and in Figs. 17 and 18 illustrate median T _max ranges of 1.5-2.3 hours for different dose levels. In addition, the exposure proportionally increases with increasing dose from 20 to 60 mcg. Re-dosing with 20 µg 1 h later in cohort 1 resulted in a 2.5-fold increase in geometric mean _Cmax and an increase in AUC.

In FIG. 19 and 20 show that in cohort 3, the 120 µg dose resulted in a significant reduction in RES compared to the pooled placebo group. It should be noted that the decrease in RES at the dose of 120 μg differs from the data for the combined placebo group at the time of 0.5 h and is maintained throughout the course of the measurement (6 h).

Example 8 Clinical study of the efficacy (sedation and antiagitation), pharmacokinetics and safety of dexmedetomidine administered intravenously to subjects suffering from schizophrenia.

The primary aim of the study was to determine the optimal intravenous (IV) dose of dexmedetomidine hydrochloride in the target population in terms of efficacy and safety in achieving excitable sedation (RASS-1) that can be reversed by verbal stimulation. When this goal was achieved in each participant, the IV infusion of dexmedetomidine hydrochloride was stopped. Another primary goal of the study was to determine the reduction in agitation levels, as determined by the PEC scores, at doses required to achieve RASS-1.

In addition, the following secondary goals were as follows.

Determination of how quickly the drug can be administered to obtain the total dose required to achieve RASS-1.

Determination of how long the sedative effect lasts after administration of the study drug is discontinued.

Determination of whether any adverse effects occur in relation to blood pressure, heart rate or respiratory center activity before or simultaneously with the achievement of the main goal. The rules for discontinuation of treatment in terms of blood pressure and heart rate, indicating a clinically significant manifestation, are as follows: fall in systolic blood pressure <90 mmHg, fall in diastolic blood pressure <60 mmHg, fall below 50 beats per minute.

Participants provided written informed consent prior to any study-related procedures. All participants were screened for inclusion and exclusion criteria. Participants were invited to the study center for screening (day -1), the day before the infusion. Baseline assessments were made on day -1 as well as on the day of infusion (day 1). Participants on day 1, prepared for infusion, were infused for up to 3 hours and monitored for sedation and any reductions in blood pressure or heart rate that met the criteria for discontinuation of treatment. Participants were not discharged from the study unit until three hours after experiencing any reduction in arousal levels (eg, RASS-1) and/or experiencing any reduction in blood pressure or heart rate that met the termination criteria. The Principal Investigator had the discretion to leave the participant overnight at the study site on the evening of Day 1 for extended monitoring, and then discharge the participant home on Day 2 if the Principal Investigator or designee determined that the participant had returned to baseline.

-60040771

The study population included 14 participants, 10 received the active drug and 4 placebo. Patients 5, 7, 8 and 9 received placebo. Patients 1, 2, 3, 4, 11, 12, 14, 16, 17, 18 were infused with dexmedetomidine hydrochloride starting at a rate of 0.2 µg/kg/h and increasing by 0.1 µg/kg/h every 30 minutes until the termination criteria were met or until the maximum duration of 3 hours was reached. Participants randomized to placebo received an appropriate intravenous infusion of placebo solution.

Table 40

Investigated Treatments

Treatment Compound Frequency Dexmedetomidine hydrochloride Precedex® Continuous infusion, increase every 30 minutes placebo normal saline Continuous infusion

After the participant became drowsy (RASS-1), the infusion was stopped. The maximum total dose administered was 1.6 μg/kg/h when either the desired level of sedation or the maximum allowable reduction in systolic or diastolic blood pressure or heart rate was reached.

During the study, participants were continuously monitored by center staff, including monitoring of blood pressure and heart rate. Intermittent electrocardiograms were performed from the start of the infusion until sedation and/or any adverse effects on blood pressure or heart rate were overcome.

When the above discontinuation criteria were met, the center stopped the infusion and the center continued to monitor the participant's vital signs every 15 minutes until the participant reached baseline or, as determined by the principal investigator, the participant achieved a stable and acceptable blood pressure level and heart rate. Return to baseline is defined as a blood pressure value within 15 mmHg. from baseline to drug administration, or a heart rate within 10 beats per minute of baseline to drug administration.

In the event that a drop in blood pressure or heart rate was considered by the investigator to be clinically significant, appropriate corrective medications could be administered in addition to discontinuing the dexmedetomidine hydrochloride infusion at the discretion of the investigator.

Adverse events (AEs), including serious adverse events (SAEs), were assessed, recorded, and reported in accordance with FDA guidelines. If any SAE is present, the study should be stopped until the cause of the SAE is determined.

Efficiency mark.

(1) Richmond Agitation-Sedation Scale (RASS): could assess the desired endpoint in terms of how quickly sleepiness was achieved (RASS -1) without causing changes in heart rate or blood pressure to a greater extent than specified by the protocol. The study was also tracked for how long the participant remained at that level of sedation; sedation was considered overcome when the participant awakened and responded spontaneously.

(2) PANSS. Change from baseline for mildly agitated patients.

(3) Global Clinical Impression of Improvement (CGI-I) (National Institute of Mental Health, 1976) ranging from 1 (improved very much) to 7 (very much worsened) from baseline. Each participant was assessed based on the severity of agitation at 15 and 30 minutes for each infusion dose at the endpoint and at the time the participant returned to baseline (in terms of level of arousal). The CGI-I score aims to determine the severity of agitation, not the severity of the disease.

(4) After stopping the infusion, participants were assessed for compliance with the discharge by the principal investigator or designee when he was satisfied that they had returned to their baseline level of receptivity and awareness without disturbances in balance, gait, and reaction time as determined by the principal investigator or designee.

Results.

(A) Efficacy study.

RASS (Richmond Agitation-Sedation Scale).

In the treatment group, 9 of 10 patients (subjects 1-3, 11, 12, 14, and 16-18) achieved a RASS score of at least -1, while in the placebo group (subjects 5 and 7-9) experienced significant sedation (see Fig. 12 and Table 41).

- 61 040771

Table 41

Shown are RASS scores in patients with schizophrenia receiving an infusion of dexmedetomidine hydrochloride and normal saline.

Infusion (minutes) RASS values after start of infusion patient number 1 t 2 T 3 t 4 t 5 R 7 R 8 R 9 R and t 12 t 14 t 16 t 17 t 18 t 0 1 3 1 1 1 1 1 1 1 1 1 1 1 0 15 -2 -1 thirty 0 0 0 1 1 1 1 0 0 0 0 0 45 0 -1 60 0 -1 0 1 1 0 1 0 0 0 0 75 -1 -1 -1 -1 90 0 1 0 0 1 0 105 120 0 0 0 0 1 -1 135 0 150 0 0 0 1 165 180 0 0 0 1

T - treatment group;

P - placebo group RES (PANSS excitation component).

In the treatment group, 9 of 10 patients (subjects 1-4, 11, 12, 14, 16, and 17) had agitation reduced to a minimum (as measured by a PEC score of 7 or below) (see Table 42 and FIG. 13).

Table 42

Shown are RES data from patients with schizophrenia receiving an infusion of dexmedetomidine and normal saline.

Time (min) RES values after start of infusion patient number 1 T 2 T 3 T 4 T 5 R 7 R 8 R 9 R I T 12 T 14 T 16 t 17 T 18 T 0 9 16 12 9 AND 12 9 13 13 13 10 10 10 15 5 13 12 9 10 12 9 13 13 13 9 9 8 thirty 12 10 8 9 9 8 12 And 13 6 6 7 45 AND 7 8 9 8 8 12 9 10 6 6 5 60 9 6 7 8 8 8 13 9 10 5 7 75 7 7 8 8 7 AND 7 8 5 5 90 7 7 9 7 AND 6 105 7 8 8 7 10 5 120 7 8 8 7 10 135 7 8 7 7 9 150 8 7 7 9 165 8 8 7 9 180 8 8 7 10

T - treatment group; R - placebo group.

(B) Pharmacokinetic study (PK study).

Dexmedetomidine levels were also measured in patients' plasma during infusion. The results are presented in table. 43. The maximum concentrations of dexmedetomidine in patients with schizophrenia (Cmax) ranged from about 22.45 pg/ml to about 406.3 pg/ml. The time to reach Cmax ranged from about 15 minutes to about 105 minutes. The average infusion rate is 0.36 μg/kg/h with a maximum rate ranging from about 0.2 μg/kg/h to about 0.6 μg/kg/h (see FIGS. 14, 15 and 16).

-

Claims (18)

Table 43 Plasma concentrations (pg/mL) of patients with schizophrenia are shown at different time points during infusion of dexmedetomidine hydrochloride and normal saline. Time (III) U] n "i.b kinzen (early n iliuiml 1iikshra.mm / m.11 1 T 2 T 3 T 4 T 5 R 7 R V R 9 R 11 t 12 t 14 I 16 I 17 I And T 0 NPPO IPKO NPPO npko npko npko npko npko npko IPKO miko npko npko 15 22.45 NPPO npko npko IPKO npko 41,I. npko IPKO 2.56 15%7 48.36 thirty 14.72 NPPO NIJ iu npko npko npko NPPO 62.91 44.S7 52.66 15.59 IPKO 54.53 45 IPKO NIKO npko npko npko npko 04.07 50.51 4D53 41.17 39.93 60 npko npko npko npko npko 15047 108.6 406.3 67.81 75 NPPO npko npko IPKO npko 158.54 72.26 90 <3 npko npko npko npko 237.83 105 npko npko npko NPPO 267.3 120 nshso npko npko IPKO 1.35 npko npko npko npko 150 npko npko npko npko MS npko npko npko peaks 180 npko npko IPKO npko E&CM visa iiist 'Mifu' AI (MII) if 75 60 149 1M and about 180 179 68 yuz 64 66 36 30 *LQQ - below the limit of quantitation; T - treatment; R - placebo. Discussion. IV administration of dexmedetomidine hydrochloride caused a >50% reduction in RES in all 7 of 10 subjects, and one subject (patient 1) responded at a C _{max of} 22 pg/ml. Five out of 10 subjects (patients 1, 2, 3, 16 and 17) showed a 40% reduction in RES with C _max <72 pg/ml. Good response rates at these plasma exposure levels indicate that sublingual administration of dexmedetomidine at similar or higher C _max exposure levels will provide good antiarrhythmic effects. As shown in Example 6 above, sublingual dexmedetomidine hydrochloride administered to healthy volunteers produced good plasma exposure levels at doses of 10, 20, and 40 µg, indicating that such doses should be appropriate to obtain good antiarrhythmic effects (e.g., when measured to reduce RES) in agitated subjects, including subjects with schizophrenia, while also not producing clinically significant deleterious effects on blood pressure and/or heart rate. CLAIM 1. Self-supporting soluble oromucosal film for oral administration, containing (i) dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) a water-soluble hydroxypropylcellulose polymer having a molecular weight of about 40,000 daltons; (iii) a water-soluble hydroxypropyl cellulose polymer having a molecular weight of about 140,000 daltons; (iv) a water-soluble hydroxypropylcellulose polymer having a molecular weight of about 370,000 daltons; and (v) a water-soluble polyethylene oxide polymer having a molecular weight of about 600,000 daltons, - 63 040771 where the specified water-soluble polymer of hydroxypropyl cellulose, having a molecular weight of about 40,000 daltons, is present in an amount of from about 3% to about 8% wt./wt. from the total mass of the film; water-soluble polymer hydroxypropylcellulose having a molecular weight of about 140,000 daltons, is present in an amount of from about 3% to about 8% wt./wt. from the total mass of the film; water-soluble polymer of hydroxypropylcellulose having a molecular weight of about 370,000 daltons, is present in an amount of from about 20% to about 40% wt./wt. from the total mass of the film; and the specified water-soluble polymer of polyethylene oxide, having a molecular weight of about 600,000 daltons, is present in an amount of from about 50% to about 60% wt./wt. from the total weight of the film. 2. The film of claim 1 wherein the only polymers present in the film are a water soluble hydroxypropyl cellulose polymer and a water soluble polyethylene oxide polymer. 3. The film according to claim 1 or 2, wherein the polymers (ii), (iii), (iv) and (v) together form a single layer film substrate. 4. The film of claim 3, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is present on the surface of the film substrate. 5. The film of claim 3, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is present within the film support. 6. A film according to any one of claims 1 to 5 which dissolves in oral mucosal fluid after about 1 minute to about 5 minutes. 7. Film according to any one of claims 1 to 6, which has a thickness of from about 20 µm to about 200 µm. 8. A film according to any one of claims 1 to 7 which covers an area from about 100 mm ² to about 300 mm ² . 9. A film according to any one of claims 1 to 8, which has a disintegration time from about 60 seconds to about 180 seconds. 10. A film according to any one of claims 1 to 9, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride and is present in an amount of from about 0.5 µg to about 200 µg. 11. The film of claim 10, wherein the dexmedetomidine hydrochloride is present in an amount of from about 0.01% to about 5% w/w, based on the total dry weight of the film. 12. A film according to any one of claims 1 to 11, which has a mucoadhesive strength equal to or greater than 1000 g, preferably from about 1000 g to about 2000 g. 13. A film according to any one of claims 1 to 12, wherein said dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 10 µg, about 20 µg, about 40 µg, about 60 µg, about 90 µg, or about 120 µg. 14. Self-supporting soluble oromucosal film for oral administration, consisting of (a) a composition containing (i) dexmedetomidine hydrochloride; (ii) hydroxypropyl cellulose having a molecular weight of about 40,000 daltons; and (iii) hydroxypropyl cellulose having a molecular weight of about 140,000 daltons; and (b) a film support containing (i) hydroxypropyl cellulose having a molecular weight of about 40,000 daltons; (ii) hydroxypropyl cellulose having a molecular weight of about 140,000 daltons; (iii) hydroxypropyl cellulose having a molecular weight of about 370,000 daltons; and (iv) a polyethylene oxide having a molecular weight of about 600,000 daltons, wherein the only polymers present in the film are a water-soluble hydroxypropyl cellulose polymer and a water-soluble polyethylene oxide polymer, wherein the water-soluble hydroxypropyl cellulose polymer having a molecular weight of about 40,000 daltons is present in an amount of from about 3%. up to about 8% wt./wt. from the total mass of the film; water-soluble polymer hydroxypropylcellulose having a molecular weight of about 140,000 daltons, is present in an amount of from about 3% to about 8% wt./wt. from the total mass of the film; water-soluble polymer of hydroxypropylcellulose having a molecular weight of about 370,000 daltons, is present in an amount of from about 20% to about 40% wt./wt. from the total mass of the film; and the specified water-soluble polymer of polyethylene oxide, having a molecular weight of about 600,000 daltons, is present in an amount of from about 50% to about 60% wt./wt. from the total mass of the film; and the composition of part (a) is present on the surface of the film substrate (b). 15. The film according to claim 14, in which the composition on the surface of the film substrate is from about 0.1% to about 10% wt./wt. from the total weight of the film. 16. The film according to any one of claims 14, 15, in which dexmedetomidine is present in the form of a hydrochloride salt and is present in an amount of from about 0.05% to about 3% wt./wt. from the total weight of the film. 17. The film according to any one of claims 14-16, in which hydroxypropyl cellulose having a molecular weight of about 40,000 daltons is present in an amount of about 5% wt./wt. from the total weight of the film. 18. The film according to any one of claims 14-17, in which hydroxypropyl cellulose having a molecular weight of about 370,000 daltons is present in an amount of about 25% wt./wt. from the total weight of the film. -