WO2024180209A1

WO2024180209A1 - Crystalline form of midazolam hydrochloride

Info

Publication number: WO2024180209A1
Application number: PCT/EP2024/055325
Authority: WO
Inventors: Bengt Westrin; Lars-Erik Briggner; Nicolas ROLLET; Justine DE LA PRUNARÈDE
Original assignee: Swipp AB
Current assignee: Swipp AB
Priority date: 2023-03-01
Filing date: 2024-03-01
Publication date: 2024-09-06
Anticipated expiration: 2025-09-01

Abstract

The present invention relates to a novel crystalline form of midazolam hydrochloride as well as uses thereof, for example in oral films for the acute treatment of ongoing seizures and/or for induction of moderate sedation or pre-sedation in a subject.

Description

P5993PC00

CRYSTALLINE FORM OF MIDAZOLAM HYDROCHLORIDE

Technical field

Background

Midazolam is a benzodiazepine drug substance. It is available as injection products for a variety of indications, but also as buccal solutions (typically up to 10 mg midazolam, per pre-determined dose, for example BUCCOLAM® oromucosal solution) for the acute treatment of ongoing seizures, and as oral solutions (typically 2 mg/mL, with recommended dose of up to 20 mg, for example VERSED® oral syrup) for moderate sedation in paediatric patients prior to diagnostic or therapeutic procedures or for pre- re-sedation before induction of anaesthesia. For those two uses of midazolam, i.e. , seizure treatment and sedation, it is clearly advantageous to have products that are easy-to-use and that may improve compliance and the dosing reliability.

The oral film as dosage form is considered easy-to-use and improving compliance and has been proposed for a large number of drug substances, for example amlodipine, buprenorphine, dexamethasone, donepezil, loperamide, naloxone, nicotine, odansetron and many others. Some examples of approved drug products for which there are human pharmacokinetic or clinical data are SUBOXONE® sublingual film (buprenorphine and naloxone) used for the treatment of addiction to opioid products; BELBUCA® buccal film (buprenorphine) used for the treatment of severe pain; and SETOFILM® orodispersible film (odansetron) used for prophylaxis or treatment of nausea and vomiting. These three products also exemplify the three main categories of oral films: sublingual films, buccal films and orodispersible films (ODF), respectively, which differ with regard to the site of administration and the intended predominant route of absorption into systemic circulation. It is generally considered that for a sublingual film, the predominant route of absorption can be both transmucosal (i.e., absorption from the oral cavity) or oral (i.e., absorption from the gastrointestinal tract), for a buccal film it is predominately transmucosal, and for an orodispersible film it is predominately oral. The main advantages with oral films are generally considered to be that they are easy to use, that they do not require water for the administration, that they are especially feasible for certain patient groups (e.g., those with difficulties swallowing tablets, or those that are unconscious when the treatment is given) and in treatment of diseases or conditions where compliance can be an issue. In addition, for oral films for which the predominant absorption route is transmucosal, the so-called first-pass effect is eliminated or reduced.

There are also disadvantages and challenges with oral films. One example is the limitation of the strength, i.e. , the content of the API, due to the minute size of an oral film. Typically, due to that, the strength of an oral film has to be 10 mg or less, although in rare cases it can be higher. This limitation of the strength is especially challenging for films in which the API is intended to be dissolved inside the film (a state which is sometimes also called “solid solution” or “molecular dispersion”). In such films, and especially at concentrations of 15 wt% and higher, the dissolved API may be prone to precipitate inside the film.

In this context, the word precipitation and precipitate refer to either a phase separation within the film or to crystallization, both of which potentially involves the API. The precipitate may wholly or partly consist of the API and may be either amorphous or crystalline or a mix thereof. If crystalline, it can also be referred to as re-crystallization because the API was originally added in crystalline form before dissolved during the manufacturing, and the re-crystallized material may have a different crystalline form than the originally added API.

Precipitation of API inside the film may have an impact on the film’s appearance and dissolution rate, and even on the human bioavailability and clinical efficacy of the product. It may thus be very unbeneficial and must usually be avoided both during manufacturing and storage.

One very obvious approach to avoid such precipitation is to design the product and/or manufacturing process so that the API is not in the dissolved state inside the film, but instead being present there as suspended, solid particles of the same identity and form as those added as API raw material during the preparation. “Same identity” here refers to the same chemical identity, same size and shape and same crystalline form, and means that the API has not undergone any dissolution or other changes during manufacturing or the subsequent storage. For example, if the API is very sparingly soluble in water and water is used as the sole process solvent, it is likely that the API will eventually be present inside the film as suspended, solid particles of the same identity as those added as raw material. It is also likely that the API will then be more physically stable inside the film during storage because dissolution and subsequent recrystallization is less likely to happen. The chemical stability, too, is likely to benefit from if the API is present inside the film as suspended, solid particles instead of being in the dissolved state.

Another challenge is the film manufacturing, which is a less established technology than for example tablet manufacturing.

The development of oral films containing midazolam as the active moiety is a case in which the various considerations mentioned above about solubilities and about the physical state of the API inside the film carry significant relevance. Midazolam is available both as the sparingly soluble base and as the more soluble salts midazolam hydrochloride and midazolam maleate. It can be hypothesized that if the base is used for preparing oral films, there may be challenges related to the in vitro and in vivo dissolution rate for the API from the finished film. If the soluble salts are used, on the other hand, there may be challenges with precipitation involving the dissolved API inside the film.

To overcome the challenge of low solubility and to achieve a high dissolution rate as well as a satisfactory storage stability for oral films containing midazolam, intermediate materials containing midazolam have been developed for subsequent incorporation into the oral films. Jithendra et al. 2015 thus describes a film prepared by first preparing a solid dispersion of midazolam and other excipients (e.g., PEG-4000, poloxamer-188, and hydroxypropyl p-cyclodextrin), then “pulverizing” that material and finally using this pulverized material as a carrier for the active ingredient for solvent casting preparation of a buccal film with hydroxypropyl methylcellulose (HPMC) as film forming polymer. The rationale for this two-staged approach is to improve the solubility/dissolution rate of the API, and “very rapid release” is eventually achieved. The midazolam concentration in the films is not explicitly reported by Jithendra et al. 2015 but it can be deduced that the concentration would vary between approximately 2.3 wt% and approximately 8.3 wt% for a film comprising 10 mg midazolam. Soroushnai et al. 2018 describes another such two-staged approach, with the rationale to incorporate a “high drug dose” despite “midazolam’s high lipophilicity and poor water solubility”. Midazolam hydrochloride is used, with which a midazolam nanosuspension is first prepared, by a high-pressure homogenization technique, using N-trimethyl chitosan, Tween-80 and polaxamer-188 as excipients. Next, the nanosuspension is freeze-dried, and finally this freeze-dried material is used for solvent casting preparation of a “fast-dissolving oral film” with hydroxypropyl methylcellulose or pullulan as film forming polymer. The reported midazolam concentration in the film is 15 wt%.

WO 2017/009446, on the other hand, describes a “bio-adhesive film or wafer” which is prepared in a more conventional way, i.e. , solvent casting preparation without any preceding preparation of any midazolam intermediate material. HPMC is used as a film-forming polymer. The intended films are described as having 0.25-2 mg midazolam strengths or even as low as 0.1 mg, or are described as typically containing 0.5-20 mg midazolam per gram of film, which corresponds to 0.05-2 wt% of midazolam in the film. However, that concentration range is quite low and WO 2017/009446 does not disclose how solubility and drug load challenges can be overcome.

CN1830447A describes a film containing midazolam maleate, and for which the filmforming polymer is either PVA or HPMC, and the plasticizer is either PEG-400 or glycerol. It is described that the dissolution rate is 7 times higher than a tablet and that all components dissolve within 30 seconds.

One limitation when using intermediate active materials, as did Jithendra et al. 2015 and Soroushnai et al. 2018, is that high concentrations of the API inside the film cannot be achieved because the intermediate material also contains substantial amounts of other excipients which takes up space in the finished film. One limitation when using midazolam base is its low solubility and the corresponding risk for a very low dissolution rate in vitro and in vivo for API from the finished film. One limitation when using the water-soluble salts midazolam hydrochloride or midazolam maleate is that they will be present inside the film in their dissolved state, and thus - unless the drug load is very low - will be prone to precipitation during storage, as explained above. WO 2022/151732 A1 describes a preparation method for a new crystal form of midazolam hydrochloride, which is named crystal form F, and uses thereof. Crystal form F is proposed to be useful for preparing pharmaceutical products, although the dosage form oral film is not mentioned.

CN 111320632 A describes two new crystal forms of midazolam hydrochloride, which are named crystal form A and crystal form B. These crystal forms are proposed to be useful for preparing pharmaceutical products. Oral administration is mentioned as one of several administration routes, but the dosage form oral film is not mentioned.

There is thus a need for the development of an oral film containing 10 mg midazolam or more, yet having an area and a thickness that are feasible for oral films which means that the concentration of midazolam inside the film can become very high, e.g., 30 wt% or more, and that - despite this high concentration - said midazolam is chemically and physically stable which is achieved by a predominantly suspended, solid state of midazolam inside the film which is not prone to re-crystallization into other crystalline forms or prone to other types of precipitation.

Summary

The present inventors have surprisingly identified a new crystalline form of midazolam hydrochloride and have developed an oral film with high concentration of said new form and demonstrated that the new form is physically stable inside the oral film.

This new form of midazolam hydrochloride is herein referred to as “new form of midazolam hydrochloride”, “new crystalline form of midazolam hydrochloride”, or just “new form”. It may also be referred to as the “API” or as “a crystalline form”, depending on the context.

In one aspect, the present invention relates to a crystalline form of midazolam hydrochloride that is characterized by having an X-ray powder diffraction pattern comprising specific peaks (2theta) at 11.0°±0.2°, 11.4°±0.2°, 12.9°±0.2°, 16.2°±0.2°, 16.5°±0.2°, 23.1°±0.2°, 24.8°±0.2°, 25.0°±0.2°, 28.6°±0.2° and 30.2°±0.2°. In one aspect, the present invention relates to a crystalline form of midazolam hydrochloride for which the X-ray powder diffraction pattern is basically as shown in Figure 4 (upper diffractogram).

In one aspect, the present invention relates to a unit dosage form in the form of an oral film comprising the new crystalline form of midazolam hydrochloride and one or more film-forming polymers.

In one aspect, the present invention relates to a process for producing a unit dosage as defined herein, wherein the process comprises the sequential steps of: a) mixing an API comprising the crystalline form of midazolam hydrochloride and one or more film-forming polymers in a process solvent to provide a wet mix; b) casting the wet mix obtained in step a) to provide a wet film; c) drying the wet film of b) to obtain a dry film; and d) cutting the dry film of c) into a unit dosage form.

In one aspect, the present invention relates to a process for producing the new crystalline form of midazolam hydrochloride, wherein the process comprises the sequential steps of: a) subjecting a powder of a crystalline form of midazolam hydrochloride that is characterized by having an X-ray powder diffraction pattern comprising specific peaks (2theta) at 9.6°±0.2°, 13.4°±0.2°, 13.9°±0.2°, 17.6°±0.2°, 19.6°±0.2°, 21.2°±0.2°, 27.5°±0.2°, and 28.4°±0.2° to relative humidities of 81% or more, such as 85% or more, such as 90% or more, for at least 1 hour, such as at least 2 hours, such as at least 24 hours, but not more than 7 days to form the crystalline form of midazolam hydrochloride according to claim 1 or 2, and b) packaging the crystalline form of midazolam hydrochloride formed in a) into containers, that are impermeable to air and humidity, at relative humidities of 70% or more, such as 81% or more, such as 90% or more.

In one aspect, the present invention relates to the new crystalline form of midazolam hydrochloride as defined herein for use as a medicament, for example for use in the acute treatment of seizures in a human subject or for use in the induction of moderate sedation or pre-sedation in a human subject. In one aspect, the present invention relates to a unit dosage form as defined herein for use in the acute treatment of seizures in a human subject.

In one aspect, the present invention relates to a unit dosage form as defined herein for use in the induction of moderate sedation or pre-sedation in a human subject.

Description of Drawings

Figure 1. Gravimetric Vapour Sorption (GVS) study of midazolam base. Stepwise curve represents the applied relative humidity (right y-axis) and the continuous curve represents the corresponding mass change (left y-axis).

Figure 2. Gravimetric Vapour Sorption (GVS) study of midazolam hydrochloride.

Stepwise curve represents the applied relative humidity (right y-axis) and the continuous curve represents the corresponding mass change (left y-axis). Initially, the humidity interaction resembles that of the base (Figure 1) but at 90 % RH there is a significant change.

Figure 3. Gravimetric Vapour Sorption (GVS) isotherm plot for midazolam hydrochloride. Lower curve with diamonds (which continues to 90 % RH, where a diamond is superimposed on a square from upper curve) represents the sorption process. Lower curve with squares represents the desorption process if the sorption process stops at 80% RH. Upper curve with squares represents the desorption process if the sorption process continues to 90 % RH. This humidity interaction indicates a structural change of midazolam hydrochloride.

Figure 4. XRPD diffractograms of midazolam hydrochloride before and after exposure to 94 % relative humidity. Lower diffractogram represents midazolam hydrochloride before, and upper diffractogram represents midazolam hydrochloride after exposure to 94 % RH during 14 days. The upper diffractogram is believed to represent a new form of midazolam hydrochloride and shows a distinct different crystalline form compared with the commercially available midazolam hydrochloride (lower diffractogram). (The vertical shifts between the diffractograms are made for clarity and do not represent actual differences in intensity. The diffractograms were not recorded at the same occasion). Figure 5. XRPD diffractogram of midazolam base before and after aqueous slurry assessment. The lower diffractogram represents before slurry assessment, and the upper diffractogram represents after slurry assessment. The upper diffractogram shows a distinct different crystalline form compared with the commercially available form in the lower diffractogram. (The vertical shifts between the diffractograms are made for clarity and do not represent actual differences in intensity. The diffractograms were not recorded at the same occasion).

Figure 6. XRPD diffractogram of midazolam hydrochloride before and after aqueous slurry assessment. The lower diffractogram represents before slurry assessment, and the upper diffractogram represents after slurry assessment. The upper curve shows a distinct different crystalline form compared with the commercially available material in the lower diffractogram. (The vertical shifts between the diffractograms are made for clarity and do not represent actual differences in intensity. The diffractograms were not recorded at the same occasion).

Figure 7. Overlay XRPD diffractograms of midazolam hydrochloride after exposure to 94 % relative humidity and after aqueous slurry assessment, respectively. Midazolam hydrochloride after exposure to 94 % RH is shown in the upper diffractogram (which is the same as in Figure 4 but with other amplification). Midazolam hydrochloride after slurry assessment is shown in the lower diffractogram (which is the same as in Figure 6 but with other amplification). It can be seen that the two diffractograms represents the same crystalline form. (The vertical shifts between the diffractograms are made for clarity and do not represent actual differences in intensity. The diffractograms were not recorded at the same occasion).

Figure 8. XRPD diffractograms of midazolam oral film after storage in ambient room temperature and 65 % relative humidity. The first diffractogram from the bottom is a reference diffractogram for the new form of midazolam hydrochloride (i.e., same diffractogram as in Figure 4 but with other amplification). The second diffractogram from bottom is the oral film after 18 days storage; the third from bottom is after 4 weeks; the fourth from bottom is after 10 weeks; the one at the top is after 16 weeks. The results indicate that there is no change in the amount or type of crystalline material inside the film over time and that said crystalline material is the new form of midazolam hydrochloride. (The vertical shifts between the diffractograms are made for clarity and do not represent actual differences in intensity. The diffractograms were not recorded at the same occasion).

Detailed description

Unit dosage form

In one aspect, the present invention relates to a unit dosage form in the form of an oral film comprising an active pharmaceutical ingredient (API) and a film-forming polymer. The terms “active pharmaceutical ingredient”, “API” and “drug substance” are used herein with the same meaning. If it specifically refers to the raw material being added during manufacturing, that is specified or is obvious from the context. The term "unit dosage form" refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity (dose) of API calculated to produce the desired therapeutic effect. The term “oral film” as used herein collectively refers to sublingual, buccal and orodispersible films (ODF), as well as any other films placed into the oral cavity aiming at systemic or local effects.

In one embodiment, the unit dosage form is an oral film for buccal administration. The term “buccal administration” as used herein refers to administration to the space in the oral cavity that is outside the teeth (when the jaws are closed) such as for example the inside of the cheek or under the upper lips. An oral film intended for buccal administration is usually referred to as a “buccal film”. Following buccal administration of an API by an oral film, the desired, predominant absorption route into systemic circulation is typically transmucosal which may also be called buccal, or buccal- transmucosal to avoid misunderstandings.

In one embodiment, the unit dosage form is an oral film for oral administration, i.e. , applied on a site that is inside the teeth (when the jaws are closed), yet not being sublingual. For example, onto the tongue. An oral film intended for such oral administration is usually referred to as an “orodispersible film” or “ODF”. Following such oral administration of an API by an oral film, the desired, predominant absorption route into systemic circulation is oral (i.e., oral-gastrointestinal).

In one embodiment, the unit dosage form is an oral film for sublingual administration. An oral film intended for sublingual administration is usually referred to as a “sublingual film”. Following sublingual administration of an API by an oral film, the desired, predominant absorption route into systemic circulation is either transmucosal or oral (i.e. , oral-gastrointestinal) or both.

In one embodiment, the unit dosage form is a mucoadhesive oral film.

In one embodiment, the API is present in the form of solid, suspended particles inside the film that has the same identity as the added API raw material. “Same identity” here refers to the same chemical identity, same size and shape and same crystalline form, and means that the API has not undergone any dissolution or other changes during manufacturing or the subsequent storage.

In one embodiment, that added API raw material is the new form of midazolam hydrochloride described below in section “Active Pharmaceutical Agent (API)”.

Dissolution rate

The terms “dissolution” and “dissolution rate” used herein have the same meaning as, for example, for a tablet, i.e., the rate with which the API becomes available in an aqueous solution surrounding the dosage form. The terms dissolution and dissolution rate apply both to the in vitro situation, for which there are several, standardized and widely accepted assessment methods, and to the in vivo situation, for which the methods are not as standardized or widely accepted. In this application, it is usually specified in the text whether “dissolution” and “dissolution rate” refer to the in vitro or the in vivo situation. If not specified, it is either evident from the context or it refers to both situations.

However, as oral films are designed to dissolve in the mouth (albeit with different desired film dissolving rates), the terms “dissolution” and “dissolution rate” may also refer to the film as such, rather than to the API. Typically, whether subject to in vivo or in vitro dissolution, an oral film typically starts to dissolve rather quickly after coming into contact with the aqueous surroundings, then continues to dissolve and maybe also starting to disintegrate into pieces, and finally becoming completely dissolved.

It should thus be understood that dissolution and dissolution rate of the API in an oral film is not conceptually the same as the dissolution and dissolution rate of the film as such. These two dissolution processes are different on the molecular level, and the dissolution rate of the API can be both faster and slower than the dissolution rate of the film, but can also be the same. If not otherwise specified in this document, the terms “dissolution” and “dissolution rate” in the present application means those of an API.

Typically, in vitro and in vivo dissolution rates correlates, at least semi-quantitatively.

The in vitro dissolution rate may be measured using the United States Pharmacopeia (USP) Dissolution Apparatus 2 - Paddle, with sinkers, 1000 mL phosphate buffer with pH 6.8, or other medium as specified, at 37°C ± 0.5°C, and stirring speed 75 rpm±3 rpm. That method is referred to as “USP Dissolution Apparatus 2” in the various embodiments below, as well as in Items. Other media used within in vitro dissolution testing in general are, for example, non-buffered water, phosphate buffer with other pH than pH 6.8, or other kind of buffers at various pH.

In one embodiment, the unit dosage form of the present invention has a moderately high in vitro dissolution rate. The term “moderately high in vitro dissolution rate” as used herein means that at least 85% of the API has been dissolved within 10 minutes in the USP Dissolution Apparatus 2 - Paddle, but no more than 97.5 % has been dissolved within 5 minutes.

In one embodiment, the film has an instantaneous dissolution rate, which is herein defined as that more than 97.5% of the API has been dissolved within 5 minutes, when studied by the USP Dissolution Apparatus 2 - Paddle, such as more than 98%, such as more than 99%, such as 100%.

Active Pharmaceutical Agent (API)

Midazolam belongs to a group consisting of benzodiazepines and benzodiazepine-like substances. The term "benzodiazepine" as used herein refers generically to a class of drugs substances that act as central nervous system depressants with sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnesic actions through the positive modulation of the GABA-A receptor complex. The term “benzodiazepine-like substances” (also known as nonbenzodiazepines or Z-drugs) refers to a class of compounds which pharmacodynamics are almost identical to benzodiazepines and therefore exhibit similar benefits, side-effects, and risks. However, benzodiazepine-like substances differ from benzodiazepines on a molecular level.

Examples of benzodiazepines and benzodiazepine-like substances are midazolam, diazepam, alprazolam, brotizolam, cinolazepam, clizolam, clobazam, clonazepam, clonazolam, clorazepate, cloxazolam, diclazepam, estazolam, flubromezepine, flunitrazepam, flurazepam, flutoprazepam, kvazepam, lorazepam, loprazolam, lormetazolam, metizolam, nitrazepam, oxazepam, phenazepam, temazolam, triazolam and pharmaceutically acceptable salts thereof.

In one embodiment, the API is midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4/7- imidazo[1,5-a][1,4]benzodiazepine, CAS number 59467-70-8) or a pharmaceutically acceptable salt thereof such as midazolam hydrochloride or midazolam maleate.

When the term “midazolam” is used without further specification in the present application, it may - unless specified otherwise - collectively refer to different forms such as midazolam base, midazolam hydrochloride, midazolam maleate, as well as hydrates or other different crystalline forms of these.

In one embodiment, the API is a new crystalline form of midazolam hydrochloride or midazolam maleate. In one embodiment, the API is a hydrate of midazolam hydrochloride or midazolam maleate.

In one embodiment, the API is a new crystalline form that has better physical stability than the presently known forms. In one embodiment, the new crystalline form has better thermodynamic stability than the presently known forms.

In one embodiment, the API is a new crystalline form of midazolam hydrochloride which - when studied with the XRPD method presented in Example 2 - is characterized by major XRPD diffractogram peaks (2theta) at, for example, 11.0°±0.2°, 11.4°±0.2°, 12.9°±0.2°, 16.2°±0.2°, 16.5°±0.2°, 23.1°±0.2°, 24.8°±0.2°, 25.0°±0.2°, 28.6°±0.2° and 30.2°±0.2°. XRPD is also referred to herein as “X-ray powder diffraction”, and the method used and referred to is presented in Example 2. In Example 4, it is described how that method is applied also to oral film samples.

If said method is applied to the commercially available form of midazolam hydrochloride, on the other hand, that form is characterized by major peaks (2theta) at, for example, 9.6°±0.2°, 13.4°±0.2°, 13.9°±0.2°, 17.6°±0.2°, 19.6°±0.2°, 21.2°±0.2°, 27.5°±0.2°, and 28.4°±0.2°, and by an absence of major peaks at the ten positions listed above for the new form. The form characterized by these eight peaks is herein referred to as “the commercially available form of midazolam hydrochloride”, “the commercially available midazolam hydrochloride”. However, it is acknowledged that there may be other crystalline forms of midazolam hydrochloride that are, have been, or will be, commercially available.

In one embodiment, the new crystalline form of midazolam hydrochloride, after being formulated as an oral film comprising a film-forming polymer and when studied with the XRPD method presented in Example 4, is characterized by major XRPD diffractogram peaks (2theta) at, for example, 11.4°±0.2°, 12.9°±0.2°, 16.2°±0.2°, 16.5°±0.2°, 23.1°±0.2°, 24.8°±0.2°, 25.0°±0.2°, 28.6°±0.2° and 30.2°±0.2°, which is essentially the same as for the new crystalline form of midazolam hydrochloride before being formulated as an oral film.

In one embodiment, the new crystalline form of midazolam hydrochloride, after being formulated as an oral film comprising a HPMC as film-forming polymer and when studied with the XRPD method presented in Example 4, is characterized by major XRPD diffractogram peaks (2theta) at, for example, 11.4°±0.2°, 12.9°±0.2°, 16.2°±0.2°, 16.5°±0.2°, 23.1°±0.2°, 24.8°±0.2°, 25.0°±0.2°, 28.6°±0.2° and 30.2°±0.2°, which is essentially the same as for the new crystalline form of midazolam hydrochloride before being formulated as an oral film.

The exact positions of XRPD peaks, and their width (sharpness) will be influence by the thickness of the studied sample, e.g., a studied film. In one embodiment, the new crystalline form of midazolam hydrochloride, after being formulated as an oral film comprising a film-forming polymer and when studied with the XRPD method presented in Example 4, is characterized by major XRPD diffractogram peaks (2theta) at, for example, 11.4°±0.5°, 12.9°±0.5°, 16.2°±0.5°, 16.5°±0.5°, 23.1°±0.5°, 24.8°±0.5°, 25.0°±0.5°, 28.6°±0.5° and 30.2°±0.5°.

In one embodiment, the new form of midazolam hydrochloride has been prepared by subjecting midazolam hydrochloride powder to relative humidities of 81% or more, such as 85% or more, such as 90% or more, for a sufficient period of time. In one embodiment, that period of time is 14 days or shorter, such as 7 days or shorter, such as 2 days.

In one embodiment, the new form of midazolam hydrochloride has been prepared by dissolving midazolam hydrochloride powder in water, and then collecting the precipitate being formed and drying it gently for a sufficient period of time at relative humidities of 30% or more, such as 50% or more, such as 60% or more, such as 70%. In one embodiment, that period of time is 14 days or shorter, such as 7 days or shorter, such as 2 days.

In one embodiment, the new crystalline form of midazolam hydrochloride is characterized by a mass increase of about 0.3 wt% when subjected to a relative humidity of 90% or more, with the procedures described in the Gravimetric Vapour Sorption (GVS) study presented in Example 1.

In one embodiment, the unit dosage form comprises at least 2.5 mg of API, such as at least 5 mg, such as at least 10 mg of API. In one embodiment, the unit dosage form comprises no more than 20 mg of API, such as no more than 15 mg, such as no more than 10 mg of API. In one embodiment, the unit dosage form comprises 2.5 to 20 mg of API, such as 5 to 15 mg, such about 10 mg, such as about 7.5 mg, such as about 5 mg of API. In one embodiment, the unit dosage form comprises about 10 mg midazolam. In one embodiment, the unit dosage form comprises about 7.5 mg midazolam. In one embodiment, the unit dosage form comprises about 5 mg midazolam.

In one embodiment, the concentration of API in the film is at least 10 wt%, such as at least 15 wt%, such as at least 20 wt%, such as at least 25 wt%, such as at least 30 wt%, such as at least 40 wt%. In one embodiment, the concentration of API in the film is no more than 80 wt%, such as no more than 70 wt%, such as no more than 60 wt%, such as no more than 50 wt%, such as no more than 40 wt%. In one embodiment, the concentration of API in the film is in the range of 10 to 60 wt%, such as in the range of 20 to 50 wt%, such as in the range of 30 to 40 wt%.

In one embodiment, in order to achieve a strength of 10 mg midazolam of the unit dosage form, yet maintaining a feasible film thickness allowing for a moderately high film dissolution rate (such as for example 70 to 110 pm thickness) and a convenient size (e.g., 1.5 x 2.5 cm), the concentration of midazolam in the dry film must be about 25 to 40 wt%.

The term “strength” is used herein to describe the content of the active pharmaceutical ingredient in the unit dosage form and is typically expressed in milligram (mg) or microgram (pg). As an oral film is a unit dose dosage form, said strength is typically identical to the dose to be administered to the patient, although sometimes more than one unit dosage can be administered and sometimes just a part of one unit dosage is administered. For a film with dimensions of 15 x 15 mm, and a coat weight of 100 g/m², a strength of 10 mg means that the concentration of API is about 27 wt% inside the film. The term “coat weight” will be explained below.

When the API is a salt of a base, or a hydrate of that salt, or a new polymorph or other new crystalline form of the API, the information about dose or strength usually refers to the amount of the free base. For example, a dose or strength of “10 mg midazolam” refers to 10 mg of midazolam of the free base, even if said midazolam was added as a salt during the preparation of the unit dosage form and even if it remains as the salt form in the unit dosage form after completed preparation.

To avoid a very slow dissolution rate for an oral film, it may be favourable if the API is dissolved in the oral film, albeit this is often associated with inferior chemical or physical stability of the API inside the film.

However, to achieve a satisfactory chemical and physical stability of an API inside an oral film, it may sometimes be more favourable if the API is suspended in the film, i.e., not dissolved, and that the suspended API particles have not undergone any changes in chemical composition, shape, size or crystalline form compared with the API raw material used for the preparation. That is referred to herein as having the “same identity” as the API raw material used for the preparation of the film.

In one embodiment, the API exists predominately in such suspended and unchanged state inside the film. In one embodiment, at least 80 wt%, such as at least 90 wt%, such as at least 95 wt%, such as at least 98 wt% of the total amount of API exists in such suspended, unchanged state in the film. In one embodiment, the concentration of API in the film is in the range of 15 to 35 wt% and at least 80 wt%, such as at least 90 wt%, such as at least 95 wt%, such as at least 98 wt% of that API exists in the suspended, unchanged state in the film.

To even further improve the physical stability of an oral film in which the API is suspended, it may sometimes be favourable that as much as possible of the API has a crystalline form that represents the most stable form of the API (i.e., most stable in that conditions, in the film). For example, a stable hydrate may be more favourable than an anhydrate in an oral film.

In one embodiment, the oral film of the present invention contains a crystalline form of midazolam hydrochloride that is more stable than the commercially available form of midazolam hydrochloride. In one embodiment, the oral film of the present invention contains a crystalline form of midazolam maleate that is more stable than the commercially available form of midazolam maleate.

In one embodiment, the oral film of the present invention contains a hydrate of midazolam hydrochloride that is more stable than the commercially available form of midazolam hydrochloride. In one embodiment, the oral film of the present invention contains a hydrate of midazolam maleate that is more stable than the commercially available form of midazolam maleate.

In one embodiment, the oral film contains the stable, new crystalline form of midazolam hydrochloride that is identified and characterized in Examples 1 - 3 of the present application. In one embodiment, at least 50 wt%, such as at least 60 wt%, such as at least 70 wt%, such as at least 80 wt%, such as at least 90 wt%, such as at least 95 wt%, such as at least 98 wt% of the API in the film is that new crystalline form of midazolam hydrochloride. In one embodiment, the concentration of API in the film is in the range of 15 to 35 wt% and at least 50 wt%, such as at least 60 wt%, such as at least 70 wt%, such as at least 80 wt%, such as at least 90 wt%, such as at least 95 wt%, such as at least 98 wt% of the API in the film is that new crystalline form of midazolam hydrochloride.

In one embodiment, the oral film contains two fractions of midazolam hydrochloride: one fraction is the stable, new crystalline form of midazolam hydrochloride that is identified and characterized in Examples 1 - 3 of the present application, and the other fraction is midazolam hydrochloride that is in a dissolved state inside the film and which thus does not have any “crystalline form”. In one embodiment, at least 15 wt%, such as at least 30 wt%, such as at least 60 wt%, such as at least 90 wt%, such as at least 95 wt% of the total amount of API in the film is the new crystalline form of midazolam hydrochloride. In one embodiment, no more than 60 wt%, such as no more than 30 wt%, such as no more than 15 wt% of the API in the film is in the dissolved state.

In one embodiment, the oral film has a moderately high dissolution rate. In one embodiment, the oral film has an instantaneous dissolution.

In one embodiment, the unit dosage form comprises two or more active pharmaceutical ingredients. In one embodiment, the total concentration or amount or API in a unit dosage form comprising two or more active pharmaceutical ingredients is equal to any of the levels presented above.

Film-forming polymers

The unit dosage form of the present invention comprises one or more film-forming polymers.

In one embodiment, the film-forming polymer is selected from the group consisting of acrylates, alginates, carrageenan, cellulose derivatives, chitosan, collagen, dendritic polymers, gelatin, gum, hyaluronic acid, maltodextrin, pectin, polyethylene glycol, polyethylene oxide, polylactic acid and derivatives or copolymers thereof, polysaccharides, pullulan, polyvinylpyrrolidone, scleroglucan, starch, starch derivatives, and polyvinyl alcohol.

In one embodiment, the film-forming polymer is selected from the group consisting of: i. HPMC 2528; ii. HPC; iii. methacrylic acid-methyl acrylate copolymers; and iv. polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

In one embodiment, the film-forming polymer is HPMC (hypromellose) which is a cellulose derivative. The term “HPMC” as used herein refers to hydroxypropyl methylcellulose, with CAS number 9004-65-3 and E number E464. HPMC is a partly O- methylated and O-(2-hydroxypropylated) cellulose and is available in several grades that differ in the substitution type as well as in molecular weight and viscosity. HPMC types may thus be given a four digit number describing the substitution type. The first two digits refer to the percentage (w/w) of methoxy-groups, while the second two digits refer to the percentage of hydroxypropoxy-groups.

The structure of the HPMC, the substitution type, and the molecular weight give rise to viscoelastic properties. As a supplement to being categorized by the substitution type, the different HPMC grades can therefore also be categorized based on their apparent viscosity. The common way to describe that is by the apparent viscosity (mPas) of a 2 wt% aqueous solution. In one embodiment, the film-forming polymer is a HPMC grade with a viscosity of at least 1 mPas, such as about 3 mPas, such as about 4 to 5 mPas, such as about 5 mPas, such as at least 10 mPas, such as about 15 mPas, such as about 50 mPas. In one embodiment, the HPMC grade has a viscosity of no more than 100 000 mPas, such as no more than 15 000 mPas, such as no more than 5 000 mPas, such as no more than 1 000 mPas, such as no more than 500 mPas, such as no more than 100 mPas.

As used herein, “HPMC Pharmacoat 603” refers to Hypromellose 2910, 3 mPas. As used herein, “HPMC Metolose 60SH-50” refers to Hypromellose 2910, 50 mPas, It is however understood that the numbers describing the substitution type are not exact, but represents a typical interval. For example, substitution type 2910 may comprise for example 28-30 % methoxy content and 7-12 % hydroxypropoxy content.

In one embodiment, the film-forming polymer is an HPMC with a substitution type of about 22-28 % for methoxy and about 25-31 % for hydroxypropoxy, such as 23-27% or 24-26% for methoxy and such 26-30 % or 27-29% for hydroxypropoxy. In one embodiment, the film-forming polymer is HPMC 2528. In one embodiment, that HPMC has a viscosity of 50-300 mPas, such as 100-200 mPas or 130-170 mPas. In one embodiment, the film-forming polymer is HPMC 2528 with a viscosity of 150 mPas. In one embodiment, the film-forming polymer is HPMC with the trade name Affinisol HPMC HME 15 LV. In one embodiment, the film-forming polymer is HPMC with the trade name Affinisol HPMC HME 100LV.

In one embodiment, the film-forming polymer is an HPMC with a substitution type of about 22-28 % for methoxy, such as 23-27% or 24-26% for methoxy, such as 25% for methoxy.

In one embodiment, the film-forming polymer is an HPMC with a substitution type of about 25-31% for hydroxypropoxy, such as 26-30%, such as or 27-29%, such as 28 for hydroxypropoxy.

In one embodiment, the film forming-polymer is a HPMC which does not have a substitution type of about 16 to 20% for methoxy and about 26 to 30 % for hydroxypropoxy, such as not about 18% for methoxy and about 28 % for hydroxypropoxy, such as not having the substitution type 1828. In one embodiment, the film-forming polymer is not a HPMC with 16-20 % methoxy content and 26-30 % hydroxypropoxy content, such as not having the substitution type 1828.

In one embodiment, the film-forming polymer is not HPMC 2910. In one embodiment, the HPMC is of not of the substitution type 2910.

In one embodiment, the film-forming polymer is HPC which is a cellulose derivative. The term “HPC” as used herein refers to hydroxypropyl cellulose, with CAS number 9004-64-2 and E number E463. HPC is available in several grades that differ in the substitution type as well as in molecular weight and viscosity.

In one embodiment, the film-forming polymer is HPC with the trade name Klucel. In one embodiment, the film-forming polymer is HPC with the trade name Klucel EF. In one embodiment, the film-forming polymer is HPC with the trade name Klucel ELF. In one embodiment, the film-forming polymer is selected from acrylates, acrylic polymers and co-polymers thereof; polyacrylic acids, polymethacrylates and copolymers thereof, and polyvinyl alcohol-polyethylene glycol graft-copolymers (for example Kollicoat, such as Kollicoat I R, which is a polymer consisting essentially of 75% polyvinyl alcohol units and 25% polyethylene glycol units).

In one embodiment, the film-forming polymer is a methacrylic acid-methyl acrylate copolymer. In one embodiment, the film-forming polymer is selected from a range of a methacrylic acid-methyl acrylate copolymers with the trade name Eudragit. In one embodiment, the film-forming polymer is selected from Eudragit E 100, Eudragit RS 100, Eudragt RL 100 and Eudragit RL PO.

In one embodiment, the film-forming polymer is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In one embodiment, that polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is a product with the trade name Soluplus.

In one embodiment, the film-forming polymer is a hypromellose acetate succinate. In one embodiment, that a hypromellose acetate succinate is a product with the trade name AQOAT AS-LG. In one embodiment, the film-forming polymer is not hypromellose acetate succinate.

In one embodiment, the film-forming polymer is gum selected from the group consisting of acacia gum, guar gum, tragacanth gum, xanthan gum and diutan gum.

In one embodiment, the film-forming polymer is alginate selected from the group consisting of sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propylene glycol alginate, alginic acid and mixtures thereof. In one embodiment, the alginate is sodium alginate, potassium alginate or ammonium alginate, or a mixture thereof. In one embodiment, one or more of these alginate salts comprises from 25 to 35 wt% by weight of a-D-mannuronate and/or from 65 to 75 wt% by weight of a-L-guluronate, and a mean molecular weight of from 30,000 g/mol to 90,000 g/mol. In one embodiment, the unit dosage form comprises at least 35 wt% film-forming polymer, such as at least 45 wt%, such as at least 50 wt%, such as at least 55 wt%, such as at least 60 wt%, such as at least 65 wt% film-forming polymer.

In one embodiment, the unit dosage form comprises no more than 80 wt% film-forming polymer, such as no more than 70 wt% such as no more than 65 wt%, such as no more than 60 wt%, such as no more than 55 wt%, such as no more than 50 wt%, such as no more than 45 wt% film-forming polymer.

In one embodiment, the unit dosage form comprises 35 to 70 wt% film-forming polymer, such as 45 to 70 wt%, such as 50 to 60 wt%, such as 55 to 65 wt% filmforming polymer. In one embodiment, the unit dosage form comprises 35 to 70 wt% HPMC, such as 45 to 70 wt%, such as 50 to 65 wt%, such as 55 to 60 wt% HPMC.

In one embodiment, the film-forming polymer has been identified and selected by a screening procedure with the following elements:

1) A number of non-toxic, volatile solvents are screened for their ability to dissolve the API.

2) Those solvents that are not dissolving the API are selected. The criterium used for “not dissolving the API” is: in an APksolvent mix with 5:95 weight ratio, not more than 5 wt% of the added API should be dissolved after stirring for 2 hours at room temperature

3) A number of film-forming polymers are then screened for their ability to be dissolved in the solvent(s) selected in step 2. The criterium used for “being dissolved in the solvent(s)” is: in an polymersolvent mix with 15:85 ratio, not more than 5 wt% of the added polymer should remain non-dissolved after stirring for 2 hours at room temperature.

4) Finally, selecting the one or more polymer that are thus being dissolved in step 3) by the solvent(s) selected in step 2).

In one embodiment, the API referred to above in this section Film-forming polymers is the stable, new crystalline form of midazolam hydrochloride that is identified and characterized in Examples 1 - 3 of the present application. Plasticizer

The mechanical properties of the film must allow for a continuous coating process and converting process, the latter of which can be rather high-speed and requires both strength and plasticity of the film. One way to achieve a satisfactory plasticity is to add one or more plasticizers. Plasticizers might be defined as small low molecular weight, non-volatile compounds added to polymers to reduce brittleness, impart flexibility, and enhance toughness for films. In general, the optimal type and concentration of plasticizer(s) depends on a range of factors, such as the type and concentration of polymer(s). The type and concentration of API, as well as its state (i.e., dissolved or suspended inside the film), may also have an impact when selecting optimal type and concentration of plasticizer(s), at least if the substance constitutes a significant fraction of the finished film e.g., more than 10 wt%.

In one embodiment, the unit dosage form of the present invention comprises an API, a film-forming polymer and one or more plasticizer(s).

In one embodiment, the plasticizer is selected from the group consisting of glycerol; glycerol monacetate; citric acid and esters thereof such as triethyl citrate (TEC); diethylene glycol; ethylene glycol; fatty acid esters; PEG, such as PEG 400, PEG 600 or PEG 4000; polyethylene- propylene glycols; propylene glycol; phthalic acid; polyalkylene oxides; sorbitol, triacetin and xylitol. In one embodiment, the plasticizer is glycerol. In one embodiment, the plasticizer is TEC. In one embodiment, the plasticizer is poloxamer 407. Poloxamer 407 is a triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol (PEG). The approximate lengths of the two PEG blocks is 101 repeat units, while the approximate length of the propylene glycol block is 56 repeat units. Thus, poloxamer 407 is a polypropylene glycol-polyethylene glycol copolymer. Poloxamer 407 is also known as Pluronic F-127, Synperonic PE/F 127 and Kolliphor P 407. In one embodiment, the plasticizer is Kollicoat IR. Kollicoat IR is a polymer comprising about 75% polyvinyl alcohol units and about 25% polyethylene glycol units, and optionally about 0.3% colloidal anhydrous silica. Thus, Kollicoat IR is a polyvinyl alcohol-polyethylene glycol copolymer. In one embodiment, the plasticizer is selected from the group consisting of glycerol; glycerol monacetate; citric acid and esters thereof such as triethyl citrate (TEC); diethylene glycol; ethylene glycol; fatty acid esters; PEG, such as PEG 400, PEG 600 or PEG 4000; polyethylene- propylene glycols; propylene glycol; phthalic acid; polyalkylene oxides; sorbitol, triacetin and xylitol.

Some film-forming polymer contains molecular elements that will contribute to the plasticity of the final film and may sometimes render it unnecessary to add a separate plasticizer. One such polymer is Kollicoat IR, in which it is the polyethylene glycol units that are believed to provide the plasticity.

In one embodiment, the unit dosage form does not comprise any plasticizer.

In one embodiment, the unit dosage form does not comprise any plasticizer and the film-forming polymer is Kollicoat IR.

In one embodiment, the unit dosage form does not comprise any plasticizer and the film-forming polymer is HPMC 2528. In one embodiment, the unit dosage form does not comprise any plasticizer and the film-forming polymer is a HPMC with the trade name Affinisol HPMC HME 15 LV. In one embodiment, the unit dosage form does not comprise any plasticizer and the film-forming polymer is a HPMC with the trade name Affinisol HPMC HME 100 LV. In one embodiment, the unit dosage form does not comprise any plasticizer and the film-forming polymer is a HPMC with 23-27 % methoxy content and 26-30 % hydroxypropoxy content.

In one embodiment, the unit dosage form does not comprise any plasticizer. In one embodiment, the unit dosage form does not comprise any plasticizer and the filmforming polymer is HPMC 1828. In one embodiment, the unit dosage form does not comprise any plasticizer and the film-forming polymer is a HPMC with 16-20 % methoxy content and 26-30 % hydroxypropoxy content.

In one embodiment, the unit dosage form comprises 3 wt% plasticizer. In one embodiment, the unit dosage form comprises more than 3 wt% but less than 5 wt% plasticizer. In one embodiment, the unit dosage form comprises at least 3 wt% plasticizer, such as at least 5 wt%, such as at least 10 wt%, such as at least 30 wt% plasticizer. In one embodiment, the unit dosage form comprises no more than 30 wt% plasticizer, such as no more than 20 wt%, such as no more than 15 wt%, such as no more than 10 wt% plasticizer. In one embodiment, the unit dosage form comprises 3 to 35 wt% plasticizer, such as 4 to 10 wt%, such as about 5 wt% plasticizer.

In one embodiment, the unit dosage form comprises a combination of two plasticizers, for which the total concentration is equal to any of the levels presented above. In one embodiment, said two plasticizers are selected from the group consisting of glycerol, TEC, poloxamer 407 and Kollicoat I R, such as glycerol and TEC, or glycerol and poloxamer 407, or glycerol and Kollicoat IR, or TEC and poloxamer 407, or TEC and Kollicoat IR, or poloxamer 407 and Kollicoat IR.

In one embodiment, the API referred to above in this section Plasticizer is the stable, new crystalline form of midazolam hydrochloride that is identified and characterized in Examples 1 - 3 of the present application.

Additives

In one embodiment, the unit dosage form further comprises one or more additives, for example a colorants, such as a pigment, a taste masking agent, and/or flavouring agents.

In one embodiment, the unit dosage form comprises an API, one or more film-forming polymers, one or more flavouring agents and a pigment but no other additives or excipients. In one embodiment, the unit dosage form comprises an API, one or more film-forming polymers, a pigment but no other additives or excipients.

In one embodiment, the pigment is selected from the group consisting of yellow iron oxide, red iron oxide and black iron oxide.

In one embodiment, the flavour(s) is such that it mitigates the sensation of a bitter emanating from the API added to the film.

In one embodiment, the unit dosage form comprises at least 0.2 wt% pigment, such as at least 0.5 wt%, such as at least 1 wt% pigment. In one embodiment, the unit dosage form comprises no more than 10 wt% pigment, such as no more than 5 wt%, such as no more than 2 wt%, such as no more than 1 wt% pigment. In one embodiment, the unit dosage form comprises 0.5 to 5 wt% pigment, such as about 1 wt% pigment. In one embodiment, the unit dosage form comprises at least 1 wt% flavour(s), such as at least 2 wt%, such as at least 5 wt%. In one embodiment, the unit dosage form comprises no more than 20 wt% flavour(s), such as no more than 10 wt% flavour(s).

In one embodiment, the API referred to above in this section Additives is the stable, new crystalline form of midazolam hydrochloride that is identified and characterized in Examples 1 - 3 of the present application.

Total composition

In one embodiment, the unit dosage form comprises 15 to 45 wt% API and 35 to 80 wt% film-forming polymer, such as 25 to 40 wt% API and 45 to 70 wt% film-forming polymer.

In one embodiment, the unit dosage form comprises 15 to 45 wt% API, 35 to 80 wt% film-forming polymer and 3 to 35 wt% plasticizer.

In one embodiment, the unit dosage form comprises 15 to 45 wt% API, 35 to 80 wt% HPMC and 3 to 15 wt% glycerol. In one embodiment, the unit dosage form comprises 30 to 45 wt% API, 50 to 60 wt% HPMC and 3 to 8 wt% glycerol. In one embodiment, the unit dosage form comprises about 31 to 35 wt% API, 60 to 64 wt% HPMC and 3 to 7 wt% glycerol. In one embodiment, the unit dosage form comprises about 33 wt% API, 61 wt% HPMC and 5 wt% glycerol. In one embodiment, the unit dosage form comprises about 33 wt% API, about 63 wt% HPMC and 4 wt% glycerol.

In one embodiment, the unit dosage form comprises 33 wt% API or a pharmaceutically acceptable salt thereof, 61 wt% HPMC, 5 wt% glycerol, 1 wt% yellow iron oxide.

In one embodiment, the unit dosage form comprises 33 wt% API or a pharmaceutically acceptable salt thereof, 66 wt% HPMC and 1 wt% yellow iron oxide.

In one embodiment, the unit dosage form comprises 33-40 wt% API or a pharmaceutically acceptable salt thereof, 59-66 wt% HPMC and 1 wt% yellow iron oxide. The amounts of the various components of the unit dosage form or the film are sometimes given as wt%. In such cases, the sum of the wt% of the components does not exceed 100 wt%.

In one embodiment, the API referred to above in this section Total composition is the stable, new crystalline form of midazolam hydrochloride that is identified and characterized in Examples 1 - 3 of the present application.

Size

One key feature for oral films is that they are thin, for example less than 250 pm, in order to be mechanically flexible and also to avoid a very slow dissolution rate.

Usually, the thinner the film, the faster the dissolution, for one and the same API and composition. For many film-forming polymers, including most variants of HPMC, a thickness of about 40 pm or less is likely to result in a very fast or even instantaneous dissolution, in vitro as well as in vivo. Likewise, for many film-forming polymers, including most variants of HPMC, a thickness of 250 pm or more is likely to result in a very slow dissolution, e.g., that less than 85% of the API has been dissolved within 10 minutes in the USP Dissolution Apparatus 2 - Paddle. It should however be understood that the dissolution rate is also largely dependent on the film-forming polymer as well as on other aspects of the composition (e.g., the use of disintegration agents) and hence there is no universal relation between thickness and dissolution rate.

Another key feature is that films should have a feasible area that fits into the oral cavity surfaces, e.g., <5 cm², yet large enough for convenient handling by the patient or the person helping the patient, e.g., >2 cm².

In one embodiment, the oral film according to this invention is 50 to 150 pm thick, such as 60 to 120 pm thick, such as 70 to 110 pm thick, such as 80 to 100 pm thick.

In one embodiment, the oral film according to this invention is 40 to 100 pm thick, such as 50 to 90 pm thick, such as 60 to 80 pm thick. The thickness of an oral film is often measured and defined by coat weight, rather than being measured as an actual thickness and presented in pm. Coat weight is the weight of the dry film per unit area and is usually presented as g/m². If the density of the dry film is 1 g/cm³, the numerical values of thickness in pm will equal that of coat weight in g/m².

In one embodiment, the unit dosage form is rectangular and has a dimension of X x Y x Z, wherein X is in the range of 0.5 to 5 cm; Y is in the range of 0.5 to 5 cm; and Z is in the range of 15 to 150 pm.

In one embodiment, X is at least 0.5 cm, such as at least 1 cm, such as at least 1.5 cm, such as at least 2 cm. In one embodiment, X is no more than 5 cm, such as no more than 4.5 cm, such as no more than 4 cm, such as no more than 3.5 cm, such as no more than 3 cm. In one embodiment, X is in the range of 0.5 to 5 cm, such as in the range of 1 to 3 cm, for example in the range of 1 to 2 cm.

In one embodiment, Y is at least 0.5 cm, such as at least 1 cm, such as at least 1.5 cm, such as at least 2 cm. In one embodiment, Y is no more than 5 cm, such as no more than 4.5 cm, such as no more than 4 cm, such as no more than 3.5 cm, such as no more than 3 cm. In one embodiment, Y is in the range of 0.5 to 5 cm, such as in the range of 1 to 3 cm, for example in the range of 2 to 3 cm.

In one embodiment, Z is at least 5 pm, such as at least 25 pm, such as at least 50 pm, such as at least 75 pm, such as at least 100 pm. In one embodiment, Z is no more than 1 mm, such as no more than 750 pm, such as no more than 500 pm, such as no more than 250 pm, such as no more than 125 pm. In one embodiment, Z is in the range of 5 pm to 750 pm, such as in the range of 30 to 150 pm, such as 50 to 120 pm, such as 70 to 110 pm.

In one embodiment, X is in the range of 0.5 to 5 cm; Y is on the range of 0.5 to 5 cm; and Z is in the range of 30 pm to 150 pm. In one embodiment, X is in the range of 1 to 3 cm; Y is on the range of 1 to 3 cm; and Z is in the range of 50 pm to 150 pm.

In one embodiment, the unit dosage form is rectangular and has a dimension of about 1.5 cm x 2.5 cm x 90 pm. In one embodiment, the unit dosage form is rectangular and has an area, i.e. , X x Y, of 1 to 6 cm², such as 1 .5 to 5 cm², such as 3 to 4.5 cm², such as 3.5 to 4 cm².

In one embodiment has a coat weight of 50 to 150 g/m², such as 75 to 125 g/m², such as 80 to 110 g/m², such as about 90 g/m².

In one embodiment, the unit dosage form is rectangular and has an area of 1 to 6 cm², such as 1.5 to 5 cm², such as 3 to 4.5 cm², such as 3.5 to 4 cm², and is 30 to 150 pm thick, such as 50 to 120 pm thick, such as 70 to 110 pm thick.

In one embodiment, the unit dosage form is rectangular and has an area, i.e., X x Y, of 1 to 6 cm², such as 1 .5 to 5 cm², such as 3 to 4.5 cm², such as 3.5 to 4 cm², and a coat weight of 50 to 150 g/m², such as 75 to 125 g/m², such as 80 to 110 g/m², such as about 90 g/m².

In one embodiment, the unit dosage form is rectangular and can be described with any of the X x Y x z descriptions above but has fully rounded corners i.e., the ends are semicircular. Such form is also referred to as a stadium form of a rectangle.

In one embodiment, the unit dosage form is rectangular and can be described with any of the X x Y x z descriptions above but all corners are rounded yet not forming the stadium form of a rectangle.

In one embodiment, the unit dosage form is oval and has an area of 2 to 5 cm², such as 2.5 to 4.5 cm².

In one embodiment, the unit dosage form is circular and has an area of 2 to 5 cm², such as 2.5 to 4.5 cm². In one embodiment, the unit dosage form is circular and has a radius of 8 mm to 13 mm.

In one embodiment, the unit dosage form consists of a single layer. In one embodiment, the API referred to above in this section Size is the stable, new crystalline form of midazolam hydrochloride that is identified and characterized in Examples 1 - 3 of the present application.

Manufacturing process

There are several principles for preparing and manufacturing oral films, for example as described in US 11,173,114 B1 and by Kathpalia and Gupte 2013. The most common principle is probably the solvent casting method which can be described as: a) Mixing the API and one or more film-forming polymers in one or more volatile solvents to provide a wet mix. Either the API is added first and obtaining a homogeneous mix before the polymer(s) is added, or the other way around, or both being added at the same time. Other excipients are also added within this step. Each one of the API and these other excipients can be either dissolved or suspended in the resulting wet mix, but the film-forming polymer(s) should in most cases be dissolved. The wet mix is typically made in a batchwise manner, and hence the wet mix batch size will be determining the batch size of the oral film manufacturing. b) Casting the wet mix obtained in step a) to provide a wet film. The wet mix is cast onto an inert release liner, with a typical thickness within 100-1000 micrometer. At lab scale, this can be made in a batchwise manner, using a sheet of the release liner. In pilot and large scale however, this is usually made in a continuous manner, with the release liner moving away from the point of coating. c) Drying said wet film to obtain the final, dry film. The wet film is dried until an essentially solvent-free, dry film is obtained, with typical thickness within 20-200 micrometer, said thickness being a function of (i) the thickness of the wet film and (ii) the dry content of the wet mix. In pilot and large scale, this step is made in a continuous manner, with the wet film on release liner typically moving through some kind of heated drying tunnel and eventually, after drying, being rolled up onto one or more mother rolls. These mother rolls can optionally be cut into daughter rolls with less width of the dry film. d) Converting said film into unit dosages by cutting it into feasible sizes and packaging these into primary containers. The dry film is rolled off its roll and cut into individual film units which are packaged into air- and water-tight pouches which become the primary containers of the unit dosage form. This step d) is often referred to as the ’’converting step”. Step d) is not “solvent casting method” perse, but it is a necessary subsequent step.

As for excipients other than the film-forming polymer in step a), several excipients can be imagined: plasticizers (e.g., glycerol), fillers, colorants, flavours, taste maskers, disintegration agents, dissolution agents, solubilizing agents, etc.

Water is the most commonly used solvent, but non-aqueous solvents, e.g., ethanol, are sometimes used as co-solvents with the aim of aiding to dissolving the API in the wet mix and keep it dissolved. Such non-aqueous solvents, e.g., ethanol, can also be used as the sole solvent, or as co-solvents together with one or more other non-aqueous solvents. This is further explained below.

There are several variants of the process described above, for example, the order in which ingredients are added in step a), or that multilayer films are made, or that the API is added in the form of a solid, particulate intermediate product that has already been mixed and pre-processed with other excipients (e.g., into a solid solution material that is pulverized).

The difference in step a) between dissolved API and suspended API is essential, because it will determine the final state of the API inside the finished dry film and thereby determine critical attributes such as dissolution rates and stability. As used herein, the term “suspended API” refers to an API in a solid, particulate state inside the film. Preferably, in that case, the identity of the API in the final film is the same as for the API starting material used for the manufacturing. As used herein, the term “dissolved API” refers to an API that is not in a solid, particulate state inside the film but instead dissolved which can also be referred to as “solid solution” or “molecular dispersion. Preferably, in that case, the API should stay in that dissolved state i.e. , not precipitating into solid particles inside the film matrix during manufacturing or storage, because such new, precipitated particles will not have the same identity as the original API starting material used for the manufacturing. However, there are exceptions to that. For example, that a maturing step is added between steps c) and d), during which the temperature and humidity conditions are such that a hitherto dissolved API is deliberately re-crystallized and thus obtain the suspended state inside the film. Or, as another possibility, that such maturing step aims at letting an API, that is in the suspended state from start, deliberately recrystallize into a different crystal form than the original form. The reasons for using such maturing process step could be for example to achieve a better physical stability and/or to achieve a better dissolution rate.

In one embodiment, a non-aqueous solvent is used.

In one embodiment, there are no other ingredients than the API, a film-forming polymer, a pigment and a flavour. In one embodiment, the film-forming polymer is HPMC.

In one embodiment, the polymer is added before the API and a homogeneous wet mix with that polymer in dissolved state is achieved before the API is added. In one embodiment, the API is added before the polymer and a homogeneous wet mix with the API in suspended state is made before the polymer is added.

In one embodiment, the wet film thickness is 300 to 800 pm, such as 400 to 700 pm, such as 550 to 650 pm.

In one embodiment, the drying is performed at 40 to 120 °C, such as 50 to 110°C, such as 60 to 100 °C. In one embodiment, the drying is performed by using several temperature zones, for example, first moving the film in a zone with 80 °C, the moving it into another zone with 95 °C, etc.

In one embodiment, the drying is performed at temperatures and relative humidities that are such that the new form of midazolam is preserved during and after the manufacturing.

In one embodiment, the drying is performed at temperatures no more than 60 °C, such as no more than 50 °C such as no more than 40 °C. In one embodiment, the drying is performed with air at relative humidity of 30% or more, such as 50% or more, such as 60% or more, such as 70%.

In one embodiment, the intermediate layer is an inert, strong, flexible polymer material such as PET. In one aspect, the present invention relates to an oral film or a unit dosage form obtainable by the process as described herein.

In one embodiment, the API referred to above in this section Manufacturing process is the stable, new crystalline form of midazolam hydrochloride that is identified and characterized in Examples 1 - 3 of the present application.

Process solvents

The choice of solvent in the manufacturing process is essential. The solvent should be volatile, it should preferably be non-toxic and non-hazardous, and it should dissolve the film-forming polymer(s). Virtually all film-forming polymers used for making oral films are water-soluble, because the eventual fate of the film is to be dissolved in the aqueous environment in the oral cavity in vivo.

Obviously, when taking these criteria into consideration, water is the most common process solvent being used in solvent casting preparation of oral films.

Many API molecules are sparingly soluble in water, and if water is the sole process solvent when oral films are made with such APIs, the added API may not dissolve in the wet mix, and the eventual dry film will then contain the API wholly or predominately in the suspended state. This may be the intention of those designing the film and does not have to be detrimental to the in vivo absorption and clinical effect of the oral film.

However, in some cases, it is instead desired that the eventual dry film should contain the API in dissolved form, for example with the aim to achieve a satisfactory in vivo dissolution rate and subsequent absorption and clinical effect. In that case, the API must be dissolved in the wet mix, and stay dissolved throughout the drying step. Using water as the sole solvent may not be sufficient for that, and the approach can then be to either use one or more non-aqueous solvents as cosolvents alongside the water, or to replace the water with one or more non-aqueous solvents.

Hence, in the literature there are three main approaches with regard to the process solvent: o Using water as solvent, with the intention that the API will be suspended in the wet mix and in the film. o Using water as solvent, with the intention that the API will be dissolved in the wet mix and in the film. o Using non-aqueous co-solvents/solvents, with the intention that the API will dissolved in the wet mix and in the film.

Alternative or supplementary ways to keep the API in the dissolved state may also be employed, such as pH adjustment or the use of solubilizing agents such as surfactants or cyclodextrin.

In addition, the inventors behind the present invention have conceived a new principle for selecting solvent, which can be applied if the intention is to keep a water-soluble API in the suspended state: o Using non-aqueous co-solvents or solvents that do not dissolve the API but which does dissolve the film-forming polymer.

Below, non-aqueous solvents and non-aqueous co-solvents are sometimes collectively referred to as “solvents”.

Such other solvents have to be volatile and should preferably be non-toxic because there may be residual amounts in the finished product. They should preferably also be non-hazardous for use in a manufacturing facility, although whether a solvent is hazardous or not depends on the process equipment and facility. The term volatile herein, when applied to non-aqueous solvents, means a solvent that has a boiling point below 100±5°C at normal atmospheric pressure, a flash point below room temperature and a vapor pressure above 1.5kPa, either when being the sole solvent or being a cosolvent in a mix together with one or more other solvents.

Examples of volatile, non-aqueous, non-toxic solvents with potential use in the solvent casting method described above are acetic acid; acetone; acetonitrile; 1 -butanol; 2- butanol; butyl acetate ; dimethyl sulfoxide (DMSO); N, N-dimethyl-acetamide (DMA); N, N-dimethyl-formamide (DMF); 1,4-dioxane; d-limonene; ethanol; ethyl acetate; formic acid; isobutyl acetate ; isopropanol; isopropyl acetate ; methanol; methyl acetate ; methyl ethyl ketone; methylene chloride; 3-methyl-1 -butanol; 2-methyl-1 -propanol; 1- methyl-2-pyrrolidone; 1 -pentanol; 1 -propanol ; 2-propanol; propyl acetate ; tetra hydrofuran (THF); and triethylamine.

The choice of solvents, when using the solvent casting method for the intention to have the API in the dissolved state inside the film, will mainly depend on the API. For most API molecules, there are public information about which solvents that are feasible, although there is rarely information of an API’s solubility in each and all of the above listed solvents. It should also be noted that the solvent must also allow the film-forming polymer to dissolve in the wet mix.

In one embodiment of the present invention, the API is not in the dissolved state inside the film, but in a suspended state. One reason for not wanting the API to be in the dissolved state inside the film, but instead being in suspended state, is to achieve a better physical and/or chemical stability of the film product.

In one embodiment of the present invention, the API is readily soluble in water and intended to be suspended inside the film. In one embodiment, a non-aqueous solvent is used for that purpose which is able to dissolve the film-forming polymer but not the API.

In one embodiment, the solvent has been identified and selected by a screening procedure with the following elements:

3) A number of film-forming polymers are screened for their ability to be dissolved in the solvent(s) selected in step 2. The criterium used for “being dissolved in the solvent(s)” is: in an polymersolvent mix with 15:85 ratio, not more than 5 wt% of the added polymer should remain non-dissolved after stirring for 2 hours at room temperature

4) Finally, selecting the one or more solvent selected in step 2) that dissolves one or more of the selected polymers in step 3). In one embodiment, the one or more solvent used belong to the group consisting of acetone, 1-butanol, 2-butanol, butyl acetate, ethyl acetate, isobutyl acetate, isopropyl acetate, methyl acetate, methyl ethyl ketone, 2-methyl-1-propanol, 1-pentanol, 1- propanol, 2-propanol, propyl acetate and triethylamine.

In one embodiment, the one or more solvent used belong to the group consisting of acetone, ethyl acetate, isobutyl acetate, methyl acetate, 1-pentanol and 2-propanol. In one embodiment, the one or more solvent used belong to the group consisting of acetone, ethyl acetate, isobutyl acetate and methyl acetate.

In one preferred embodiment, the solvent used is ethyl acetate.

In one embodiment, the solvent used is ethyl acetate, the API is the new form of midazolam hydrochloride, and the manufacturing process used is described by step a)- d) in the section Manufacturing process above.

In one embodiment, the solvent used is ethyl acetate, the API is the new form of midazolam hydrochloride, and the amount of residual ethyl acetate is not less than 1 000 ppm (parts per million), such as not less than 5 000 ppm, such that not less than 10 000 ppm, such as less not than 25 000 ppm.

In one embodiment, the API referred to above in this section Process solvents is the stable, new crystalline form of midazolam hydrochloride that is identified and characterized in Examples 1 - 3 of the present application.

Biological activity and medical use

In one aspect, the present invention relates to a unit dosage form as described herein for use as a medicament.

In one aspect, the present invention relates to a unit dosage form as described herein for use in the acute treatment of seizures in a subject. In one embodiment, the seizures are caused by epilepsy or another disease or condition that may cause seizures.

In one embodiment, the subject is suffering from epilepsy or another disease or condition that may cause seizures. In one embodiment, the epilepsy is generalised epilepsy or partial epilepsy.

In one embodiment, the disease or condition that may cause seizures is selected from the group consisting of fever caused by malaria, fever of other causes, poisoning, tetanus, brain tumours, Lennox-Gastaut syndrome, tuberous sclerosis complex and Dravet syndrome.

In one embodiment, the seizures are selected from the group consisting of cluster seizures, seizure convulsions, convulsions, spasms, prolonged acute convulsive seizures, stereotypic episodes of frequent seizure activity that are distinct from a patient’s usual seizure pattern, status epilepticus and convulsive refractory status epilepticus.

In one embodiment, the seizures are ongoing, acute seizures.

In one embodiment, the unit dosage form used for such treatment of various seizures is an oral film which is buccally applied. Such films are often referred to as “buccal films”.

In one aspect, the present invention relates to a unit dosage form as described herein for use in moderate sedation before diagnostic, therapeutic or surgical procedures or pre-sedation before anaesthesia. In one embodiment, the diagnostic, therapeutic or surgical procedures include but it limited to these kinds of procedures within odontology.

In one aspect, the present invention relates to use of a unit dosage form as described herein in moderate sedation before diagnostic, therapeutic or surgical procedures or pre-sedation before anaesthesia.

In one embodiment, the unit dosage form used for such moderate or pre-sedation is an oral film which is applied onto the tongue. Such films are often referred to as orodispersible films or “ODF”. In one embodiment, the unit dosage form used for such moderate or pre-sedation is an oral film that is sublingually applied. Such films are often referred to as “sublingual films”.

In one embodiment, the unit dosage form used for such moderate or pre-sedation is an oral film that is buccally applied. Such films are often referred to as “buccal films”.

In one embodiment, the subject is a mammal, such as a human. In one embodiment, the subject is a dog, a horse or a cat.

In one aspect, the present invention relates to a method of treating seizures in a subject, said method comprising administering the unit dosage form as described herein.

In one aspect, the present invention relates to the use of the unit dosage form as described herein in the manufacture of a medicament for use in the acute treatment of seizures in a subject.

Items

1. A crystalline form of midazolam hydrochloride that is characterized by having an X-ray powder diffraction pattern comprising specific peaks (2theta) at 11.0°±0.2°, 11.4°±0.2°, 12.9°±0.2°, 16.2°±0.2°, 16.5°±0.2°, 23.1°±0.2°, 24.8°±0.2°, 25.0°±0.2°, 28.6°±0.2° and 30.2°±0.2°.

2. A crystalline form of midazolam hydrochloride that is characterized by having an X-ray powder diffraction pattern comprising specific peaks (2theta) at 11.0°±0.2°, 11.4°±0.2°, 12.9°±0.2°, 16.2°±0.2°, 16.5°±0.2°, 23.1°±0.2°, 24.8°±0.2°, 25.0°±0.2°, 28.6°±0.2° and 30.2°±0.2°, but not comprising specific peaks (2theta) at 16.9°±0.2° or 26.9°±0.2°,

3. A crystalline form of midazolam hydrochloride that is characterized by a mass increase, compared with the commercially available form, of about 0.3 wt% at a relative humidity of 90%. The crystalline form of midazolam hydrochloride according to any one of Item 1 to 3, wherein the crystalline form has an improved thermodynamical stability compared with a commercially available crystalline form of midazolam hydrochloride that is characterized by having an X-ray powder diffraction pattern comprising specific peaks (2theta) at 9.6°±0.2°, 13.4°±0.2°, 13.9°±0.2°, 17.6°±0.2°, 19.6°±0.2°, 21.2°±0.2°, 27.5°±0.2°, and 28.4°±0.2°. A process for producing a crystalline form of midazolam hydrochloride, wherein the process comprises the sequential steps of: a) subjecting a powder of the commercially available form of midazolam hydrochloride to relative humidities of 81% or more, such as 85% or more, such as 90% or more, for a sufficient period of time for the crystalline form of midazolam hydrochloride to be formed, and b) packaging the resulting material into containers, that are impermeable to air and humidity, at relative humidities of 70% or more, such as 81% or more, such as 90% or more. The process according to item 5, wherein the period of time in step a) is at least 1 hour, such as at least 2 hours, such as at least 24 hours, but not more than 7 days. A process for producing a crystalline form of midazolam hydrochloride, wherein the process comprises the sequential steps of: a) dissolving midazolam hydrochloride in water, b) after a sufficient period of time for the crystalline form of midazolam hydrochloride to precipitate, collecting the precipitate being formed, c) gently drying the precipitate formed during a) to b) for a sufficient period of time at relative humidities of 30% or more, such as 50% or more, such as 60% or more, such as 70% or more, such as 81% or more, such as 90% or more, and d) packaging the resulting material into containers, that are impermeable to air and humidity. 8. The process according to item 7, wherein the period of time in step b) is at least

30 minutes, such as at least 1 hour, such as at least 6 hours, but no more than 2 days.

9. The process according to any one of items 7 or 8, wherein the period of time in step c) is at least 1 hour, such as at least 6 hours, such as at least 1 days, such as at least 1 week, but no more than 2 weeks, and is made at a temperature not more than 100°C, such as not more than 75°C, such as not more than 50°C.

10. A unit dosage form in the form of an oral film comprising the crystalline form of midazolam hydrochloride according to any one of items 1 to 4, and one or more film-forming polymers.

11. A unit dosage form in the form of an oral film comprising the crystalline form of midazolam hydrochloride that has been manufactured according to any one of items 5 to 9, and one or more film-forming polymers.

12. The unit dosage form according to any one of items 10 or 11 , which comprises a crystalline form of midazolam hydrochloride that is characterized by having an X-ray powder diffraction pattern comprising specific peaks (2theta) at 11.4°±0.2°, 12.9°±0.2°, 16.2°±0.2°, 16.5°±0.2°, 23.1°±0.2°, 24.8°±0.2°, 25.0°±0.2°, 28.6°±0.2° and 30.2°±0.2.

13. The unit dosage form according to any one of items 10 to 12, wherein the total concentration of midazolam in the film is in the range of 10 to 50 wt%, and wherein the unit dosage form comprises the crystalline form of midazolam hydrochloride in both in a solid, suspended state inside the film, and in a dissolved state inside the film.

14. The unit dosage form according to item 13, wherein at least 5 %, such as at least 10 %, such as at least 25 %, such as at least 50 % of the total amount of midazolam hydrochloride in the film is present as the crystalline form of midazolam hydrochloride. 15. The unit dosage form according to any one of items 13 or 14, wherein no more than 95 %, such as no more than 90 %, such as no more than 75 %, such as no more than 50 % of the total amount of midazolam hydrochloride in the film is present in the dissolved state.

16. The unit dosage form according to any one of items 10 to 15, wherein the unit dosage form comprises at least 2.5 mg, such as at least 5 mg, such as at least 10 mg of midazolam (defined as the base).

17. The unit dosage form according to any one of items 10 to 16, wherein the unit dosage form comprises no more than 20 mg, such as no more than 15 mg, such as no more than 10 mg of midazolam (defined as the base).

18. The unit dosage form according to any one of items 10 to 17, wherein the unit dosage form comprises 2.5 to 20 mg, such as 5 to 15 mg, such about 10 mg, such as about 7.5 mg, such as about 5 mg of midazolam (defined as the base).

19. The unit dosage form according to any one of items 10 to 18, wherein the unit dosage form comprises about 10 mg midazolam (defined as the base).

20. The unit dosage form according to any one of items 10 to 18, wherein the unit dosage form comprises about 7.5 mg midazolam (defined as the base).

21. The unit dosage form according to any one of items 10 to 18, wherein the unit dosage form comprises about 5 mg midazolam (defined as the base).

22. The unit dosage form according to any one of items 10 to 18, wherein the unit dosage form comprises about 2.5 mg midazolam (defined as the base).

23. The unit dosage form according to any one of items 10 to 22, wherein the concentration of the new form of midazolam hydrochloride inside the film is at least 2.5 wt%, such as at least 5 wt%, such as at least 15 wt%, such as at least 25 wt%, such as at least 50 wt%. The unit dosage form according to any one of items 10 to 23, wherein the concentration of the new form of midazolam hydrochloride inside the film is no more than 98 wt%, such as no more than 90 wt%, such as no more than 75 wt%, such as no more than 50 wt%. The unit dosage form according to any one of items 10 to 24, wherein the total concentration of midazolam hydrochloride in the film is in the range of 10 to 50 wt%. The unit dosage form according to any one of items 10 to 25, wherein the crystalline form of midazolam hydrochloride is present in the form of crystalline particles inside the film. The unit dosage form according to any one of items 10 to 26, wherein the crystalline form of midazolam hydrochloride is suspended inside the film of the unit dosage form The unit dosage form according to any one of items 10 to 27, wherein the filmforming polymer is soluble in ethyl acetate. The unit dosage form according to any one items 10 to 28, wherein the filmforming polymer is selected from the group consisting of: a) HPMC 2528; b) HPC; c) methacrylic acid-methyl acrylate copolymers; d) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The unit dosage form according to any one of items 10 to 28, wherein the filmforming polymer is selected from the group consisting of acrylates, alginates, carrageenan, cellulose derivatives, chitosan, collagen, dendritic polymers, gelatine, gum, hyaluronic acid, maltodextrin, pectin, polyethylene glycol, polyethylene oxide, polylactic acid and derivatives or copolymers thereof, polysaccharides, pullulan, polyvinylpyrrolidone, scleroglucan, starch, starch derivatives, and polyvinyl alcohol. 31. The unit dosage form according to according to any one of items 10 to 28, wherein the film-forming polymer is hypromellose (HPMC).

32. The unit dosage form according to according to item 31 , wherein the filmforming polymer is a HPMC with a viscosity of at least 1 mPas, such as about 3 mPas, such as about 4 to 5 mPas, such as about 5 mPas, such as at least 10 mPas, such as about 15 mPas, such as about 50 mPas.

33. The unit dosage form according to any one of items 31 or 32, wherein the filmforming polymer is a HPMC with a viscosity of no more than 100 000 mPas, such as no more than 15 000 mPas, such as no more than 5 000 mPas, such as no more than 1 000 mPas, such as no more than 500 mPas, such as no more than 100 mPas.

34. The unit dosage form according to any one of items 31 to 33, wherein the filmforming polymer is HPMC with a substitution type of about 25 to 31% for hydroxypropoxy, such as 26 to 30%, such as or 27 to 29%, such as 28% for hydroxypropoxy.

35. The unit dosage form according to any one of items 31 to 33, wherein the filmforming polymer is a HPMC with a substitution type of about 22 to 28 % for methoxy and about 25 to 31 % for hydroxypropoxy, such as 23 to 27% or 24 to 26% for methoxy and such as 26 to 30 % or 27 to 29% for hydroxypropoxy.

36. The unit dosage form according to item any one of items 31 to 35, wherein the HPMC is of substitution type 2528.

37. The unit dosage form according to any one of items 31 to 36, wherein the filmforming polymer is HPMC with a viscosity of 50-300 mPas, such as 100-200 mPas or 130-170 mPas.

38. The unit dosage form according to any one of items 31 to 37, wherein the filmforming polymer is HPMC with a viscosity of 150 mPas. 39. The unit dosage form according to item 31 , wherein the film-forming polymer is HPMC with the trade name Affinisol HPMC HME 5 LV.

40. The unit dosage form according to item 31 , wherein the film-forming polymer is HPMC with the trade name Affinisol HPMC HME 100 LV.

41. The unit dosage form according to any one of items 31 to 33 or 37 or 38, wherein the film forming-polymer is a HPMC which does not have a substitution type of about 16 to 20% for methoxy and about 26 to 30 % for hydroxypropoxy, such as not about 18% for methoxy and about 28 % for hydroxypropoxy, such as not having the substitution type 1828.

42. The unit dosage form according to any one of items 31 to 33, 37 or 38, wherein the HPMC is of not of the substitution type 2910.

43. The unit dosage form according to item 30, wherein the film-forming polymer is not hypromellose acetate succinate.

44. The unit dosage form according to item 30, wherein the film-forming polymer is selected from acrylates, acrylic polymers and co-polymers thereof; polyacrylic acids, polymethacrylates and co-polymers thereof, and polyvinyl alcoholpolyethylene glycol graft-copolymers.

45. The unit dosage form according to item 30, wherein the film-forming polymer is a methacrylic acid-methyl acrylate copolymer.

46. The unit dosage form according to item 30, wherein the film-forming polymer is selected methacrylic acid-methyl acrylate copolymers with the trade name Eudragit.

47. The unit dosage form according to item 46, wherein the film-forming polymer is selected from Eudragit E 100, Eudragit RS 100, Eudragit RL 100 and Eudragit RL PO. 48. The unit dosage form according to item 44, wherein the film-forming polymer is a polymer consisting essentially of 75% polyvinyl alcohol units and 25% polyethylene glycol units.

49. The unit dosage form according to item 44, wherein the film-forming polymer is Kollicoat, such as Kollicoat IR.

50. The unit dosage form according to item 30, wherein the film-forming polymer is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

51. The unit dosage form according to item 30, wherein the film-forming polymer is a product with the trade name Soluplus.

52. The unit dosage form according to item 30, wherein the film-forming polymer is gum selected from the group consisting of acacia gum, guar gum, tragacanth gum, xanthan gum and diutan gum.

53. The unit dosage form according to item 30, wherein the film-forming polymer is alginate selected from the group consisting of sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propylene glycol alginate, alginic acid and mixtures thereof.

54. The unit dosage form according to item 53, wherein the alginate is sodium alginate, potassium alginate or ammonium alginate, or a mixture thereof.

55. The unit dosage form according to any one of items 53 or 54, wherein one or more of the alginate salts comprises from 25 to 35 wt% by weight of a-D- mannuronate and/or from 65 to 75 wt% by weight of a-L-guluronate, and a mean molecular weight of from 30,000 g/mol to 90,000 g/mol.

56. The unit dosage form according to any one of items 10 to 55, wherein the unit dosage form comprises at least 35 wt% film-forming polymer, such as at least 45 wt%, such as at least 50 wt%, such as at least 55 wt%, such as at least 60 wt%, such as at least 65 wt% film-forming polymer. 57. The unit dosage form according to any one of items 10 to 56, wherein the unit dosage form comprises no more than 80 wt% film-forming polymer, such as no more than 70 wt% such as no more than 65 wt%, such as no more than 60 wt%, such as no more than 55 wt%, such as no more than 50 wt%, such as no more than 45 wt% film-forming polymer.

58. The unit dosage form according to any one of items 10 to 57, wherein the unit dosage form comprises or consists of 35 to 80 wt% film-forming polymer, such as 45 to 80 wt%, such as 50 to 65 wt%, such as 55 to 60 wt% film-forming polymer.

59. The unit dosage form according to any one of items 10 to 58, wherein the unit dosage form comprises or consists of 15 to 45 wt% midazolam hydrochloride and 35 to 80 wt% film forming polymer, such as 25 to 40 wt% midazolam hydrochloride and 50 to 75 wt% film-forming polymer.

60. The unit dosage form according to any one of items 10 to 59, wherein the unit dosage form comprises or consists of at least 20 wt% midazolam hydrochloride and 35 to 80 wt% film-forming polymer.

61. The unit dosage form according to any one of items 10 to 60, wherein the unit dosage form is in comprises or consists of at least 20 wt% midazolam hydrochloride and 60 to 80 wt% film-forming polymer.

62. The unit dosage form according to any one of items 10 to 61, wherein the unit dosage form comprises or consists of 30 to 40 wt% midazolam hydrochloride and 60 to 80 wt% film-forming polymer.

63. The unit dosage form according to any one of items 10 to 62, wherein the unit dosage form comprises or consists essentially of about 33 wt% midazolam hydrochloride and about 67 wt% film-forming polymer.

64. The unit dosage form according to any one of items 10 to 63, wherein the unit dosage form comprises or consists of at least 20 wt% midazolam hydrochloride and 35 to 80 wt% film-forming polymer. The unit dosage form according to any one of items 10 to 64, wherein the unit dosage form comprises or consists of at least 20 wt% midazolam hydrochloride and 60 to 80 wt% film-forming polymer. The unit dosage form according to any one of items 10 to 65, wherein the unit dosage form comprises or consists of 30 to 40 wt% midazolam hydrochloride and 60 to 80 wt% film-forming polymer. The unit dosage form according to any one of items 10 to 66, wherein the unit dosage form comprises or consists essentially of about 33 wt% of midazolam hydrochloride and about 67 wt% film-forming polymer. The unit dosage form according to any one of items 59 to 67, wherein the midazolam hydrochloride is the new crystalline form of midazolam hydrochloride. The unit dosage form according to any one of items 10 to 68, wherein the unit dosage form further comprises one or more plasticizers. The unit dosage form according to item 69, wherein the one or more plasticizers are selected from a group consisting of glycerol; glycerol monacetate; citric acid and esters thereof such as triethyl citrate (TEC); diethylene glycol; ethylene glycol; fatty acid esters; PEG, such as PEG 400, PEG 600 or PEG 4000; polyethylene- propylene glycols; propylene glycol; phthalic acid; polyalkylene oxides; sorbitol, triacetin and xylitol. The unit dosage form according to any one of items 69 or 70, wherein the plasticizer is glycerol. The unit dosage form according to any one of items 69 or 70, wherein the plasticizer is TEC. The unit dosage form according to any one items 69 or 70, wherein the plasticizer is poloxamer 407. 74. The unit dosage form according to any one of items 69 or 70, wherein the plasticizer is Kollicoat IR.

75. The unit dosage form according to any one of items 10 to 74, wherein the unit dosage form comprises at least 3 wt% plasticizer, such as at least 5 wt%, such as at least 10 wt%, such as at least 30 wt% plasticizer.

76. The unit dosage form according to any one of items 10 to 75, wherein the unit dosage form comprises no more than 30 wt% plasticizer, such as no more than 20 wt%, such as no more than 15 wt%, such as no more than 10 wt%, such as no more than 5 wt% plasticizer.

77. The unit dosage form according to any one of items 10 to 76, wherein the unit dosage form comprises 3 to 35 wt% plasticizer, such as 4 to 10 wt%, such as about 5 wt% plasticizer.

78. The unit dosage form according to any one of items 10 to 74, wherein the unit dosage form comprises more than 3 wt% but less than 5 wt% plasticizer.

79. The unit dosage form according to any one of items 10 to 74, wherein the unit dosage form comprises about 3 wt% plasticizer.

80. The unit dosage form according to any one of items 10 to 79, wherein the /unit dosage form comprises a combination of two plasticizers, for which the total concentration is equal to any of the levels presented above.

81. The unit dosage form according to any one of items 10 to 80, wherein the unit dosage form comprises a combination of two plasticizers selected from group consisting of glycerol, TEC, poloxamer 407 and Kollicoat IR, such as glycerol and TEC, or glycerol and poloxamer 407, or glycerol and Kollicoat IR, or TEC and poloxamer 407, or TEC and Kollicoat IR, or poloxamer 407 and Kollicoat IR. 82. The unit dosage form according to any one of items 10 to 74, wherein the unit dosage form comprises 15 to 45 wt% midazolam hydrochloride, 35 to 80 wt% film-forming polymer and 3 to 35 wt% plasticizer.

83. The unit dosage form according to any one of items 10 to 71 , wherein the unit dosage form comprises 15 to 45 wt% midazolam hydrochloride; 35 to 80 wt% HPMC and 3 to 15 wt% glycerol.

84. The unit dosage form according to any one of items 10 to 68, wherein the unit dosage form does not comprise any plasticizer.

85. The unit dosage form according to item 84, wherein the film-forming polymer is Kollicoat IR.

86. The unit dosage form according to item 84, wherein the film-forming polymer is a HPMC with the trade name Affinisol HPMC HME 15 LV.

87. The unit dosage form according to item 84, wherein the film-forming polymer is a HPMC with the trade name Affinisol HPMC HME 100 LV.

88. The unit dosage form according to item 84, wherein the film-forming polymer is a HPMC with 23-27 % methoxy content and 26-30 % hydroxypropoxy content.

89. The unit dosage form according to item 84, wherein the film-forming polymer is HPMC 2528.

90. The unit dosage form according to item 84, wherein the film-forming polymer is not a HPMC with 16-20 % methoxy content and 26-30 % hydroxypropoxy content, such as not having the substitution type 1828.

91. The unit dosage form according to item 84, wherein the film-forming polymer is is not HPMC 2910. 92. The unit dosage form according to any one of items 10 to 91, wherein the unit dosage form comprises one or more additives selected from a group consisting of colorants, pigments, taste masking agents and flavouring agents.

93. The unit dosage form according to any one of items 10 to 92, wherein the unit dosage form consists of midazolam hydrochloride, one or more film-forming polymers, one or more flavouring agents and a pigment.

94. The unit dosage form according to any one of items 10 to 93, wherein the unit dosage form consists of midazolam hydrochloride, one or more film-forming polymers and a pigment.

95. The unit dosage form according to any one of items 92 to 94, wherein the pigment is yellow iron oxide.

96. The unit dosage form according to any one of items 92 to 94, wherein the pigment is red iron oxide.

97. The unit dosage form according to any one of items 92 to 94, wherein the pigment is black iron oxide.

98. The unit dosage form according to any one of items 10 to 97, wherein the unit dosage form comprises at least 0.2 wt% pigment, such as at least 0.5 wt%, such as at least 1 wt% pigment.

99. The unit dosage form according to any one of items 10 to 98, wherein the unit dosage form comprises no more than 10 wt% pigment, such as no more than 5 wt%, such as no more than 2 wt%, such as no more than 1 wt% pigment.

100. The unit dosage form according to any one of items 10 to 99, wherein the unit dosage form comprises 0.5 to 5 wt% pigment, such as about 1 wt% pigment. 101. The unit dosage form according to any one of items 10 to 100, wherein the unit dosage form comprises a flavouring agent that mitigates the bitter sensation emanating from the midazolam hydrochloride.

102. The unit dosage form according to any one of items 10 to 101, wherein the unit dosage form comprises at least 1 wt% flavouring agent, such as at least 2 wt%, such as at least 5 wt% flavouring agent.

103. The unit dosage form according to any one of items 10 to 102, wherein the unit dosage form comprises no more than 20 wt% flavouring agent, such as no more than 10 wt% flavouring agent.

104. The unit dosage form according to any one of items 10 to 103 with the proviso that the sum of the wt% of the components does not exceed 100 wt%.

105. The unit dosage form according to any one of items 10 to 104, wherein the unit dosage form is 50 to 150 pm thick, such as 60 to 120 pm thick, such as 70 to 110 pm thick, such as 80 to 100 pm thick.

106. The unit dosage form according to any one of items 10 to 105, wherein the unit dosage form is 40 to 100 pm thick, such as 50 to 90 pm thick, such as 60 to 80 pm thick.

107. The unit dosage form according to any one of items 10 to 106, wherein the unit dosage form has a dimension of X x Y x z, wherein X is in the range of 0.5 to 5 cm; Y is in the range of 0.5 to 5 cm; and Z is in the range of 15 to 150 pm.

108. The unit dosage form according to any one of items 10 to 107, wherein the unit dosage form has a dimension of X x Y x z, wherein X is at least 0.5 cm, such as at least 1 cm, such as at least 1.5 cm, such as at least 2 cm.

109. The unit dosage form according to any one of items 10 to 108, wherein the unit dosage form has a dimension of X x Y x z, wherein X is no more than 5 cm, such as no more than 4.5 cm, such as no more than 4 cm, such as no more than 3.5 cm, such as no more than 3 cm. . The unit dosage form according to any one of items 10 to 109, wherein the unit dosage form has a dimension of X x Y x z, wherein X is in the range of 0.5 to 5 cm, such as in the range of 1 to 3 cm, for example in the range of 1 to 2 cm. . The unit dosage form according to any one of items 10 to 110, wherein the unit dosage form has a dimension of X x Y x z, wherein Y is at least 0.5 cm, such as at least 1 cm, such as at least 1.5 cm, such as at least 2 cm. . The unit dosage form according to any one of items 10 to 111, wherein the unit dosage form has a dimension of X x Y x z, wherein Y is no more than 5 cm, such as no more than 4.5 cm, such as no more than 4 cm, such as no more than 3.5 cm, such as no more than 3 cm. . The unit dosage form according to any one of items 10 to 112, wherein the unit dosage form has a dimension of X x Y x z, wherein Y is in the range of 0.5 to 5 cm, such as in the range of 1 to 3 cm, for example in the range of 2 to 3 cm. . The unit dosage form according to any one of items 10 to 113, wherein the unit dosage form has a dimension of X x Y x z, wherein Z is at least 5 pm, such as at least 25 pm, such as at least 50 pm, such as at least 75 pm, such as at least 100 pm. . The unit dosage form according to any one of items 10 to 114, wherein the unit dosage form has a dimension of X x Y x z, wherein Z is no more than 1 mm, such as no more than 750 pm, such as no more than 500 pm, such as no more than 250 pm, such as no more than 125 pm. . The unit dosage form according to any one of items 10 to 115, wherein the unit dosage form has a dimension of X x Y x z, wherein Z is in the range of 5 m to 750 pm, such as in the range of 30 to 150 pm, such as 50 to 120 pm, such as 70 to 110 pm. . The unit dosage form according to any one of items 10 to 116, wherein the unit dosage form has a dimension of X x Y x z, wherein X is in the range of 0.5 to 5 cm; Y is on the range of 0.5 to 5 cm; and Z is in the range of 30 pm to 150 pm. . The unit dosage form according to any one of items 10 to 117, wherein the unit dosage form has a dimension of X x Y x z, wherein X is in the range of 1 to 3 cm; Y is on the range of 1 to 3 cm; and Z is in the range of 50 pm to 150 pm. . The unit dosage form according to any one of items 10 to 118, wherein the unit dosage form is rectangular and has dimensions of about 1 .5 cm x 2.5 cm x 90 pm. . The unit dosage form according to any one of items 10 to 119, wherein the unit dosage form is rectangular and has an area X x Y of 1 to 6 cm², such as 1 .5 to 5 cm², such as 3 to 4.5 cm², such as 3.5 to 4 cm². . The unit dosage form according to any one of items 10 to 120, wherein the unit dosage form has a coat weight of 50 to 150 g/m², such as 75 to 125 g/m², such as 80 to 110 g/m², such as about 90 g/m². . The unit dosage form according to any one of items 10 to 121 , wherein the unit dosage form has a rectangular form and an area of 1 to 6 cm², such as 1.5 to 5 cm², such as 3 to 4.5 cm², such as 3.5 to 4 cm², and is 30 to 150 pm thick, such as 50 to 120 pm thick, such as 70 to 110 pm thick. . The unit dosage form according to any one of items 10 to 122, wherein the unit dosage form has a rectangular form and the area. X x Y is 1 to 6 cm², such as 1.5 to 5 cm², such as 3 to 4.5 cm², such as 3.5 to 4 cm², and a coat weight of 50 to 150 g/m², such as 75 to 125 g/m², such as 80 to 110 g/m², such as about 90 g/m². 124. The unit dosage according to any one of items 10 to 106, wherein the unit dosage form is oval and has an area of 2 to 5 cm², such as 2.5 to 4.5 cm²

125. The unit dosage form according to any one of items 10 to 106, wherein the unit dosage form is circular and has an area of 2 to 5 cm², such as 2.5 to 4.5 cm².

126. The unit dosage form according to item 125, wherein the unit dosage form has a radius of 8 mm to 13 mm.

127. The unit dosage form according to any one of items 10 to 124, wherein the unit dosage form comprises 10 mg midazolam (here defined as the base) and has dimensions of about 1.5 cm x 2.5 cm x 70 to 110 pm.

128. The unit dosage form according to any one of items 10 to 127, wherein the unit dosage form consists of a single layer.

129. The unit dosage form according to any one of items 10 to 128, wherein the film has a moderately high in vitro dissolution rate.

130. The unit dosage form according to any one of items 10 to 128, wherein the film has an instantaneous dissolution.

131. The unit dosage form according to any one of items 129 or 130, wherein the dissolution medium of the USP Dissolution Apparatus 2 - Paddle is phosphate buffer pH 6.8.

132. The unit dosage form according to any one of items 129 or 130, wherein USP Dissolution Apparatus 2 - Paddle is conducted at 37°C ± 0.5°C, 75 rpm in 1000 mL phosphate buffer pH 6.8.

133. The unit dosage form according to any one of items 129 or 130, wherein the dissolution medium of the USP Dissolution Apparatus 2 - Paddle is phosphate buffer pH 6.8 with 0.08% Tween20. 134. The unit dosage form according to any one of items 129 or 130, wherein USP Dissolution Apparatus 2 - Paddle is conducted at 37°C ± 0.5°C, 75 rpm in 1000 mL phosphate buffer pH 6.8 with 0.08% Tween20.

135. The unit dosage form according to any one of items 129 or 130, wherein the dissolution medium of the USP Dissolution Apparatus 2 - Paddle is water.

136. The unit dosage form according to any one of items 129 or 130, wherein USP Dissolution Apparatus 2 - Paddle is conducted at 37°C ± 0.5°C, 75 rpm in 1000 mL water.

137. The unit dosage form according to any one of items 10 to 136, wherein the unit dosage form is a mucoadhesive film.

138. The unit dosage form according to any one of items 10 to 137, wherein the unit dosage form is an oral film for buccal administration.

139. The unit dosage form according to any one of items 10 to 137, wherein the unit dosage form is an oral film for oral administration.

140. The unit dosage form according to any one of items 10 to 137, wherein the unit dosage form is an oral film for sublingual administration.

141. The unit dosage form according to any one of items 10 to 140 for use as a medicament.

142. The unit dosage form according to any one of items 10 to 141 for use in the acute treatment of seizures in a subject.

143. The unit dosage form for use according to item 142, wherein the seizures are caused by epilepsy or another disease or condition that may cause seizures. 144. The unit dosage form for use according to any one of items 142 or 143, wherein the subject is suffering from epilepsy or another disease or condition that may cause seizures.

145. The unit dosage form for use according to item 144, wherein the epilepsy is generalised epilepsy or partial epilepsy.

146. The unit dosage form for use according to item 144, wherein the disease or condition that may cause seizures is selected from the group consisting of fever caused by malaria, fever of other causes, poisoning, tetanus, brain tumours, Lennox-Gastaut syndrome, tuberous sclerosis complex and Dravet syndrome.

147. The unit dosage form for use according to any one of items 142 to 146 wherein the seizures are selected from the group consisting of cluster seizures, seizure convulsions, convulsions, spasms, prolonged acute convulsive seizures, stereotypic episodes of frequent seizure activity that are distinct from a patient’s usual seizure pattern, status epilepticus and convulsive refractory status epilepticus.

148. The unit dosage form for use according to any one of items 142 to 147 wherein the seizures are ongoing, acute seizures.

149. The unit dosage form for use according to any one of items 142 to 148, wherein the unit dosage form is an oral film for buccal administration.

150. The unit dosage form according to any one of items 10 to 141 for use in the induction of moderate sedation or pre-sedation in a subject.

151. The unit dosage form according to any one of items 10 to 141 for use in moderate sedation before diagnostic, therapeutic or surgical procedures or presedation before anaesthesia.

152. The unit dosage form for use according to item 151 , wherein the diagnostic, therapeutic or surgical procedures are within odontology. . The unit dosage form for use according to any one of items 141 to 152 or 150 to 152, wherein the unit dosage form is to be applied orally, i.e. , onto the tongue. . The unit dosage form for use according to any one of items 141 to 152 or 150 to 152, wherein the unit dosage form is to be applied sublingually. . The unit dosage form for use according to any one of items 141 to 152 or 150 to 152, wherein the unit dosage form is to be applied buccally. . The unit dosage form according to any one of items 10 to 140 for use in a method of acute treatment of seizures and/or for induction of moderate sedation or pre-sedation in a subject, wherein the unit dosage form is for oral administration. . The unit dosage form according to any one of items 10 to 140 for use in a method of acute treatment of seizures and/or for induction of moderate sedation or pre-sedation in a subject, wherein the unit dosage form is for buccal administration. . The unit dosage form according to any one of items 10 to 140 for use in a method of acute treatment of seizures and/or for induction of moderate sedation or pre-sedation in a subject, wherein the unit dosage form is for sublingual administration. . The unit dosage form for use according to any one of items 141 to 158, wherein the subject is a mammal. . The unit dosage form for use according to item 159, wherein the mammal is a human. . The unit dosage form according to items 159, wherein the mammal is a dog, horse or a cat. 162. A method for treating seizures in a subject, comprising administering the unit dosage according to any one of items 10 to 140 to the subject in need thereof.

163. A method for induction of moderate sedation or pre-sedation in a subject, comprising administering the unit dosage according to any one of items 10 to 140 to the subject.

164. Use of the unit dosage form according to any one of items 10 to 140 in the manufacture of a medicament for the treatment of seizures.

165. Use of the unit dosage form according to any one of items 10 to 140 in the manufacture of a medicament for induction of moderate sedation or presedation in a subject.

166. A process for producing a unit dosage form according to any one of items 10 to 140, wherein the process comprises the sequential steps of: a) mixing an API comprising the crystalline form of midazolam hydrochloride and one or more film-forming polymers in a process solvent to provide a wet mix; b) casting the wet mix obtained in step a) to provide a wet film; c) drying the wet film of b) to obtain a dry film; and d) cutting the dry film of c) into a unit dosage form.

167. The process according to item 166, wherein the API is added before the one or more film-forming polymers are added, and a homogeneous mix, with the API in suspended state, is achieved before the film-forming polymers are added.

168. A process according to any one of items 166 to 167, wherein step a) comprises the sequential steps of: i. mixing the API with the solvent to obtain a homogenous suspension; ii. optionally adding a plasticizer and/or a pigment to the suspension in i) and mixing to obtain a homogenous mix; and iii. adding the film-forming polymer to the mix of ii) and mixing to obtain a wet mix in which the film-forming polymer is dissolved but the API is not dissolved.

169. The process according to item 166, wherein the one or more film-forming polymers is dissolved in the solvent before the API is added.

170. The process according to item 169, wherein step a) comprises the sequential steps of: i. mixing the film-forming polymer in process solvent to obtain a homogenous solution; ii. adding the API and optionally a plasticizer and/or a pigment to the solution in a) and mixing to obtain a wet mix in which the filmforming polymer is dissolved but the API is not dissolved.

171. The process according to any one of items 166 to 170, wherein the process solvent is able to dissolve the film-forming polymer.

172. The process according to any one of items 166 to 171 , wherein the process solvent does not dissolve the API.

173. The process according to any one of items 166 to 171 , wherein the process solvent is a solvent wherein no more than 10 wt%, such as no more than 5 wt%, such as no more than 2.5 wt% of the midazolam hydrochloride of the new form is dissolved after stirring a mixture of midazolam hydrochloride:solvent in a 5:95 weight ratio for 2 hours at room temperature.

174. The process according to any one of items 166 to 173, wherein the process solvent dissolves the film-forming polymer.

175. The process according to any one of items 166 to 173, wherein the process solvent is a solvent wherein no more than 10 wt%, such as no more than 5 wt%, such as no more than 2.5 wt%, of the added film-forming polymer is non-dissolved after stirring a mixture of film-forming polymer/solvent in a 15:85 weight ratio for 2 hours at room temperature. 176. The process according to any one of items 166 to 175, wherein the process solvent is a non-aqueous solvent.

177. The process according to any one of items 166 to 175, wherein the process solvent is essentially free from water and comprises or consists of one or more non-aqueous solvents.

178. The process according to any one of items 166 to 170, wherein the process solvent comprises or consists of one or more solvent selected from the group consisting of acetone, 1-butanol, 2-butanol, butyl acetate, ethyl acetate, isobutyl acetate, isopropyl acetate, methyl acetate, methyl ethyl ketone, 2- methyl-1-propanol, 1-pentanol, 1-propanol, 2-propanol, propyl acetate and triethylamine.

179. The process according to any one of items 166 to 170, wherein the process solvent is selected from the group consisting of acetone, ethyl acetate, isobutyl acetate, methyl acetate, 1-pentanol and 2-propanol.

180. The process according to any one of items 166 to 170, wherein the process solvent is selected from the group consisting of acetone, ethyl acetate, isobutyl acetate and methyl acetate.

181. The process according to any one of items 166 to 170, wherein the process solvent is ethyl acetate.

182. The process according to any one of items 166 to 170, wherein the solvent comprises or consists of water and one or more non-aqueous solvents.

183. The process according to any one of items 166 to 182, wherein at least 90 wt% of the total amount of the film-forming polymer is dissolved in the wet mix, such as at least 95 wt%, such as at least 98 wt%, such as 100 wt%.

184. The process according to any one of items 166 to 183, wherein not more than 20 wt% of the total amount of API is dissolved in the wet mix, such as not more than 10 wt%, such as not more than wt 5%, such as not more than 2.5 wt%.

185. The process according to any one of items 166 to 184, wherein at least

80 wt% of the total amount of the API remains suspended throughout the process, such as at least 90 wt%, such as at least 95 wt%, such as at least 98 wt%.

186. The process according to any one of items 166 to 185, wherein the filmforming polymer(s) but not the API dissolves in the wet mix in step a), thereby achieving a dry film in step c) in which the API is suspended as solid particles inside the formed film.

187. The process according to any one of items 166 to 186, wherein the suspended API has the same particle size and crystalline type as the API that was added in step a).

188. The process according to any one of items 166 to 187, wherein the dry film is a monolayered film.

189. The process according to any one of items 166 to 188, wherein the film comprises no other ingredients than the API, the film-forming polymer, plus a colorant and/or a flavouring agent.

190. The process according to any one of items 166 to 189, wherein the filmforming polymer is selected from the group consisting of: i. HPMC 2528; ii. HPC; iii. methacrylic acid-methyl acrylate copolymers; and iv. polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

191. The process according to item 190, wherein the process solvent is ethyl acetate. 192. The process according to any one of items 166 to 191 , wherein the solvent is ethyl acetate and the API is the new form of midazolam hydrochloride.

193. The process according to any one of items 166 to 192, wherein the wet film thickness is 300 to 800 pm, such as 400 to 700 pm, such as 550 to 650 pm.

194. The process according to any one of items 166 to 193, wherein the drying is performed at 40 to 120°C, such as 50 to 110°C, such as 60 to 100°C, such as 40 to 100°C, such as 40 to 80°C.

195. The process according to any one of items 166 to 193, wherein the drying is performed at temperatures no more than 60 °C, such as no more than 50 °C such as no more than 40 °C.

196. The process according to any one of items 166 to 195, wherein the drying is performed with air at relative humidity of 30% or more, such as 50% or more, such as 60% or more, such as 70% or more.

197. The process according to any one of items 166 to 196, wherein the drying is performed by using several temperature zones.

198. The process according to anyone of items 166 to 197, wherein the wet film is dried until the residual process solvent content is no more than 5 wt%, such as no more than 4 wt%, such as no more than 3 wt% such as no more than 2 wt%, such as no more than 1 wt%.

199. The process according to any one of items 166 to 198, wherein the amount of residual process solvent in the dry film is not less than 1 000 ppm (parts per million), such as not less than 5 000 ppm, such that not less than 10 000 ppm, such as less not than 25 000 ppm.

200. The process according to any one of items 166 to 199, wherein the solvent is ethyl acetate, the API is the new form of midazolam hydrochloride, and the amount of residual ethyl acetate is not less than 1 000 ppm (parts per million), such as not less than 5 000 ppm, such that not less than 10 000 ppm, such as less not than 25 000 ppm.

201 . An oral film obtained by the process according to any one of items 166 to 200.

202. A unit dosage form obtained by the process of any one of items 166 to 200.

203. A crystalline form of midazolam hydrochloride for which the X-ray powder diffraction pattern is basically as shown in Figure 4 (upper diffractogram).

204. The crystalline form according to any one of items 1 or 203 for use for use as a medicament.

205. The crystalline form according to any one of items 1 or 203 for use for the acute treatment of seizures in a subject.

206. The crystalline form according to any one of items 1 or 203 for use for use in the induction of moderate sedation or pre-sedation in a subject.

207. The crystalline form according to any one of items 1 or 203 for use in moderate sedation before diagnostic, therapeutic or surgical procedures or presedation before anaesthesia.

208. A method for treating seizures in a subject, comprising administering the crystalline form according to any one of items 1 or 203 to the subject in need thereof.

209. A method for induction of moderate sedation or pre-sedation in a subject, comprising administering the crystalline form according to any one of items 1 or 203 to the subject. 210. Use of the crystalline form according to any one of items 1 or 203 in the manufacture of a medicament for the treatment of seizures.

211. Use of the crystalline form according to any one of items 1 or 203 in the manufacture of a medicament for induction of moderate sedation or presedation in a subject.

Examples

Materials

Materials/excipients used in the Examples below, and their intended functions, are presented in this table:

Example 1. Gravimetric Vapour Sorption (GVS) study of midazolam base and midazolam hydrochloride

As water is the dominating process solvent within oral film manufacturing, and as air humidity is a critical environmental storage factor for finished oral films, it is recommendable to study the humidity interaction for the APIs potentially being used. Methods

An DVS-1 instrument from Surface Measurement Systems was used. A few mg of the API was added into Al pan and exposed to stepwise relative humidity (RH) changes during two consecutive cycles according to; 20-30-40-50-60-70-80-70-60-50-40-30-20- 10-0-10-20-30-40-50-60-70-80-90-80-70-60-50-40-30-20-10-0 %RH using open loop mode. The experiments were performed using a gas flow rate of 200 ml/min and at 25 °C. The dm/dt criteria applied was 0.001 weight-%/min during a 5 minute window, with a maximum allowed time of 150 minutes for all steps, except for the steps at 0% RH which had no criteria but were set to 6 hours.

Results

For midazolam base, the results are shown in Figure 1 . The humidity interaction was very low and there was no indication of any structural changes.

For midazolam hydrochloride, the results are shown in Figure 2. Initially, the humidity interaction resembled that of the midazolam base but at 90 % RH there was a significant sorption, which may indicate a structural change. The isotherm plot of the same run is shown in Figure 3 and clearly indicates a change at no later than 90 % RH.

Conclusions

It was concluded that: o midazolam hydrochloride may undergo a structural change, induced by high relative humidities.

Example 2. XRPD diffractograms of midazolam hydrochloride before and after exposure to 94% relative humidity

In order to further study the nature of the induced structural change of midazolam hydrochloride that was observed in Example 1 , a few mg of midazolam hydrochloride was prepared on a XRPD wafer sample holder and investigated prior exposure and after exposure to 94 % RH for several days. The material after exposure to 94 % RH for several days was hypothesized to be of same or similar nature as the sample obtained at 90% RH in the GVS experiment in Example 1.

Methods A PanAlytical X’Pert Pro Instrument from Malvern Panalytical Ltd was used. XRPD measurements were performed using a Cu-anode (45 kV/40 mA), and either a Ka-1 monochromator (1.540598 A) and X’celerator detector, or a Nickel filter producing Ka radiation (1.54184A) and a Pixcel detector. The 2-theta range was 2-35° using a scan speed of 0.02 7s or 0.03 7s and a step size of either 0.017° or 0.013°. Slow spinning sample holders were used. The samples were smeared out on zero background wafers of Si, producing a flat powdered surface. The measurements were performed using a programmable incident divergency slit.

Results

The result is shown below in Figure 4. It can be seen that a new structural form of midazolam hydrochloride had indeed been formed in Example 1 and 2. The new form is crystalline and has a different XRPD diffractogram compared with the commercially available midazolam hydrochloride that had been purchased. This new crystalline form (upper diffractogram) is characterized by major XRPD diffractogram peaks (2theta) at, for example, 11.0°±0.2°, 11.4°±0.2°, 12.9°±0.2°, 16.2°±0.2°, 16.5°±0.2°, 23.1°±0.2°, 24.8°±0.2°, 25.0°±0.2°, 28.6°±0.2° and 30.2°±0.2°. The commercially available midazolam hydrochloride (lower diffractogram), on the other hand, is characterized by major peaks (2theta) at, for example, 9.6°±0.2°, 13.4°±0.2°, 13.9°±0.2°, 17.6°±0.2°, 19.6°±0.2°, 21.2°±0.2°, 27.5°±0.2°, and 28.4°±0.2°, and by an absence of major peaks at the ten positions listed above for the new form.

The modest weight changes shown in Figure 3 in Example 1 does not support the formation of a conventional stoichiometric hydrate (e.g., a monohydrate or a dihydrate, etc.) but the results clearly prove the necessity of presence of minor amount of water for the formation of this form. The new form will herein be referred to as a “new crystalline form” or a “new form” of midazolam hydrochloride. To the best of the present inventors’ knowledge, this new form has not before been described in the literature.

It was also realized, that a preparation method of that new form had been devised, albeit here in small scale: subjecting midazolam hydrochloride powder to relative humidities of 90 % or higher for a sufficient period of time.

Conclusions

It was concluded that: o a new crystalline form of midazolam hydrochloride had been identified, and o a preparation method to obtain that new form had been identified.

Example 3. Aqueous slurry assessment of midazolam base and midazolam hydrochloride

As the new form of midazolam hydrochloride had been induced by elevated humidity, it was hypothesized that it could also be prepared by subjecting midazolam hydrochloride to water. This was made by a so-called aqueous slurry assessment. Midazolam base was also studied, as a reference.

Methods

A suspension of about 20 mg (for the base) or about 100 mg (for the hydrochloride) in about 1.1 mL aqueous solution of 10 % glycerol was prepared and subjected to stirring with magnetic flea for 7 days in room temperature. (The addition of glycerol was due to the fact that glycerol is a potential plasticizer for oral films, but is not believed to have significantly influenced the results of the assessment, compared with if pure water would have been used). Any dissolution and/or precipitation was visually observed, and the suspended solid material eventually remaining was collected on a porous disc allowing the aqueous solution to escape and leaving the semi-dry, solid material available for XRPD studies using the method explained in Example 2.

Results

Midazolam base apparently did not dissolve but remained as a slurry (suspension). However, it was found that the slurry assessment nevertheless resulted in a crystalline form which was different from the crystalline form of the midazolam base, as well as being different from the commercially available form of midazolam hydrochloride and the new form of midazolam hydrochloride hydrate, both of which are characterized by XRPD in this Example 3 as well as in Example 2. This can be seen in the XRPD results for midazolam base shown in Figure 5.

Midazolam hydrochloride, on the other hand, rapidly dissolved, but after a few minutes, a precipitation was formed, which was eventually collected and studied by XRPD. The XRPD results for midazolam hydrochloride are shown in Figure 6. The slurry assessment resulted in a crystalline form which was different from the crystalline form of the commercially available midazolam hydrochloride. In Figure 7, the XRPD diffractogram of midazolam hydrochloride after slurry assessment (i.e., from Figure 6) is presented together with the XRPD diffractogram of midazolam hydrochloride after exposure to 94% relative humidity (i.e., from Figure 4). This comparison shows that these two materials have essentially the same XRPD diffractogram profile, i.e., that the midazolam hydrochloride after slurry assessment also had obtained the new crystalline form identified in Example 1 - 2.

Furthermore, as the new form of midazolam hydrochloride during this slurry experiment materialized subsequently to the dissolution of the commercially available midazolam hydrochloride, it was realized that the new form (whether prepared as in Example 1, Example 2 or this Example 3) is a thermodynamically more stable form in aqueous solutions than the commercially available form.

Conclusions:

It was concluded that the new, crystalline form of midazolam hydrochloride o can be prepared in at least three ways, o is more thermodynamically stable than the commercially available form of midazolam hydrochloride, and o is of potential use as API in oral films aimed to deliver the active moiety midazolam.

Example 4. XRPD studies of midazolam oral film after storage in ambient room temperature and 65 % relative humidity up to 16 weeks

In Example 3 it was concluded that the new form of midazolam hydrochloride is more stable than the commercially available form, when assessed as a solid, non-formulated material. In this Example 4, the physical stability of the new form when present in an oral film was studied.

Methods

Film preparation: The oral film was prepared with non-continuous, lab-scale method. The wet mix batch size was about 12 g, in a 25 mL glass beaker, and was manually mixed (spatula) for about 10 minutes and then allowed to swell in a refrigerator at 5 °C for about 2 days. The dry content of the wet mix was about 29 wt%. Air bubbles were removed by mild centrifugation (4000 rpm for 2 minutes). The wet mix was coated onto an inert sheet, using an Adjustable Micrometer Film Applicator (1117/150 mm) from TQC Sheen in the UK. The wet film thickness was estimated to about 400 pm. After drying for about 40 minutes at 100 °C in a laboratory heating oven (Binder GmbH, Germany), a dry film was obtained. After being allowed to rest overnight at ambient room temperature, covered by a glass plate, the coat weight was measured and determined to be about 70 g/m². The film had satisfactory visual appearance, but was not subjected to any further controls or tests (e.g., midazolam content, in vitro dissolution, etc.). The composition of the final dry film was 32.4 wt% API, 12.5 wt% glycerol, 27.5 wt% HPMC Pharmacoat 603 and 27.5 wt% Metolose.

XRPD study: The same equipment and method as in Example 2 were used, with the following exceptions or supplementary information: The samples were pieces of film attached to the sample holder using double adhesive tape, i.e., Si wafers were not used. The film samples were run using limited angular range with prolonged collection time using repeating scan in order improve detection limits. Collection time was almost 5 h over 8° as 9 repetitive scans from 11 to 19° (scan speed 0.0047 7s, step size 0.0084°).

Stability study conditions’. Once mounted on the XRPD sample holder, the film sample was subjected to ambient room temperature and 65 % relative humidity throughout the study. It was stored without primary package, i.e., it remained fully exposed to these surrounding storage conditions throughout the study.

Results

The results are shown in Figure 8 and indicate that there was no change in the amount or type of crystalline material inside the film over time and that said crystalline material is the new form of midazolam hydrochloride, and remains so.

It is acknowledged that XRPD diffractogram peaks arising from API inside a film are never as sharp and precisely located as for pure API powders. This is due to the fact that the films, albeit being regarded as ’’thin” objects, are not “thin” compared with mounted powder samples, and the thicker the film, the more potential displacement of a peak and the less sharp. Despite this, Figure 8 clearly shows that the oral film does not contain any other crystalline form that the new form identified in Example 1 - 2.

Conclusions

It was concluded that: o the new crystalline form of midazolam hydrochloride can be physically stable also inside an oral film.

References

• Jithendra et al., Panacea Journal of Pharmacy and Pharmaceutical Sciences (2015), 4:4, 801-816

• Soroushnai et al., Current Drug Delivery (2018), 15, 9, 1294-1304

• Wasilevska, K. et al., Acta Pharm. (2019), 69, 155-176 • WO 2017/009446

• CN 1 830447 A

• US 11 ,173,114 B1

• Kathpalia H. and Gupte A, Current Drug Delivery (2013), 10, 667-684

• WO 2022/151732 A1 • CN 111320632 A

Claims

2. A crystalline form of midazolam hydrochloride for which the X-ray powder diffraction pattern is basically as shown in Figure 4 (upper diffractogram).

3. A unit dosage form in the form of an oral film comprising the crystalline form of midazolam hydrochloride according to any one of claims 1 or 2, and one or more film-forming polymers.

4. The unit dosage form according to claim 3, wherein at least 5 %, such as at least 10 %, such as at least 25 %, such as at least 50 % of the total amount of midazolam hydrochloride in the film is present as the crystalline form of midazolam hydrochloride.

5. The unit dosage form according to any one of claims 3 or 4, wherein the unit dosage form comprises about 10 mg midazolam (defined as the base).

6. The unit dosage form according to any one of claims 3 to 5, wherein the concentration of the crystalline form of midazolam hydrochloride inside the film is at least 2.5 wt%, such as at least 5 wt%, such as at least 15 wt%, such as at least 25 wt%, such as at least 50 wt%.

7. The unit dosage form according to any one of claims 3 to 6, wherein the concentration of the crystalline form of midazolam hydrochloride inside the film is no more than 98 wt%, such as no more than 90 wt%, such as no more than 75 wt%, such as no more than 50 wt%.

8. The unit dosage form according to any one of claims 3 to 7, wherein the filmforming polymer is selected from the group consisting of: o HPMC 2528; o HPC; o methacrylic acid-methyl acrylate copolymers; and o polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer

9. The unit dosage form according to any one of claims 3 to 8, wherein the unit dosage form comprises or consists of 15 to 45 wt% midazolam hydrochloride and 35 to 80 wt% film forming polymer, such as 25 to 40 wt% midazolam hydrochloride and 50 to 75 wt% film-forming polymer.

10. A process for producing a unit dosage form according to any one of claims 3 to 9, wherein the process comprises the sequential steps of: a) mixing an API comprising the crystalline form of midazolam hydrochloride and one or more film-forming polymers in a process solvent to provide a wet mix; b) casting the wet mix obtained in step a) to provide a wet film; c) drying the wet film of b) to obtain a dry film; and d) cutting the dry film of c) into a unit dosage form.

11. The process according to claim 10, wherein step a) comprises the sequential steps of:

(i) mixing the film-forming polymer in process solvent to obtain a homogenous solution;

(ii) adding the API and optionally a plasticizer and/or a pigment to the solution in a) and mixing to obtain a wet mix in which the film-forming polymer is dissolved but the API is not dissolved.

12. The process according to any one of claims 10 or 11, wherein the process solvent is ethyl acetate.

13. The crystalline form according to any one of claims 1 or 2 for use for use as a medicament.

14. The crystalline form according to any one of claims 1 or 2 for use for the acute treatment of seizures in a subject and/or for use for use in the induction of moderate sedation or pre-sedation in a subject.

15. A process for producing the crystalline form of midazolam hydrochloride according to any one of claims 1 or 2, wherein the process comprises the sequential steps of: a) subjecting a powder of a crystalline form of midazolam hydrochloride that is characterized by having an X-ray powder diffraction pattern comprising specific peaks (2theta) at 9.6°±0.2°, 13.4°±0.2°, 13.9°±0.2°, 17.6°±0.2°, 19.6°±0.2°, 21.2°±0.2°, 27.5°±0.2°, and 28.4°±0.2° to relative humidities of 81 % or more, such as 85% or more, such as 90% or more, for at least 1 hour, such as at least 2 hours, such as at least 24 hours, but not more than 7 days to form the crystalline form of midazolam hydrochloride according to claim 1 or 2, and b) packaging the crystalline form of midazolam hydrochloride formed in a) into containers, that are impermeable to air and humidity, at relative humidities of 70% or more, such as 81% or more, such as 90% or more.