HK1195252B - Intranasal benzodiazepine pharmaceutical compositions - Google Patents

Description

Intranasal benzodiazepine pharmaceutical compositions

RELATED APPLICATIONS

This application claims benefit and priority from U.S. provisional application serial No. 61/469940, filed on 3/31/2011, the disclosure of which is hereby incorporated by reference in its entirety.

Technical Field

The present invention relates generally to intranasal pharmaceutical compositions comprising benzodiazepines and methods of use thereof that can provide therapeutic effects without lowering blood pressure and/or pulse following administration.

Background

Acute Recurrent Seizures (ARS), also known as sequential, group or progressive seizures, are a serious neurological emergency. These increased seizure activity cases are associated with significant morbidity and mortality, are debilitating, and can progress to persistent epilepsy. The goal of treatment is to terminate seizure activity quickly, since the longer the case of untreated ARS, the more difficult its control and the greater the risk of permanent brain damage.

The current treatment for ARS is Intravenous (IV) administration of benzodiazepines (benzodiazepines). Intravenous administration, however, requires skilled personnel and transportation to a medical facility, which delays the initiation of treatment. Treatment delay is associated with longer episodes, more difficult episodes to terminate, prolonged hospitalization, higher mortality, and reduced quality of life.

Most exacerbations occur at home, at work or at school. Studies over the last 15 years have demonstrated that out-of-hospital treatment is very effective and can be performed by family members or emergency physicians. An alternative treatment for ARS is rectal administration of diazepam. However, this treatment has not been fully utilized. Rectal administration is inconvenient if the episode occurs outside of home, and administration and maintenance of some difficulty during the episode. In addition, many patients, particularly older children and adults, as well as caregivers, object to rectal administration. Thus, there is a need for a rapid, more convenient and socially acceptable route of administration to effectively manage seizure emergencies.

Intranasal treatment can be easily and safely administered by the patient or caregiver and can improve management of seizure emergencies. Intranasal administration of benzodiazepines can make drug treatment more rapid and discreet to administer, can be more easily implemented, and can provide an alternative to rectal administration, which can be more appealing to patients and caregivers. However, it is difficult to develop such intranasal formulations capable of dissolving a sufficient concentration of benzodiazepine within the actual dosage volume for intranasal administration.

The present invention addresses the aforementioned shortcomings in the art by providing an intranasal pharmaceutical composition comprising a sufficient concentration of benzodiazepines to provide a practical dosage volume. In addition, these compositions can provide therapeutic effects without lowering blood pressure and/or pulse after administration.

Summary of The Invention

The present invention provides intranasal pharmaceutical compositions comprising benzodiazepines that can be suitable for treating seizures (e.g. ARS). The pharmaceutical compositions of the present invention may be advantageous due to the ease, rapidity and convenience of intranasal administration compared to other administration forms such as intravenous and rectal administration and due to social acceptance and the degree of training required for intranasal administration. The pharmaceutical composition may also advantageously provide a therapeutic effect after administration without lowering blood pressure and/or pulse. In addition, the pharmaceutical compositions may show benefits by exhibiting a consistent and/or low coefficient of variation, and may provide sufficient concentrations of benzodiazepines to provide a practical dosage volume for intranasal administration.

In one aspect, the pharmaceutical composition comprises from about 1% to about 10% by weight of a benzodiazepine, such as diazepam or a pharmaceutically acceptable salt thereof, from about 40% to about 47% by weight of a glycol ether, such as diethylene glycol monoethyl ether, and from about 45% to about 55% by weight of one or more fatty acid esters. In some embodiments of the invention, the composition further comprises from about 0.5% to about 3% by weight of water.

In another aspect, the invention provides a pharmaceutical composition comprising from about 1% to about 15% by weight of a benzodiazepine, such as diazepam or a pharmaceutically acceptable salt thereof, from about 43% to about 55% by weight of a glycol ether, such as diethylene glycol monoethyl ether, from about 16% to about 18% by weight of one or more fatty acid esters, from about 22% to about 25% by weight of N-methyl-2-pyrrolidone, from about 1% to about 5% by weight of water and from about 5% to about 10% by weight of ethanol.

Another aspect of the invention provides a pharmaceutical composition for the intranasal administration of benzodiazepines, comprising a benzodiazepine such as diazepam or a pharmaceutically acceptable salt thereof, a glycol ether such as diethylene glycol monoethyl ether, and one or more fatty acid esters, wherein plasma levels of diazepam exhibit a Coefficient of Variation (CV) of less than about 40% after administration to a human subject.

In another aspect, the invention provides a method of preventing a reduction in blood pressure and/or pulse in a subject during administration of a benzodiazepine, such as diazepam, for treating an episode, comprising intranasally administering to the subject in need thereof a therapeutically effective amount of any of the pharmaceutical compositions of the invention.

The foregoing and other aspects of the present invention will now be described in more detail with reference to other embodiments described herein. It is to be understood that the present invention may be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

Drawings

FIG. 1 shows the results of the above treatments in formulations 1 (treatment A), 2 (treatment B) and(treatment C) mean diazepam concentration-time curves (0-24h) following dosing.

FIGS. 2A-L show the individual diazepam concentration-time curves (0-240h) for each individual participating in the study.

FIG. 3A shows the results for DZNS formulation 1 (treatment A), DZNS formulation 2 (treatment B) and(treatment C) mean desmetazepam concentration-time profile after dosing.

FIG. 3B shows the results for DZNS formulation 1 (treatment A), DZNS formulation 2 (treatment B) and(treatment C) mean nordroxydiazepam concentration-time curve following administration.

FIG. 3C shows the results for DZNS formulation 1 (treatment A), DZNS formulation 2 (treatment B) andmean diazepam concentration-time curve after administration (treatment C).

FIG. 4 shows thatMean change from pre-dose in systolic blood pressure after administration of either formulation 1or formulation 2.

FIG. 5 shows thatMean change from pre-dose in diastolic blood pressure after administration of either formulation 1or formulation 2.

FIG. 6 shows thatMean change in heart rate from pre-dose after formula 1or formula 2 administration.

FIG. 7 shows thatMean change from pre-dose in breath after administration of either formulation 1or formulation 2.

FIG. 8 shows thatMean change from pre-dose in oxygen saturation level after formulation 1or formulation 2 administration.

FIG. 9 shows spray pattern images of DZNS formulation 2 using modified (A) and standard (B) vial holders.

FIG. 10 shows spray pattern images of DZNS formulation 1 using modified (A) and standard (B) vial holders.

FIG. 11 shows spray pattern images of DZNS formulation 2 using modified (A) and standard (B) vial holders.

FIG. 12 shows spray pattern images of DZNS formulation 1 using modified (A) and standard (B) vial holders.

Detailed Description

The present invention will now be described more fully hereinafter. This invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in this specification and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

Unless defined otherwise, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of this application and the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. All publications, patent applications, patents, and other references mentioned are incorporated by reference herein in their entirety.

Likewise, "and/or" as used herein refers to and includes any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted as alternative options ("or").

Unless the context indicates otherwise, it is expressly stated that different features of the invention described herein can be used in any combination. For example, features described in relation to one embodiment may also be used in and combined with other embodiments and aspects of the invention.

Furthermore, the present invention also contemplates that, in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted.

For purposes of illustration, if the specification refers to a complex comprising components A, B and C, it is expressly stated that either A, B or C, or a combination thereof, may be omitted and discarded.

The conjunction "consisting essentially of" (and grammatical variations) as used herein should be interpreted to include the materials or steps "and those materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. See InreHerz, 537f.2d549, 551-52, 190u.s.p.q.461, 463(CCPA1976) (highlighted as before); see also MPEP § 2111.03. The term "consisting essentially of, as used herein, should not therefore be construed as being equivalent to" comprising ".

The term "about" as used herein, when referring to a measurable value such as an amount or concentration (e.g., the amount of benzodiazepine in a pharmaceutical composition), is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount.

All patents, patent applications, and publications mentioned herein are incorporated by reference in their entirety. In case of conflict between the terms, the present specification will control.

I. Pharmaceutical composition

The present invention provides intranasal pharmaceutical compositions comprising a benzodiazepine active agent. As used herein, "benzodiazepine" refers to compounds that contain a benzodiazepine structure and are known to be useful, or subsequently determined to be useful, in treating seizures. Benzodiazepines include, but are not limited to, alprazolam, bromodiazepam, methotrexate, clonazepam, chlordiazepam, diazepam, estazolam, flunomide, trifluorometalam, ketazolam, naloxon (1orazepam), midazolam (midazolam), nitro diazepam, dehydroxy diazepam, pramazepam (prazepam), quazepam (quazepam), hydroxy diazepam, triazolam (triazolam), pharmaceutically acceptable salts thereof, and mixtures thereof. As used herein, unless otherwise indicated, benzodiazepines refer to structures and mixtures thereof including all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. The individual stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of benzodiazepines are also within the scope of the invention. Unless otherwise indicated, all tautomeric forms, solvates and hydrates of benzodiazepines are also within the scope of the invention. In a particular embodiment of the invention, the benzodiazepine is diazepam or a pharmaceutically acceptable salt thereof.

As used herein, a "pharmaceutically acceptable salt" is a salt that retains the desired biological activity of the parent benzodiazepine compound and does not impart undesirable toxicological effects. Examples of such salts are (a) acid addition salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; and salts with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; (b) salts formed from anionic elements, such as chlorine, bromine, and iodine; and (c) basic salts such as ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine.

The benzodiazepine may be present in an amount of about 1% to about 20% by weight of the pharmaceutical composition. In some embodiments of the invention, the benzodiazepine is present in an amount of about 1% to about 15% or about 1% to about 10% by weight of the pharmaceutical composition. In particular embodiments of the invention, the benzodiazepine is present in an amount of about 1%, 1.5%, 2%, 2.5%, 3%, 3.75%, 4%, 4.5%, 5%, 5.5%, 6%, 6.25%, 6.75%, 7%, 7.5%, 8%, 8.75%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, or any range therein. In certain embodiments of the invention, the pharmaceutical compositions of the invention comprise about 2mg of benzodiazepine to about 15mg of benzodiazepine per 100 μ L of pharmaceutical composition, or any range therein, such as, but not limited to, about 5mg to about 10mg of benzodiazepine per 100 μ L of pharmaceutical composition. In some embodiments of the invention, a pharmaceutical composition of the invention comprises about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15mg of benzodiazepine per 100 μ L of the pharmaceutical composition. In a specific embodiment of the invention, the pharmaceutical composition of the invention comprises about 9mg of benzodiazepine per 100 μ L of the pharmaceutical composition, and in certain embodiments, about 10mg of benzodiazepine per 100 μ L of the pharmaceutical composition.

In one aspect of the invention, the pharmaceutical composition comprises, consists essentially of, or consists of: (i) benzodiazepines, (ii) at least one glycol ether and (iii) at least one fatty acid ester. As used herein, "glycol ether" refers to an aliphatic ether of ethylene glycol or diethylene glycol, wherein the glycol ether comprises R-O-R ' or R-O-R ' -O-R, wherein R is an aliphatic group and R ' is the remaining glycol portion of the compound. When the glycol ether comprises R-O-R', the diol moiety is- (CH)₂)₂-OH or- (CH)₂)₂-O-(CH₂)₂-OH, and when the glycol ether comprises R-O-R'when-O-R, the diol moiety is- (CH)₂)₂-or- (CH)₂)₂-O(CH₂)₂-. The aliphatic part of the glycol ether, i.e. R, may be C₁-C₈Aliphatic groups, which may be saturated, unsaturated, linear, branched, and/or cyclic. Exemplary glycol ethers include, but are not limited to, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-butyl ether, and any combination thereof. In some embodiments of the invention, at least one glycol ether is diethylene glycol monoethyl ether, such as for exampleAvailable commercially from Gattefoss.

The at least one glycol ether may be present in an amount of about 30% to about 80% by weight of the pharmaceutical composition. In particular embodiments of the invention, the at least one glycol ether is present in an amount of about 35% to about 60%, about 35% to about 47%, about 37% to about 46%, about 40% to about 47%, about 43% to about 55%, or about 43% to about 50% by weight of the pharmaceutical composition. In certain embodiments of the invention, the at least one glycol ether is present in an amount of about 30%, 30.5%, 31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34%, 34.5%, 35%, 35.5%, 36%, 36.5%, 37%, 37.5%, 38%, 38.5%, 39%, 39.5%, 40%, 40.5%, 41%, 41.5%, 42%, 42.5%, 43%, 43.5%, 44%, 44.5%, 45%, 45.6%, 45.7%, 45.8%, 46%, 46.5%, 47%, 47.5%, 48%, 48.5%, 49%, 49.5%, 50%, 50.5%, 51%, 51.5%, 52%, 52.5%, 53%, 53.5%, 54%, 54.5%, 55%, 55.5%, 56%, 56.5%, 57%, 57.5%, 58%, 58.5%, 59%, 59.5%, 60%, 60.5%, 61.5%, 62%, 63.5%, 64.5%, 66%, 67.5%, 64.5%, 67%, 66%, 67%, 64.5%, 67%, 66.5%, 67%, 64.5%, or a mixture thereof, 67.5%, 68%, 68.5%, 69%, 69.5%, 70%, 70.5%, 71%, 71.5%, 72%, 72.5%, 73%, 73.5%, 74%, 74.5%, 75%, 75.5%, 76%, 76.5%, 77%, 77.5%, 78%, 78.5%, 79%, 79.5%, 80%, or any range therein. In some embodiments of the invention, as the amount of benzodiazepine in the composition increases, the amount of at least one glycol ether in the composition decreases accordingly, and vice versa.

As used herein, "fatty acid ester" refers to a compound comprising R-C (O) -O-groups, wherein R comprises C₁-C₂₄Aliphatic groups, which may be saturated, unsaturated, linear, branched, cyclic, substituted, and/or unsubstituted. For example, in some embodiments of the invention, the fatty acid ester may comprise R-C (O) -O-R ', wherein R and R' each comprise C₁-C₂₄Aliphatic groups, which may be the same or different, may be saturated, unsaturated, straight chain, branched, cyclic, substituted, and/or unsubstituted. In other embodiments of the invention, the fatty acid ester may comprise a glyceride moiety and 1, 2 or 3R-C (O) -O-groups. Exemplary fatty acid esters include, but are not limited to, caprylocaproyl polyoxylglyceride, isopropyl palmitate, oleoyl polyoxylglyceride, sorbitan monolaurate 20, methyl laurate, ethyl myristate, ethyl palmitate, ethyl linoleate, propyl isobutyrate, isopropyl laurate, isopropyl myristate, polysorbate 20, propylene glycol monocaprylate, and any combination thereof. The at least one fatty acid ester may be present in the composition in an amount of about 5% to about 60%, about 5% to about 29%, about 10% to about 30%, about 16% to about 18%, about 30% to about 60%, about 40% to about 55%, or about 45% to about 55% by weight of the pharmaceutical composition. In particular embodiments, the at least one fatty acid ester is present in an amount of about 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5% >,13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.7%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 30.5%, 31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34%, 34.5%, 35%, 35.5%, 36%, 36.5% 37%, 37.5%, 38%, 38.5%, 39%, 39.5%, 40%, 40.5%, 41%, 41.5%, 42%, 42.5%, 43%, 43.5%, 44%, 44.5%, 45%, 45.6%, 45.7%, 45.8%, 46%, 46.5%, 48.5%, 51.53%, 49.5%, 51.5%, 49.5%, 52%, 49.5%, 50%, 52%, 53%, 52%, 52.5%, 50%, 53%, 52%, 50%, 5%, 25%, 25.5%, 25, 54%, 54.5%, 55%, 55.5%, 56%, 56.5%, 57%, 57.5%, 58%, 58.5%, 59%, 59.5%, 60%, or any range therein.

In some embodiments of the invention, the at least one fatty acid ester is selected from the group consisting of caprylocaproyl polyoxylglyceride, isopropyl palmitate, sorbitan monolaurate 20, and any combination thereof. In other embodiments of the present invention, the at least one fatty acid ester is selected from the group consisting of caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, sorbitan monolaurate 20, and any combination thereof. In a further embodiment of the invention, the at least one fatty acid ester is selected from methyl laurate, propylene glycol monocaprylate and any combination thereof.

In certain embodiments of the invention, caprylocaproyl polyoxylglycerides, such as are commercially available from Gattefoss é, for exampleThe amount may be present in an amount of about 5% to about 40%, about 5% to about 25%, about 20% to about 38%, or about 26% to about 34% by weight of the pharmaceutical composition. In some embodiments, the caprylocaproyl polyoxylglyceride is present in an amount of about 5%, 5.5%, 6%, 6.25%, 6.75%, 7%, 7.5%8%, 8.75%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 30.3%, 30.4%, 30.5%, 31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34%, 34.5%, 35%, 35.5%, 36%, 36.5% 37%, 37.5%, 38%, 38.5%, 39%, 39.5%, 40%, or any range therein.

Isopropyl palmitate may be present in an amount of about 2% to about 15% or about 5% to about 10% by weight of the pharmaceutical composition. In some embodiments, the isopropyl palmitate is present in an amount of about 2%, 2.5%, 3%, 3.75%, 4%, 4.5%, 5%, 5.5%, 6%, 6.25%, 6.75%, 7%, 7.22%, 7.3%, 7.5%, 8%, 8.75%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, or any range therein.

Sorbitan monolaurate 20, such as is commercially available, for example, fromIs/are as follows20 may be present in an amount of about 1% to about 20% or about 5% to about 15% by weight of the pharmaceutical composition. In some embodiments, the sorbitan monolaurate 20 is present in an amount of about 1%, 1.5%, 2%, 2.5%, 3%, 3.75%, 4%, 4.5%, 5%, 5.5%, 6%, 6.25%, 6.75%, 7%, 7.5%, 8%, 8.75%, 9%, 9.5%, 10%, 10.5%, 10.8%, 11%, 11.2%, 11.4%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16% >, or,16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, or any range therein.

Oleoyl polyoxylglycerides, such as are commercially available from Gattefoss éMay be present in an amount of about 2% to about 15% or about 5% to about 10% by weight of the pharmaceutical composition. In some embodiments, the oleoyl polyoxylglyceride is present in an amount of about 2%, 2.5%, 3%, 3.75%, 4%, 4.5%, 5%, 5.5%, 6%, 6.25%, 6.75%, 7%, 7.22%, 7.5%, 8%, 8.75%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, or any range therein.

The methyl laurate may be present in an amount of from about 5% to about 15% or from about 9% to about 10% by weight of the pharmaceutical composition. In some embodiments, the methyl laurate is present in an amount of about 5%, 5.5%, 6%, 6.25%, 6.75%, 7%, 7.5%, 8%, 8.75%, 9%, 9.5%, 10%, 10.5%, 10.8%, 11%, 11.2%, 11.4%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, or any range therein.

Propylene glycol monocaprylate, for example, Capryol such as that commercially available from Gattefoss^TM90 may be present in an amount of about 5% to about 15% or about 7% to about 9% by weight of the pharmaceutical composition. In some embodiments, propylene glycol monocaprylate is present in an amount of about 5%, 5.5%, 6%, 6.25%, 6.75%, 7%, 7.5%, 7.6%, 8%, 8.75%, 9%, 9.5%, 10%, 10.5%, 10.8%, 11%, 11.2%, 11.4%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, or any range therein.

The amount of water present in the pharmaceutical composition of the present invention may optionally be from about 0% to about 10% by weight of the pharmaceutical composition. In particular embodiments, water is present in an amount of about 0.5% to about 5%, about 0.5% to about 3%, or about 1% to about 5% by weight of the pharmaceutical composition. In certain embodiments, water is present in an amount of about 0%, 0.25%, 0.5%, 0.75%, 0.95%, 1%, 1.5%, 1.9%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.25%, 6.75%, 7%, 7.5%, 8%, 8.75%, 9%, 9.5%, 10%, or any range therein.

The pharmaceutical compositions of the present invention may optionally comprise an alcohol. Exemplary alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-butanol, and tert-butanol. In a particular embodiment of the invention, the pharmaceutical composition comprises ethanol. The alcohol may be present in an amount of about 0% to about 10% or about 5% to about 10% by weight of the pharmaceutical composition. In certain embodiments, the alcohol is present in an amount of about 0%, 0.25%, 0.5%, 0.75%, 0.95%, 1%, 1.5%, 1.9%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.25%, 6.75%, 7%, 7.5%, 7.6%, 8%, 8.75%, 9%, 9.5%, 10%, or any range therein.

N-methyl-2-pyrrolidinone, for example, such as is commercially available from Intema specialty productsMay optionally be present in the pharmaceutical compositions of the present invention. In some embodiments of the invention, N-methyl-2-pyrrolidone is present in an amount of about 0% to about 30%, about 10% to about 30%, about 20% to about 30%, or about 22% to about 25% by weight of the pharmaceutical composition. In certain embodiments, N-methyl-2-pyrrolidone is present in an amount of about 0%, 0.25%, 0.5%, 0.75%, 0.95%, 1%, 1.5%, 1.9%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.25%, 6.75%, 7%, 7.5%, 8%, 8.75%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 1%, 1.5%, 1%, or a combination thereof4%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 22.7%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, or any range therein.

In one aspect of the invention, the pharmaceutical composition comprises about 1% to about 10% by weight diazepam or a pharmaceutically acceptable salt thereof, about 40% to about 47% by weight diethylene glycol monoethyl ether and about 45% to about 55% by weight of one or more fatty acid esters. In other embodiments, the pharmaceutical composition further comprises from about 0.5% to about 3% by weight of water.

Another aspect of the invention provides a pharmaceutical composition comprising about 1% to about 10% by weight diazepam or a pharmaceutically acceptable salt thereof, about 60% to about 80% by weight diethylene glycol monoethyl ether, about 5% to about 29% by weight one or more fatty acid esters and about 0.5% to about 3% by weight water. In another aspect of the invention, the pharmaceutical composition comprises about 1% to about 10% by weight diazepam or a pharmaceutically acceptable salt thereof, about 40% to about 47% by weight diethylene glycol monoethyl ether, about 26% to about 34% by weight caprylocaproyl polyoxylglyceride, about 5% to about 10% by weight isopropyl palmitate, about 5% to about 15% by weight sorbitan monolaurate 20, and about 0.5% to about 3% by weight water. Another aspect of the present invention provides a pharmaceutical composition comprising about 1% to about 10% by weight diazepam or a pharmaceutically acceptable salt thereof, about 40% to about 47% by weight diethylene glycol monoethyl ether, about 26% to about 34% by weight caprylocaproyl polyoxylglyceride, about 5% to about 10% by weight oleoyl polyoxylglyceride, and about 5% to about 15% by weight sorbitan monolaurate 20.

In another aspect of the invention, the pharmaceutical composition comprises about 1% to about 15% by weight diazepam or a pharmaceutically acceptable salt thereof, about 43% to about 55% by weight diethylene glycol monoethyl ether, about 16% to about 18% by weight one or more fatty acid esters, about 22% to about 25% by weight N-methyl-2-pyrrolidone, about 1% to about 5% by weight water, and about 5% to about 10% by weight ethanol.

In another aspect of the invention, the pharmaceutical composition comprises about 1% to about 15% by weight diazepam or a pharmaceutically acceptable salt thereof, about 43% to about 55% by weight diethylene glycol monoethyl ether, about 9% to about 10% by weight methyl laurate, about 7% to about 9% by weight propylene glycol monocaprylate, about 22% to about 25% by weight N-methyl-2-pyrrolidone, about 1% to about 5% by weight water and about 5% to about 10% by weight ethanol.

The pharmaceutical composition may optionally comprise one or more additional components such as, but not limited to, carriers, excipients, viscosity enhancers, preservatives, stabilizers, antioxidants, binders, disintegrants, wetting agents, lubricants, colorants, flavors, corrigents, suspending agents, emulsifiers, solubilizers, buffers, tonics, detergents, tranquilizers, sulfur-containing reducing agents, and the like.

The pharmaceutical compositions of the present invention may be formulated according to conventional techniques for intranasal administration. See, e.g., Remington, the science and practice of practicen pharmaceutical (20 th edition, 2000). For example, the intranasal pharmaceutical compositions of the present invention may be formulated as an aerosol (this term includes both liquid and dry powder aerosols). The aerosol of liquid particles may be generated by any suitable means, for example by a pressure driven aerosol nebulizer or an ultrasonic nebulizer, as known to those skilled in the art. See, for example, U.S. patent No. 4501729. Aerosols of solid particles may likewise be generated using any solid particulate pharmaceutical aerosol generator, by techniques known in the pharmaceutical arts. As another example, the pharmaceutical composition of the present invention may be formulated in a ready-to-dissolve form that provides a lyophilized portion of the pharmaceutical composition and a dissolved solution portion of the pharmaceutical composition.

In some embodiments of the invention, the pharmaceutical composition is in the form of an aqueous suspension, which may be prepared from a solution or suspension. With respect to solutions or suspensions, dosage forms may be composed of lipophilic substances, liposomes (phospholipid vesicles/membranes) and/or micelles of fatty acids (e.g. palmitic acid). In particular embodiments, the pharmaceutical composition is a solution or suspension that is capable of dissolving in the fluids secreted by the nasal epithelial mucosa, which advantageously enhances absorption.

The pharmaceutical composition may be an aqueous solution, a non-aqueous solution or a combination of water and a non-aqueous solution.

Suitable aqueous solutions include, but are not limited to, hydrogels, aqueous suspensions, aqueous microsphere dispersions, aqueous liposome micelles, aqueous microemulsions, and any combination of the foregoing, or any other aqueous solution capable of dissolving in the fluids secreted by the nasal mucosa. Exemplary non-aqueous solutions include, but are not limited to, non-aqueous gels, non-aqueous suspensions, non-aqueous microsphere dispersions, non-aqueous liposome dispersions, non-aqueous emulsions, non-aqueous microemulsions, and combinations of any of the foregoing, or any other non-aqueous solution capable of being dissolved or mixed into the fluids secreted by the nasal mucosa.

Examples of powder formulations include, but are not limited to, simple powder mixtures, micronized powders, powder microspheres, coated powder microspheres, liposomal dispersions, and combinations of any of the foregoing. The powder microspheres may be formed from various polysaccharides and celluloses, including but not limited to starch, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, alginate polyvinyl alcohol, gum arabic, chitosan, and any combination thereof.

In particular embodiments, the composition is one that is at least partially or even substantially (e.g., at least 80%, 90%, 95%, or more) soluble in fluids secreted by the nasal mucosa (e.g., the mucosa of cilia surrounding olfactory receptor cells of the olfactory epithelium) to promote absorption. Alternatively or additionally, the composition may be formulated with carriers and/or other substances that facilitate the dissolution of the agent in nasal secretions, including, but not limited to, fatty acids (e.g., palmitic acid), gangliosides (e.g., GM-1), phospholipids (e.g., phosphatidylserine), and emulsifiers (e.g., polysorbate 80).

It will be appreciated by those skilled in the art that nasal secretions will alter the pH of the administered dose as the pH range within the nasal cavity can be as wide as 5-8, since the volume of the pharmaceutical composition administered is generally small. Such changes can affect the concentration of unionized drug available for absorption. Thus, in representative embodiments, the pharmaceutical composition further comprises a buffering agent to maintain or adjust the pH in situ. Typical buffers include, but are not limited to, acetate, citrate, prolamine, carbonate, and phosphate buffers.

In an embodiment of the invention, the pH of the pharmaceutical composition is selected such that the internal environment of the nasal cavity after administration is on the acidic to central side, which (1) is capable of providing the active compound in un-ionized form for absorption, (2) prevents growth of pathogenic bacteria in the nasal passages, which is more likely to occur in alkaline environments, and (3) reduces the likelihood of inflammation of the nasal mucosa.

For liquid and powder sprays or aerosols, the pharmaceutical compositions may be formulated to have any suitable and desirable particle or droplet size. In exemplary embodiments, the particles or droplets have a major and/or average size equal to or greater than about 1, 2.5, 5, 10, 15, or 20 microns and/or equal to or less than about 25, 30, 40, 45, 50, 60, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, or 425 microns (including combinations of all of the foregoing). Representative examples of suitable ranges for the majority and/or average particle or droplet size include, but are not limited to, about 5-100 microns, about 10-60 microns, about 175-325 microns and about 220-300 microns, which promote deposition of an effective amount of the active compound in the nasal cavity (e.g., in the upper third of the nasal cavity, upper ducts, olfactory region and/or sinus region to the target olfactory nerve pathway). Typically, particles or droplets smaller than about 5 microns will be deposited in the trachea or even the lungs, while particles or droplets of about 50 microns or larger will typically not reach the nasal cavity and are deposited in the anterior nose.

International patent publication WO 2005/023335 (kurve technology, Inc.) describes particles and droplets having diameter dimensions suitable for the practice of representative embodiments of the present invention. For example, the average diameter of the particles or droplets may be about 2-50 microns, about 5-40 microns, about 5-35 microns, about 5-30 microns, about 5-20 microns, about 5-17 microns, about 5-30 microns, about 10-25 microns, about 10-15 microns, about 11-50 microns, about 11-30 microns, about 11-20 microns, about 11-15 microns, about 12-17 microns, about 15-25 microns, about 15-27 microns, or about 17-23 microns.

In particular embodiments, the particles or droplets have an average diameter of about 5 to 30 microns, about 10 to 20 microns, about 10 to 17 microns, about 10 to 15 microns, about 12 to 17 microns, about 10 to 15 microns, or about 10 to 12 microns.

Further, the average diameter of the particles or droplets may be about 10-20 microns, about 10-25 microns, about 10-30 microns, or about 15-30 microns.

The particles may be "substantially" of the average diameter or size described herein, i.e., at least about 50%, 60%, 70%, 80%, 90%, or 95% or more of the particles have the indicated diameter or size range.

The composition is optionally delivered as a nebulized or atomized liquid having the droplet size described above.

In particular embodiments, the pharmaceutical composition is isotonic to slightly hypertonic, e.g., the osmolarity range is about 150-550 mOsM. As another specific example, the pharmaceutical composition is isotonic, having an osmolarity range of, for example, about 150-350 mOsM.

Depending on the particular method of intranasal administration, it may be desirable to extend the residence time of the pharmaceutical composition in the nasal cavity (e.g., in the upper third of the nasal cavity, upper tract, olfactory region and/or sinus region), e.g., to enhance absorption. Thus, the pharmaceutical composition may optionally be formulated with: bioadhesive polymers, gums (e.g. xanthan gum), chitosan (e.g. highly purified cationic polysaccharides), pectin (or any carbohydrate capable of thickening when applied to the nasal mucosa such as a gel or emulsifier), microspheres (e.g. starch, albumin, dextran, cyclodextrin), gels, liposomes, carbomers, polyvinyl alcohol, alginates, gum arabic, chitosan and/or cellulose (e.g. methyl or propyl; hydroxyl or carboxyl; carboxymethyl or hydroxypropyl) which are agents that increase residence time in the nasal cavity. As another approach, increasing the viscosity of the formulation may also provide a means of prolonging contact of the agent with the nasal epithelial cells. The pharmaceutical compositions may be formulated as nasal emulsions, ointments or gels, which provide the advantage of topical administration due to their viscosity.

Moist and highly vascularized membranes promote rapid absorption; thus, the pharmaceutical composition may optionally comprise a wetting agent, especially in the case of a gel-based composition, in order to ensure a sufficient intranasal moisture content. Examples of suitable humectants include, but are not limited to, glycerin or glycerol, mineral oil, vegetable oil, film conditioners, tranquilizers, and/or sugar alcohols (e.g., xylitol, sorbitol; and/or mannitol). The concentration of wetting agent in the pharmaceutical composition will vary depending on the agent and formulation selected.

The pharmaceutical composition may also optionally include absorption enhancers, such as agents that inhibit enzyme activity, reduce mucus viscosity or elasticity, reduce mucociliary clearance, open tight junctions, and/or solubilize the active compound. Chemical enhancers are known in the art and include chelating agents (e.g., EDTA), fatty acids, bile salts, surfactants, and/or preservatives. Enhancers for permeation may be particularly useful when formulating compounds that exhibit poor membrane permeability, lack lipophilicity, and/or are degraded by aminopeptidases. The concentration of the absorption enhancer in the pharmaceutical composition will vary depending on the agent and formulation selected.

Preservatives may optionally be added to the pharmaceutical composition in order to prolong shelf life. Suitable preservatives include, but are not limited to, benzyl alcohol, parabens, thimerosal, chlorobutanol, and algicidal amines and combinations of the foregoing. The concentration of the preservative will vary depending on the preservative used, the compound to be formulated, the formulation, and the like. In representative embodiments, the preservative is present in an amount of about 2% by weight or less.

The pharmaceutical composition may optionally include an odorant (as described in EP0504263B 1) to provide odor perception to aid in inhalation of the composition to facilitate delivery to the olfactory region and/or to trigger transmission through olfactory neurons.

As another option, the composition may include a flavoring agent, for example, to enhance taste and/or acceptance of the composition by the individual.

Methods of treatment

Another aspect of the invention provides a pharmaceutical composition for intranasal administration of a benzodiazepine, such as diazepam, to an individual. The term "intranasal administration" as used herein refers to a systemic form of benzodiazepine administration whereby the benzodiazepine is introduced into one or both of the nasal passages of an individual so that the benzodiazepine contacts the nasal mucosa and is absorbed into the systemic circulation. In certain embodiments, a therapeutically effective amount is administered. Intranasal administration of the pharmaceutical compositions of the present invention may include a single administration or multiple administrations of the composition.

The present invention is useful in both veterinary and medical applications. Suitable individuals for the present invention include, but are not limited to, mammals. The term "mammal" as used herein includes, but is not limited to, primates (e.g., apes and humans), non-human primates (e.g., monkeys, baboons, chimpanzees, gorillas), bovines, ovines, caprines, ungulates, porcines, equines, felines, canines, lagomorphs, finpods, rodents (e.g., rats, buchners, and mice), and the like. In some embodiments of the invention, the subject is a human. Human subjects include both males and females and subjects of all ages, including neonates, infants, juveniles, adolescents, adults and elderly subjects.

In some embodiments of the invention, the plasma levels of benzodiazepines exhibit a Coefficient of Variation (CV) of less than about 50%, less than about 40%, less than about 30%, or less than about 20% by intranasal administration to an individual. In a particular embodiment, the benzodiazepine is diazepam. As used herein, "coefficient of variation" refers to the standard deviation from the maximum benzodiazepine concentration (C) in an individual's serum or plasma_max) Or the area under the curve (AUC) plotted along the ordinate (Y-axis) against time along the abscissa (X-axis) for serum or plasma concentrations of benzodiazepines.

The intranasal pharmaceutical compositions of the present invention may in some embodiments provide greater absorption and/or greater bioavailability of benzodiazepines as compared to intravenous and/or rectal administration of benzodiazepines containing.

Another aspect of the present invention is based on the finding that after intranasal administration of a pharmaceutical composition to an individual, the blood pressure and/or pulse of the individual is maintained at a consistent level. As used herein, "consistent level" refers to a measure or unit of value that remains within about 25% or less of the initial or control value (which is the value taken prior to administration of the pharmaceutical composition). As used herein, "before administration" refers to less than 1 hour, e.g., less than 30 minutes, 15 minutes, 10 minutes, or 5 minutes, prior to administration of the composition. In some embodiments of the invention, the value is maintained at about 20% or less, about 15% or less, about 10% or less, or about 5% or less of the initial value prior to administration of the pharmaceutical composition. After administration of the composition, the subject's blood pressure and/or pulse may, in some embodiments, remain at a consistent level for at least about 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, 10 hours, or more.

The subject's blood pressure is maintained, in some embodiments, within about 25/25 mmHg (SBP/DBP) of the subject's blood pressure prior to administration of the composition. In other embodiments, the subject's blood pressure remains within about 20/20 mmHg, about 15/15 mmHg, about 10/10 mmHg, or about 5/5 mmHg (SBP/DBP) of the subject's blood pressure prior to administration of the composition.

The subject's pulse is maintained, in some embodiments, within 10 beats/minute of the subject's pulse prior to administration of the composition. In other embodiments, the subject's pulse is maintained within 9 beats/minute, 8 beats/minute, 7 beats/minute, 6 beats/minute, or 5 beats/minute of the subject's pulse prior to administration of the composition.

In another aspect, the present invention provides a method of treating or preventing seizures in an individual, comprising intranasally administering to the individual in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention. As used herein, an "in need" individual refers to an individual who would benefit from the therapeutic and/or prophylactic effects of the pharmaceutical compositions of the present invention. For example, an individual may be experiencing an attack, having experienced an attack, exhibiting or showing an impending attack signal or symptom, and/or be a population at risk (e.g., the individual may be at risk of or more prone to an attack).

By the terms "treat", "treating" or "treatment" (and grammatical variations thereof) is meant reducing, at least partially ameliorating or lessening the severity of a disease condition in an individual, and/or achieving some reduction, alleviation or lessening of at least one clinical symptom and/or delaying the development of a disease or disorder.

The terms "prevent", "preventing" and "prevention" (and grammatical variations thereof) refer to reducing and/or delaying the onset and/or progression of a disease, disorder and/or clinical symptom and/or reducing the severity of the onset and/or progression of a disease, disorder and/or clinical symptom in an individual relative to what would occur without the use of the methods of the invention. The disease, disorder and/or clinical symptom may be completely prevented, e.g., completely absent. Prevention can also be partial, such that the individual's disease, disorder, and/or clinical symptoms occur and/or onset and/or progression less severe than would occur without the use of the present invention.

The term "therapeutically effective amount" as used herein refers to an amount of a benzodiazepine capable of eliciting a therapeutically useful response in an individual. It will be understood by those skilled in the art that the therapeutic effect need not be complete or curative, as long as some benefit is provided to the individual.

Seizures that can be treated and/or prevented according to the methods of the present invention include, but are not limited to, primary generalized seizures (primarynerizzire), such as absence seizures, atypical seizures, myoclonic seizures, flaccid seizures (atonic seiture), tonic seizures, clonic seizures, tonic-clonic seizures, and grand mal epilepticus; partial seizures such as simple partial seizures, complex partial seizures, and secondary systemic seizures (secondarygenized seizure); non-epileptic seizures; acute recurrent attacks; and persistent epilepsy. As used herein, "acute recurrent episodes" refers to episodes of a group or mass of primary systemic episodes and/or portions, which occur within a short period of time, e.g., 30 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less, in which the individual regains consciousness between episodes. As used herein, "persistent epilepsy" refers to an epileptic event in which a primary generalized seizure and/or partial seizure lasts longer than about 5 minutes or in which a series of generalized seizures and/or partial seizures occur in greater than about 5 minutes without complete recovery of consciousness between seizures. Acute recurrent seizures are associated with persistent epilepsy and can progress or transform into others.

In another aspect, the invention provides a method of preventing an individual from lowering blood pressure and/or pulse during the treatment of an episode by administering a benzodiazepine, such as diazepam, comprising intranasally administering a therapeutically effective amount of a pharmaceutical composition of the invention to a patient in need thereof.

In some embodiments, the pharmaceutical composition is delivered to the upper third of the nasal cavity, the upper tract, the olfactory region, and/or the sinus region of the nose. The olfactory region is a small area located in the upper third of the nasal cavity, typically about 2-10 cm for humans²(25 cm for cats)²) For deposition and absorption by olfactory epithelial cells, followed by neuronal transmission by the olfactory receptor. Located at the top of the nasal cavity, in the upper conduit, this olfactory region is desirable for delivery because it is the only known component of the body in which the CNS comes into extended contact with the environment (Bois et al, fundamentals of ocular mineral, page 184, w.b. saunders co., philia., 1989).

The compositions of the present invention are administered in a manner compatible with dosage formulations, in amounts that will be effective for the desired result. In particular embodiments, the pharmaceutical composition is administered to the individual in a therapeutically effective amount (as described above). The amount to be administered depends on a number of factors such as, for example, the individual to be treated and the severity of the disease condition. The precise amount of active ingredient that needs to be administered may depend on the judgment of the practitioner. Typically, the dose per individual is 5 μ g, 50 μ g or 250 μ g, up to 5mg, 10mg, 20mg or 100mg per dose.

Exemplary doses include from about 0.001, 0.01, or 0.1 to about 1, 5, 10, or 20 mg/dose, e.g., once, twice, or three times daily, 2-4 times weekly, once weekly, 2-3 times monthly, or as needed by the individual.

The compound may be administered for a duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer (e.g., chronic life-long therapy).

Any suitable dosing regimen may be followed. For example, the dosing frequency may be once a week dosing. The dosing frequency may be once daily dosing. The dosing frequency may be greater than once weekly dosing. The dosing frequency may be greater than once daily dosing, for example any of 2, 3, 4, 5 or greater than 5 doses per day. The dosing frequency may be intermittent (e.g., once daily dosing for 7 days followed by 7 days without dose for any 14 day period, e.g., 2 months, 4 months, 6 months, or longer). The dosing frequency may be continuous (e.g., once a week dosing for several weeks).

In other embodiments, the methods of the invention may be performed by self-medication, as desired.

Any dosing frequency may be used in any dose. Furthermore, any dosing frequency and/or dose may be used with any of the pharmaceutical compositions described herein.

The pharmaceutical composition can be delivered in any suitable administration volume. In representative embodiments of the invention, the administration volume for intranasal administration ranges from about 25 microliters to 200 microliters or about 50 to 150 microliters or about 50, 100, 250, or 500 microliters to about 1, 2, 3, 3.5, or 4 milliliters. Typically, the volume of administration is selected to be large enough to allow an effective amount, but sufficiently small, of the benzodiazepine to dissolve to prevent a therapeutically significant amount of the benzodiazepine from escaping from the anterior chamber of the nose and/or draining into the throat, the back nose.

Intranasal administration of the pharmaceutical compositions of the present invention may be accomplished by any known method. In particular embodiments, intranasal administration is by inhalation (e.g., using an inhaler, nebulizer or spray device), optionally, by a nebulizer, tube, catheter, syringe, dropper, packer, pipette, gauze, or the like. By way of further illustration, the pharmaceutical composition may be administered intranasally as: (1) nasal drops, (2) powder or liquid sprays or aerosols, (3) liquid or semisolid for injection, (4) liquid or semisolid by swab, gauze or other similar means of application, (5) gel, cream or salve, (6) infusion or (7) by injection, or by any means now known or later developed in the art. In particular embodiments, the method of administration is by nasal drops, spray, or aerosol. As used herein, an aerosol may be used to deliver a powder, a liquid, or a dispersion (a solid in a liquid).

In representative embodiments, the pharmaceutical formulation is directed upward during administration to enhance delivery to the upper third of the nasal cavity (e.g., the olfactory epithelium in the olfactory region) and the lateral walls (e.g., the nasal epithelium). Further, orienting the individual's head in a retro-inverted position or orienting the individual's body in a Mygind position or a position to a prayer of mecca may be used to facilitate delivery to the olfactory region.

The formulation may be provided in a single dosage form or in multiple dosage forms. In the latter case, a dosimeter means may be provided. In the case of a dropper or pipette, this may be achieved by the patient or caregiver administering an appropriate predetermined volume of the composition. In the case of spraying, this can be achieved, for example, by means of a metered atomizing spray pump.

Another aspect of the invention is an intranasal spray device comprising the pharmaceutical composition of the invention.

Many devices for nasal administration are known in the art. Exemplary devices include particle dispersion devices, bi-directional devices, and devices using a chip-based ink-jet process. ViaNase (kurve technologies, inc., usa) uses a controlled particle dispersion process (e.g., an integrated nebulizer and particle dispersion chamber apparatus, as described in international patent publication WO 2005/023335). Optinosie and Optimiz (OptiNose, AS, Norway) and DirectHaler (Direct-Halera/S, Denmark) are examples of two-way nasal delivery devices. Ink-jet dispensers (ink-jet dispensers) are described in U.S. Pat. No.6325475(MicroFabtechnologies, Inc., USA), anddrug droplets of millimeter-sized chips were used. Devices relying on iontophoresis/sonophoresis/electromigration are also known, as described in U.S. patent No.6410046 (intrabraining international nv, Curacao, AN). These devices contain electrodes to which a drug reservoir (drug reservoir) is attached that is inserted into the nose. Iontophoresis, electromigration, or sonophoresis, with or without a chemical permeation enhancer, may be used to deliver the drug to the target area (e.g., olfactory area). Other commercially available nasal applicators are, for example, Pfeiffer unit-dose and double-dose systems, Valois single-sprayer, double-dose and single-powder systems or Becton-Dickinson Accuspray^TMProvided is a system. Also suitable are glass or plastic bottles with commercially available metering pump spray heads.

Intranasal drug delivery devices are also described in U.S. patent No.6715485 (OptiNoseAS); U.S. Pat. No.6325475(Microfabtechnologies, Inc.); U.S. Pat. No.6948492 (Universal of KentuckyResearchFoundation); U.S. Pat. No.6244573(Lytesyde, LLC); U.S. Pat. No.6234459(Lytesyde, LLC); U.S. Pat. No.6244573(Lytesyde, LLC); U.S. Pat. No.6113078(Lytesyde, LLC); U.S. Pat. No.6669176(Lytesyde, LLC); U.S. Pat. No.5724965(Respironics Inc.); and U.S. patent publication nos. US 2004/0112378 a 1; US 2004/0112379A 1; US 2004/0149289A 1; US 2004/0112380A 1; US 2004/0182388A 1; US 2005/0028812A 1; US 2005/0235992A 1; US 2005/0072430A 1 and US 2005/0061324A 1.

In addition, the pharmaceutical compositions of the invention may optionally be administered in combination with one or more other therapeutic agents, e.g., other therapeutic agents useful in treating and/or preventing seizures or seizure-related side effects. Exemplary therapeutic agents include, but are not limited to, anti-seizure agents such as, for example, azadirachtin,Deludine, ethosuximide, felbamate,Gabapentin (gabapentin),Lamotrigine (lamotrigine), levetiracetam (levetiracetam), luminol,Oxcarbazepine (oxcarbazepine), phenobarbital, and,Phenytoin, primidone, beta-cyclodextrin,Tiagabine (tiagabine),Valproic acid,And Zonisamide, antidepressants, such as, for example, amitriptyline, NMDA receptor antagonists, ion channel antagonists, nicotinic receptor antagonists, and anti-Parkinson agents, such as, for example, benzethynamide (deprenyl), amantadine, levodopa, and methyldopazine. Other therapeutic agents include, but are not limited to barbiturates (e.g., phenobarbital and pentobarbital), steroids (e.g., adrenocorticotropic hormones such as teicoplanin (tetracosactide) acetate), and anticonvulsants (e.g., hydantoins (phenytoin, ethiytoin, etc.), oxazolidines (trimethadione, etc.), succinimides (ethosuximide, etc.), phenylacetureas (phenylacetyl urea, acetylphenylbutyryl urea, etc.), sulfonamides (sulthamine), acetazolamide, etc.), aminobutyric acid(e.g., gamma-amino- β -hydroxybutyric acid, etc.), sodium valproate and its derivatives (e.g., valproic acid, propylvaleramide, valproic acid pivalate (pivoxil), sodium valproate, half-sodium valproate), azathioprine, viagatrine, tiagabine (tiagabine), and amantadine), and/or any other therapeutic agent that can benefit an individual.

As used herein, administration of two or more compounds "in combination" means that the two compounds are administered within sufficient proximity in time to alter the biological effect of one in the presence of the other. The two compounds may be administered simultaneously in the same or different formulations, or sequentially. Simultaneous administration can be carried out by mixing the compounds prior to administration or by administering the compounds in two different formulations, e.g., at the same time point, but at different anatomical locations or using different routes of administration. As used herein, "simultaneous" or "simultaneous" means sufficiently close in time to produce a combined effect (i.e., simultaneous may be simultaneous, or it may be two or more events occurring shortly before or after each other).

The invention is explained in more detail in the following non-limiting examples.

Examples

Example 1

A development-labeled, three-phase, crossover study was conducted to identify two formulations, diazepam intranasal spray (DZNS) versus diazepam rectal gelRelative bioavailability in healthy volunteers.

The research objective is as follows:

-1. determining the pharmacokinetics of diazepam according to a single intranasal dose of 10mg, DZNS formulation 1 and DZNS formulation 2.

According to both formulations, with a single rectal dose of 10mgIn contrast, relative bioavailability of diazepam was assessed.

-3. evaluating the safety and tolerability of two DZNS formulations (DZNS formulation 1 and DZNS formulation 2).

Research and design:

this is a single-center, open-label, three-phase, randomized crossover study. 12 healthy adult male or non-pregnant, non-lactating female individuals were enrolled in the study, aged between 18 and 50 years, inclusive, and screened for body weights between 50 and 90kg, inclusive. During each dosing period, the individual received one of the following treatments in a randomized order:

a single 10mg dose of DZNS formulation 1 (see table 1 below) administered as a 5mg spray (100 μ Ι) in each nostril, used in the morning. (batch No. 2010J128A)

A single 10mg dose of DZNS formulation 2 (see table 2 below) administered as a 5mg spray (100 μ Ι) in each nostril, used in the morning. (batch No. 2010J118A)

-In a single 10mg dose, byAcuDial^TMRectal administration, morning use. (batch No.: CEDH; deadline: 05/2014)

Table 1: DZNS formulation 1

Table: DZNS formulation 2

Individuals who give up prematurely after the first dose has not been replaced. A screening period of up to 21 days was performed before the start of the treatment period. On day 0 of each dosing period, subjects performed a minimum of 10 hour investigations of study units prior to dosing to evaluate for continued adequacy. Individuals received their first treatment dose in the morning (day 1). Study drug was administered by the investigator.

Is in accordance withThe instructions for dosing provided in the package insert. After dosing, the subject receiving the rectal dose remains in a lateral position (i.e., lying on his side) for 60 minutes, after which the subject is allowed to move fully ambulatory, if necessary and if the subject is able to and is assisted by clinical personnel. After dosing, the subject is asked to avoid bowel movements for at least 4 hours, if possible. Immediately after dosing, gauze was placed on the anus of the individual and visual signs of drug leakage were examined by the investigator after 15min (minutes), 30min and 1 hour of dosing. Any observations of leaks were recorded. The previous gauze was replaced with new gauze at 15min and 30 min. Gauze was permanently removed 1 hour after dosing.

Individuals receiving an intranasal dose were asked to blow their nose gently once just prior to administration of the first of two intranasal diazepam sprays (one for each nostril). Before and after intranasal administration, the individual's nasal mucosa and throat are examined and any observations of redness, edema, or allergy, or nasal or pharyngeal discomfort reported by the individual are recorded. The subjects were dosed supine with their heads in a neutral position (facing up) and held in this position for 10 minutes after dosing.

After placing the individual in a supine position with their head in a neutral position (facing straight up), the designated research crew followed the following steps:

1. the nasal spray tip was inserted into the middle of the right nostril, holding the tip center towards the back of the nose.

2. Indicating that the individual is not attempting to exhale or inhale the spray.

3. The actuator at the bottom of the nasal spray device is pressed hard with the thumb.

4. Steps 1-3 are repeated for delivery of the second spray into the left nostril, and then removing the nasal spray tip from the nose.

Both sprays were administered to the subject within about 15 seconds. After 10 minutes of maintaining the supine position after dosing, the individual is then placed in a sitting position (without restriction of head position or movement) of 45 degrees of recline until 60 minutes after dosing, after which full ambulatory movement is allowed if the individual is able and assisted by clinical personnel as needed. It is desirable that the individual dose not blow their nose for at least 4 hours after administration, if possible. Any visual signs of drug leakage from the nostrils were recorded after 15min, 30min and 1 hour of dosing.

Individuals remained confined to the study unit until after 24 hours (day 2) vital sign measurements and blood sample collection, at which time they were approved for departure. The individual will return to the clinic for outpatient visits (PK blood sample collection and vital signs) the following hours after the dose: 48 (day 3), 96 (day 5), 144 (day 7), 192 (day 9) and 240 (day 11). Each dose was administered separately in a minimum phase of elimination of 14 days. After the last blood draw for the last dosing period, study exit procedures were performed.

Each intranasal formulation was provided in a 5ml amber glass, screw-cap bottle, labeled with formulation name, lot number and storage conditions. The Pfeiffer dual-dose nasal spray device is provided by aptar pharma (cogers, new york). The Pfeiffer dual-dose device is a disposable nasal spray device capable of only 2 actions (one spray/nostril). Each Pfeiffer dual-dose device is provided as 4 separate parts: vials, vial stoppers, vial holders, and actuators.

Prior to dosing, pharmacy personnel of the clinical research unit fill the nasal spray device vial with the appropriate DZNS formulation to be administered to each individual, and then assemble the device according to the procedure provided by aptar pharma. After filling and assembly of the nasal spray devices, pharmacy personnel label each device with the DZNS formulation, which contains the filling day and the number of individuals assigned to receive the dose.

The device delivers 0.100mL of the DZNS formulation in one spray. Each dose was administered as two sprays (giving one spray/nostril within 15 seconds) containing 5mg of DZNS formulation; the total intranasal dose/administration delivered was therefore 10 mg.

Safety: the investigators evaluated safety using the following parameters: physical examination, vital signs, pulse oximetry clinical laboratory assessments, ECG, individual sensitivity observations, nasal and pharyngeal inflammation/inflammation examinations (for intranasal dosing), and reported or observed adverse events. The individual is monitored for any adverse events from pre-dosing to study completion.

Pharmacokinetics: during each dosing period, a total of 19 consecutive blood samples were collected from each individual at the following times: predose and post8, 15, 30 and 45 minutes doses, and post1, 1.5, 2, 3, 4, 6, 9, 12, 24, 48, 96, 144, 192 and 240 hours doses. Blood samples were analyzed for diazepam plasma concentration and its major metabolites desmethyl, desmethyldiazepam and hydroxydiazepam using an efficient bioanalytical assay. Plasma concentration time data were summarized by formulation/treatment and descriptive statistics were performed at each schedule time point. Individual and average concentration-time curves are provided for each treatment.

Individual diazepam concentration data using nominal sampling times were analyzed using a non-compartmentalization method (phoenixwinnonnlinversion 6.1). The following PK parameters for diazepam were determined: c_max，T_max，C_last，T_last，λ_z，t1/2，AUC_last，AUC_infExtrapolated% AUC. As used herein, "C_max"refers to the maximum or peak serum or plasma concentration of a benzodiazepine, such as diazepam, in the individual following administration of the benzodiazepine or a formulation comprising the benzodiazepine. "T" as used herein_max"means that the benzodiazepine reaches C_maxThe time taken. As used herein, "C_last"refers to the last quantifiable concentration of a benzodiazepine or a formulation containing a benzodiazepine after dosing. "T" as used herein_last"means that the benzodiazepine reaches C_lastThe time taken. The term "λ" as used herein_z"refers to the elimination constant of benzodiazepines such as diazepam. The term "t 1/2" as used herein refers to the elimination half-life of benzodiazepines such as diazepam. "AUC" as used herein_last"refers to benzodiazepines such as diazepam from 0 hours to T_lastArea under the concentration-time curve of (c). "AUC" as used herein_inf"refers to the area under the concentration-time curve of a benzodiazepine such as diazepam from 0 hours to infinity. These PK parameters were summarized using descriptive statistics for each formulation. As used herein, "F_rei"refers to the relative bioavailability of benzodiazepines such as diazepam. Relative bioavailability (F)_{Question asked}) Is AUC as a test and reference formulation_infThe ratio of the values is calculated. PK data for diazepam metabolites were summarized using descriptive statistics, andand drawing.

Data from 12 individuals who completed at least one treatment during the study was included in the pharmacokinetic analysis. Lack of data for individuals 204 and 206 to useAnd treatment of individual 202 with DZNS formulation 2. Concentration-time data below the quantification limit (BLQ) were treated as zero (0.00 ng/mL) in data summarization and descriptive statistics. In pharmacokinetic analysis, BLQ concentration was treated as 0 from time-zero high to the time at which the first quantifiable concentration was observed; the embedded and/or terminal BLQ concentration is treated as "missing".

Summary of results

Pharmacokinetic results:

figure 1 shows the mean concentration-time data for the 0-24 hour period and figure 2 shows the individual diazepam concentration-time curves.

Diazepam is rapidly absorbed from all three formulations and the mean peak plasma concentration occurs 1-1.5 hours after dosing. The highest mean plasma concentrations were 221+62.2 ng/mL at 1.00h for DZNS formulation 1, 257+56.7 ng/mL at 0.75h for DZNS formulation 2, andfor 122+113 ng/mL at 1.50 h. After this peak, the concentration decayed in a biphasic manner, and the end-stage began approximately 24 hours after dosing. For most individuals, quantifiable concentrations of diazepam were observed throughout the 240h interval. After dosing cycles 2, 3 and 4, low predose diazepam concentrations were observed in most individuals regardless of the 336-hour phase of elimination. This concentration was very low (1 ng/mL or less on average) and was only about 0.5% of the peak concentration.

In contrast to any of the intranasal test formulations,the mean diazepam concentration after administration of the formulation was quite low. Concentration-time mapping of individual individuals revealed that several individuals appeared to be derived fromThe bioavailability of diazepam of the formulation is very poor or poor. Specifically, individuals 201, 202, and 211 had peak diazepam concentrations of only 6.39, 6.33, and 14.0 ng/mL, respectively, indicating very low bioavailability, and individuals 203 and 207 had concentrations of 58.0 and 63.6 ng/mL, indicating relatively low bioavailability. In contrast, the remaining 5 acceptsThe peak concentration in the treated subjects was 151-299 ng/mL.

As at 50%The variability of the test formulation was much greater than that of either intranasal treatment as a result of the low concentrations observed in the treated individuals. For example, the% CV at 1 hour post-dosing is 28.2% for DZNS formulation 1, 22.6% for DZNS formulation 2 and for DZNS formulation 2Is 87.3%.

Although the specific cause of low concentration after rectal diazepam is unknown, it is noted that 4 out of 5 individuals with low bioavailability have formulation leakage, although drug administration was carefully performed as indicated by the label. No evidence of leakage was noted in individuals with good bioavailability.

The results of the pharmacokinetic analysis are shown in table 3 below. For theTreatment, mean C_maxIs 137ng/mL and varies greatly as evidenced by CV 88%. Mean T_maxWas 1.75 hours. AUC_intThe average was 4393h ng/mL and CV was 88%.

Andin contrast, C of DZNS formulation 1_maxThe average was 246 ng/mL and showed low variability as evidenced by CV 29%. Mean T_maxWas 1.13 hours. AUC_infThe average was 6969h ng/mL and the CV was 24%.

For DZNS formulation 2, C_maxThe average was 287 ng/mL and the CV was 14%. Mean T_maxIs 0.95 hour. AUC_infThe average was 6918h ng/mL and the CV was 21%.

Table 3: according toSummary of pharmacokinetic parameters of diazepam administered with DZNS formulation 1or DZNS formulation 2

The average concentration-time curves for diazepam, N-desmethyl diazepam, norhydroxyazepam and hydroxyazepam were plotted on the semi-log axis in figure 3. The metabolite concentrations showed similar curves for each of the 3 treatments. Calculated C of diazepam metabolite and parent diazepam (metabolite/diazepam)_maxAnd AUC_infThe ratio indicates that desmetazepam is the most abundant metabolite of diazepam compared to the other 2 metabolites (desmethylhydroxyazepam and hydroxydiazepam). For DZNS formulation 1, DZNS formulation 2 andin particular, AUC of desmetazepam_infThe ratios are about 2.09, 2.02 and 3.00, respectively. AUC of the other 2 metabolites nordroxydiazepam and hydroxydiazepam_infThe ratio is about 0.05-0.21, indicating that they are less metabolites of diazepam after intranasal and rectal administration.

Safety results:

a total of 46 Adverse Events (AEs) were reported during the study (table 4). Of the 46 AEs, 41 were moderate, 4 were moderate (dizziness 30 minutes after treatment of B [ DZNS formulation 2], starting at approximately 20 hours after dosing; 1 individual developed euphoria and somnolence 6 hours after treatment of a [ DZNS formulation 1], and toothache after treatment a), and 1 was severe (severe trauma AE, fracture of the thigh bone 6 days after treatment B). Thirty-nine (39) AEs were considered by the investigator to be potentially relevant, and 7 were considered to be potentially unrelated to study drug. There was an SAE, which was attributed to trauma of fracture of the left femur caused by an automobile accident, which occurred 6 days after receiving treatment B. The investigator judged SAE serious and was probably unrelated to study drug.

The most commonly reported post-dose AE was lethargy (n = 7; 3 after treatment a, 2 after treatment B, and treatmentThe latter 2, throat inflammation (n = 7; 3 after treatment a and 4 after treatment B), and dysgeusia (n = 6; 2 after treatment a and 4 after treatment B).

Table 4: treatment of A (DZNS formulation 1), treatment of B (DZNS formulation 2) or treatmentFollowed by adverse events.

Percent received individuals (AE events) were based on the number of individuals exposed to each study drug

The percentage of events is based on the number of events reported

Adverse events reflecting the local effects of intranasal formulations such as throat irritation or taste disturbance (occurring in 17-36% of individuals receiving these formulations) and less common signs or symptoms of burning, oral malodor and nasal inflammation in the nose or throat occur at about the same frequency in both nasal formulations but rarely in rectal formulations. All these AEs were moderate and resolved within 3 hours. AEs reflecting central effects of diazepam, such as lethargy or drowsiness, occurred at approximately equal frequency in the three treatment groups (18-30% of individuals administered each formulation reported either AE). These AEs were also modest, but had greater variability over the duration, typically lasting several hours.

Nasal formulation post-dose nasal and pharyngeal inflammation/inflammation evaluations demonstrated signs or symptoms for 6 individuals, which were generally moderate, occurred within the first hour after dose administration, and lasted less than 1 hour. One individual developed rhinitis signs 24 hours after dosing, which lasted for approximately 1 day.

Table 5 below provides the mean vital sign values at the pre-dose (immediately prior to dosing) for each treatment group. Figures 4-8 show the mean change from pre-dose for each vital sign measurement 4 hours after dosing.

Table 5: mean vital sign values at predose

Following administration, mean systolic and diastolic blood pressures were reduced by 22-26mmHg and heart rate by 9-10bpm 1 hour after dosing (FIGS. 2-4). The systolic blood pressure of each individual ranged from-1 to-41 mmHg and the diastolic blood pressure from-8 to-33 mmHg the first hour after dosing. At the same 1 hour interval, the individual heart rate varied from +4 to-24 bpm. No AE was reported about these changes in vital signs. By comparison, no significant change from the pre-dose was observed in mean blood pressure or heart rate after intranasal formulation administration. No meaningful changes from the pre-dose were seen in respiratory or oxygen saturation levels after all three treatments were administered.

Since the effect of rectally delivered diazepam on blood pressure and heart rate observed in this study was not significantly correlated with systemic blood levels of diazepam, it was unclear whether this effect was related to some interaction between the route of administration and the diazepam or the outcome of the intrarectal method administration itself.

For each treatment group (DZNS formulation 1, DZNS formulation 2 or) Individual vital signs of systolic blood pressure, diastolic blood pressure and heart rate at the pre-dose (i.e. immediately before dosing) and during 24 hours after treatment dosing were collected.

And (4) conclusion:

diazepam based on 1n (C)_max) Is based on the sum of the maximum exposure of 1n (AUC)_last) And 1n (AUC)_inf) The total systemic exposure after intranasal administration of the test formulations (DZNS formulation 1 and DZNS formulation 2) was significantly higher than the reference productThe diazepam pharmacokinetic parameter values were comparable for the two intranasal DZNS test formulations.

In summary, the safety profiles of the three formulations were similar, except for the local, transient and generally moderate nasal/pharyngeal adverse event ratios in the two intranasal formulationsThe formulations are more prevalent.Following administration, but not after intranasal formulation, the heart rate is reduced by about 9-10bpm and the systolic and diastolic blood pressures are each reduced by about 22-26 mmHg. These changes were also present in 5 individuals following rectal administration, which showed very poor or poor bioavailability of diazepam, suggesting that the reduction in heart rate and blood pressure may be due to rectal mode of administration rather than systemic pharmacological effects of diazepam.

Example 2

The goal of this study was to characterize a dual dose diazepam nasal spray via droplet size distribution measured by laser diffraction using malverspraytec.

DNZS formulation 1 (see table 1) and DNZS formulation 2 (see table 2) were filled into Pfeiffer dual-dose pumps, which were fitted with two different types of vial holders. All spray pumps were automatically actuated using sprayviewnsxautomaticedactualstate. The droplet size distribution was measured using malverspraytec. The drive parameters for the dual-dose nasal spray pump are provided by the device manufacturer. The software parameters for the SprayVIEWNSP were derived from our previous experience with similar types of designs.

Malverspraytec operates on the principle of laser diffraction and is a commonly used technique to characterize the droplet size distribution from a nasal spray. The droplet size distribution is characterized by the following specifications: volume distribution (Dv10, Dv50, Dv90), span and percentage (%) less than 10 μm, according to fdaguidence for industry: NasalSprayandinhaliotion solution, Suspension, and SprayDrugproducts-Chemistry, manufacturing and controls evaluation, month 7 2002 and FDADraftGuidineaneforIndustry: bioavailabililtyand Bioequivalenence Studies for Nasal Aerosol and Nasal SpraysforLocalAction, 4 months 2003.

Definition of

Driving: the process of discharging the nasal spray.

Spray weight: the weight of the formulation emitted from the nasal spray unit by a single actuation (initial unit weight-final unit weight). The target spray weight for a two-dose diazepam nasal spray was approximately 100 mg.

Dv 50: the volume median diameter or Dv50 value indicates that 50% of the distribution contained in the droplets is less than this value, while the other half contained in the droplets is greater than this value. Likewise, Dv10 and Dv90 values indicate that the distribution contained in 10% and 90% of the droplets, respectively, is less than these values.

Span: the span is measured during the laser diffraction test. It quantifies the droplet spread size distribution and is calculated by the following equation: dv90-Dv 10/Dv 50.

Percentage (%) less than 10 μm: the percentage of less than 10 μm is related to the percentage of droplet size distribution of 10 microns or less in diameter when measured by laser diffraction.

Test execution

The diazepam bulk formulation was stored at room temperature and the diazepam nasal spray (filled unit) was stored vertically at room temperature. The spray weight is recorded on a spray weight spreadsheet designated for this item. All test data and observations were recorded on designated laboratory notebooks.

preparation/Assembly of diazepam formulations

Vial assembly method

The diazepam preparation does not require shaking. 230 μ l of each formulation (either DZNS formulation 1or DZNS formulation 2) was transferred to each vial using an Eppendorf pipette. Care was taken not to wet the sidewalls while filling. The filled vials were inserted into metal vial holders. The rubber plug was inserted into the rubber plug holder until the holder and the upper surface of the plug were flush. The rubber stopper holder was placed vertically on the metal vial holder. The assembly shell was placed vertically on the rubber stopper holder. The assembled shell is then lowered sufficiently to insert the rubber stopper into the vial. The assembly shell and rubber stopper holder were removed. Vials are removed from the metal vial holder by rotating the metal vial holder up and down.

Dual dose device assembly method

The plastic vial holder is placed vertically under the filled vial (now called the vial holder assembly). The vial holder assembly is placed into a final assembly aid. The dual dose pre-assembly was mounted on a vial holder. The preassembly is pushed completely down onto the assembly aid so that the adapter lower edge contacts the aid.

Method for determining droplet size distribution double-dose diazepam nasal spray

The driver and software parameters described in Table 6 were used for the droplet size distribution using SprayVIEWNSSx-MS and MalveSpraytec.

Table 6: driver parameters for SprayVIEWNSSxActualationStation and software parameters for MalvemSpraytec

Filling and assembling the Pfeiffer apparatus. A total of 12 cells were selected. The initial unit weight is recorded. The droplet sizes for two drives per unit are measured. The tip was wiped with a Kimwipe and each unit weighed after each spray to calculate the weight of each spray. The stabilization phase is a manual selection by the analyst of the histogram obtained for each drive to analyze the Droplet Size Distribution (DSD). From the malverspraytec toolbar; the analyst selects the relative timing of View and highlight (relatedtiming). The malverspraytec method control variable file (. pcl) and the data file (. dat) are stored. The malverspraytec cover page, PSD and PCV tables were printed. Data were recorded in spray weight worksheets, lab notebooks and malvespraytec. Dv10, Dv50, Dv90, span,% <10 μm and spray weight are reported.

Results and discussion

The objective of this study was to characterize a bi-dose diazepam nasal spray of two formulations fed in a Pfeiffer bi-dose pump mounted with two different types of vial holders. DZNS formulation 2 is a high viscosity formulation and DZNS formulation 1 is a low viscosity formulation. Both DZNS formulation 1 and DZNS formulation 2 were tested using standard and modified vial holders. This modified vial holder design is designed to modify the feather profile (plumeprofil) of these formulations by increasing the double dose pressure point at the drive time, according to the device manufacturer (Pfeiffer).

In vitro spray characterization of both formulations was based on spray pattern analysis measured according to malvespraytec. A total of 24 drives were tested by one analyst (3 devices x2 formulation x2 type vial holder x2 drives).

See tables 7 and 8 below for the mean droplet sizes produced by the modified and standard vial holder. The data comparison can be found in table 9.

Table 7: overall mean droplet size from modified vial rack

Table 8: bulk mean droplet size from standard vial rack

Table 9: comparison between DZNS formulation 1 and DZNS formulation 2 when tested with modified vial holder and standard vial holder

As shown in table 9, it was observed that the droplet size data for DZNS formulation 1 and DZNS formulation 2 were quite different. Dv10, Dv50 and Dv90 values obtained from DZNS formulation 2 were higher than those obtained from DZNS formulation 1. Without being bound to a particular theory, this may be attributed to the fact that the high viscosity DZNS formulation 2 produced a fluid-like spray with large droplet particles (including sputtering), and the low viscosity formulation DZNS formulation 1 produced better formed feathers (plume), producing much smaller droplet particles. Thus compared to DZNS formulation 2 (larger% droplet size distribution with diameter of 10 microns or less), DZNS formulation 1 produced better span (larger spread of feathers) and higher% <10 μm. This data indicates a significant effect of viscosity on the droplet size distribution of these formulations.

Based on information obtained from the device manufacturer, the improved vial holder was designed to increase the pressure point of the dual dose device, thereby producing a smaller fluid-like spray from the DZNS formulation 2. However, the overall droplet size distribution data from the modified vial rack is comparable to that from the standard vial rack.

Summary and conclusion

The fully-actuated spray met the acceptance limit defined by the single actuation content of 85-115% of the target spray weight (100mg), which thus indicates that the fully-formed spray was analyzed.

Example 3

The objective of this study was to characterize a two-dose diazepam nasal spray via feather geometry analysis (plumegemetreyanalysis) as measured by SprayVIEWNSP.

DNZS formulation 1 (see table 1) and DNZS formulation 2 (see table 2) were filled into Pfeiffer dual-dose pumps, which were fitted with two different types of vial holders. All spray pumps were automatically driven using sprayviewnsxautomaticedactualstation. Feather geometry was measured using SprayVIEWNSP. The drive parameters for the dual-dose nasal spray pump are provided by the device manufacturer. The software parameters for the SprayVIEWNSP were derived from our previous experience with similar types of devices.

Feather geometry is an in vitro test used to characterize pump performance. This test is performed by analysis of a two-dimensional image of the plum (emittedplus) emission. Feather geometry analysis will be performed using SprayVIEWNSP, which is a non-impact laser chip-based instrument. Feather geometry is characterized by the following metrics: spray angle and feather width, which is according to fdaguidence for industry: NasalSprayandinhaliotion solution, Suspension, and SprayDrugproducts-Chemistry, manufacturing and controls evaluation, month 7 2002 and FDADraftGuidineaneforIndustry: bioavailabililtyand Bioequivalenence Studies for Nasal Aerosol and Nasal SpraysforLocalAction, 4 months 2003.

Definition of

The actions are as follows: the process of discharging the nasal spray.

Spray weight: the weight of the formulation emitted from the nasal spray unit by a single actuation (initial unit weight-final unit weight). The target spray weight for a two-dose diazepam nasal spray was approximately 100 mg.

Spray angle: angle of the feathers fired as measured from the spray cone and the top of the spray nozzle.

Feather width (plumewidth): feather width at a given distance from the spray nozzle. For this study, feather width will be measured at a feather width of 3 cm from the spray nozzle.

Test execution

The diazepam bulk formulation was stored at room temperature and the diazepam nasal spray unit (filled) was stored upright at room temperature. The spray weight is recorded on a spray weight spreadsheet designated for this item. All test data and observations were recorded on designated laboratory notebooks.

preparation/Assembly of diazepam formulations

Vial assembly method

The diazepam preparation does not require shaking. 230 μ l of each formulation (either DZNS formulation 1or DZNS formulation 2) was transferred to each vial using an Eppendorf pipette. Care was taken not to wet the sidewalls while filling. The filled vials were inserted into metal vial holders. The rubber plug was inserted into the rubber plug holder until the holder and the upper surface of the plug were flush. The rubber stopper holder was placed vertically on the metal vial holder. The assembly shell was placed vertically on the rubber stopper holder. The assembled shell is then lowered sufficiently to insert the rubber stopper into the vial. The assembly shell and rubber stopper holder were removed. The vials were removed from the metal vial holder by rotating the metal vial holder up and down.

Dual dose device assembly method

The plastic vial holder is placed vertically under the filled vial (now called the vial holder assembly). The vial holder assembly is placed into a final assembly aid. The dual dose pre-assembly was mounted on a vial holder. The preassembly is pushed completely down onto the assembly aid to the dispenser lower aid.

Method for determining feather geometric double-dose diazepam nasal spray

The drives and piece numbers from table 10 were used for feather geometry with SprayVIEWNSx and SprayVIEWNSP.

Table 10: number of drives for SprayVIEWNSP and number of pieces for SprayVIEWNSSxActualation station

Filling and assembling the Pfeiffer apparatus. 12 units. The initial unit weight is recorded. The feather geometry was measured per unit of drive. Each spray weight will be weighed with a Kimwipe and each unit weighed after each spray. sprayVIEW feather geometry (sprayVIEWPLLUMEGeometryReport). Data are recorded in spray weight tabulation laboratory notebooks and SprayVIEWNSP. Spray angle feather width and spray weight.

Results and

the goal of this study was to characterize a bi-dose diazepam nasal spray of the formulation given in Pfeiffer bi-doses contained different vial racks. DZNS formulation 2 is a mild formulation and DZNS formulation 1 is a mild formulation. DZNS formulation 1 and DZNS formulation 2 were tested with a standard vial holder. This entered the vial holder, manufactured by the device (Pfeiffer), through the double dose upon actuation, to enter the feathering of the formulation.

Spray characterization of the formulations was based on feather geometry analysis as measured by SprayVIEWNSP. One analyst tested 24 drives (3 devices x2 vial rack of formulation x2 x2 drives).

The feather geometry of the incoming and target vial holders, tables 11 and 12 below. Data are shown in table 13.

Table 11: flat feather geometry of incoming vial rack

Table 12: flat feather geometry for labelling vial holders

Table 13: DZNS formulation 1 and DZNS formulation 2 when tested with incoming vial holder and standard vial holder

In table 13 and fig. 9-10, it was observed that the feather geometry data for DZNS formula 1 and DZNS formula 2 were different. The spray angle and feather width of DZNS formulation 2 were lower than those of DZNS formulation 1. In the absence, this is due to the fact that the degree DZNS formulation 2 sprays (feathers), low-degree formulation DZNS formulation 1 feathers, large feathers and wide horns.

This data is tabulated for the feather geometry of this formulation when dispensed using a Pfeiffer dual dose device.

The vial holder was used as a small spray for DZNS formulation 2 in a dual dose device, depending on the device. Incoming vial rack spray pattern data is used to label the vial rack.

Knot and knot

The complete spray was analyzed in the test degree defined by the single actuation of the target spray weight (100mg) of the actuated spray from 85 to 115%.

Example 4

The objective of this study was to characterize the dual dose diazepam nasal spray, as measured by SprayVIEWNSP, spray pattern analysis.

DNZS formulation 1 (table 1) and DNZS formulation 2 (table 2) were filled into Pfeiffer dual doses, which contained different vial holders. The spray used was actuated using sprayviewnsxautomaticedactualstation. The spray pattern was measured using SprayVIEWNSP. A drive train for a dual dose nasal spray. The number of pieces for the SprayVIEWNSP was tested on the device of the noodles.

The spray pattern was tested for characterization. This test is performed by analysis of a two-dimensional image of the emitted child (emittedplus). Spray pattern analysis was performed using SprayVIEWNSP, which is a non-impact laser chip-based instrument. Characterized measures of spray pattern: d_max(D_Muscle)D_min(D_{Sun (Sun)}) And degree of sum (ovarityratio), which is in accordance with fdaguidecforindustry: NasalSprayandinhaliotion solution, Suspension, and SprayDrugproducts-Chemistry, manufacturing and controls evaluation, month 7 2002 and FDADraftGuidineaneforIndustry: bioavailabililtyand Bioequivalenence Studies for Nasal Aerosol and Nasal SpraysforLocalAction, 4 months 2003.

Definition of

Driving: the process of discharging the nasal spray.

Spray weight: the weight of the formulation emitted from the nasal spray unit by a single actuation (initial unit weight-final unit weight). The target spray weight for a two-dose diazepam nasal spray was approximately 100 mg.

D_max: the most straight measured on the spray pattern image. D_maxThrough the center of the spray image (image-wise intensity).

D_min: measured on the spray pattern imageThe most straight of the amount. D_mmThrough the center of the spray image (image-wise intensity).

Degree: d_maxD_min. The amount of this spray. Dividing into the following parts: the spray pattern is the image plane (%).

Test execution

The diazepam bulk formulation was stored at room temperature and the diazepam nasal spray unit (filled) was stored upright at room temperature. The spray weight is recorded on a spray weight spreadsheet designated for this item. The data tested and observations were recorded on designated laboratory notebooks.

preparation/Assembly of diazepam formulations

Vial assembly method

The diazepam preparation does not require shaking. 230 μ l of each formulation (either DZNS formulation 1or DZNS formulation 2) was transferred to each vial using an Eppendorf pipette. Care was taken not to wet the sidewalls while filling. The filled vials were inserted into metal vial holders. The rubber plug was inserted into the rubber plug holder until the holder and the upper surface of the plug were flush. The rubber stopper holder was placed vertically on the metal vial holder. The assembly shell was placed vertically on the rubber stopper holder. The assembled shell is then lowered sufficiently to insert the rubber stopper into the vial. The assembly shell and rubber stopper holder were removed. Vials are removed from the metal vial holder by rotating the metal vial holder up and down.

Dual dose device assembly method

The plastic vial holder is placed vertically under the filled vial (now called the vial holder assembly). The vial holder assembly is placed into a final assembly aid. The dual dose pre-assembly was mounted on a vial holder. The preassembly is pushed completely down onto the assembly aid to the dispenser lower aid.

Method for measuring spray pattern double-dose diazepam nasal spray

The drives and numbers given in table 14 were used for the spray plots using SprayVIEWNSx and SprayVIEWNSP.

Table 14: number of drives for SprayVIEWNSP and number of pieces for SprayVIEWNSSxStation

Filling and assembling the Pfeiffer apparatus. 12 units. The initial unit weight is recorded. The spray pattern for each unit actuation was measured. Each unit will be weighed with a Kimwipe and after each spray to weigh each spray weight. sprayVIEW spray Pattern

. Data were recorded in spray weight tabulation lab notebooks and SprayVIEWNSP. D_minD_maxDegree and spray weight.

Results and

the objective of this study was to characterize a bi-dose diazepam nasal spray of the formulation given in Pfeiffer bi-doses contained different vial racks. According to DZNS formula 2 is

The mild formulation and DZNS formulation 1 are mild formulations. DZNS formulation 1 and DZNS formulation 2 were tested using a standard vial holder. This entered the vial holder, manufactured by the device (Pfeiffer), through the double dose upon actuation, to enter the feathering of the formulation.

The characterization of the spray of the formulation was based on spray pattern analysis as measured by SprayVIEWNSP. One analyst tested 24 drives (3 devices x2 vial rack of formulation x2 x2 drives).

Flat spray patterns for incoming and target vial holders, tables 15 and 16 below. The data are shown in Table 17.

Table 15: flat spray pattern of incoming vial rack

Table 16: flat spray pattern for labeling vial racks

Table 17: for both the incoming vial holder and the standard vial holder, for both DZNS formulation 1 and DZNS formulation 2.

In table 17 and fig. 11-12, it was observed that the spray pattern data for DZNS formulation 1 and DZNS formulation 2 were different. DZNS formulation 1D_maxD_rninAnd% to DZNS formula 2. This is true because of the low D of formulation 2 for the formulation DZNS_maxD_rninAnd% flour spray, low-concentration formulation feathers, large spray pattern. DZNS formulation 1

Degree of DZNS formulation 2. (degree 1 is a graph).

This data is tabulated for the spray pattern of this formulation when dispensed using a Pfeiffer dual dose device.

The vial holder was used as a dual dose device to deliver a small spray of DZNS formulation 2, as per the device. Incoming vial rack spray pattern data is used to label the vial rack.

Knot and knot

The table analyzes the complete spray as a test defined by a single actuation of 85-115% of the spray actuated, target spray weight (100 mg).

Example 5

The following formulations and/or pre-varied degrees of diazepam and its components were prepared. In one embodiment, the formulation is administered in a pre-weight dose to the subject. In its formulation, the preparation is used for promoting the sex and/or using of diazepam

Preparation 1

Preparation 2

Preparation 3

Preparation 4

Preparation 5

Preparation 6

Preparation 7

Preparation 8

Preparation 9

Preparation 10

Preparation 11

Preparation 12

Preparation 13

Preparation 14

Formulation 15

Preparation 16

Preparation 17

Example 6

The following formulations were prepared to further the degree and/or degree of diazepam in the formulations and achieved diazepam for nasal administration. The preparation is diazepam added last time in an actual formula. In the actual formulation, diazepam was excluded until the upper fluid. In its formulation, diazepam is incorporated into the dimer and divided by 10 before its constituents.

Preparation 18

Formulation 18 was analyzed by HPLC for 8.66% diazepam in% wt/wt diazepam preparation.

Preparation 19

Formulation 19 was analyzed by HPLC for 8.70% diazepam in% wt/wt diazepam preparation.

Preparation 20

Formulation 20 was analyzed by HPLC for 8.90% diazepam in% wt/wt diazepam degree formulation.

Preparation 21

Formulation 21 was analyzed by HPLC for 9.68% diazepam in% wt/wt diazepam preparation.

Preparation 22

Formulation 22 was analyzed by HPLC for 9.55% diazepam in% wt/wt diazepam preparation.

Degree of API of diazepam in a dose

Preparation method knot

Based on the agents given above, it is possible to use,performance was the most potent agent of diazepam, and a degree of diazepam of 9.72%. Each of the upper formulations was prepared by partitioning post transcutol hp into the formulations. Except for formulation 20, each formulation component was (from)To) times, and in order of the benzodiazepine

And (4) liquid. In addition to preparation 20, diazepam is added to each preparation, and

the following steps. The method is GMP-based, and does not require use after API entryAPI flushing. After completion, each formulation was analyzed by HPLC to determine the diazepam degree. For formulation 20, the same formulation as formulation 19 was used. The method of preparation 20 was carried out with the inclusion of diazepamMiddle and upper 10min

At a placeAnd diazepam. After treatment, each dose was added. Until a knot is made.

Knot

Formulation 19 and formulation 20, to diazepam degree. However, it is possible to use a single-layer,is a dose of the first preparation. Degree of (c) degree of diazepam in the preparation. Unlike, the extent of diazepam in the formulation is dependent on the extent of diazepamDegree of (1). The maximum diazepam in the above preparation is diazepamDegree of (d), which is 9.68%.

Example 7

Single 20mg dose diazepam nasal spray (DZNS) vs single 20mg dose in subjects who were enrolled in a one-shot study(diazepam straights) pairings and mobility of DZNS.

The research objective is as follows:

single 20mg nasal (IN) dose of DZNS versus single 20mg straight dosePair of AcuDial (diazepam) (BA)

Kinetic (PK) Properties of DZNS at 5mg and 20mg

The totipotency and the specificity of DZNS

The research method comprises the following steps: this is a single-center labeled study. At each dose, one of the following is scheduled:

a single 5mg nasal dose of DZNS, one 2.5mg spray (100. mu.l) per nose

A single 20mg nasal dose of DZNS, one 10mg spray (100. mu.l) per nose or

Direct single 20mg dose of Diastat. 24 of the annual and sexual subjects of the study. 14, minimum divided dose. And the target for: 18-50 years old, general, the result is determined by Electrocardiogram (ECG) and laboratory results, the weight of the future or used method is 88-111kg, or the weight is heavy>11lkg and an index (BMI) of less than or equal to 31 kg/m²And (5) testing the sexual performance.

Test formulations:

5mg nasal dosage formulation

20mg nasal dosage formulation

: one (single dose) in each course of 12 doses.

Marking:

: was performed in this study I. Knot of PK analysis.

Moving: a solution for use in a method for determining the degree of diazepam and aziepam (desdiazepam). At 5101530 and 45 minutes and 11.5246912244896144192 and 240 hours (19 in the course of each dosing) at and after dosing.

Completeness: complete hair appearance (TEAE) laboratory characterization quantification 12ECG nose and hair/individual observation and severity (C-SSRS).

Method of producing a composite material：

Using analysis: all of the groups. Groups studied with one or more doses were used throughout. PK this whole group, its, and degree data are for non-PK number or dose of sexual BA.

The global performance study was used to quantify the AE laboratory characterization of study observations 12ECG nose and hair/individual degree observations and C-SSRS. All will be used for all its manifestations and, except for PK data, it will be used for PK.

Treatment and integrity analysis for each measurement sum time, the following is scaled:

-a quantity: the minimum and maximum number in the (n) flat Standard (SD) are observed.

-a component: on each level of the component, the quantity and score of the study results.

Fruit, and assay-based.

The study was completed and the number and fraction of the study-in-progress doses given in each group. And the basis (annual weight and BMI) by group, using the standard. Gives the results of research and observation, and the same formula

Kinetic analysis

Use (N average SD number [ CV%)]Min and max) for each of diazepam and desdiazepam. Number of PKs from the following by non-means: maximum degree of observation (C)_max) Time of maximum degree (T)_max) From 0 to 24 hours after dose administration, the degree-time plane of upward logarithmic downward method of use (AUC)_0-24) From 0 to the last measured degree, the degree-time surface of the log-up-down method (AUC) is used_last) Push from time 0 to large degree-time

Lower surface (AUC)_inf) The fraction of AUC over the last measured degree (AUC)_ext) The numbers by log degree (λ z), (t 1/2), the apparent scores, (Vz/F), the apparent divisions (CL/F), and (M/P). The PK of (a) is tabulated by group and the minimum maximum sum N in SD is given for the number of PKs and for the geometric mean CV% mean.

PK number C of diazepam in test and control formulations for BA fractions_maxAUC_0-24AUC_lastAnd AUC_infIs performed using an analysis of the use (ANOVA), the next sum, as a component, using the initial data and the log of the data. Using the log-turn data and a single test run,

several (tested) positions (CI) (90%). In contrast, the sum CI for the log-transformed data is presented.

Dosage pass dosage C at 5mgDZNS dosage and 20mgDZNS dosage_maxAUC_0-24And AUC_infResults and by dose of CL/F.

The results observed in the faceted DZNS study were a subgroup analysis of BAs using a single test run, performed with individual BAs after Diastat and without individual BAs after Diastat (this was observed).

Analysis of pleiotomy

The group failed by total fractional time (PT) was by PT passage and by investigational nature. Both the observed peace and average of the dose and quantification are predicted by group sum time. The number and composition of the nose and/or hair/hair pass through the composition. The number and composition of each of the degrees of flatness (in sum) are calculated by group. Results from a lab number 12ECG and the qualitative C-SSRS findings.

And the treatment results:

24, 20 out of the study were completed. The 4 out ones, 2 are not out of the square. 22 individuals of 5mg DZNS and 23 individuals of both 20mg DZNS and 20mg Diastat.

Of the 24, 20 (83%) were sexual and 4 (17%) were sexual. The year is 34.0(6.77) in the plain (SD) and 21-46 in the year. More than a few are (N = 1354%) whose ones are either not (N = 833%) and local (N = 313%). With more than a few western or cents (N = 1458%), non-western or

Minutes (N = 1042%). The BMI of the strain is 26-43 kg/m²(Flat [ SD)]：31.2[3.63])。

And (3) dynamic results:

degree data-Di xiPan (Pan)

After administration of 20mg of Diastat, the dose of DZNS, the individual diazepam BA was lower (<1/10 flat C observed in individuals_maxBA of (d). Studies were performed 5153045 and 60 points after using Diastat, and one was observed in 7 of the 3 low BA individuals at the 5min maximum. Most of the PKs, for PK (whichever is not excluded) and for PK with less than 20mg of low BA after Diastat. The subgroup of PK of individuals with low BA after less than 20mg Diastat was the best group for the 20mg DZNS group and was of importance in this study. After each administration (low BA after no Diastat), diazepam, the flatness appeared 1-1.5 hours after dosing. The flattest (+ SD) degree of 5mg DZNS was 96.3+27.7 ng/mL at 1.00 hours, 20mg DZNS was 350+103 ng/mL at 1.00 hours, and control (Diastat) (low BA after no Diastat) was 352+92.9 ng/mL at 1.50 hours. In this regard, the degree is double-sided, beginning approximately 24-48 hours after dosing. Also, it is up to about 50% of the population that is observedThe 48 hour diazepam concentration was slightly higher than the 24 hour concentration regardless of treatment.

Plasma concentration data-norcistinePan (Pan)

Desmetazepam is often detectable during dosing periods 2 and 3 prior to dosing, and is almost always detectable 240 hours after dosing of each therapeutic dose. This result indicates that the major accumulation between treatments is due to the particularly long half-life of diazepam in this group of individuals. Therefore, to allow comparison between treatments without prior diazepam administration, the proposed results were directed to dosing phase 1. These results indicate that the concentration of desmetazepam is very slowly concentrated over time, with the mean peak plasma concentration occurring 96-144 hours after dosing. The highest mean (+ SD) plasma concentration was 9.9+3.1 ng/mL at 144 hours for 5mg DZNS, 37.3+13.0 ng/mL at 96 hours for 20mg DZNS, and 35.5 + -14.5 ng/mL at 96 hours for 20mg Diastat (excluding individuals with low BA after Diastat administration). The mean plasma desmetazepam concentration-time data curves over 336 hours of dosing phase 1 (including pre-dose samples of dosing phase 2) were similar, excluding individuals with low BA after administration of 20mg of Diastat, indicating that there were no differences in the route of administration in the metabolism of diazepam to desmetazepam.

Non-compartmentalized PK parameters-DiscoPan (Pan)

A summary of non-compartmental PK parameters for diazepam is presented in table 18. Median value T_maxValue similar to average T_maxValues (1.0 hours after both 5mg and 20mg DZNS and 1.25 hours after 20mg Diastat [ excluding individuals with Low BA)])。

The estimated half-life value of diazepam is long and variable according to all treatments. The half-life ranges were 44.5-243 hours (5mg of DZNS), 48.1-221 hours (20mg of DZNS) and 43.8-234 hours (20mg of Diastat counter therapy, excluding individuals with low BA). Although the variation between individuals was quite high (52-57% CV), the variation within individuals appeared to be very low; that is, PK values within an individual are generally consistent across the three treatment groups.

Because of the long diazepam half-life, there is a time to calculate AUC_infThe tail extrapolated considerable AUC. Clearance (CL/F) values were similar in treatment. The Vz/F values are large and comparable in treatment.

Table 18: diazepam: non-compartmental PK parameters summary for PK group (not including individuals with low BA after Diastat administration)

Non-compartmentalized PK parameters-desmethazepam

a is given in units of (h) for AUC^*ng/mL)

The nordiazepam non-compartmental PK parameters can be reliably estimated using only dosing phase 1 results due to the long-term observed half-life and sustained accumulation in each subsequent 2-cycle study. Table 19 gives a summary of the non-compartmentalized PK parameters for desmetazepam for dosing phase 1. C_maxThe results indicate that the maximum concentration of desmetazepam is about one tenth of that of diazepam, regardless of whether treatment is applied. Median value T_maxThe values were 144 hours after 5mg of DZNS, 96 hours after 20mg of DZNS and 120 hours after 20mg of Diastat (excluding individuals with low BA). The half-life evaluation was very long. Extrapolation of a significant percentage of AUC as a result of the long half-life of desmetazepam resulted in a very high AUC_infThe value is obtained.

Table 19: dosing period 1: desepazepam non-compartmental PK parameter summary for PK cohorts (not including individuals with low BA following Diastat administration)

^aN =7 for t1/2 and AUCinf;

^bn =5 for t1/2 and AUCinf;

taken together, the results indicate that there is no difference IN the route of administration for the formation of desmetazepam between IN and rectal administration.

Comparable BA assay

As suggested above (plasma concentration data-diazepam), 3 individuals showed very low plasma diazepam concentrations after administration of 20mg of diazatat, and therefore, in addition to the complete PK population, the relative BAs were sub-analyzed using two single-sided test procedures with individuals with good BAs. Individuals with low BA after not including administration of Diastat were based on C_maxAnd a summary of the distribution of AUC values.

When the analysis included 3 individuals with low BA after administration of Diastat, the ratio of the test formulations, for C_max、AUC_0-24、AUC_lastAnd AUC_infMore than 100% and a CI of 90% of the ratio outside the 80% -125% tolerance interval (accetaneinterval). This result is likely due not only to the effect of the 3 exception on the ratio, but also to the distribution of the data. In contrast, when 3 individuals with low BA were excreted outside the analysis after administration of Diastat, for C_max(85.30, 113.64) and AUC_0-24(80.23, 97.72) 90% of CI was within the 80-125% tolerance interval and for AUC_last(75.44, 94.42) and AUC_inf (75.34, 91.68) is slightly outside it.

Dose proportionality analysis

Due to the long half-life of diazepam observed (which ranges from 44.5 to 243 hours in individuals and treatments), there is some carry-over for diazepam, especially for individuals with a long half-life of diazepam, i.e. those over 80-100 hours. This carry-over is most important when treatment with 20mg of DZNS or 20mg of Diastat is followed by treatment with 5mg of DZNS. Therefore, the data for dose proportionality assessment must be corrected by: the residual diazepam from the previous dose was subtracted from the measured time-varying concentration of each individual using the average terminal rate constant value for that individual.

The results of two single-sided tests show that for C_max、AUC_0-24、AUC_infAnd CL/F, 90% CI all within the standard equivalence interval of 80-125%, indicating that 5mg DZNS treatment exhibited dose proportionality with 20mg DZNS treatment.

Safety results:

in the 5mg DZNS, 20mg DZNS and 20mg Diastat treatment groups, 21 individuals (96%), 23 individuals (100%) and 17 individuals (74%) reported at least one TEAE, respectively, and the same number and percentage of individuals in each group reported at least one treatment-related TEAE. The strength of all TEAEs was moderate or moderate. There were no SAEs and TEAEs that caused discontinuation.

Most TEAEs reflect abnormalities in one of three systemic organ classes: ocular diseases; disorders of the nervous system; or respiratory, thoracic and mediastinal disorders. The most common TEAE was increased tears, approximately the same IN both IN dose groups (82% and 78% of individuals IN 5mg and 20mg DZNS treated groups, respectively) as compared to no individual reporting IN the 20mg Diastat treated group. Such TEAEs usually occur within the immediate or few minutes of dosing, are always modest, and are of short duration (< 3 hours). The second most common TEAE is lethargy. Lethargy appears to be dose related; similar frequencies (52% and 61% incidence, respectively) were reported in the 20mg DZNS and 20mg Diastat treatment groups compared to 23% of the individuals reporting this TEAE in the 5mg DZNS treatment group. Other prevalent TEAEs (runny nose, rhinitis, nasal congestion and nasal discomfort) may reflect local effects or may be dose-related systemic TEAEs (i.e. dizziness, similar frequencies were reported in the 20mg DZNS and 20mg Diastat treatment groups [ 17% and 22%, respectively ]), compared to the 5% formation in the 5mg DZNS treatment group.

No clinically significant observations or changes in other safety parameters were determined in the population of individuals during the course of the study based on physical examination, clinical laboratory assessments, or the results of ECG. No positive C-SSRS was found.

In any of the three treatment groups, there were no significant clinical changes in pulse oximetry, HR, respiratory rate, or body temperature after dosing. Furthermore, there was no significant clinical change IN SBP, DBP or HR following IN dosing with 5mg DZNS or 20mg DZNS. However, after rectal administration of 20mg diastat, SBP and DBP (but not HR) were each reduced by an average of about 15-17mmHg at time points 15 and 30 minutes post dose administration, which returned to the predose value of 1 hour post dose, the next time point evaluated. This pattern was also observed in 3 individuals with low BA after administration of Diastat. These drops in blood pressure were generally symptom-independent after administration of a 20mg dose of Diastat.

For nasal and pharyngeal inflammation/inflammation assessment, nasal signs or symptoms, typically signs of nasal redness, blockage, or runny nose, were most common in the 5mg DZNS-treated group at 0.5 hours post-dose (7 out of 23 individuals [ 32% ]) and 20mg DZNS-treated group at 1 hour post-dose (10 out of 23 individuals [ 48% ]). The majority of nasal diseases and symptoms were resolved by 8 hours post dose (0 individuals reported in the 5mg DZNS-treated group and 3 in 23 individuals reported in the 20mg DZNS-treated group [ 13% ]). These frequencies are similar to or less than the pre-dose percentage. Similarly, the percentage of individuals with signs or symptoms in the nasal cavity 24 hours after dosing was similar to or less than the pre-dose results (1 [ 5% ] in 22 individuals in the 5mg DZNS treated group and 1 [ 4% ] in 23 individuals in the 20mg DZNS treated group). Pharyngeal signs or symptoms are less prevalent; no more than 2 (9%) of 23 individuals in any DZNS treatment group at any time point reported them. Individuals with pharyngeal signaling or symptoms were absent after 24 hours of dosing.

For individual sensitivity observations, in the 5mg DZNS treated group (82-100%), more individuals were sensitive at post-dose time points up to 4 hours post-dose for more than the 20mg DZNS (35-87%) and 20mg Diastat (44-96%) treated groups. The time point for least sensitive individuals after all three treatments was 1 hour after the dose (82%, 35% and 44% of individuals in 3 treatment groups, respectively). At 1 hour post dose, non-sensitive individuals first comatose if they were given a dose of DZNS (18%, 39% and 13% in the 5mg DZNS, 20mg DZNS and 20mg Diastat treated groups, respectively); however, if they were given 20mg of Diastat, the non-sensitive individuals first slept but could wake up (0, 26% and 44% in the 5mg DZNS, 20mg DZNS and 20mg Diastat treatment groups, respectively). Greater than or equal to 75% of all 3 treatment groups were sensitive by 2 hours post dose, except 4 hours post dose (70% sensitive) in the 20mg DZNS treatment group. At 4 hours post-dose, 5%, 22% and 4% of individuals were drowsy in the 5mg DZNS, 20mg DZNS and 20mg Diastat treatment groups, respectively, and 0, 9% and 4% of individuals were asleep but wakeable in the respective treatment groups. All individuals were dose sensitive after 24 hours, and none of the individuals were determined to be asleep but not arousable at any time during the study.

And (4) conclusion:

pharmacokinetics

The results of this study indicated that BA, as evidenced by the rate and extent of absorption of diazepam at DZNS doses from IN20mg, was comparable to 20mg of Diastat administered rectally.

PK of IN diazepam doses of 5mg and 20mg DZNS is proportional to Cmax and AUC.

No differences IN route of administration were observed IN metabolism of diazepam to desmetazem after rectal administration of IN.

Safety feature

As expected, the overall dose and formulation (5mg and 20mg DZNS and 20mg of Diastat) were well adapted to the safety profile.

The safety profile of the test products (5mg and 20mg DZNS) was similar to the reference product (Diastat), except that local, transient and persistent mild nasal/pharyngeal TEAE and other adverse nasal/pharyngeal observations were observed more frequently after administration of DZNS than with Diastat. In addition, systemic TEAEs, such as lethargy and dizziness, and the observation of reduced sensitivity, were more prevalent after administration of two 20mg dose formulations (20mg DZNS and 20mg Diastat) compared to 5mg DZNS.

Example 8

GLP toxicity studies were performed in rabbits with intranasal 2.5% diazepam formulations (below).

2.5% intranasal dosage formulation

Rabbits tolerated intranasal administration of 50 μ L dose of this formulation three times a week for 26 weeks, which delivered approximately 1.25mg of diazepam per dose. This is considered the maximum feasible dose volume and it means that rabbits receive about the same volume/surface area as patients receiving the recommended therapeutic dose. The only effect of chronic dosing is minimal local inflammation at the dosing site in the nasal cavity and sinuses, which resolves when dosing is stopped.

The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein. All publications, patent applications, patents, patent publications, and other references cited herein are incorporated by reference in their entirety for their teachings in connection with sentences and/or paragraphs that are relevant to the reference.

Claims (17)

1. A pharmaceutical composition comprising 2.50% to 10% by weight diazepam or a pharmaceutically acceptable salt thereof, 40.70% to 48.20% by weight diethylene glycol monoethyl ether, 9.50% by weight methyl laurate, 7.60% by weight propylene glycol monocaprylate, 22.70% by weight N-methyl-2-pyrrolidone, 1.90% by weight water and 7.60% by weight ethanol.

2. The pharmaceutical composition of claim 1, comprising 2.50% by weight diazepam or a pharmaceutically acceptable salt thereof, 48.20% by weight diethylene glycol monoethyl ether, 7.60% by weight propylene glycol monocaprylate, 9.50% by weight methyl laurate, 22.70% by weight N-methyl-2-pyrrolidone, 7.60% by weight ethanol and 1.90% by weight water.

3. The pharmaceutical composition of claim 1, comprising 3.75% by weight diazepam or a pharmaceutically acceptable salt thereof, 46.95% by weight diethylene glycol monoethyl ether, 7.60% by weight propylene glycol monocaprylate, 9.50% by weight methyl laurate, 22.70% by weight N-methyl-2-pyrrolidone, 7.60% by weight ethanol and 1.90% by weight water.

4. The pharmaceutical composition of claim 1, comprising 5.00% by weight diazepam or a pharmaceutically acceptable salt thereof, 45.70% by weight diethylene glycol monoethyl ether, 7.60% by weight propylene glycol monocaprylate, 9.50% by weight methyl laurate, 22.70% by weight N-methyl-2-pyrrolidone, 7.60% by weight ethanol and 1.90% by weight water.

5. The pharmaceutical composition of claim 1, comprising 6.25% by weight diazepam or a pharmaceutically acceptable salt thereof, 44.45% by weight diethylene glycol monoethyl ether, 7.60% by weight propylene glycol monocaprylate, 9.50% by weight methyl laurate, 22.70% by weight N-methyl-2-pyrrolidone, 7.60% by weight ethanol and 1.90% by weight water.

6. The pharmaceutical composition of claim 1, comprising 7.50% by weight diazepam or a pharmaceutically acceptable salt thereof, 43.20% by weight diethylene glycol monoethyl ether, 7.60% by weight propylene glycol monocaprylate, 9.50% by weight methyl laurate, 22.70% by weight N-methyl-2-pyrrolidone, 7.60% by weight ethanol and 1.90% by weight water.

7. The pharmaceutical composition of claim 1, comprising 8.75% by weight diazepam or a pharmaceutically acceptable salt thereof, 41.95% by weight diethylene glycol monoethyl ether, 7.60% by weight propylene glycol monocaprylate, 9.50% by weight methyl laurate, 22.70% by weight N-methyl-2-pyrrolidone, 7.60% by weight ethanol and 1.90% by weight water.

8. The pharmaceutical composition of claim 1, comprising 10.00% by weight diazepam or a pharmaceutically acceptable salt thereof, 40.70% by weight diethylene glycol monoethyl ether, 7.60% by weight propylene glycol monocaprylate, 9.50% by weight methyl laurate, 22.70% by weight N-methyl-2-pyrrolidone, 7.60% by weight ethanol and 1.90% by weight water.

9. A pharmaceutical composition comprising 2.50% to 10% by weight diazepam or a pharmaceutically acceptable salt thereof, 40.60% to 48.10% by weight diethylene glycol monoethyl ether, 30.30% to 30.40% by weight caprylocaproyl polyoxylglyceride, 7.22% to 7.30% by weight isopropyl palmitate, 10.80% to 10.83% by weight sorbitan monolaurate 20 and 0.95% to 1.00% by weight water.

10. The pharmaceutical composition of claim 9, comprising 2.50% by weight diazepam or a pharmaceutically acceptable salt thereof, 48.10% by weight diethylene glycol monoethyl ether, 7.30% by weight isopropyl palmitate, 10.80% by weight sorbitan monolaurate 20, 30.30% by weight caprylocaproyl polyoxylglyceride and 1.00% by weight water.

11. The pharmaceutical composition of claim 9, comprising 3.75% by weight diazepam or a pharmaceutically acceptable salt thereof, 46.85% by weight diethylene glycol monoethyl ether, 7.30% by weight isopropyl palmitate, 10.80% by weight sorbitan monolaurate 20, 30.30% by weight caprylocaproyl polyoxylglyceride and 1.00% by weight water.

12. The pharmaceutical composition of claim 9, comprising 5.0% by weight diazepam or a pharmaceutically acceptable salt thereof, 45.60% by weight diethylene glycol monoethyl ether, 7.30% by weight isopropyl palmitate, 10.80% by weight sorbitan monolaurate 20, 30.30% by weight caprylocaproyl polyoxylglyceride and 1.00% by weight water.

13. The pharmaceutical composition of claim 9, comprising 5.0% by weight diazepam or a pharmaceutically acceptable salt thereof, 45.60% by weight diethylene glycol monoethyl ether, 7.22% by weight isopropyl palmitate, 10.83% by weight sorbitan monolaurate 20, 30.40% by weight caprylocaproyl polyoxylglyceride and 0.95% by weight water.

14. The pharmaceutical composition of claim 9, comprising 6.25% by weight diazepam or a pharmaceutically acceptable salt thereof, 44.35% by weight diethylene glycol monoethyl ether, 7.30% by weight isopropyl palmitate, 10.80% by weight sorbitan monolaurate 20, 30.30% by weight caprylocaproyl polyoxylglyceride and 1.00% by weight water.

15. The pharmaceutical composition of claim 9, comprising 7.50% by weight diazepam or a pharmaceutically acceptable salt thereof, 43.10% by weight diethylene glycol monoethyl ether, 7.30% by weight isopropyl palmitate, 10.80% by weight sorbitan monolaurate 20, 30.30% by weight caprylocaproyl polyoxylglyceride and 1.00% by weight water.

16. The pharmaceutical composition of claim 9, comprising 8.75% by weight diazepam or a pharmaceutically acceptable salt thereof, 41.85% by weight diethylene glycol monoethyl ether, 7.30% by weight isopropyl palmitate, 10.80% by weight sorbitan monolaurate 20, 30.30% by weight caprylocaproyl polyoxylglyceride and 1.00% by weight water.

17. The pharmaceutical composition of claim 9, comprising 10.00% by weight diazepam or a pharmaceutically acceptable salt thereof, 40.60% by weight diethylene glycol monoethyl ether, 7.30% by weight isopropyl palmitate, 10.80% by weight sorbitan monolaurate 20, 30.30% by weight caprylocaproyl polyoxylglyceride and 1.00% by weight water.