WO2019226753A1 - Benzodiazepine formulations - Google Patents

Abstract

This disclosure describes improved formulations for the delivery of a therapeutic benzodiazepine compound to the nasal mucosa. In one embodiment, the disclosure provides a formulation of midazolam suitable for intranasal administration. The formulations of the disclosure may be particularly useful in the treatment of epilepsy, as an abortive or rescue therapy when breakthrough seizures or seizure clusters are experienced by a patient. The formulations may also be useful in other therapeutic applications, such as procedural sedation.

Description

BENZODIAZEPINE FORMULATIONS

CONTINUING APPLICATION DATA

This application claims the benefit of U.S. Provisional Application Serial No. 62/676,502, filed May 25, 2018, which is incorporated by reference herein.

SUMMARY

The present disclosure relates to improved formulations for the delivery of a therapeutic benzodiazepine compound to the nasal mucosa. In one embodiment, the disclosure provides a formulation of midazolam suitable for intranasal administration. The formulations of the disclosure may be particularly useful in the treatment of epilepsy, as an abortive or rescue therapy when breakthrough seizures or seizure clusters are experienced by a patient. The formulations may also be useful in other therapeutic applications, such as procedural sedation.

TECHNICAL FIELD

Midazolam is a potent benzodiazepine derivative with sedative, anxiolytic, hypnotic, amnesic, anticonvulsant and muscle relaxant pharmacological properties. However, oral administration of midazolam is disfavored due to degradation and first-pass elimination. Furthermore, in the treatment of seizures, it is desirable to achieve a suitable blood concentration in a short amount of time to realize rapid onset of action. Intravenous (“IV”) and intramuscular (“IM”) administration is possible with rapid onset. However, IV or IM administration requires specialized equipment and training, may itself evoke fear or panic in a patient, and may result in serious cardiorespiratory side effects such as respiratory depression and hypotension. IV or IM administration is typically reserved for hospital or emergency room settings, where appropriate monitoring of the patient may be conducted and where interventional care is available.

Intranasal formulations of midazolam have been explored in an effort to overcome the shortcomings of other routes of administration and to provide a suitable and convenient therapy using midazolam. Intranasal delivery of midazolam is a very attractive mode of administration for a number of reasons. Intranasal drug administration is relatively pain-free, results in rapid drug absorption and avoids hepatic first-pass elimination. An additional advantage is the ease of administration, leading to better patient compliance. Furthermore, a suitable system for the delivery of a therapeutic intranasal formulation may allow for a caregiver to effectively dose a patient who is suffering from a seizure, without having to first transport the patient to an emergency care facility, and without the need for specialized training, expertise, or equipment.

The mucosa of the nasal cavity is constructed from a highly vascularized tissue and has a much higher permeability than other mucosal surfaces. The extensive network of blood capillaries under the mucosal surface in the nasal mucosa is well suited to provide a rapid and effective systemic absorption of drugs, vaccines and biologicals. Moreover, the nasal epithelial membrane in effect contains a single layer of epithelial cells (pseudostratified epithelium) and, therefore, is more suited for drug administration than other mucosal surfaces having squamous epithelial layers.

Nasal administration of midazolam may result in pharmacokinetic and pharmacodynamic profiles which are similar to those observed after intravenous injections. (See, for example, Wermeling, U.S. Published Patent App. US2004/0176359). A number of early studies demonstrated the beneficial effects of intranasally administered midazolam in patients, both in children and adults. (See summary and references cited in W02005/067893 at pp. 2-3.) When administered nasally, midazolam appears to have a rapid onset of action (about 10 minutes) and a relatively short duration of action (30 to 60 minutes). Nasal administration of midazolam has been observed to suppress acute seizures and improve the EEG background in epileptic children. In adult patients undergoing gastrointestinal endoscopy, intranasal administration of midazolam has been used for the induction of sedation, and the intranasal route has been shown to cause fewer side effects than intravenous injection.

While such studies demonstrated the proof-of-concept for nasally administered midazolam, it should be noted that early studies were done using available injectable solutions (for example, VERSED® or DORMICEIM®) containing midazolam at concentrations of up to 5 mg/mL. The injectable solution is not fit-for-purpose when used intranasally. Therapeutic doses of midazolam may range from 1-10 mg, so dosing the injectable solution intranasally often requires the dosing of 1-5 mL of solution in order to achieve the absorption of a therapeutic dose. When such large volumes of liquid are administered intranasally, a large portion of the volume drops out of the nose and/or will be swallowed, resulting in both loss of a portion of the dose, and in part of the dose being administered orally rather than nasally. Inconsistent and unpredictable amounts of midazolam are absorbed. Furthermore, the nasal administration of such large volumes of solution also accounts for a number of unpleasant side effects sometimes experienced by patients, including lachrymation, burning sensations, irritation in the nose and throat, and general discomfort.

It is therefore clear that it would be desirable to have a fit-for-purpose formulation for intranasal administration of midazolam. For efficient and comfortable nasal drug delivery, volumes of about 200 microliters (“pL”) (approximately 100 pL into each nostril) are normally the maximum that should be administered to a patient. More preferably, only 100 pL administered to one nostril would be administered. Ideally, the formulation is administered to the nasal mucosa in the form of a spray. Furthermore, suitable nasal formulations also must conform to variety of other parameters, such as compatibility with nasal mucosa, viscosity, and chemical and physical stability.

Midazolam is available as an acid-addition salt (for example, hydrochloride; maleate). While an aqueous solution of the hydrochloride salt may be made at a concentration of approximately (~) 5 mg/mL, such a solution has a pH of ~3.3 which renders it harmful to, if not incompatible with, nasal mucosa. Therefore, several approaches have been employed using solubilizers in an effort to obtain a suitable concentration of midazolam acid salts at a physiologically compatible pH. Merkus (U.S. Patent 7,700,588 and W02005/067893) reports compositions of midazolam in concentrations of 35-100 mg/mL. The disclosed compositions include a midazolam acid salt and solubilizer, such as propylene glycol, glycerol, polyethylene glycol, povidone, ethanol, or the like. However, such compositions are deficient for practical use because they are characterized by a pH in the range of 2.5-4 which is painful or uncomfortable for the patient, and potentially detrimental to nasal mucosa. W02005/067893 includes an overview of prior efforts in formulating midazolam with solubilizers for intranasal administration.

Midazolam is also available in the free base form. The free midazolam base is rather lipophilic. Its partition coefficient P between n-octanol and phosphate buffer of pH 7.5 has been reported to be about 475. The observed water solubility of midazolam free base is approximately 0.01 mg/mL. The low solubility of midazolam free base in water presents difficulty in formulating aqueous formulations of midazolam suitable for nasal administration. Gizurarson (U.S. Patents 8,217,033, 8,809,322, 9,289,432 and 9,687,495) and Gizurarson, et al. (European Patent 2121025; W02008/089426) report the use of alkoxy- polyethylene glycols, particularly methoxy-polyethylene glycol, in suitable formulations of poorly soluble therapeutic agents, including midazolam. The published patents and applications report that when an alkoxy-polyethylene glycol is used in such a formulation, the therapeutic agent may be solubilized more easily and in larger amounts than when other excipients are used. In addition, the resulting formulations are less viscous than formulations employing other solubilizing excipients. The formulations containing alkoxy-polyethylene glycols were also reported to cause less irritation and have less undesirable aftertaste (for example, a petroleum like after taste) upon nasal administration than when other excipients, such as propylene glycol, are used.

As reported by Gizurarson, employing a methoxy-polyethylene glycol, such as mPEG- 350, as a significant portion of the formulation enables midazolam free base to be used rather than an acid-addition salt. The resulting formulation, being free from acidic components, is thus is characterized by a physiologically compatible pH. Furthermore, employing mPEG-350 potentially allows for a sufficient quantity of midazolam to be dissolved in a -100 pL volume, such that an effective therapeutic dose could be delivered nasally.

In light of the foregoing, it is clear that there is an unmet need for a midazolam formulation which is specifically formulated for intranasal administration, in order to overcome all of the various disadvantages associated with the previously known formulations. It is therefore an aim of the present disclosure to provide a nasal spray formulation with a sufficiently high midazolam concentration to allow adequate doses of midazolam to be conveniently and comfortably administered via the intranasal route in an appropriate volume of a physiologically compatible solution. The formulation should also cause as little irritation as possible and have as high a bioavailability as possible. For such a formulation to be practical in field use, it furthermore needs to be chemically and physically stable, and be characterized by an appropriate viscosity in order to provide a suitable spray pattern upon actuation of a spray device.

Based on the foregoing considerations and on the promising aspects of a midazolam formulation comprising mPEG-350 as a solubilizer, significant clinical studies were undertaken by ETpsher-Smith Laboratories, Inc. (succeeded by Proximagen, LLC) examining the safety and efficacy of a formulation in the treatment of seizure clusters. A multi-site study called ARTEMIS-l : Acute Rescue Therapy in Epilepsy With Midazolam Intranasal Spray-l (ClinicalTrials.gov Identifier: NCT01390220) was conducted to evaluate the safety and efficacy of an investigational intranasal formulation (ETSL261) in the outpatient treatment of subjects with seizure clusters.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graphical depiction of apparent saturation solubility for midazolam in certain exemplary solvent vehicles of varying water content (Solvent Vehicle S-l to S-5) at t = 4 weeks. DEFINITIONS

In describing embodiments of the invention, specific terminology is used for the sake of clarity. The disclosure, however, is not intended to be limited to the specific terms so selected, and it is to be understood that each term so selected includes all technical equivalents that operate similarly.

The term “midazolam” refers to the chemical designated by the EJPAC name:

8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[l,5-a][l,4]benzodiazepine (CAS 59467-70- 8). The free base form has a molecular formula of C18H13CIFN3 and is characterized by a molecular weight of 325.77 g/mol. Midazolam free base may be prepared in a stable crystalline form at standard conditions, having a melting point of approximately 158-160 °C. The molecular formula chemical structure of midazolam free base is shown below:

Midazolam free base is preferred for use in the compositions and formulations disclosed herein. Pharmaceutical -grade midazolam free base is commercially available from a number of sources. Midazolam salts, such as hydrochloride salt and maleate salt, are also commercially available. Midazolam salts may also be employed in the compositions and formulations disclosed herein; however, in order to maintain a physiologically compatible pH, it would be desirable to use salts of weak acids rather than salts of strong acids; or to use a combination of salts of weak acids and strong acids; or a combination of free base along with one or more salts of either weak acids or strong acids (or a combination thereof). In any event, the therapeutic dose would be determined based on the free base equivalent.

The terms“methoxypolyethylene glycol” and“mPEG” refer to poly(ethylene glycol) methyl ether. Methoxypolyethylene glycol is generally represented by the structure:

where n (that is, the number of repeating oxy ethylene units) is greater than 1, typically 3 or greater. mPEG may be prepared in a variety of forms, typically identified by the number average molecular weight (M_n). Commercially available mPEG is available, for example, having average Mn of 350, 550, 750, 2000, and 5000 g/mol.

The term“mPEG-350” refers to a specific grade of mPEG having an average molecular weight (Mn) of -350 g/mol (“~” is used to indicate“approximately” herein). With reference to the structure above, mPEG-350 is comprised of a mixture of polymer chains having an average “n” in the range of 7 to 8. Suitable mPEG-350 (CAS 9004-74-4) is commercially available from suppliers such as Sigma-Aldrich and Dow Chemical Company (for example, CARBOWAX SENTRY Methoxypolyethylene Glycol).

The terms“polyethylene glycol” and“PEG” refer to the polymer commonly known as polyethylene glycol, also called polyethylene oxide. Polyethylene glycol is generally represented by the structure:

where n (that is, the number of repeating oxy ethylene units) is greater than 1, typically 3 or greater. As employed in the compositions and formulations disclosed herein, the polyethylene glycol is typically a linear polyethylene glycol characterized by M_n of -400. Other suitable polyethylene glycols may be used as equivalents, as will be appreciated by those skilled in the art. A variety of pharmaceutical-grade PEG products are readily commercially available.

The terms“propylene glycol” and“PG” refer to the chemical 1, 2-propanediol, also called 2-hydroxypropanol (CAS 57-55-6). Propylene glycol is a diol having a linear molecular formula of CH3CHOHCH2OH and is characterized by a molecular weight of 76.095 g/mol. Pharmaceutical -grade propylene glycol is readily available from commercial suppliers.

The terms“ethanol” and“ethanol, 190-proof’ refer interchangeably to the commonly available pharmaceutical grade of ethyl alcohol (CAS 64-17-5), a linear alcohol having a linear molecular formula of CH3CH2OH. The terms“ethanol” and“ethanol, 190-proof’ are not used herein to refer to ethyl alcohol, but are used herein to refer to a mixture of ethyl alcohol and a small percentage of water.“Ethanol, 190-proof’ generally contains -95% ethyl alcohol and -5% water (by volume) in an undenatured stable azeotropic mixture. Pharmaceutical-grade 190-proof ethanol is readily commercially available from a variety of sources. ETnless clearly indicated otherwise, only“Ethanol, 190 proof, ETSP” was used in the solvent vehicles, formulations, and compositions described herein.

Furthermore, in the examples and describing embodiments described herein, stated percentages are based on the components that are combined to make the stated composition. In other words, and by way of example only, if a composition were prepared by combining 10% ethanol, 190-proof (pharmaceutical grade; by weight), and 90% water (pharmaceutical grade; by weight), it would be characterized herein as“90 wt.-% water”. No correction would be made to the stated percentage based on the small fraction of water that is contributed from the 190-proof ethanol.

The term“ethanol” is used herein in examples and in describing embodiments, and refers to 190-proof ethanol as stated above; however, it will be recognized that a similar composition could be formed using another grade of ethyl alcohol (such as“absolute” ethyl alcohol), combined with an appropriate quantity of water, and such a composition would be regarded as an equivalent to the described embodiment. By way of example only, a composition that is described herein as 20% ethanol, 190-proof (pharmaceutical grade; by weight) and 80% water (pharmaceutical grade; by weight) could be approximated using a mixture of 19% ethyl alcohol, absolute (by weight) and 81% water (by weight). Such a substitute would be considered an equivalent in the context of the present disclosure, as those skilled in the art will appreciate.

The phrase “pharmaceutical grade” denotes that the referenced component meets appropriate quality testing specified by United States Pharmacopeia (USP), National Formulary (NF), European Pharmacopeia (EP), or other relevant standard-setting organization.

The term“about” means“approximately.” The terms“about” or“approximately” are used to denote that a quantity may be permitted to vary somewhat from the stated quantity without diminishing or departing from the characteristic properties of a composition.

The term“precipitation” refers to either a crystalline or amorphous solid form separating or“coming out of’ a solution.“Precipitate” refers to the crystalline or solid material that has come out of solution.

The terms“weight-percent”,“w/w” and“wt.-%” are used interchangeably to denote a weight-percent based on the overall mass of a composition. By way of example, if a composition is 25 wt.-% of Component A, then 100 g of the composition contains 25 g of Component A and 75 g of other components. Also, the phrase“by weight” is used similarly; the same composition could be referred to as“25% Component A, by weight.” In all cases,“weight” as used herein refers to mass (in grams or other suitable units) and not to the force applied by the mass.

The phrase “solvent vehicle” is used herein to denote a combination of inactive pharmaceutical excipients which act as a solvent and a delivery vehicle for an active pharmaceutical ingredient (“API”).“Solvent vehicle” refers to the combination of excipients but excludes the API (even if present). (That is, the API is the solute, not part of the solvent vehicle.) In the context of the present disclosure, a solvent vehicle is liquid-phase, but could include components that are solid phase when not in the solvent vehicle, so long as they are solubilized when in the solvent vehicle.

The phrase“saturation solubility” is a characteristic of a solvent vehicle and refers to a saturation concentration (generally in mg/mL) for a particular API, at room temperature, under equilibrium conditions. Essentially this is the maximum stable concentration for the API in the solvent vehicle. The saturation solubility is generally measured by exposing a solvent vehicle to excess API, allowing equilibrium to be established, and then quantitatively determining the concentration of API in the saturated solvent vehicle. The phrase“solubility margin” for a composition refers to the relative amount by which the saturation solubility of an API in a solvent vehicle exceeds the actual concentration of the API in the composition (where the composition is the solvent vehicle plus the dissolved API). By way of example, if the saturation solubility of Compound A in Solvent Vehicle V is 25 mg/mL, and the actual concentration of Compound A in a composition composed of Compound A dissolved in Solvent Vehicle V is 20 mg/mL, then the solubility margin is 25% (calculated as (25 - 20)/20 * 100%).

The term“epilepsy” refers to a chronic neurological disorder characterized by recurrent unprovoked seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or synchronous neuronal activity in the brain. The most widespread classification of the epilepsies divides epilepsy syndromes by location or distribution of seizures (as revealed by the appearance of the seizures and by EEG) and by cause. Syndromes are divided into localization- related epilepsies, generalized epilepsies, or epilepsies of unknown localization. Epilepsy syndromes are further divided by presumptive cause: idiopathic, symptomatic, and cryptogenic. Forms of epilepsy are well-characterized and reviewed.

The term “procedural sedation” means a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate unpleasant procedures while maintaining cardiorespiratory function. Procedural sedation is intended to result in a depressed level of consciousness that allows the patient to maintain oxygenation and airway control independently. Procedural sedation, also called conscious sedation, may be suitably employed by a medical practitioner in situations involving noninvasive or minimally invasive procedures, for example. Procedures which may permit temporary procedural sedation include, by way of example only: medical procedures such as cardioversion, setting fractures, draining abscesses, reducing dislocations, etc.; certain diagnostic procedures such as endoscopy, imaging procedures, etc.; certain dental procedures.

The words“preferred” and“preferably” refer to features or embodiments that may afford certain benefits, under certain circumstances. However, other features or embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the disclosure. The term“comprises” and variations thereof do not have a limiting meaning where these terms appear in the description and embodiments.

The term“consisting of’ means including, and limited to, whatever follows the phrase “consisting of.” That is, “consisting of’ indicates that the listed elements are required or mandatory, and that no other elements may be present.

The term“consisting essentially of’ indicates that any elements listed after the phrase are included, and that other elements than those listed may be included provided that those elements do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements.

Unless otherwise specified,“a,”“an,”“the,” and“at least one” are used interchangeably and mean one or more than one.

Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range (for example, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

For any method disclosed herein that includes discrete steps, the steps may be conducted in any feasible order. And, as appropriate, any combination of two or more steps may be conducted simultaneously.

All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified.

Reference throughout this specification to“one embodiment,”“an embodiment,”“certain embodiments,” or“some embodiments,” etc., means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, and so forth used in the specification and described embodiments are to be understood as being modified in all instances by the term“about.” Accordingly, unless otherwise indicated to the contrary, the numerical parameters set forth in the specification and described embodiments are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the doctrine of equivalents to the scope of the described embodiments, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the compositions and formulations disclosed herein are approximations, the numerical values set forth in the specific examples are reported as precisely as is suitable. All measured numerical values, however, inherently contain a range necessarily resulting from the standard deviation found in their respective testing measurements.

DETAILED DESCRIPTION

The present disclosure provides midazolam formulations which are specifically formulated for, and suitable for, intranasal administration. The disclosure provides sprayable formulations with a sufficiently high midazolam concentration to allow adequate doses of midazolam to be conveniently and comfortably administered via the intranasal route in an appropriate volume of a physiologically compatible solvent vehicle. The formulations of the disclosure cause little or no irritation to a patient’s nasal mucosa, and provide sufficient bioavailability to produce the desired physiological effect (when administered at the appropriate dosage). The formulations disclosed herein are chemically and physically stable, and are characterized by an appropriate viscosity which allows a suitable spray pattern upon actuation of a spray device.

The formulations may be particularly useful in the treatment of epilepsy, as an abortive or rescue therapy when breakthrough seizures or seizure clusters are experienced by a patient. The formulations may also be useful in other therapeutic applications, such as procedural sedation. The disclosure further provides a single-use device for administering the disclosed formulations that is practical and convenient in field use.

A main concern of the present disclosure is to provide midazolam formulations that present little or no risk that the active ingredient may precipitate out of solution during ordinary storage conditions prior to use. It was discovered by the present inventors that certain known formulations, while suitable in many respects for administration as a nasal spray, suffered from a shortcoming that was not immediately apparent. These known formulations were observed to form a precipitate during routine storage tests, and were subsequently discovered to contain a concentration of midazolam that was too near the equilibrium saturation solubility for the solvent vehicle. These formulations were deemed too unstable for further development, since in real- world use, a pharmaceutical product would be subjected to some temperature fluctuation prior to use, and it is known that saturation solubility varies with temperature.

Formation of a precipitate during storage is highly concerning for a number of reasons. Formation of a precipitate means that the remaining solution is below strength with respect to the therapeutic agent, that is, it would fail to meet the label claim. Formation of a precipitate could, in practice, result in a clogged spray device, which would result the failure to deliver some or all of a dose upon actuation.

In real-world use, these risks are completely unacceptable. At the point of use, a patient (or the patient’s caregiver) would likely be unaware of the potential for the delivery of no therapeutic agent or a sub-therapeutic dose of the therapeutic agent. Since the formulations of the disclosure are intended for use in serious medical conditions including states of seizure, the patient cannot be put in this situation.

Accordingly, one aim of the present inventors was to provide pharmaceutical compositions that provide an adequate solubility margin. In particular, this disclosure provides pharmaceutical compositions comprising midazolam disposed in a solvent vehicle, characterized in that the equilibrium saturation solubility of midazolam in the solvent vehicle is at least 30% greater than the midazolam concentration in the composition (that is, a 30% solubility margin). More preferably, the solubility margin is at least about 50%, at least about 70%, or at least about 100%.

For the previously known formulations mentioned above, one known approach was to apply one or more heating steps to solubilize the midazolam. However, the present inventors observed that this approach simply masks or increases the risk of a precipitate forming during storage, because the resulting solution is near saturation or possibly even supersaturated. Therefore, it was another aim of the inventors to provide pharmaceutical compositions that could be conveniently and efficiently made without heating steps, while still providing an adequate solubility margin.

It was surprisingly discovered, as reported below, that the equilibrium saturation solubility of known solvent vehicles could be dramatically adjusted with only a slight reduction in the water fraction of the solvent vehicle, with corresponding slight adjustments of the organic fraction of the solvent vehicle. Accordingly, it is possible to provide a stable pharmaceutical composition comprising midazolam in a solvent vehicle that retains all the desirable features (viscosity, sprayability, physiologically compatible pH) of known formulations, but additionally provides a solubility margin, rendering the composition safe for use after storage under ordinary storage conditions.

As mentioned above, a significant amount of development work and clinical studies were done on a midazolam formulation comprising mPEG-350 as a solubilizer. As part of the development program, a single-use device comprising a suitable pharmaceutical composition was the intended commercial product to be delivered to consumers. The product’s desired capabilities included both patient and caregiver considerations.

The intended patient population was patients (generally epilepsy patients) who require control of intermittent bouts of increased seizure activity (for example, seizure clusters, acute repetitive seizures). Epilepsy is generally treated using one or more anti-epileptic drugs (for example, anticonvulsants) or other therapy, with a primary goal of reducing or eliminating seizures. In practice, varying degrees of success are achieved in the treatment of individual patients. Even in well-controlled patients, episodic seizure activity such as breakthrough seizures or seizure clusters may be experienced.

Breakthrough seizures occur when a patient experiences sudden seizure(s) following a sustained period of freedom from seizures. Seizure clusters occur as a flurry or cluster of seizures close in time, with a return to baseline between events. Seizure clusters are also known as serial seizures, repetitive seizures or acute repetitive seizures (ARS).

A secondary goal of epilepsy treatment is to enable patients to lead lifestyles consistent with their capabilities. Important considerations include quality of life, reduction of side effects from primary medications, ease and convenience of care or seizure treatment, and ability to respond to seizure occurrences.

During development, it was determined that the patient and caregiver may both prefer an intranasal route of drug administration during bouts of seizure activity, as compared to the current standard of care (a rectally delivered gel, DIASTAT®). A portable and hand-held product capable of convenient, safe, effective, and reliable use in emergency seizure situations was considered a long-felt need.

A single-use device, also known as a unit-dose system (UDS), was recognized as capable of intranasal delivery of a small volume of a drug formulation, in the form of a spray. The ETDS is a safe, convenient, ready -to-use primer-less system capable of delivering approximately 100 pL of a liquid drug formulation in a single actuation. The UDS system was selected based upon the recognized UDS system characteristics meeting the patient and caregiver convenience and usability requirements. The combination product delivers a dose in the form of spray having a well-characterized spray pattern and droplet size distribution.

In one embodiment, the present disclosure provides a pharmaceutical composition comprising about 49.0 wt.-% mPEG-350; about 17.0 wt.-% PEG-400; about 6.0 wt.-% propylene glycol; about 7.0 wt.-% ethanol; about 1 to about 7 wt.-% midazolam; and about 14 to about 20 wt.-% water. In another embodiment, the pharmaceutical composition consists essentially of the foregoing components in the stated quantities. In another embodiment, the pharmaceutical composition consists of the foregoing components in the stated quantities.

In another embodiment, the disclosure provides a pharmaceutical composition suitable for administration as a nasal spray, comprising midazolam disposed in a solvent vehicle, and providing an adequate solubility margin with respect to the midazolam. Such compositions comprise midazolam disposed in a solvent vehicle comprising: mPEG-350, PEG-400, propylene glycol, ethanol, and water; and are characterized in that the equilibrium saturation solubility of midazolam in the solvent vehicle at room temperature is at least about 100% greater than the midazolam concentration in the composition. In another embodiment, the equilibrium saturation solubility of midazolam in the solvent vehicle at room temperature is at least about 70% greater than the midazolam concentration in the composition. In another embodiment, the equilibrium saturation solubility of midazolam in the solvent vehicle at room temperature is at least about 50% greater than the midazolam concentration in the composition. In another embodiment, the equilibrium saturation solubility of midazolam in the solvent vehicle at room temperature is at least about 30% greater than the midazolam concentration in the composition. In one particular embodiment of the foregoing, the pharmaceutical composition comprises at least 47 wt.-% mPEG-350.

Other embodiments include pharmaceutical compositions according to the exemplary formulations provided below.

Pharmaceutical compositions provided by this disclosure are found to be stable physically and chemically throughout the shelf life of the product (for example, 24 months or longer) when stored at recommended storage conditions of 20°C to 25°C (68°F to 77°F). No precipitate has been observed for any composition according to the embodiments disclosed herein under storage conditions. The disclosed compositions are characterized by an appropriate viscosity (-20-30 cP) which allows a suitable and reproducible spray pattern upon actuation of a spray device. The disclosed compositions are also characterized by a physiologically compatible apparent pH, and may be applied to a nasal mucosa without causing damage or significant irritation. Certain disclosed compositions were selected for further development and clinical studies.

The disclosure further provides a single-use device that is practical and convenient in field use. The device includes a vessel containing the subject compositions, and an actuator, such that actuation delivers the composition to a patient’s nasal mucosa in the form of a spray. Any suitable vessel, such as a stoppered glass vial, may be employed. The actuator may include multiple components, including, for example, a vial holder and actuator body. Suitable device components, and arrangements of components, will be appreciated and understood by those skilled in the art. In one embodiment, about 125 pL of the pharmaceutical composition is disposed in the vessel prior to actuation.

The disclosure further provides methods for the treatment or alleviation of a seizure, comprising the step of administering to the nasal mucosa of a patient in need of such treatment, a subject composition in the form of a spray.

The disclosure further provides methods for procedural sedation; for example, methods for sedating a patient as described above for a medical, dental, or diagnostic procedure. Such methods comprise the steps of administering to the nasal mucosa of patient a subject composition in the form of a spray; and allowing a sufficient time for the patient to reach a suitable state of sedation before initiating the medical, dental, or diagnostic procedure.

In one embodiment of the methods, administering the composition to the patient delivers about 100 pL of the pharmaceutical composition to the patient’s nasal mucosa. In another embodiment, administering the composition to the patient delivers about 2 to about 8 mg midazolam to the patient’s nasal mucosa. In another embodiment, administering the composition to the patient delivers about 4 to about 6 mg midazolam to the patient’s nasal mucosa. In particular embodiments, administering the composition to the patient delivers about 2.5 mg, about 5 mg, or about 7.5 mg of midazolam to the patient’s nasal mucosa. The subject compositions may be prepared using conventional methods known to those skilled in the art, and using conventional equipment. In practice, it was found to be useful to combine the water component with a portion of mPEG-350 component, with mixing, to obtain a premix. Separately, the ethanol component and the remaining components of the solvent vehicle were mixed, and then the midazolam added and mixed. Finally, the water/mPEG-350 premix was added with mixing to obtain the desired formulation. The liquid composition was then filtered using a 0.22 micrometer (alternatively,“micron,” or“pm”) filter, and then transferred to a bulk hold container prior to filling of the vessels.

SELECTED TEST METHODS

Apparent pH Test - In characterizing the subject and exemplary compositions, a standard pH probe and meter were used. Since the subject compositions are composed primarily of organic components rather than aqueous solvent, the pH reported by the meter and probe is not a true pH (that is, the negative log of the hydrogen or hydronium ion concentration) but is referred to herein as“apparent pH.” (Refer to Chapter <79l> pH of ETSP 40.)

In the context of the present disclosure, the apparent pH of compositions intended for nasal administration is meaningful in that a composition exhibiting a“neutral” apparent pH in the range of about 6 to about 9 is physiologically compatible with the nasal mucosa, while a composition exhibiting an apparent pH outside of that range may be irritating or possibly harmful to the nasal mucosa.

The Apparent pH Test is done using a standard, commercially available pH meter, equipped with a probe suitable for use with a small volume of fluid. The pH meter and probe is standardized using standard pH 7 and pH 10 buffer solutions. Once standardized, the probe is immersed into the test sample (at room temperature), and the apparent pH is recorded when the meter reading has stabilized. (If the tested sample provides a reading outside the pH range for which the meter and probe is calibrated, the meter and probe are re-standardized using appropriate bracketing buffer solutions, and the test is repeated.)

Viscosity Test - The Viscosity Test is done using a Brookfield viscometer equipped with a water bath capable of maintaining 25 ± 1 °C, and a CPE-40 spindle. The viscometer is first calibrated using Standard Fluid 10 with spindle RPM setting at 12, and then using Standard Fluid 50 with spindle RPM setting at 6. For both standard fluids, the recorded measurement is verified to be within acceptance criteria for the instrument model, standard fluid label claim, and spindle.

For testing of unit-dose finished product (for example, a small volume, such as -0.125 mL, of composition disposed in a capped glass vial), the sample testing is done by opening a number of vials (for example, 8-10) of finished product, pooling the contents in a suitable vessel, and then taking care to thoroughly mix (such as by vortexing) the pooled sample. For a bulk composition, an appropriate sample is obtained.

The sample testing is then done using 0.5 mL of the subject fluid, with the spindle RPM setting at 6, after temperature equilibration. Results are calculated as appropriate, and reported in centipoise (cP).

Visual Test - Due to the poor solubility of midazolam in aqueous solutions, a visual test is performed to establish whether midazolam or any other substance has precipitated or crystallized out of the composition. For the Visual Test, the test composition is visually observed under suitable lighting conditions. A test composition fails if, at any time after the composition is initially prepared, there is any visual evidence of crystallization or precipitation. The test composition passes if there is no such observation.

COMPARATIVE EXAMPLE

Formulations of midazolam having potencies of 25 mg/mL, 50 mg/mL, and 75 mg/mL (denoted C-l to C-3) were prepared according to Table 1. These formulations are similar in makeup to certain formulations reported in Examples 3 and 4 of W02008/089426.

Table 1 : Comparative formulations of midazolam (expressed as w/w % of final formulation).

In routine bulk hold storage tests, Formulation C-3 (75 mg/mL MDZ) formulation failed the Visual Test within one week. A significant quantity of crystallization or precipitation occurred under ordinary storage conditions. Additional precipitate was observed after two weeks and beyond. The formulation was deemed unsuitable for pharmaceutical use or commercialization, due to performance and safety concerns.

Furthermore, because of the significant problem posed by the observed precipitation of midazolam, solubility studies were undertaken to understand the solubility behavior of midazolam in the comparative formulations. Based on these studies (some of which are reported below), it was found that the saturation solubility of midazolam in a formulation approximating Formulation C-2 (that is, -21% w/w water) was approximately 60 mg/mL, with a solubility margin of only -20%. Even though precipitation was not observed by the Visual Test for Formulation C-2, this formulation was deemed unsuitable for pharmaceutical use or commercialization, due to performance and safety concerns.

Similarly, it was estimated by extrapolation that the solubility of midazolam in a formulation approximating Formulation C-l (that is, -23% w/w water) was about 40 mg/mL. Even though precipitation was not observed by the Visual Test for Formulation C-l, this formulation was also deemed unsuitable for pharmaceutical use or commercialization, due to performance and safety concerns.

EXAMPLES

Solubility Study 1 -

A first solubility study was undertaken in order to evaluate the equilibrium solubility of midazolam in each of the five components of the solvent vehicle. In a l0-mL glass vial, 5 mL of one component of the solvent vehicle (mPEG-350, PEG-400, PG, 190-proof ethanol, or water) was mixed with 2-2.5 g of midazolam (0.1 g for water). Each vial was stoppered and capped, and heated in a 100° C water bath for 20 minutes with gentle shaking. Each vial was observed to contain excess midazolam, with the exception of the ethanol vial, so an excess of midazolam was added to it. The vials were then kept at room temperature on an orbital shaker (200 rpm) for one week.

After one week, the presence of undissolved particulate was confirmed for each vial. Particulate matter was allowed to settle out, and then supernatant was filtered through a 0.22 pm filter into a separate glass vial. An aliquot was then transferred, diluted and assayed using a suitable HPLC quantitative separation method.

The observed concentration of midazolam (apparent saturation solubility) for each of the solvent system components is reported in Table 2.

Table 2: Apparent saturation solubility for midazolam in solvent vehicle components.

Solubility Study 2 -

A second solubility study was undertaken to evaluate key parameters affecting midazolam solubility in solvent vehicles of varying makeup. Solvent Vehicles S-l to S-5, which are based on Formulation C-2 but include no midazolam and varying quantities of water, were prepared according to Table 3. Test vials were prepared and treated as above, except that (after addition of excess midazolam) only half of the samples for each solvent vehicle were heated while half were left unheated. The vials were then kept at room temperature on an orbital shaker (200 rpm) for four weeks.

Table 3: Formulations for Solvent Vehicles S-l to S-5.

* As indicated in the description, this calculation does not include the minor contribution of water from the Ethanol component. At 1 week, 2 weeks, and 4 weeks, the presence of undissolved particulate was confirmed for each vial, and a sample from each Solvent Vehicle was filtered and assayed for midazolam content in the supernatant fluid, as described above. Assay data is reported in Table 4. Table 4: Apparent saturation solubility for midazolam in Solvent Vehicle S-l to S-5.

The data in Table 4 indicates that there is an indirect correlation between water content and midazolam saturation solubility, with higher water concentration yielding a lower midazolam saturation solubility. No significant difference was observed between the heated and unheated samples. It also appears that equilibrium was generally reached within the first week.

Data is represented graphically in Fig. 1. It is apparent that the midazolam solubility is very sensitive to water content. A small decrease in water content may effect an unexpectedly large increase in midazolam saturation solubility. As indicated above, a solvent vehicle containing -21% water (w/w) has a saturation solubility of midazolam of approximately 60 mg/mL, while reducing water content to -14% in the solvent vehicle increases the saturation solubility to approximately 140 mg/mL.

Solubility Study 3 -

A confirmatory study was performed to verify that the saturation solubility could be substantially increased by reducing the water content for a target formulation. To establish an adequate safety and stability margin, it was desired to use a solvent vehicle that exhibited a midazolam saturation solubility that was substantially higher than the targeted midazolam concentration for a pharmaceutically suitable formulation. A margin of 70% or greater (meaning that the saturation solubility is at least 70% higher than the targeted concentration), preferably 80-100% or greater, was desired. Providing a solubility margin was desirable to render the formulation much less susceptible to recrystallization or precipitation problems under long-term storage, and to make the formulation less susceptible to issues presented by temperature variance experienced under real-world storage conditions.

For this study, a 50 mg/mL midazolam concentration was targeted. Based on the results of Solubility Study 2, a water content of -17% was targeted in order to achieve a saturation solubility of -90 mg/mL or greater (that is, a margin of 80% or greater). Solvent Vehicle S-6 was prepared based on S-3, except that the weight-percent of certain components was increased while keeping the water component at -17%. The formulation of Solvent Vehicle S-6 is given in Table 5, along with the hypothetical targeted final formulation (for example, a formulation with

Solvent Vehicle S-6 and including 50 mg/mL dissolved midazolam).

Table 5: Formulation of Solvent Vehicle S-6 based on a hypothetical 50 mg/mL targeted midazolam formulation.

Test vials were prepared by transferring about 10 g of Solvent Vehicle S-6 into each of 9 scintillation vials. An excess of midazolam was added to each, and the vials were stoppered and capped. Vials were not heated, but kept at room temperature on an orbital shaker (200 rpm) for 7 days. At 3 days, 5 days, and 7 days, the presence of undissolved particulate was confirmed for each vial, and a sample from each vial was filtered and assayed for midazolam content in the supernatant fluid, as described above.

At 3 days, the measured midazolam concentration was 94.73 mg/mL, at 5 days the measured concentration was 96.31 mg/mL, and at 7 days the measured concentration was 96.63 mg/mL. This experiment confirmed that a solubility margin of 90% or greater (93% in this case) could be achieved by slightly modifying the solvent vehicle to reduce the water content while increasing other components of the solvent vehicle.

Similar tests were performed for formulations targeted to achieve 12.5 mg/mL, 25 mg/mL, and 75 mg/mL midazolam. For 12.5 mg/mL, a solubility margin of -400% was realized relative to the target concentration; for 25 mg/mL, a solubility margin of -228% was realized; for 75 mg/mL, a solubility margin of -53% was realized.

Exemplary Formulations -

Based on the foregoing observations and the unexpected degree of sensitivity on water content, the following formulations F-l to F-4 were prepared having reduced water content relative to the Comparative Formulations. One advantage of this set of exemplary formulations is that the relative proportion of mPEG:PEG:PG:EtOH is fixed (49: 17:6:7), and together is 79% (w/w) of the final formulation. Therefore, a range of formulations may be prepared by first preparing an intermediate solvent vehicle that may then be used for final preparation of a variety of strengths.

Table 6: Exemplary midazolam formulations F-l to F-4 (expressed as wt.-% of final formulation).

Characterization of Formulation F-3 -

Formulation F-3 was selected for further characterization and development. A midazolam nasal spray combination product has been developed as a single-use, unit-dose nasal spray dosage form. The finished combination product consists of drug product (midazolam in a solvent vehicle; Formulation F-3), disposed in an assembly of commercially available, off-the-shelf device components. All device components are assembled and used as intended by the parts manufacturers. Actuation of the combination product delivers a single 100 pL volume, equivalent to a 5 mg dose of midazolam, in the form of a spray.

A stoppered glass vial is the primary container for the midazolam and solvent vehicle. A vial holder and actuator body are secondary and do not come into direct contact with the drug product. The combination product is housed in a blister pack (tertiary packaging).

The manufacturing process for the combination product consists of compounding a bulk drug product solution (midazolam in solvent vehicle), filling 0.125 mL of the drug product into a glass vial, which is then sealed with rubber stopper. In addition, nitrogen, an inert gas, was used to purge the headspace during manufacture. The vial was then assembled in combination with the vial holder and actuator body device components.

In the characterization tests reported below, commercially available device components were assembled to form the delivery system. The device components were identical to those used in the commercial product Narcan® (NDA# 208411) manufactured by ADAPT Pharma Inc. For testing, the device was disassembled, the glass vial removed, and suitable sampling done from the glass vial. Test measurements were observed for many samples in primary stability studies. Storage conditions were 25 °C and 60% relative humidity. Typical measurements for selected relevant characteristics of Formulation F-3 are reported in Table 7.

Table 7: Selected characteristics and test measurements for Formulation F-3 prepared in a unit- dose spray configuration.

Furthermore, spray performance and characteristics were evaluated using standard testing methods. The spray performance measures evaluated across multiple dosage strengths included pump delivery, droplet size distribution (DSD) and spray pattern. Both DSD and spray pattern tests were carried out at 2 distances (3 cm and 6 cm), while spray pattern was evaluated for area and ovality. Additional studies performed examined pump delivery, plume geometry, device orientation, vibration and drop testing, temperature cycling, and photostability. See July 2002 FDA Guidance on Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products - Chemistry, Manufacturing, and Controls Documentation.

Only aggregated typical results or established parameters are reported here (as compared to individual data). In short, the unit-dose system consistently delivered 100 pL of drug formulation (100-101% of target) and was independent of formulation viscosity for the representative samples. Based on droplet size distribution testing, the Dio criteria was established (for both spray distances) to be NLT 12.0 pL; Dso was established to be 50.0 - 300 pm; and D90 established as NMT 500.0 pm. Observed Dio results were generally in the range 40-70 pm; observed D50 results were generally in the range 110-180 pm; observed D90 results were generally in the range 250-330 pm.

In addition, a temperature cycling study was performed on two lots of finished combination product (that is, vials containing Formulation F-3, installed in spray device). Temperature was cycled between -10 °C and 40 °C on a l2-hour cycle, over four weeks. No precipitate was observed for any test vial, indicating that Formulation F-3 is suitable for typical in-use storage conditions. In addition, all other acceptance criteria (including pump delivery, spray content uniformity, droplet size distribution, and viscosity) were all acceptable after thermal cycling.

The inventions described herein may take on various modifications and alterations without departing from the spirit and scope thereof. The above disclosure is not intended to describe each possible embodiment or every implementation of the present inventions. Practice of the present inventions is not limited to the exact details shown and described, for variations obvious to one skilled in the art will be included within the invention. The foregoing detailed description and examples have been given for clarity of understanding only. No unnecessary limitations are to be understood therefrom. EXEMPLARY EMBODIMENTS

A pharmaceutical composition comprising:

about 49.0 wt.-% mPEG-350;

about 17.0 wt.-% PEG-400;

about 6.0 wt.-% propylene glycol;

about 7.0 wt.-% ethanol;

about 1 to about 7 wt.-% midazolam; and

about 14 to about 20 wt.-% water. A pharmaceutical composition consisting essentially of:

about 49.0 wt.-% mPEG-350;

about 17.0 wt.-% PEG-400;

about 6.0 wt.-% propylene glycol;

about 7.0 wt.-% ethanol;

about 1 to about 7 wt.-% midazolam; and

about 14 to about 20 wt.-% water. A pharmaceutical composition consisting of:

about 49.0 wt.-% mPEG-350;

about 17.0 wt.-% PEG-400;

about 6.0 wt.-% propylene glycol;

about 7.0 wt.-% ethanol;

about 1 to about 7 wt.-% midazolam; and

about 14 to about 20 wt.-% water. A pharmaceutical composition suitable for administration as a nasal spray, comprising at least 25 mg/mL midazolam disposed in a solvent vehicle comprising:

mPEG-350;

PEG-400;

propylene glycol;

ethanol; and

water; wherein the saturation solubility of midazolam in the solvent vehicle at room temperature is at least about 100% greater than the midazolam concentration in the composition. A pharmaceutical composition suitable for administration as a nasal spray, comprising about 50 mg/mL midazolam disposed in a solvent vehicle comprising:

mPEG-350;

PEG-400;

propylene glycol;

ethanol; and

water;

wherein the saturation solubility of midazolam in the solvent vehicle at room temperature is at least about 50% greater than the midazolam concentration in the composition. A pharmaceutical composition suitable for administration as a nasal spray, comprising about 75 mg/mL midazolam disposed in a solvent vehicle comprising:

mPEG-350;

PEG-400;

propylene glycol;

ethanol; and

water;

wherein the saturation solubility of midazolam in the solvent vehicle at room temperature is at least about 30% greater than the midazolam concentration in the composition. The composition of any of embodiments 4-6, wherein the composition comprises at least 47 wt.-% mPEG-350. The composition of any of embodiments 4-7, wherein the composition comprises about 5 to about 15 wt.-% ethanol. The composition of any of embodiments 4-8, wherein the composition comprises about 6 to about 10 wt.-% ethanol. The composition of any of embodiments 4-9, wherein the composition comprises about 6 to about 8 wt.-% ethanol. The composition of any of embodiments 4-10, wherein the composition comprises about 10 to about 30 wt.-% PEG-400. The composition of any of embodiments 4-11, wherein the composition comprises about 15 to about 20 wt.-% PEG-400. The composition of any of embodiments 4-12, wherein the composition comprises about 2 to about 10 wt.-% propylene glycol. The composition of any of embodiments 4-13, wherein the composition comprises about 4 to about 8 wt.-% propylene glycol. The composition of any of embodiments 4-14, wherein the composition comprises about 5 to about 7 wt.-% propylene glycol. The composition of any preceding embodiment, wherein the midazolam is introduced into the composition as the free base form. The composition of any preceding embodiment, wherein the composition comprises about 4 to about 7 wt.-% midazolam free base, and about 14 to about 17 wt.-% water. The composition of any preceding embodiment, wherein the composition comprises about 16 to about 19 wt.-% water. The composition of any preceding embodiment, wherein the composition comprises less than 18 wt.-% water. The composition of any preceding embodiment, wherein the composition comprises less than 17 wt.-% water. The composition of any preceding embodiment, wherein the composition comprises less than 15 wt.-% water. The composition of any preceding embodiment, wherein the concentration of midazolam in the composition is about 12.5 mg/mL to about 75 mg/mL. The composition of any preceding embodiment, wherein the concentration of midazolam in the composition is about 50 mg/mL. The composition of any preceding embodiment, wherein the composition is suitable for administration as a nasal spray. A pharmaceutical composition suitable for administration as a nasal spray, according to any of Formulations F-l to F-4 as set out in Table 6. The composition of any preceding embodiment, wherein the composition is characterized by a viscosity in the range of 20 to 30 cP (measured according to the Viscosity Test described herein). The composition of any preceding embodiment, wherein the composition is characterized by an apparent pH in the range of 6 to 9 (measured according to the Apparent pH Test described herein). The composition of any preceding embodiment, wherein the composition is characterized by an apparent pH in the range of 6.5 to 8 (measured according to the Apparent pH Test described herein). A method for treating or alleviating a seizure, comprising the step of administering to the nasal mucosa of a patient in need of such treatment, a pharmaceutical composition according to any preceding embodiment, in the form of a spray. The method of embodiment 29, wherein administering the composition to the patient delivers about 100 pL of the pharmaceutical composition to the patient’s nasal mucosa. The method of embodiment 29-30, wherein administering the composition to the patient delivers about 5 mg midazolam to the patient’s nasal mucosa. A method for sedation of a patient for a medical, dental, or diagnostic procedure, comprising: administering to the nasal mucosa of patient a pharmaceutical composition according to any of embodiments 1-28, in the form of a spray; allowing a sufficient time for the patient to reach a suitable state of sedation before initiating the medical, dental, or diagnostic procedure. The method of embodiment 32, wherein administering the composition to the patient delivers about 100 pL of the pharmaceutical composition to the patient’s nasal mucosa. The method of embodiment 32-33, wherein administering the composition to the patient delivers about 2.5 mg midazolam to the patient’s nasal mucosa. The method of embodiment 32-33, wherein administering the composition to the patient delivers about 5 mg midazolam to the patient’s nasal mucosa. The method of embodiment 32-33, wherein administering the composition to the patient delivers about 7.5 mg midazolam to the patient’s nasal mucosa. A single-use device capable of delivering a pharmaceutical composition from a vessel to a patient’s nasal mucosa in the form of a spray, the device comprising a vessel and an actuator, wherein the pharmaceutical composition is disposed in the vessel prior to actuation, and wherein the pharmaceutical composition is described by any of embodiments 1-28. The device of embodiment 37, wherein about 125 pL of the pharmaceutical composition is disposed in the vessel prior to actuation. The device of any of embodiments 37-38, wherein upon actuation, about 100 pL of the pharmaceutical composition is delivered to the patient’s nasal mucosa in the form of a spray. The device of any of embodiments 37-39, wherein upon actuation, about 2.5 mg of midazolam dispersed in the pharmaceutical composition is delivered to the patient’s nasal mucosa in the form of a spray. The device of any of embodiments 37-39, wherein upon actuation, about 5 mg of midazolam dispersed in the pharmaceutical composition is delivered to the patient’s nasal mucosa in the form of a spray. The device of any of embodiments 37-39, wherein upon actuation, about 7.5 mg of midazolam dispersed in the pharmaceutical composition is delivered to the patient’s nasal mucosa in the form of a spray.

Claims

What is claimed is:

1. A pharmaceutical composition comprising:

about 49.0 wt.-% mPEG-350;

about 17.0 wt.-% PEG-400;

about 6.0 wt.-% propylene glycol;

about 7.0 wt.-% ethanol;

about 1 wt.-% to about 7 wt.-% midazolam; and

about 14 wt.-% to about 20 wt.-% water.

2. A pharmaceutical composition consisting essentially of:

about 49.0 wt.-% mPEG-350;

about 17.0 wt.-% PEG-400;

about 6.0 wt.-% propylene glycol;

about 7.0 wt.-% ethanol;

about 1 wt.-% to about 7 wt.-% midazolam; and

about 14 wt.-% to about 20 wt.-% water.

3. A pharmaceutical composition consisting of:

about 49.0 wt.-% mPEG-350;

about 17.0 wt.-% PEG-400;

about 6.0 wt.-% propylene glycol;

about 7.0 wt.-% ethanol;

about 1 wt.-% to about 7 wt.-% midazolam; and

about 14 wt.-% to about 20 wt.-% water.

4. A pharmaceutical composition suitable for administration as a nasal spray, comprising at least 25 mg/mL midazolam disposed in a solvent vehicle comprising:

mPEG-350;

PEG-400;

propylene glycol;

ethanol; and water;

wherein the saturation solubility of midazolam in the solvent vehicle at room temperature is at least about 100% greater than the midazolam concentration in the composition.

5. A pharmaceutical composition suitable for administration as a nasal spray, comprising about 50 mg/mL midazolam disposed in a solvent vehicle comprising:

mPEG-350;

PEG-400;

propylene glycol;

ethanol; and

water;

wherein the saturation solubility of midazolam in the solvent vehicle at room temperature is at least about 50% greater than the midazolam concentration in the composition.

6. A pharmaceutical composition suitable for administration as a nasal spray, comprising about 75 mg/mL midazolam disposed in a solvent vehicle comprising:

mPEG-350;

PEG-400;

propylene glycol;

ethanol; and

water;

wherein the saturation solubility of midazolam in the solvent vehicle at room temperature is at least about 30% greater than the midazolam concentration in the composition.

7. The composition of any one of claims 4 to 6, wherein the composition comprises at least 47 wt.-% mPEG-350.

8. The composition of any one of claims 4 to 7, wherein the composition comprises about 5 wt.-% to about 15 wt.-% ethanol.

9. The composition of any one of claims 4 to 8, wherein the composition comprises about 6 wt.-% to about 10 wt.-% ethanol.

10. The composition of any one of claims 4 to 9, wherein the composition comprises about 6 wt.-% to about 8 wt.-% ethanol.

11. The composition of any one of claims 4 to 10, wherein the composition comprises about 10 wt.-% to about 30 wt.-% PEG-400.

12. The composition of any one of claims 4 to 11, wherein the composition comprises about 15 wt.-% to about 20 wt.-% PEG-400.

13. The composition of any one of claims 4 to 12, wherein the composition comprises about 2 wt.-% to about 10 wt.-% propylene glycol.

14. The composition of any one of claims 4 to 13, wherein the composition comprises about

4 wt.-% to about 8 wt.-% propylene glycol.

15. The composition of any one of claims 4 to 14, wherein the composition comprises about

5 wt.-% to about 7 wt.-% propylene glycol.

16. The composition of any one of the preceding claims, wherein the midazolam is introduced into the composition as the free base form.

17. The composition of any one of the preceding claims, wherein the composition comprises about 4 wt.-% to about 7 wt.-% midazolam free base, and about 14 wt.-% to about 17 wt.-% water.

18. The composition of any one of the preceding claims, wherein the composition comprises about 16 wt.-% to about 19 wt.-% water.

19. The composition of any one of the preceding claims, wherein the composition comprises less than 18 wt.-% water.

20. The composition of any one of the preceding claims, wherein the composition comprises less than 17 wt.-% water.

21. The composition of any one of the preceding claims, wherein the composition comprises less than 15 wt.-% water.

22. The composition of any one of the preceding claims, wherein the concentration of midazolam in the composition is about 12.5 mg/mL to about 75 mg/mL.

23. The composition of any one of the preceding claims, wherein the concentration of midazolam in the composition is about 50 mg/mL.

24. The composition of any one of the preceding claims, wherein the composition is suitable for administration as a nasal spray.

25. A pharmaceutical composition suitable for administration as a nasal spray, according to any of Formulations F-l to F-4 as set out in the following table, wherein the component amounts are expressed as wt.-% of final formulation:

26. The composition of any one of the preceding claims, wherein the composition is characterized by a viscosity in the range of 20 cP to 30 cP, measured according to the Viscosity Test.

27. The composition of any one of the preceding claims, wherein the composition is characterized by an apparent pH in the range of 6 to 9, measured according to the Apparent pH Test.

28. The composition of any one of the preceding claims, wherein the composition is characterized by an apparent pH in the range of 6.5 to 8, measured according to the Apparent pH Test.

29. A method for treating or alleviating a seizure, comprising the step of administering to the nasal mucosa of a patient in need of such treatment, a pharmaceutical composition according to any preceding embodiment, in the form of a spray.

30. The method of claim 29, wherein administering the composition to the patient delivers about 100 pL of the pharmaceutical composition to the patient’s nasal mucosa.

31. The method of claim 29 or claim 30, wherein administering the composition to the patient delivers about 5 mg midazolam to the patient’s nasal mucosa.

32. A method for sedation of a patient for a medical, dental, or diagnostic procedure, comprising:

administering to the nasal mucosa of patient a pharmaceutical composition according to any one of claims 1 to 28, in the form of a spray;

allowing a sufficient time for the patient to reach a suitable state of sedation before initiating the medical, dental, or diagnostic procedure.

33. The method of claim 32, wherein administering the composition to the patient delivers about 100 pL of the pharmaceutical composition to the patient’s nasal mucosa.

34. The method of claim 32 or claim 33, wherein administering the composition to the patient delivers about 2.5 mg midazolam to the patient’s nasal mucosa.

35. The method of claim 32 or claim 33, wherein administering the composition to the patient delivers about 5 mg midazolam to the patient’s nasal mucosa.

36. The method of claim 32 or claim 33, wherein administering the composition to the patient delivers about 7.5 mg midazolam to the patient’s nasal mucosa.

37. A single-use device capable of delivering a pharmaceutical composition from a vessel to a patient’s nasal mucosa in the form of a spray, the device comprising a vessel and an actuator, wherein the pharmaceutical composition is disposed in the vessel prior to actuation, and wherein the pharmaceutical composition is described by any one of claims 1 to 28.

38. The device of claim 37, wherein about 125 pL of the pharmaceutical composition is disposed in the vessel prior to actuation.

39. The device of claim 37 or claim 38, wherein upon actuation, about 100 pL of the pharmaceutical composition is delivered to the patient’s nasal mucosa in the form of a spray.

40. The device of any one of claims 37 to 39, wherein upon actuation, about 2.5 mg of midazolam dispersed in the pharmaceutical composition is delivered to the patient’s nasal mucosa in the form of a spray.

41. The device of any one of claims 37 to 39, wherein upon actuation, about 5 mg of midazolam dispersed in the pharmaceutical composition is delivered to the patient’s nasal mucosa in the form of a spray.

42. The device of any one of claims 37 to 39, wherein upon actuation, about 7.5 mg of midazolam dispersed in the pharmaceutical composition is delivered to the patient’s nasal mucosa in the form of a spray.