Hydrocortisone based oral dispersible film and uses thereof

Abstract

Orodispersible film (ODF) is an innovative drug formulation that allows for adjustable dosing and improved patient compliance. It is administered into the mouth where it dissolves, making it suitable for children. The present invention provides an optimized ODF gel formulation and an optimal ODF containing therapeutic doses of hydrocortisone-type corticosteroids (HTC). This ODF is thin, flexible and transparent, and suitable for production in hospital pharmacy using standard equipment. The ODF of the invention allows accurate hydrocortisone levels to be released systemically in patients in need thereof, and its good physico-chemical stability is herein demonstrated for several months. This opens up new opportunities for use in pediatric patients, notably for children suffering from congenital adrenal hyperplasia.

Description

[0001] Hydrocortisone based oral dispersible film and uses thereof

[0002] SUMMARY OF THE INVENTION

[0003] Orodispersible film (ODF) is an innovative drug formulation that allows for adjustable dosing and improved patient compliance. It is administered into the mouth where it dissolves, making it suitable for children. The present invention provides an optimized ODF gel formulation and an optimal ODF containing therapeutic doses of hydrocortisone-type corticosteroids (HTC). This ODF is thin, flexible and transparent, and suitable for production in hospital pharmacy using standard equipment. The ODF of the invention allows accurate hydrocortisone levels to be released systemically in patients in need thereof, and its good physico-chemical stability is herein demonstrated for several months. This opens up new opportunities for use in pediatric patients, notably for children suffering from congenital adrenal hyperplasia.

[0004] DESCRIPTION OF THE PRIOR ART

[0005] Patient acceptability has been defined as the overall ability and willingness of the patient and their caregiver to administer the medicines as intended. This can have a major effect on adherence and, therefore, effectiveness of treatments. The EMA requires evidence of the suitability of dosage forms to be included in all Paediatric Investigation Plans (PIPs) where possible, and for patient acceptability to be assessed during pharmaceutical and clinical development. In particular, acceptability of children's medication is crucial because of the characteristics that are inherent to children, in particular difficulty in swallowing and high sensitivity for tastes (

[0027] —

[0029] ). This is light of the well-acknowledged problems of oral liquid dosage forms, such as medication errors (e.g. risk of under or over dosing due to inappropriate dosing and risk of poor therapeutic outcome due to difficulty in using oral administration device) as well as the low acceptability of parenteral and rectal drug delivery. Orally dissolving tablets (ODTs) have emerged to overcome this problem. However, for some patient populations, the fear of swallowing the solid dosage form (tablet, capsule), and the risk of asphyxiation remains despite short dissolution / disintegration times. In this context, there is a growing interest in orodispersible thin film (ODF) formulations: when placed on the tongue, ODFs are immediately wetted with saliva and therefore quickly dispersed and / or dissolved to release the drug for systemic and / or local absorption. They are less disturbing and more acceptable to patients, as they are thin and flexible in their natural structure. Accordingly, ODFs allow for better compliance in populations with swallowing difficulties, such as the elderly patients and children. As the pharmaceutical process guarantees uniformity of mass and content, the ODF can be cut into multiple fragments whose surface area corresponds to the dose to be administered ensuring the patient’s required dose is pre-prepared by the pharmacist ([4]). Recent studies have been conducted comparing palatability and acceptability between ODF and syrup in pediatric subjects. One study showed improved acceptability in patients between two days and twelve months old and better swallowability in patients over six months of age when compared with syrup ([5]). In another report, children aged six months to five years old including their caregivers, reported good acceptance of ODF ([6]).

[0006] The most frequently perceived advantages of ODFs are ease of administration and reduced risk that the medicine is spat out. Besides, some caregivers report an assumption that young children automatically start to chew items entering their mouth. On a manufacturing point of view, the production of ODF can be carried out using a simple and manual process or fully automated, and can therefore easily be produced in hospital or community pharmacies.

[0007] Nevertheless, ODFs have been so far only used for niche clinical conditions and it is unclear why ODFs are not more widely used. One limitation is that a therapeutic effect must be achievable at the low doses that can be loaded into the polymeric film. The lack of established quality control / quality assurance criteria and related methodologies may be a further barrier.

[0008] Moreover, it is desirable to produce solid (yet flexible) and manipulable ODFs to facilitate the different phases involved in film manufacturing operations: handling during the production phase (i.e. demolding, cutting and packaging), transport and storage, and finally, when it comes to administering the drug (i.e. ODF unpackaging, administration) ([4]). It is therefore necessary to produce ODFs that are not fragile and do not break during transport.

[0009] Several methods for ODF production have been investigated recently, in particular 3D printing and solvent casting. The most suitable method for community or hospital pharmacies is solvent casting, as it is relatively easy to set up and much cheaper than 3D printing ([8]). In this context, it will be advantageous to produce an ODF formulation that could form ODFs with solvent casting processes, as well as with 3D-printing technologies, depending on available devices. Another advantage of ODFs is their ability to rapidly disintegrate in the mouth. Among the parameters influencing disintegration, the water solubility of the active agent plays a critical role, facilitating the disintegration process in the saliva. Moreover, it is difficult to incorporate water-insoluble agents into ODFs, due to non-uniform repartition of the agent in the initial water-based formulation and thus in the final ODF. This is why, due to its hydrophobic backbone structure, the poorly water-soluble hydrocortisone (HOT) drug has rarely been formulated into ODFs so far.

[0010] The ODFs of the invention differ from the ODF disclosed in the prior arts such as W02005 / 102271 in that they do not contain the same polymer I plasticizer I surfactant agents. Moreover, the ODFs of the prior art contain non-soluble forms of HOT resulting in a non- homogenous repartition of the drug in the final film, or HOT soluble forms complexed with toxic excipients such as propylene glycols.

[0011] In this context, there is a need for the development of a suitable formulation and manufacturing method for the production of a solid and stable ODF that can release calibrated and reproducible doses of hydrocortisone-type corticosteroids (HTC), without toxic excipients, in order to treat elderly patients and children in need thereof.

[0012] The present invention solves this need by identifying new tools and processes to generate highly efficient hydrocortisone-releasing ODFs.

[0013] These hydrocortisone-releasing ODFs are produced by using an ODF gel formulation having an optimized gel viscosity that allows smooth casting or 3D printing, and is also appropriate to keep the gel fairly compact during the final drying steps. Importantly, this ODF gel formulation contains no clots nor aggregates and does not shrink when drying on a silicon-coated surface; It can be stored during at least two months without alteration of the drug stability and content. It can be degassed in less than 24h and becomes dry in less than 24h, what is compatible with in situ manufacturing in hospital units.

[0014] The resulting hydrocortisone-releasing ODFs are particularly advantageous since they are easily disintegrated in contact of saliva, where they release a calibrated and uniform amount of the HTC drug in less than 2 minutes. Furthermore, although they are thin, elastic and flexible, the films are strong enough, non-sticky and resistant, so as to be easily removed from a silicon- coated surface, with easy subsequent handling. Finally, once protected in appropriate packaging such as anti-UV blisters, the films can be stored during at least 84 days without alteration of their organoleptic parameters (taste, aspect, structure) nor alteration of the HTC drug stability and therapeutic effect. DESCRIPTION OF THE INVENTION

[0015] To enhance its water solubility for pharmaceutical applications, hydrocortisone-type corticosteroids (HTC) can be chemically modified into a more water-soluble derivative. One approach is to convert them into a salt form such as sodium succinate which is much more soluble in water than the original drug.

[0016] Other strategies involve complexation or encapsulation with cyclodextrins, surfactants, nanoparticles or liposomes.

[0017] More generally, solubilization strategies include: (i) salt formation, by adjusting the pH of the medium to favor the ionized, more soluble form of the drug; (ii) complexation with suitable complexing agents such as cyclodextrins, which can encapsulate hydrophobic molecules and improve their apparent solubility; (iii) incorporation of surfactants, such as polysorbate 80 (Tween 80), which reduce surface tension and facilitate solubilization of poorly water-soluble compounds; (iv) incorporation into nanosized micelles and (v) use of co-solvents, including lower alcohols or glycols (e.g., ethanol, propylene glycol), to increase the solubility of hydrocortisone through solvent polarity modification (see for example

[0030] ). These approaches can be used individually or in combination, depending on the desired formulation characteristics and stability requirements.

[0018] The present invention uses any soluble forms of HTC, wherein said HTC is chosen in the group consisting of: hydrocortisone, hydrocortisone acetate, hydrocortisone hemi succinate, cortisone, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, and prednisone (see figure 4 of

[0030] ).

[0019] In a preferred embodiment, the soluble form of HTC does not involve excipients that are known or are suspected of being toxic or having side effects in human beings, in particular in elderly and / or pediatric populations.

[0020] Thus, in a more preferred embodiment, the soluble form of HTC does not include propylene glycol or alcohols in general.

[0021] In the present invention, a more preferred approach to solubilize HTC is rather to use cyclodextrin-encapsulated HTC (as proposed in

[0030] , which is incorporated herein by reference) or to convert the HTC into an ester by reacting it with an organic acid such as succinic acid. This is the case with hydrocortisone hemisuccinate (HMS or “hydrocortisone hydrogen succinate”), which is an ester of hydrocortisone and succinic acid. The ester group increases hydrophilicity due to its polar nature, thereby increasing solubility in aqueous solutions. When HMS is administered, esterase enzymes present in the blood and other tissues rapidly cleave the hemisuccinate moiety from the molecule, converting it back into active hydrocortisone. HMS can also spontaneously transform into HCT when put in contact with a liquid solution.

[0022] Example 2 below discloses an alternative to HMS which is to use a mixture of hydrocortisone base with hydroxypropyl- -cyclodextrins.

[0023] The present inventors herein propose to use a solubilized form of HTC to produce HTC- releasing ODFs. Using solubilized HTC helps the solubilization of the corticosteroid drug into water-based formulations and hence its homogeneous dispersion in such formulations. Various preparation methods and formulations were tested to identify the best formulation compositions in which solubilized HTC could be rapidly and easily solubilized, to eventually produce an ODF having the targeted structural, organoleptic, and therapeutic advantageous properties mentioned above. These properties were assessed by visual and manual inspection and by testing for uniformity of mass, drug content, drug stability, thickness and dissolution parameters.

[0024] Interestingly, the present inventors’ results show that the optimized gel formulation of the invention can be stored during few months at low temperatures, and therefore extemporaneously used and transported. Moreover, this gel formulation is compatible with gel casting or 3D-printing manufacturing processes.

[0025] More importantly, the resulting ODFs are shown to be acceptable in terms of dissolution / disintegration rate, mass uniformity, content and stability. Also, these ODFs are thin and flexible, but strong enough to be easily removed from silicon-coated supports and subsequently handled. When the dried films are put in contact with a liquid, the drug is readily released at an accurate and reproducible level (Figures 3 and 7). Finally, the inventors showed with an HPLC-stability assay that the HCT drug in the final ODF remains stable for at least 295 days when the ODF is stored in an anti-UV blister at room temperature (Figures 4, 5 and 8).

[0026] To conclude, the formulation and ODFs of the invention successfully satisfied all the tests, including content uniformity and stability, as shown in the examples below. ODF gel formulations of the invention

[0027] The present invention thus relates to original and improved ODF gel formulations containing solubilized HTC such as HMS, said formulations being useful in various ODF-manufacturing processes, for example in solvent casting or 3D-printing processes. The excipients used in the formulations (typically hydroxypropyl cellulose or HPC, glycerol, povidone, sucralose, surfactant, and flavoring agent) being commonly available and easy to handle, the ODF gel formulations of the invention and the resulting ODFs can be easily produced in hospital pharmacy production units.

[0028] As shown in the experimental part below, the components and quantities of the excipients present in the ODF gel formulation of the invention have been optimized so that i) all of them are completely solubilized in few hours, ii) the gel does not shrink during drying on a casting surface and iii) they produce ODFs having the targeted structural, organoleptic, and therapeutic properties mentioned above.

[0029] In a first aspect, the present invention relates to an Orodispersible Film (ODF) gel formulation having a viscosity comprised between 1000 and 10000 mPa.s-1, said gel formulation containing an effective amount of a polymer agent, of a plasticizer, of a surfactant, and between 0.1 and 0.5% of a solubilized form of HTC, wherein all these ingredients are completely solubilized and wherein the gel formulation is degassed.

[0030] In a preferred embodiment, in this gel formulation :

[0031] - said polymer agent is chosen among pullulan, gelatin, maltodextrin, hydroxypropyl methyl cellulose, chitosan, sodium alginate, carboxymethyl cellulose, hydroxypropyl cellulose, and polyvinyl pyrrolidone, or combinations thereof,

[0032] - said plasticizer is chosen among glycerol, glycerin, sorbitol, mannitol, propylene glycol, triacetin, citrate ether, starch, or combinations thereof, and / or

[0033] - said surfactant is chosen among sorbitan oleate, glyceryl monolineate, and polysorbate, or combinations thereof.

[0034] The ODF gel formulation of the invention contains a polymer agent that will ensure that the polymerization occurs rapidly and homogenously and that the final film is sufficiently resistant, stable and homogenous. In a preferred embodiment, the ODF gel formulation of the invention contains hydroxypropyl cellulose (HPC) and / or polyvinyl pyrrolidone (povidone) as polymer agent(s). The gel formulation of the invention preferably contains a mixture of hydroxypropyl cellulose (HPC) and polyvinyl pyrrolidone (such as povidone K25). In the ODF of the invention, povidone is useful both for polymerizing the gel and for helping the film disintegration afterwards.

[0035] The disintegration of the dry final ODFs produced from gel formulations according to the invention and containing various amount of HPC was compared with the disintegration of industrially manufactured and marketed ondansetron ODFs (Setofilm®). While the disintegration times of the 5% and 6% HPC formulations were judged to be long, the disintegration time of the 4% HPC formulations was faster and tended to be close to the disintegration time measured for Setofilm® (

[0021] ). Consequently, ODF formulations with 4% HPC are preferred. Nevertheless, increasing the HPC content can be considered if tensile strength is unsatisfactory using 4% of HPC, although this can lead to a delay in the disintegration time of the ODF as no significant difference between 4-6% HPC in terms of gel viscosity and ODF strength was observed. On the other hand, an HPC concentration lower than 4% has a higher risk of making ODF final textures more brittle and fragile. Thus, in a more preferred embodiment, the ODF gel formulation of the invention contains between 4 to 6% of HPC.

[0036] The ODF gel formulation of the invention preferably also contains between 2 and 10%, typically about 5%, of another polymer agent such as povidone K25. This will strengthen the texture of the ODF once dried, but may further delay its disintegration.

[0037] If necessary, the disintegration time could however be reduced by the addition of conventional superdisintegrant, such as sodium starch glycolate, croscarmellose sodium, or crospovidone, to the gel formulation of the invention.

[0038] The ODF gel formulation of the invention contains a plasticizer that will ensure that the final film obtained after drying the gel is sufficiently flexible and elastic to be handled without breaking. In a preferred embodiment, the ODF gel formulation of the invention contains glycerol as plasticizer. In a more preferred embodiment, the ODF gel formulation contains 1.5% of glycerol as plasticizer. Yet, as the 1 % glycerol formula is less sticky, reducing the glycerol to 1% could be further considered, if less stickiness is required (e.g. for packaging). In a more preferred embodiment, the ODF gel formulation of the invention therefore contains between 1 to 1.5% of glycerol.

[0039] The ODF gel formulation of the invention contains a surfactant agent that will ensure that the different excipients and the drug are homogenously mixed and solubilized, favours the liberation of the drug during dissolution, and facilitates the spreading of the gel on the silicon surface. In a preferred embodiment, the ODF gel formulation of the invention contains between 0.15 to 0.2% of a surfactant. In a more preferred embodiment, the ODF gel formulation of the invention contains, as surfactant, a mixture of glyceryl monolineate and polysorbate 80 (75 / 25%; w / w) that has an advantageous hydrophilic I lipophilic balance (HLB) around 4.5. Other useful surfactants are cited above and can be used instead of this mixture.

[0040] In a particular embodiment, said polymer agent is a mixture of hydroxypropyl cellulose (HPC) and polyvinyl pyrrolidone (povidone), said plasticizer is glycerol and said surfactant is a mixture of glyceryl monolineate and polysorbate.

[0041] In a preferred embodiment, the ODF gel formulation of the invention contains :

[0042] - between 4 and 6% w / w of hydroxypropylcellulose,

[0043] - between 4 and 8% w / w of polyvinyl pyrrolidone,

[0044] - between 1 and 1 .5 % w / w of glycerol,

[0045] - between 0.15 and 0.2% w / w of a mixture of glyceryl monolineate and polysorbate 80, and

[0046] - between 0.1 and 1% w / w of a solubilized form of HTC such as HMS,

[0047] - water.

[0048] In a preferred embodiment, the ODF gel formulation of the invention contains 0.3% of a solubilized form of HTC such as HMS. This precise amount was calculated so that after the gel is casted onto a silicon-coated surface to form a 1 .7 mm thick film and dryed appropriately until a thickness of 0.2 mm is reached, a 1cmx2cm rectangle fragment thereof would contain precisely 1 mg of HTC.

[0049] As used herein, the term “HTC” designates a hydrocortisone-type corticosteroid drug selected from: hydrocortisone, hydrocortisone acetate, cortisone, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, and prednisone.

[0050] In a preferred embodiment, the term “solubilized form of HTC” is a hydrocortisone complexed with a cyclodextrin (cf.

[0030] ), a pharmaceutically acceptable soluble salt of hydrocortisone-type corticosteroid, hydrocortisone-type corticosteroid incorporated into a surfactant, hydrocortisone-type corticosteroid dissolved in an alcohol, preferably it is hydrocortisone hemisuccinate (also referred to as hydrocortisone hydrogen succinate or HMS).

[0051] In a more preferred embodiment, the ODF gel formulation of the invention contains HTC, HMS or hydrocortisone complexed with a cyclodextrin, such as p-cyclodextrin, e.g., with a hydroxypropyl- -cyclodextrin, as exemplified below. As explained in

[0030] , the cyclodextrins (CDs) are a class of molecules composed of a -D-glucopyranose units, linked by the a -1 ,4 glycosidic bonds. They act as a hydrophobic cavity that can enclose other compounds - here the HTC. All the commonly naturally occurring cyclodextrins are a , p and y cyclodextrins can be used in the context of the invention. They consist of six, seven, and eight glucose subunits, respectively, large-ring cyclodextrins (LR-CDs), with nine to more than several hundred units. Apart from native CDs, multiple CD derivatives, such as hydroxypropyl HP- 3 -CD and sulfobutyl ether (SBE)- 3 -CD, have been developed and investigated for their enhanced solubility, ability to form complexes, and toxicological characteristics, demonstrating their significant utility. Additional alterations involve the replacement of one or more primary hydroxyl group with glucosyl or maltosyl groups through an a -(1— >6) glycosidic linkage at the narrow rim of the CD. Specifically, in the sulfoalkyl ether derivatives (SAE-CD), the addition of an anionic substituent greatly enhances the ability of the parent CD to dissolve in water and reduces its potential for causing kidney damage, hence improving its safety profile

[0030] , All these CDs can be used to encapsulate and solubilize the HTC in the context of the present invention.

[0052] In a preferred embodiment, the ODF gel formulation of the invention also contains a tastemasking agent, a sweetener, a flavor, a coloring agent and / or a saliva stimulator. These optional excipients are well-known in the art (

[0014] ).

[0053] Preferred flavors are for example chosen among: anise, apple, apricot, banana, blackberry, blueberry, caramel, cherry, chocolate, coconut, coffee, cocoa, coca cola, cranberry, blackcurrant, redcurrant, grape, grapefruit, grenadine, lemon, maple, mint, orange, walnut, passion fruit, peach, pear, pineapple, plum, raspberry, strawberry, tangerine, tutti frutti, and vanilla. Cola and strawberry flavors are herein preferred.

[0054] The proportion of flavor in the ODF gel formulation of the invention can be for example comprised between 0.1 and 5%, preferably between 0.1% and 3%, more preferably between 0.1 and 2%, even more preferably of about 0.5%.

[0055] An exemplary composition of the ODF gel formulation of the invention is provided below, in the Table 9 of the examples.

[0056] As shown on Figure 6, the stability of the HTC drug present in such a gel formulation is increased when the gel is kept at +4°C or at -20°C. Therefore, in a preferred embodiment, the ODF gel formulation of the invention is stored for several weeks, or even for several months, at +6°C or below, preferably at -20°C, when the casting or printing process is to be performed later, extemporaneously. Importantly, the results of the inventors show that the ODF gel formulation of the invention can be safely and stably kept for at least two months at -20°C.

[0057] Manufacturing methods

[0058] Gel formation and complete solubilization of all the ingredients are obtained in the context of the invention in a single step by stirring the mix containing all the ingredients during an appropriate time.

[0059] If the mix is left at room temperature, this step can take few hours (between 2 and 24hours, preferably between 5 and 15 hours, more preferably about 10h to 12h). It is possible to warm the mix until 40°C - 50°C so as to accelerate the solubilization process of HPC in particular. If the mix is heated, the gel formation I solubilization step shall be shorter (typically less than 15 minutes). Assessment of the complete solubilization of the ingredients can be done by any conventional means.

[0060] As explained above, the excipients of the gel formulation of the invention and their quantities are chosen so that the viscosity of the ODF gel formulation of the invention is finally comprised between 1000 - 10000 mPa.s'1. In a particular embodiment, this viscosity is preferably comprised between 1000 and 5000 mPa.s'1or between 1000 and 3000 mPa.s'1or between 1000 and 2000 mPa.s'1. This viscosity can be measured e.g. by using a rotational viscometer of the ROT AVISO lo-vi from IKA, having a spindle such as SP-2, at a rotation speed of 10 rpm during 90 minutes, at 23°C (+ / - 3°C), as proposed in the examples below.

[0061] The first step of the invention is therefore finished when the gel formulation reaches the target viscosity range and when all the ingredients present in the mixture are completely solubilized.

[0062] During this mixing under stirring, unwanted air bubbles are usually incorporated to the gel formulation. Eliminating air bubbles is however crucial for ensuring a uniform and defect-free final ODF. The air bubbles can be removed from the gel of the invention by slow and careful mixing during at least 5, 6, 7, 8, 9 or 10 hours, vacuum degassing using a vacuum chamber (reducing the degassing duration to few minutes), centrifugation (if the gel is fluid enough), vibrations, or simply by letting the gel rest for at least 15, 20, or 24 hours.

[0063] The ODF gel formulation of the invention is thus typically produced by implementing the following method : a) mixing the polymer agent, the plasticizer, the surfactant, and the solubilized form of HTC (and optionally the other ingredients mentioned above), b) stirring until complete dissolution and until a viscosity of 1000 to 10000 mPa.s-1is achieved, c) removing the air bubbles contained in the mix.

[0064] Once the ODF gel formulation is obtained, it can be stored for at least two months without being altered (see example below + Figures 4, 5 and 8). Hence, the gel formulation can be packaged and distributed to the users who may want to manufacture their own film extemporaneously.

[0065] The method for producing the ODF gel formulation of the invention therefore optionally contains a step d) of packaging the gel formulation in appropriate doses, by conventional means.

[0066] The ODF gel formulation of the invention as disclosed above can be used to make HTC- releasing ODFs with two main manufacturing methods, namely solvent casting or 3D-printing.

[0067] The surface on which the gel is casted or printed should be chosen carefully so that the final ODF can easily be removed from it. It should also be made of food grade materials. In this context, the inventors evaluated several kinds of surface, and identified that greaseproof paper, glass plate, and liner are not appropriate. The best tested surfaces were alimentary- silicon, giving a smooth film that was easy to demold. In a preferred embodiment, the surface onto which the gel formulation of the invention is casted or printed is thus a silicon-coated food grade surface.

[0068] The solvent casting method is the most generally utilized method to prepare ODFs because of its simple preparation, low processing cost, and ease of application. In brief, the water-soluble ingredients described above are simply mixed under stirring so as to provide the ODF gel formulation described above. The homogenous and viscous solution obtained at the end of the gel formation I solubilization step is then simply poured onto a casting surface, until the target size and thickness of the film is obtained on the surface (this target size I thickness depending on the characteristics of the final dried film to be obtained, having in mind that the size reduction during drying is of about 70-90%).

[0069] On another hand, a number of 3D printing methods can be applied to the production of ODF films: Inkjet printing, Fused Deposition Modeling, Stereolithography, Pressure-Assisted Microsyringe (PAM), or any other 3D-printer device that can handle and be compatible with alimentary products. Inkjet Printing uses a non-contact printing process where the film-forming solution is deposited in a layer-by-layer fashion onto a substrate; the active pharmaceutical ingredients can be precisely placed within the matrix, allowing for personalized dosing. Fused Deposition Modeling (FDM), commonly used for thermoplastic polymers, could be adapted to create ODFs from thermoplastic polymers that are safe for ingestion; the filament used would consist of a blend of pharmaceutical ingredients and a polymer that dissolves quickly in saliva. Stereolithography (SLA) involves the use of light to cure a photo-reactive resin layer by layer; resins that are appropriate for oral consumption and that can disintegrate in the saliva could be used to create intricate ODF designs with this technology. Pressure-Assisted Microsyringe (PAM) utilizes a microsyringe to dispense viscous solutions containing the drug and filmforming polymers directly onto a substrate, which can then be dried to form the film. Each 3D printing technology for ODF production has its own advantages, such as the ability to produce complex dosage forms, personalized medicines with accurate dosing, and the potential for on- demand printing.

[0070] In a preferred embodiment, the ODF of the invention can be printed by using pharmaceutical 3D printers such as the M3DI MAKER from FabrX, allowing fully personalized human and veterinary precision medicine manufacture.

[0071] The homogenous and viscous solution obtained at the end of the gel formation I solubilization step is loaded in the 3D printer and the parameters of the printer should be set to the target size and thickness wanted on the surface (this target size I thickness depending on the characteristics of the final dried film to be obtained, having in mind that the size reduction during drying is of about 70-90%).

[0072] In the manufacturing method of the invention, the size and the thickness of the casted or printed gel on the surface should be adjusted so that they lead to an appropriate ODF film size and thickness after the drying step. In the example of the invention, where the concentration of HTC in the gel formulation was of 0.3% w / v and where each final ODF single unit has a surface of 2 cm2and a thickness of 0.2mm and should deliver 1mg of HTC, the casted gel had typically a thickness of about 1.7 mm before drying occurs.

[0073] It is also possible to cast or print droplets on the surface, so as to avoid final cutting; in the context of the example, i.e. , when the gel formulation contains 0.3% of HTC, the surface of the droplet should be of about 2 cm2so that it delivers 1 mg of HTC per each intake.

[0074] Once “casted” or “printed” on the surface, the ODF gel formulation is left drying so that a dry final ODF film is formed, eventually containing less than 90% of water content. Such a drying step can be performed at room temperature or by warming the films up to 40°C - 50°C (e.g., in an oven) to accelerate the drying process. Depending on the chosen temperature, the drying step can last for one to 24h. In a preferred embodiment, the spread gels are left at 23+ / -2° C for 3 to 15 hours, typically for 10 hours when almost 90% of the water content is evaporated (Figure 1).

[0075] The dried films obtained after evaporation of the solvents are then carefully separated from the surface. Depending on the amount of active substance they contain, they can be cut into pieces of the desired size.

[0076] Altogether, the manufacturing method of an ODF according to the invention typically involves the following main steps: a) mixing in water all the ingredients of the ODF gel formulation of the invention, as described above, until a gel is formed and complete solubilization of all the ingredients is achieved, b) degassing the ODF gel formulation obtained in step a), c) casting or 3D-printing the degassed gel formulation of step b) onto a silicon-coated surface, d) drying the casted or printed ODF gel formulation until less than 30% of water content is present in the ODF film, e) optionally, cutting the ODF film to obtain an appropriate size, and / or separating the ODF film from the surface.

[0077] This method is useful for obtaining the dry, thin, and flexible hydrocortisone-releasing ODFs of the invention, that could be easily administered to children and elderly patients in need to hydrocortisone treatments.

[0078] All the details of these steps of the manufacturing method are explained above and need not be repeated here. They apply mutatis mutandis to this method.

[0079] The method for manufacturing the ODF of the invention also optionally contains a step f) of packaging the ODF in appropriate water-proof packaging (anti-UV blisters, etc.).

[0080] ODF of the invention

[0081] In another aspect, the present invention relates to the final ODF obtained by means of the manufacturing method described above. This ODF is herein referred to as the “ODF of the invention”, or to the “HTC ODF of the invention” or to the “hydrocortisone-releasing ODF of the invention” because it contains a define amount of HTC such as HMS (typically 1 mg) which can be released in the mouth of the patient once swallowed or put in the mouth. An “orodispersible film” or “ODF” is constituted by “single- or multilayer sheets of suitable materials, to be placed in the mouth where they disperse rapidly” according to the European Pharmacopeia ([7]). These innovative dosage forms are taken orally but do not require water for ingestion and absorption as do conventional drugs. ODFs should not be confused with buccal films that are designed to remain on the cheek mucosa for a long time.

[0082] The main components of the ODF of the invention are the solubilized form of HTC as disclosed above, a polymeric agent such as cellulosic agent, a plasticizer such as glycerol and the other excipients described above to improve the ODF structure, texture, disintegration abilities and mouthfeel ([9],

[0010] ). Its low water content ensures improved microbiological and chemical stabilities, comparable to solid oral forms (

[0011] ).

[0083] As shown in the examples detailed below, the ODF film of the invention more preferably contains:

[0084] Between 0.1 g / cm2and 1 g / cm2of a solubilized form of HTC, representing between 2- 3% w / w of the ODF film,

[0085] Between 15 and 35% w / w of HPC,

[0086] Between 20 and 45% w / w of polyvinyl pyrrolidone,

[0087] Between 5 and 15% w / w of glycerol,

[0088] Between 0.5 and 2.0% w / w of a mixture of glyceryl monolineate and polysorbate 80 (75% / 25% w / w respectively),

[0089] Less than 30% w / w of water, preferably less than 20% w / w, more preferably less than 10%, of water.

[0090] More preferably, the ODF film of the invention contains :

[0091] Between 0.1 g / cm2and 1 g / cm2of a solubilized form of HTC, representing between 2- 3% w / w of the ODF film,

[0092] Between 25 and 32% w / w of HPC,

[0093] Between 35 and 42% w / w of polyvinyl pyrrolidone,

[0094] Between 10 and 13% w / w of glycerol,

[0095] Between 0.8 and 2% w / w of a mixture of glyceryl monolineate and polysorbate 80 (75% / 25% respectively),

[0096] Less than 20% w / w, preferably less than 10%, of water.

[0097] In another embodiment, the ODF film of the invention contains:

[0098] Between 0.1 g / cm2and 1 g / cm2of HMS or of a cyclodextrin-encapsulated hydrocortisone, representing between 2-3% w / w of the ODF film, Between 15 and 35% w / w of HPC,

[0099] Between 20 and 45% w / w of polyvinyl pyrrolidone,

[0100] Between 5 and 15% w / w of glycerol,

[0101] Between 0.5 and 2.0% w / w of a mixture of glyceryl monolineate and polysorbate 80 (75% / 25% w / w respectively),

[0102] Less than 30% w / w of water, preferably less than 20% w / w, more preferably less than 10%, of water.

[0103] More preferably, the ODF film of the invention contains :

[0104] Between 0.1 g / cm2and 1 g / cm2of HMS or of a cyclodextrin-encapsulated hydrocortisone, representing between 2-3% w / w of the ODF film,

[0105] Between 25 and 32% w / w of HPC,

[0106] Between 35 and 42% w / w of polyvinyl pyrrolidone,

[0107] Between 10 and 13% w / w of glycerol,

[0108] Between 0.8 and 2% w / w of a mixture of glyceryl monolineate and polysorbate 80 (75% / 25% respectively),

[0109] Less than 20% w / w, preferably less than 10%, of water.

[0110] Alternatively, the ODF of the invention may contain :

[0111] Between 0.1 g / cm2and 1 g / cm2of HMS, representing between 2-3% w / w of the ODF film,

[0112] Between 15 and 30% w / w, preferably between 20 and 25% w / w of HPC,

[0113] Between 20 and 40% w / w, preferably between 20 and 30% w / w of polyvinyl pyrrolidone,

[0114] Between 5 and 15% w / w, preferably between 5 and 10% w / w of glycerol,

[0115] Between 0.5 and 1.5% w / w, preferably between 0.8 and 1.2% w / w of a mixture of glyceryl monolineate and polysorbate 80 (75% / 25% respectively),

[0116] Less than 30% w / w, preferably less than 20% w / w, more preferably less than 10%, of water.

[0117] The ODFs of the invention are clear and bright, flexible, non-sticky and resistant to handling and transportation.

[0118] According to the European Pharmacopeia, dissolution assay is the only mandatory test for ODF ([7]). In the present case, complete ODF dissolution is achieved in approximately 5 minutes, which is in line with European pharmacopoeia standards requiring a maximum dissolution time of 45 min for a standard release dosage form. The uniformity of the mass and thickness of the films of the invention are also acceptable for production. The different values measured (e.g. mass, thickness, content) were reproducible within the same batch and between different batches.

[0119] In a preferred embodiment, the ODFs of the invention contain 0.5 g / cm2of a solubilized form of HTC, for example 0.5 g / cm2of HMS.

[0120] When the HMS content in the final ODF is of 0.5 g / cm2, the surface of the ODF of the invention is preferably of 2 cm2and its thickness of less than 0.3mm, typically of about 0.2mm, so that the film is thin, flexible, easily dissolves in the mouth and delivers 1 mg of HMS / HCT in the mouth of the patient. It can have for example a rectangle shape of 1cmx2cm.

[0121] The ODF of the invention typically contains 1 mg of HTC, for example 1 mg of HMS, which is a multiple of the unit dose usually administered per day to children.

[0122] Importantly, the ODFs of the invention are stable and can be safely stored at room temperature more than 2 months: the results of the examples below show that the proportion of HMS / HCT in the ODFs of the invention do not vary over time and remain stable (~2-3%) for at least 84 days (Figures 4 and 5). In addition, no changes were observed in the organoleptic characteristics or texture of the ODFs of the invention after 84 days of storage at room temperature.

[0123] Interestingly, the ODFs of the invention contain a low residual water content. This advantageously promotes good microbiological and chemical stability and prevents the need for preservatives in the ODF (

[0024] ). Thus, in a preferred embodiment, the ODFs of the invention do not contain any preservatives or conservatives such as phenols, parabens, phthalates or sodium benzoate, which are known to cause adverse effects in growing and pubertal populations (

[0025] ), and to cause neonatal neurotoxicity and / or metabolic acidosis (

[0020] ). Since the ODFs of the invention are preferably devoid of such chemical preservatives, they are safer to use than many oral liquid formulations for infants.

[0124] Finally, the pH value of the ODF of the invention is about 6.5, which is consistent with mucosal and oral acceptability.

[0125] In the context of the invention, the term “about” refers to the normal variation or range of error for a given value or range known to the person of skills in the art. It usually means a value or range within (i.e. , ±) 20%, 10%, 5%, 2% or 1% of a given value or range. Therapeutic uses

[0126] Pharmacokinetics studies in humans following ODF dosing have shown that absorption patterns (e.g. Tmax) reflect an absorption localized to lower gastro-intestinal tract rather than the oral cavity (

[0021] ).

[0127] For the ODF formula that contains HMS, exposure of the ingested HMS to acidic and / or basic pH conditions within the gastro-intestinal system will favor the formation of the HOT, which is known to have an oral bioavailability of over 90% (

[0022] ). In addition, it has been reported that the plasma elimination half-live of HMS following an intravenous dosing is only about 5-6 minutes, with a peak plasma level of HCT being reached at about 10 minutes in humans, reinforcing the chemical instability of HMS in vivo (

[0023] ). Based on these arguments, HMS is likely to be a pro-drug for oral treatment, with pharmacokinetic characteristics, in particular oral absorption, similar to oral formulations with HCT. As HMS dissolves in the mouth through the ODF, it is possible to achieve a faster absorption time (i.e. Tmax) than with solid HCT pharmaceutical formulations.

[0128] The present invention relates to the ODFs of the invention, as defined above, for their use as a medicament. It also relates to the use of the ODFs of the invention, for the manufacture of a medicament.

[0129] Congenital adrenal hyperplasia is a group of autosomal recessive genetic disorders that result in a total or partial deficiency of an enzyme involved in adrenal steroidogenesis. The mutation found in over 95% of cases results in a deficiency of 21 -hydroxylase which impaired at least cortisol biosynthesis ([1]). In the most severe clinical manifestation, salt-wasting occurs when the deficit also affects aldosterone production. These patients are at risk of hyponatremia and hyperkalemia, severe hypotension, and shock ([2]). Hormone replacement therapy with glucocorticoids and / or mineralocorticoids is the standard of care. Because of its short half-life, hydrocortisone (HCT) is the best glucocorticoid for this indication in children. To mimic the physiological hormonal peak, an HCT formulation with immediate drug release is administered in 3 doses per day (10 to 15 mg / m2 / day), corresponding to ~1 to 2 mg per dose for a child ([3]). However, the very few HCT-containing orally available products are not appropriate for use at low dosing levels in the pediatric population. The main oral treatment for children remains the preparation of HCT hard capsules, which are predominantly prepared by hospital and community pharmacies and vary greatly in terms of product qualities.

[0130] In this context, the ODFs of the invention are preferably used for treating patients, in particular children, suffering from congenital adrenal hyperplasia. In other words, they are used for the manufacture of a medicament intended to treat patients, in particular children, suffering from congenital adrenal hyperplasia. The present invention also relates to methods for treating patients, in particular children, suffering from congenital adrenal hyperplasia, said methods involving the administration of the ODFs of the invention into the mouth of the patients, where the HTC drug is released systemically.

[0131] HTC I hydrocortisone may be also administered systemically for treating several other conditions, including:

[0132] - Adrenal insufficiency: This includes primary adrenal insufficiency (Addison's disease) or secondary adrenal insufficiency due to pituitary dysfunction. Hydrocortisone is used as hormone replacement therapy.

[0133] Severe allergic reactions: For anaphylaxis or severe asthma exacerbations, systemic hydrocortisone can be life-saving.

[0134] - Autoimmune conditions: Systemic lupus erythematosus, vasculitis, and other autoimmune disorders may be treated with hydrocortisone to suppress an overactive immune response.

[0135] Inflammatory bowel diseases: In conditions like severe ulcerative colitis or Crohn's disease flares, systemic hydrocortisone may be used to control inflammation.

[0136] - Acute flare-ups of multiple sclerosis: To reduce the inflammation of the nerves during a flare-up of the disease.

[0137] Organ transplantation: Hydrocortisone is used to prevent organ rejection after transplantation by suppressing the immune system.

[0138] Chronic inflammatory conditions, such as rheumatoid arthritis, where lower doses may be used for longer-term management, and higher doses might be used for acute flares. Shock and severe hypotension: Hydrocortisone can be used in the treatment of septic shock or other forms of acute circulatory failure if it is associated with adrenal insufficiency.

[0139] In another particular embodiment, the ODFs of the invention are used for treating patients, in particular elderly and children, suffering from adrenal insufficiency, allergic reactions, autoimmune conditions, multiple sclerosis, chronic inflammatory conditions, hypotension, or organ transplantation. In other words, they are used for the manufacture of a medicament intended to treat patients, in particular elderly or children, suffering from adrenal insufficiency, allergic reactions, autoimmune conditions, multiple sclerosis, chronic inflammatory conditions, hypotension, or organ transplantation. The present invention also relates to methods for treating patients, in particular elderly or children, suffering from adrenal insufficiency, allergic reactions, autoimmune conditions, multiple sclerosis, chronic inflammatory conditions, hypotension, or organ transplantation, said methods involving the administration of the ODFs of the invention, as described above, into the mouth of the patients, where the HTC drug is released systemically.

[0140] FIGURE LEGENDS

[0141] Figure 1 displays the ODF (4% HPC formula) water loss upon drying it at two different temperatures (23°C or 40°C).

[0142] Figure 2 shows the typical HMS ODF (4% HPC formula) colored with incorporation of carmine red for the purpose of the photography.

[0143] Figure 3 shows the evolution of HMS and HCT release (%) during ODF dissolution study of an ODF obtained by gel casting (mean ± SD; n = 3 per batch).

[0144] Figure 4 shows the ODF drug content expressed as total HMS and HCT concentration when an ODF film obtained by gel casting is stored at 23 ± 2° C, calculated as the ratio of the concentration on the day tested to the concentration on day 0; values are mean ± SD (n = 3).

[0145] Figure 5 shows the ODF (4% HPC formula) content in HMS and HCT when stored at 23 ± 20C, calculated as the ratio of their concentration to the total concentration (HMS and HCT); values are mean ± SD; n=3.

[0146] Figure 6 shows the remaining concentration in HMS+HCT of the ODF formulation of Table 9 in syringes kept for 56 days at -20°C, +4°C or +22°C.

[0147] Figure 7 shows the evolution of HMS+HCT release (%) during ODF dissolution study of an ODF obtained by 3D-printing.

[0148] Figure 8 shows the ODF drug content expressed as total HMS and HCT concentration when an ODF film obtained by 3D-printing is stored at 23 ± 2° C, calculated as the ratio of the concentration on the day tested to the concentration on day 0; values are mean ± SD (n = 3).

[0149] EXAMPLES

[0150] Example 1: ODF with HMS

[0151] I. Materials and methods

[0152] 1. Drugs and Chemicals Pharmaceutical grade pure powder of hydrocortisone micronized (HCT), Hydroxypropylcellulose GF grade (HPC) (Klucel GF® 300mPa.s), sucralose, povidone K25 were purchased from Inresa pharmaceutical (Bartheim, France). Hydrocortisone 21- hemisuccinate sodium salt Upjohn (HMS) was obtained from SERB pharmaceutical (Paris, France). Ondansetron ODF at 4 mg (Setofilm®) was purchased from Norgine (Rueil- Malmaison, France). Pharmaceutical grade polysorbate 80 (tween 80) and glycerol were obtained from Cooper (Melun, France). Pharmaceutical grade glyceryl monolinoleate (Maisine®) was kindly provided by Gattefosse (Saint-Priest, France), cola flavour was obtained from IFF (Tillburg, Netherland). Acetonitrile and orthophosphoric acid were of analytical grade, and purchased from VWR chemicals (Fontenay-sous-Bois, France). Distilled sterile water was purchased from Aguettant (Lyon, France).

[0153] 2. Validation of Stability-Indicating Liquid Chromatography HMS and HCT assay

[0154] 2.1 . Equipment and analytical conditions

[0155] HMS and HCT assay were performed by a high-performance liquid chromatography (HPLC) system (Dionex, Ultimate 3000, Thermo Scientific, Villebon-sur-Yvette, France) with HPG- 3200SD quaternary pump and WPS-3000TSL autosampler, coupled to a Dionex MWD-3000 diode array detector (DAD). HPLC system data acquisition (e.g., peak time, area under peak) was carried out using the Chromeleon® software (v6.80 SP2, Thermo Scientific). A Polaris® C18 column (250 x 4.6 mm; particle size, 5 pm; Agilent, Les Ulis, France) was used. The mobile phase consisted of a 30 / 70% (v / v) mix of acetonitrile and water adjusted to pH 2.0 with orthophosphoric acid. The flow rate, injection volume and the wavelength for quantification were set at 1.0 mL / min, 50 pL and 254 nm, respectively.

[0156] 2.2. Validation of the HPLC assay method

[0157] The HPLC stability indicating method has been developed for the detection and quantification of both HMS and HCT. Their respective calibration curves were used for quantification and validated according to the ICH guidelines by assessing the linearity, accuracy, specificity, and precision (

[0012] ).

[0158] Two stock solutions of HMS were prepared daily over three days by dilution of HMS with the mobile phase to a final concentration of 1 mg / mL.These stock solutions were used to independently prepare five calibration standards (ranging from 20 and 80 pg / mL) and three quality controls (25; 50; and 75 pg / mL, recorded in triplicate). Two stock solutions of HCT were also prepared daily over three days by dilution of HCT with the mobile phase to a final concentration of 50 pg / mL. These stock solutions were used for the independent preparation of nine calibration standards (ranging from 0.50 and 50 pg / mL) and three quality controls at each of the following concentrations: 0.8, 5 and 40 pg / mL.

[0159] For both calibration curves, the slope, intercept, and correlation coefficient (r2) were calculated each day to study linearity. Accuracy was determined using quality controls and expressed as the percentage of recovery determined by the following equation 1 : (Experimental concentration) / (Theoretical concentration) x 100 , with ± 5% as acceptance criteria.

[0160] Matrix effect was assessed by comparing calibration curve of HMS or HCT in water and in presence of all formula excipients.

[0161] Method precision was studied using quality controls recorded in triplicate on three independent days. The intra-days analysis was performed by calculating the relative standard deviation (RSD) of calculated compared to theoretical concentration on each quality control recorded in triplicate the same day (n = 3). The inter-days analysis was performed by calculating the RSD on each quality control recorded over three days (n = 9). Additionally, repeatability was estimated by recording 10 times a 50 pg / mL solution of HMS and calculating the RSD.

[0162] The limit of detection (LOD) and limit of quantification (LOQ) for HMS and HCT were evaluated based on response standard deviation and calibration curve slope based on the following equations:

[0163] LOD = (s(intercept)) / (s(slope)) x 3.3; LOQ = (s(intercept)) / (s(slope)), where s(intercept) and s(slope) are the standard deviation of the y-intercept and slope of the calibration curve, respectively.

[0164] 2.3. Selectivity of the HMS and HCT Analytical Method

[0165] Solutions of HCT and HMS at 50 pg / mL were prepared to obtain typical chromatogram. The selectivity of the method was ensured so that no chromatographic peak of an excipient or degradation product coincided with that for HMS and HCT. Chromatograms of HMS in the presence of all formula excipients were visually inspected to detect changes in shape of the peak as well as by the analysis of the HMS peak UV spectra recorded by DAD (200-400 nm).

[0166] To ensure that the method could be used as stability indicated, forced degradations of HMS and HCT solutions were conducted in three conditions: acidic (0.1M HCI), alkaline (0.1M NaOH) and oxidative (3% H2O2). Temperature was at 23 ± 2°C for HMS, and 40 ± 2°C for HCT acidic and alkaline stress, and 40°C ± 2°C for both HMS and HCT for the oxidative stress studies. Samples were taken and analyzed at selected time points.

[0167] To perform the forced degradation study, two stock solutions of HMS and HCT were prepared (200 pg / mL) according to the GERPAC protocol (

[0013] ). These solutions were then diluted in equal parts with either aqueous 0.1 M HCI, 0.1 M NaOH or 3% H2O2 and at a controlled temperature. After a selected reaction time, each solution was pH-neutralized if needed, and mobile phase was added to obtain a final 1 / 4thdilution.

[0168] Chromatograms were visually inspected as well as the HMS / HCT peak UV spectra to detect any changes or coelution of degradation product.

[0169] 3. ODF Formulation studies

[0170] 3.1 . Preparation of the casting solution and ODFs

[0171] ODF are prepared in four main steps: (1) preparation of the casting solution, (2) air removal and gelation, (3) casting process, (4) film formation by drying

[0172] Each step has been the subject of optimization though the variations of different parameters:

[0173] (1) The homogeneity of the casting solution has been improved through formulation testing by comparing the dissolution / content of HCT or the HMS in the casting solution. The order of inclusion of the components and management of the solution temperature (23°C or 40°C) were also investigated and evaluated by visual inspection.

[0174] (2) Air bubble removal was assessed with or without a five minutes ultrasound bath (Branson 2510, VWR) and then left at +4°C or 23°C for 10h, and evaluated by visual inspection.

[0175] (3) Two casting methods were evaluated: casting drops of the desired volume or casting a large area that is cut to the desired size after drying.

[0176] Casting surface was evaluated on four different materials: food grade greaseproof paper, glass, polyolefin liner and food grade silicon. The gel was cast on the support in an area of 5 cm x 20 cm and -1 ,700 pm thick. Drying and demolding were investigated. Drying was carried out at 23 ± 2°C for 24h. This study was performed three times on each surface material.

[0177] (4) Drying was assessed by casting 1,000 mg of gel onto a food grade silicon surface and evaluated at three temperature conditions: 23 ± 2°C, 40 ± 2°C, and 60 ± 2°C in the proofer (n = 3 per condition). The weight was measured at different time points using an analytical balance (Mettler Toledo AG204, Viroflay, France), and compared to the initial value by calculation of the water loss on drying (%) using this formula; Equation 2:

[0178] Loss on drying = (Weight 1 -Weight 2 ) I (Weight 1) x 100, with Weight 1 = weight of the film at start time (tO), and Weight 2 = weight of the film at another chosen time.

[0179] 3.2. ODF preformulation testing

[0180] Pre-formulation tests were carried out to understand the effect of the main excipients in the absence of API. The formulations tested are listed in Table 1. ODFs were formed by dropping 1 mL of casting solutions onto greaseproof paper and dried for 24 hours at room temperature. The mechanical properties of the films were assessed by visual and manual inspection. Texture, stretch resistance and handling were evaluated by manually manipulating the films. Each parameter was scored out of 5 by the operator, with 5 being the best score. The individual scores were then added together to give a total score out of 15, 15 being the best.

[0181] Table 1. ODF formulations for preliminary testing

[0182] Formulation HPC (%) Glycerol (%) Povidone K25 (%) Water (up to) (%)

[0183] PF1 9 0 0 100

[0184] PF2 9 2 0 100

[0185] PF3 9 4 0 100

[0186] Al 3 2 2 100

[0187] A2 3 2 5 100

[0188] A3 3 2 10 100

[0189] Bl 5 2 2 100

[0190] B2 5 2 5 100

[0191] Cl 9 2 2 100

[0192] C2 9 2 5 100

[0193] 3.3. Formula optimization

[0194] To find an optimal ODF formulation, the selected component proportions were varied as described in Table 2. Table 2. Concentration range of excipients tested for optimisation of ODF formulation

[0195] HMS in HPC Glycerol Povidone Surfactant Sucralose Cola Water

[0196] HCT (%) (%) K25 (%) (%) (%) flavour (%) (up to) (%) equivalent (%) 0.30 2 - 8 0.5 - 3.0 5 - 10 0 - 0.4 0.25 0.5 100

[0197] API: An appropriate amount of HMS was incorporated to produce 0.5 mg / cm2ODF.

[0198] Polymeric agents: gel viscosity and film hardness were improved by varying the percentage of HPC and povidone. The gel viscosity had to be low enough to allow smooth casting and not too low to keep the gel fairly compact during drying. The films produced had to be strong enough not to break during demolding and handling.

[0199] Plasticizer : concentration was optimized by the preparation of five batches of films with increased glycerol concentration: 0.5%, 1%, 1.5%, 2% and 3%. Five pharmacists were asked to rate each film on three criteria: flexibility, stretch resistance, and non-stickiness of the film.

[0200] Each criterion was scored from 1 to 5, with 5 being the best.

[0201] Surfactant: as described by Cupone et al (

[0014] ), the use of a silicon surface requires a surfactant with an hydrophilic / lipophilic balance (HLB) around 4.5 to prevent the gel from shrinkage of the gel during drying. Therefore, a mixture of glyceryl monolinoleate / polysorbate 80 (75 / 25%; w / w) was chosen.

[0202] Sucralose and flavor: cola flavor is described as good at masking bitterness. In this aim, it has been incorporated with sucralose at the usual concentrations.

[0203] The dynamic viscosity of the 4% HPC gel once degassed was measured using a Rotavisc®

[0204] Lo-vi (I KA, Staufen im Breisgau, Deutschland). Measurements were conducted at 23 ± 2°C during at least 45 min using a SP-2 probe (IKA) at 5 and 10 rpm, and a SP-1 probe (IKA) at 3 rpm.

[0205] 4. 3D printing

[0206] An alternative of gel casting is 3D printing. The ODF formulations of the invention were used to be printed with the M3DIMAKER pharmaceutical printer of FABRX. The parameters which have been used are disclosed in the following table. i : i : i

[0207] 5. ODF Characterization assay

[0208] Unless otherwise specified, the characterization studies were performed on formulation containing 4% HPC, 1.5% glycerol, 5% povidone K25, 0.2% surfactant, 0.25 % sucralose and 0.5% cola flavor.

[0209] 5.1. Gel uniformity

[0210] Gel uniformity was assessed by preparing a 50 mL gel and taking samples from the top, middle and bottom of the gel. Five samples were taken from each level and analyzed by HPLC for HMS and HCT content.

[0211] 5.2. ODF mass and thickness uniformity

[0212] Mass uniformity for single-dose preparation was determined according to the European Pharmacopeia (method 2.9.5) ([7]). Twenty ODFs (1x2 cm) randomly selected from the same batch were then individually weighed on an analytical balance.

[0213] Thickness was measured on the same twenty ODFs using a numeric caliper (Dexter, Lille, France) with lower limit of detection at 0.1 mm and precision of 0.02 mm. Both tests were performed on batches with 4%, 5% or 6% of HPC.

[0214] 5.3. ODF content uniformity

[0215] The uniformity of the content was assessed after casting on a surface of 24.4x8.4 cm with a thickness of 1 ,700 pm. Once dried, a strip of 0.2 cm in width was withdrawn from the end of each side. The film was then divided into three equal areas: left, middle and right. Each area was then cut into 32 film sections of 1x2 cm (corresponding to 1 mg of hydrocortisone base). Three film sections from each area were analyzed for HMS and HCT content by HPLC.

[0216] 5.4. ODF disintegration time

[0217] In the absence of a European Pharmacopoeia monograph, the test was performed using the same methodology as described by El-Setouhy et al. (

[0016] ). A 1x2 cm film (2 cm2) was placed in a Petri dish (diameter: 4.5 cm) filled with 10 mL of phosphate buffer (0.1 M, pH 6.8). The Petri dish was placed on a hot plate with magnetic stirring (AM3003 Bioblock, Fisher scientific, I llkirch, France). The temperature was maintained at 37 ± 2°C and the stirring speed was set at 100 rpm. The time of the first break time and the time of complete disintegration time were measured using a timer. The time of the first break was determined visually as the time at which the first film change / alteration occurred. The time at which the observer estimated that almost 90% of the total film had disintegrated was defined as the time of disintegration. Each test was performed in triplicate by the same observer on 4%, 5% and 6% HPC formulations. The disintegration time was also measured with the ondansetron ODF Setofilm® 4mg.

[0218] 5.5. pH determination

[0219] The pH of ODF was measured after dissolving a film in 2 mL of distilled water using a pH meter (Mettler-Toledo, Viroflay, France).

[0220] 5.6. Residual water content

[0221] The measurement of the residual water content is carried out by placing three ODFs in the drying oven set at 105°C for a period of 1 hour. The initial and final weights are measured on analytical balance (Mettler Toledo) and water loss was calculated according to the Equation 2 (

[0018] ).

[0222] 5.7. Dissolution assay

[0223] The dissolution assay was performed on three films of 1x2 cm and three different batches (n = 9). Each film was placed in a 20mL vial containing 20mL of phosphate buffer (0.1 M, pH 6.8). The vials were placed on a magnetic stirrer with a heating plate maintained at 37°C and a stirring speed of 500 rpm (AM3003 Bioblock, Fisher scientific, I llkirch, France). Twelve samples of 1mL each were collected at 0, 0.5, 1 , 1.5, 2, 3, 4, 5, 7.5, 10, 15 and 30 min. Each 1mL of sample was compensated with an equal volume of buffer. At each sampling time n, the amount of HMS and HCT collected at sampling time n-1 is added to the measured concentration to compensate for the amount previously sampled. Results are reported as a percentage of drug released (both HMS and HCT) compared to the theoretical concentration corrected for the surface are of the ODF.

[0224] 5.8. Drug Stability study

[0225] ODF (1x2 cm) were placed in Medi-Dose® anti-UV individual blisters (Pero’s, Saint-Priest, France) and stored at ambient temperature (23 ± 2°C; 55 ± 5% relative humidity). Three ODFs obtained by gel casting and three ODFs obtained by 3D-printing were tested at selected time points: 0, 3, 5, 10, 14 days and weekly up to 60 days. HMS and HCT content were assessed simultaneously using the stability-indicating liquid chromatography and respective calibration curves. Stability was determined by evaluating the percentage of the initial concentration remaining at each time point. Stability is defined as the recovery of at least 90% of the initial combined HMS and HCT concentration. The results are expressed as a percentage of the remaining HMS and HCT content compared to the initial concentration after correction by the surface of the ODF (Figures 4 and 8 for casted ODFs and 3D-printed ODFs respectively).

[0226] Organoleptic parameters such as aspects and texture were also noted at each time point.

[0227] 5.9. Data Analysis

[0228] Data analysis was performed using Excel 365 (Microsoft, Seattle, WA, USA) and Prism (GraphPad Software, version 7.04, San Diego, CA, USA). Descriptive statistics for continuous variables were expressed as mean ± standard deviation (SD) unless otherwise specified.

[0229] / / . Results

[0230] 1. Validation of Stability-Indicating Liquid Chromatography HMS and HCT Assay

[0231] 1.1. Validation of the HPLC Assay Method

[0232] HMS calibration curve was linear between 20 pg / mL and 80 pg / mL (Table 3) (y = 1.442 (± 0.019) x + 1.196 (± 1.062); r2 = 0.998). The HMS retention time was -20.5 min. Selectivity was obtained and no matrix effect was demonstrated. As shown in Table 4, HMS assay precision was <4% and accuracy was no less than 95% for all HMS concentration tested, and the repeatability was < 3% (n = 9). The HMS LCD and LOQ were 2.4 pg / mL and 7.4 pg / mL, respectively, which was acceptable for the concentration range measured.

[0233] Table 3. Precision and accuracy of the HMS calibration curve

[0234] HMS Calculated

[0235] . RSD Accuracy

[0236] Concentration concentration ± SD

[0237] ( g / mL) (pg / mL)( / o) ( / o)

[0238] 20 19.9± 0.4 1.8% 99.3 ± 1.8

[0239] 35 35.0 ± 0.8 2.2% 99.9 ± 2.2

[0240] 50 50.1 ± 1.1 2.1% 100.3 ± 2.2

[0241] 65 65.4 ± 1.5 2.2% 100.6 ± 2.2

[0242] 80 79.7 ± 1.9 2.4% 99.6 ± 2.4

[0243] SD : Standard deviation ; RSD : Relative standard deviation Table 4. Intra and inter-day precision and accuracy results at three HMS concentration levels

[0244] Intra-Day Validation Inter-Day Validation

[0245] , Mean calculated „„ Mean calculated „„ Mean

[0246] Theoretical „ RSD Accuracy „ RSD

[0247] „ . Day Concentration ± SD „z, > Concentration ± SD „z zAccuracy

[0248] Concentrationy(%) % %

[0249] (pg / mL) (Pg / mL) (M=9) (Pg / mL) (n = 9) ± SD (%)

[0250] 1 25.1 ± 0.1 0.5 100.5

[0251] 25 2 24.9 ± 0.1 0.3 99.6 24.8 ± 0.4 1.6 99.1 ± 1.6

[0252] 3 24.3 ± 0.1 0.3 97.4

[0253] 1 51.7 ± 0.1 0.1 103.5

[0254] 50 2 49.3 ± 0.1 0.1 98.7 49.7 ± 1.8 3.8 99.4 ± 3.8

[0255] 3 48 ± 0.1 0.3 96.1

[0256] 1 77.1 ± 0.1 0.2 102.8

[0257] 75 2 74.5 ± 0.1 0.1 99.3 74.4 ± 2.8 3.8 99.1 ± 3.8

[0258] 3 71.4 ± 0.3 0.5 95.3

[0259] SD : Standard deviation ; RSD : Relative standard deviation

[0260] HCT calibration curve was linear between 0.50 pg / mL and 50 pg / mL (Table 5) (y = 2.132 (± 0.004) x + 0.164 (± 0.086); r2 = 0.999). The HCT retention time was ~9.5min. Selectivity was assessed - there was no peak deformation or change in UV spectra in the presence of excipients and no matrix effect was demonstrated. As shown in Table 6, HCT assay precision was <2% and accuracy was no less than 95% for all HCT concentration tested, and the repeatability was < 3% (n = 9). The HCT LCD and LOQ were 0.13 pg / mL and 0.40 pg / mL, respectively, which was acceptable for the concentration range measured.

[0261] Table 5. Precision and accuracy of the HCT calibration curve

[0262] HCT Calculated RSD

[0263] Concentration concentration ± SD Accuracy (%)

[0264] (pg / mL) (pg / mL)

[0265] 0,5 0.5 ± 0.1 1.18 95.4 ± 1.1

[0266] 1 1.0 ± 0.1 1.90 100.5 ± 1.9

[0267] 4 3.9 ± 0.1 0.06 96.4 ± 0.1

[0268] 10 10.2 ± 0.1 0.54 101.9 ± 0.5 50 50.0 ± 0.1 0.26 99.9 ± 0.3

[0269] SD : Standard deviation ; RSD : Relative standard deviation Table 6. Intra and inter-day precision and accuracy results at three HCT concentration levels

[0270] Intra-Day Validation Inter-Day Validation

[0271] HCT Mean calculated

[0272] _ . _ Mean calculated _ _ Mean

[0273] Theoretical Da _ _ RSD Accuracy Concentration ± RSD

[0274] . Concentration ± SD . Accuracy

[0275] Coneentahon < ») ( ^) ® ( ^)± SD (%)

[0276] 1 0.8 ± 0.1 5.3 103.0

[0277] 0.8 2 0.8 ± 0.1 2.7 100.5 0.8 ± 0.1 1.62% 101.1 ± 1.6

[0278] 3 0.8 ± 0.1 1.5 99.9

[0279] 1 5.1 ± 0.1 2.6 102.4

[0280] 5 2 5.1 ± 0.1 1.9 102.7 5.1 ± 0.1 0.27% 102.4 ± 0.3

[0281] 3 5.1 ± 0.1 2.7 102.1

[0282] 1 39.4 ± 0.1 0.2 98.6

[0283] 40 2 39.5 ± 0.2 0.5 98.6 39.5 ± 0.1 0.24% 98.8 ± 0.2

[0284] 3 39.6 ± 0.3 0.4 99.0

[0285] SD : Standard deviation ; RSD : Relative standard deviation

[0286] 1.2 Selectivity of the HMS and HCT Analytical Method The HMS chromatogram shows three peaks with retention times of ~9.2 min (~ 2% of total area), ~11min (~ 1 % of total area) and ~20.5min (97% of total area). The HCT chromato-gram shows one peak with retention times of ~9 min. HCT and HMS can be identified at ~9 min and -20.5 min, respectively.

[0287] HMS is particularly sensitive under acidic and alkaline conditions, as shown by forced degradation studies (Table 7). Under these conditions, the degradation of HMS is associated with the appearance of HCT in an inversely proportional manner. HCT is also sensitive to extreme pH conditions but to a lesser extent than HMS (Table 7). In those conditions, degradations peaks with similar retention times regarding the two molecules were found.

[0288] Table 7. Forced degradation of the HCT and HMS

[0289] Stress Conditions and Time of . . Retention Time of the Detected

[0290] Drug , / o Remaining ,

[0291] Analysis Degradation Product(s) (min)

[0292] Acidic (0. IM, 40°C, 30 min) 77% 3.9; 7.8; 8.4; 19.4

[0293] Alkaline (0. IM, 40°C, 30 min) 53% 3.9; 6.5; 7.8; 8.4; 11.1; 19.4; 30.1

[0294] HCT

[0295] Oxidative (3%, 40°C, 24h) 90% No degradation peak detected

[0296] (Heating, 40°C, 24h) 92% No degradation peak detected

[0297] Acidic (0.1M, 23°C, 15 min) 52% 9.2; 11.1 hmsAlkaline (0. IM, 23°C, 15 min) < LOQ 7.7; 8.1; 9.2

[0298] Oxidative (3%, 40°C, 24h) 77% No degradation peak detected

[0299] (Heating, 40°C, 24h) 97% No degradation peak detected HCT: hydrocortisone; HMS: hydrocortisone hemisuccinate

[0300] No degradation products co-eluted with HCT or HMS peaks. Furthermore, no peak deformation or modification of the UV spectra of HCT or HMS were observed. Thus, the developed method indicates good specificity for studying HMS and HCT degradation and allows its use as a stability indicating method.

[0301] 2. ODF Formulation studies

[0302] 2.1 . Preparation of the casting gel and ODFs

[0303] Several conditions and parameters were studied to optimize ODFs during all four preparation steps:

[0304] (1) Preparation of the casting solution: to obtain a perfectly homogenous gel, all the components except the HMS and HPC are mixed in the water. Once perfectly solubilized, the solution is heated at 40° C, as HPC is insoluble over 38° C. This temperature avoids the formation of small gelatinous masses and therefore improves dispersion of the HPC. These steps are mandatory to avoid clots and aggregates in the casting gel, resulting in ODF that will break at the slightest contact. To limit the exposure of the API to heating process, it is incorporated just before the HPC. The solution is then brought to room temperature under stirring, allowing the gel to form gradually.

[0305] (2) Degassing and gel formation: The solution is left to stand for several hours (~ 10h) until the HPC is completely solubilized. It is ready for spreading when the gel is visually completely homogeneous and the air bubbles completely removed. The absence of air bubbles is essential for obtaining a complete ODF with a reproducible and accurate API content. Degassing at +4C showed no effect versus ambient temperature as it took several hours to remove all the entrapped air. Use of the ultrasonic bath for 5 min helped to raise air bubbles in the upper half of the recipient, saving a few hours on this stage.

[0306] (3) Casting process: the greaseproof paper did not allow a good drying. The paper absorbs too much water resulting in uneven thickness and discontinuities in the film. Glass plate allows the formation of a smooth film but demolding was impossible. Liner allows the formation of a smooth film with very easy demolding, but it was difficult to stretch the liner enough resulting in irregularities in the thickness of the film. Alimentary silicon was the best tested surface giving a smooth film that was easy to demold. This surface has been selected for the rest of study.

[0307] (4) Drying and solvent evaporation has been investigated at three temperatures: room temperature (23 ± 2°C), 40 ± 2°C and 60 ± 2°C. The results are shown in Figure 1. The 60°C condition could not be studied because the gel was dephasing. Loss on drying at 24h was found to be 83.4 ± 0.4% at room temperature and 84.9 ± 0.1 % at 40 ± 2°C. Drying at 40°C allows to reach 78.4 ± 1.3% of loss in 6 hours, in comparison room temperature reaches 79.8 ± 1.5% in 9 hours. Droplet casting allows precise casting but requires considerable space between the deposits to prevent them from coalescing. In addition, the ODFs produced present a “coffee-stain” morphology that is not suitable. Casting a large area then cutting the ODF to the desired dimension seems to be a better technique for a larger scale production. Therefore, this method can be preferably used to produce the formulation of the invention.

[0308] 2.2. ODF preformulation test

[0309] Formulations PF1 , PF2 and PF3 produced three very different types of film. PF1 was very hard and not elastic, and therefore brittle. PF2 and PF3 were as hard as PF1 , but the elasticity increased with the percentage of glycerol. All three formulations took hours to disintegrate. PF3 was too oily in texture. PF2 films were slightly sticky, but produced elastic, flexible films. The percentage of glycerol in PF2 was selected as a standard for further research.

[0310] Povidone K25 was added to the formulation to improve disintegration. It was also found to increase the viscosity of the casting solution. Solutions A1 , A2 and A3 were prepared with less HPC. Formulations containing 2% povidone (A1 , B1 and C1) took more than 300 sec to disintegrate while 5% (A2, B2 and C2) took between 60 sec to 300 sec at and 10% (A3) between 45 to 300 sec. Similar results were observed between B1 and B2 and between C1 and C2. Film texture was affected by povidone with films appearing less flexible and elastic, with little difference in disintegration time between 5% and 10%. Therefore, 5% was selected as the standard.

[0311] To assess the casting solutions viscosities, different percentages of HPC were prepared. Degassing was completed in less than 24h for formulations A and B, which was not the case for formulation C. The viscosity difference between A2 and B2 did not appear to affect the ODF preparations during casting them by drops. Consequently, these formulations were selected for further study.

[0312] 2.3. ODF formulation optimization

[0313] API: HMS was chosen as the API because of its greater solubility, which enables a homogeneous gel to be obtained.

[0314] HPC and povidone K25: 5% povidone formulations were considered optimal as the other percentages tested (i.e. 7.5 and 10%) resulted in non-flexible ODF with a “plastic” appearance even with a low percentage of HPC (3%).

[0315] Feeling of casting gel between 4-6% of HPC seemed to be optimal, no differences between these percentages could be detected by visual and manual inspection. Percentage above 6% caused jolts while spreading the gel, resulting in noticeable irregularities in the casting. Percentages below 4% (e.g. 2.5%, 3%) were considered too liquid. Glycerol: concentrations investigated were 0.5%, 1%, 1.5%, 2% and 3%. The 2 and 3% glycerol formulations were considered too adhesive for operator handling and were discarded from the study. Other results are shown in Table 8.

[0316] Table 8. Scoring of the ODF formulations according to the glycerol content (4% HPC formula)

[0317] Glycerol 0.5% 1.0% 1.5%

[0318] Flexibility ( / 5) ± SD 1.4 ± 0.5 3.2 ± 1.1 4.6 ± 0.5

[0319] Stretch resistance ( / 5) ± SD 1.4 ± 0.9 3.8 ± 1.3 4.2 ± 0.8 Stickiness ( / 5) ± SD 4.0 ± 0.7 3.6 ± 0.5 3.0 ± 1.0 Total score ( / 15) ± SD 7.2 ±1.5 10.6 ± 0.3 11.8 ± 0.3

[0320] SD: Standard deviation

[0321] The 0.5% formulation was considered the worst as the films produced were very brittle. The 1% and 1.5% formulations appear to be adequate, with the 1.5% formulation scoring the highest but the 1% formulation being judged to be more balanced and less sticky. Surfactant (glyceryl monolinoleate / tween 80; 75% / 25%): without surfactant in the formulation, the film showed significant shrinkage at one or two corners of the film area during drying. At 0.1 % some holes started to appear in the film. Good results were obtained at 0.15% and 0.2% with no shrinkage and with acceptable elasticity. Above 0.2% the elasticity increased and was not optimal, difficult, or impossible to handle / manipulate. These various tests resulted in the formulation shown in Table 9. When this gel formulation is casted with a thickness of 1 ,700 pm, a large film of 0.5 mg / cm2is obtained. After drying it is cut at 1 per 2 cm to give 1 mg of HCT equivalent per ODF fragment. A typical ODF obtained by using the casting process and formulation of the invention are shown in Figure 2.

[0322] Table 9. Composition of casting gel for HMS ODF

[0323] Composition

[0324] Ingredients _ (. / o) _

[0325] HMS (in equivalent 0.30

[0326] HCT)

[0327] HPC 4.0 - 6.0

[0328] Glycerol 1.5

[0329] Povidone K25 5.0

[0330] Surfactant 0.20

[0331] Sucralose 0.25

[0332] Cola flavor 0.50 Water (Up to) 100

[0333] The stability of the HMS+HCT drugs in the gel formulation of Table 9 was assessed for two months at various temperatures, when loaded in syringes, prior to casting or printing. The drug appears to be affected by the storage at 22°C, and it is therefore recommended to keep the gel at -20°C or at +4°C when long storage is required.

[0334] 3. Characterization assay

[0335] 3.1. Casting gel uniformity

[0336] The HMS contents of the upper, middle, and bottom zones were 104.6 ± 1.0%, 103.1 ± 2.0% and 104.4 ± 1.5% of the target value, respectively. The average content was 104.1 ± 1.5%.

[0337] 3.2. Gel viscosity

[0338] The dynamic viscosity of the degassed gel was measured using the SP-2 probe at 1 761 mPa. s'1at 10 rpm and 1686 mPa.s'1at 5 rpm. Using the SP-1 probe, the viscosity was measured at 1830 mPa.s'1.

[0339] 3.3. ODF mass and thickness uniformity

[0340] The average mass and thickness of dry ODF as a function of HPC composition are shown in Table 10. The 5% and 6% formulations appeared similar whereas the 4% formulation appeared lighter and thinner. Regardless of the formulation, ODFs were very similar in each batch with SD <0.2mm.

[0341] Table 10. Influence of HPC content on mass and thickness of HMS ODF (2 cm2; n = 20)

[0342] HPC 4% HPC 5% HPC 6%

[0343] ODF mass ± SD (mg) 26.7 ± 1.7 42.1 ± 3.1 38. 8 ± 3.0

[0344] ODF thickness ± SD

[0345] 0.11 ± 0.10 0.17 ± 0.10 0.16 ± 0.10 (mm)

[0346] SD: Standard deviation

[0347] 3.4. Content uniformity

[0348] The amount of total API (as mean ± SD; n = 3) expressed as HCT equivalent (mg) for 2 cm2ODF is 1.03 ± 0.06 mg, 0.98 ± 0.11 mg and 0.96 ± 0.0.6 mg, in the left, middle and right areas, respectively. The average content is 98.5% of the expected target value, and all films were in the range of 100 ± 15% of the expected content. 3.5. Disintegration time

[0349] The disintegration times as a function of HPC content and compared to Setofilm® are shown in Table 11. Both the time to first break and the time to complete disintegration increase significantly with the HPC content.

[0350] Table 11. HMS ODF time for disintegration and break (n=3)

[0351] Setofilm® HPC 4% HPC 5% HPC 6%

[0352] First break time (mean ± SD) (s) 35 ± 10 62 ± 39 264 ± 68 * 511 ± 101 **

[0353] Time for complete disintegration _ 1 620 ± 114 2 073 ± 234

[0354] 219 ± 149 541 ± 86 *

[0355] (mean ± SD) (s)

[0356] SD: Stan dard deviation; (* p < 0.05; ** p < 0.01; *** p < 0.001 as compared to

[0357] Setofilm

[0358] 3.6. pH determination

[0359] The average pH of a HMS ODF was found to be 6.53 ± 0.08 (n = 3).

[0360] 3.7. Residual water content

[0361] The residual water content of HMS ODF is 9.0 ± 1.2 % (n = 3) according to equation 2 with a weight of 23.6 ± 1.2 mg measured after 1 h.

[0362] 3.8. Dissolution test

[0363] The results of the dissolution test are shown in Figure 3 for the casted ODF, and in Figure 7 for the 3D-printed ODF. For both, the target concentration of 50.0 ± 2.5 pg / mL HMS+HCT is reached after approximately 5 minutes.

[0364] 3.9. Stability study

[0365] No variation of more than 10% in content within a film has been shown (Figure 4, Figure 8). The proportions of HMS and HOT did not otherwise vary during the stability study (Figure 5). In addition, no change in organoleptic characteristics were noted in 3D-printed or in gel casted ODF films.

[0366] Importantly, it is observed that the residual content in HCT in the ODF after 295 days of storage at room temperature is of 98.5% in average (+ / - 0,9%)

[0367] 3.10. Final composition of the ODF

[0368] The residual mass of all the components of the ODF of Table 9 was calculated after drying of the ODF formulation of Table 9.

[0369] The results are provided in Table 12. Table 12. % Residual mass of the component of the ODF

[0370] Example 2 : ODF with HCT / CD Another soluble form of hydrocortisone (HCT) was introduced in a ODF according to the invention. This soluble form is a mixture of hydrocortisone base with the hydroxypropyl- - cyclodextrins Kleptose®, produced by Roquette (hereafter called “HCT / CD”). A molar ratio of 2:1 (cyclodextrin: HCT) was used. This ratio appears to be sufficient to fully solubilize the hydrocortisone, as previously described in the literature. The ODFs of the invention are prepared with HCT / CD as described above for the HMS ODFs (see table 9).

[0371] The dosage of the HCT content in three different parts of the gel formulation and in five final ODFs was made as explained above, by HPLC (see example 1 , 1.2).

[0372] The results are shown in Table 13:

[0373] Table 13: Relative error in HCT content of gel sampled at different positions (n=3) and five ODFs made from the same gel (n=5).

[0374] From these data, it can be concluded that the homogeneity of gel formulations and ODFs incorporating HCT / CD is very good.

[0375] Also, it appears that ODFs incorporating HCT / CD have the same targeted structural, organoleptic, and therapeutic advantageous properties as the HMS ODFs disclosed above.

[0376] Morover, the resulting HCT / CD ODFs are acceptable in terms of structural behavior (they are thin and flexible) and in terms of dissolution / disintegration rate, mass uniformity, content and stability.

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Claims

CLAIMS1. An Orodispersible Film (ODF) gel formulation having a viscosity comprised between 1000 and 5000mPa.s'1by using a rotational viscometer of the ROTAVISC lo-vi from IKA, having a spindle SP-2, at a rotation speed of 10 rpm during 90 minutes, at 23° C (+ / - 3° C), said gel formulation containing an effective amount of :- hydroxypropylcellulose,- polyvinyl pyrrolidone,- glycerol,- a mixture of glyceryl monolineate and polysorbate 80,- a solubilized form of a hydrocortisone-type corticosteroid (HTC) chosen among hydrocortisone, hydrocortisone acetate, cortisone, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, and prednisone, and- water, wherein all these ingredients are completely solubilized and wherein the gel formulation is degassed.

2. The ODF formulation of claim 1 , wherein said solubilized form of HTC is chosen in the group consisting of : hydrocortisone complexed with a cyclodextrin, a pharmaceutically acceptable soluble salt of hydrocortisone, hydrocortisone incorporated into a surfactant, hydrocortisone dissolved in an alcohol, and hydrocortisone hemisuccinate (HMS).

3. The ODF formulation of claim 1 or 2, wherein said solubilized form of HTC is hydrocortisone hemisuccinate (HMS) or a cyclodextrin-encapsulated hydrocortisone.

4. The ODF formulation of claim 1 or 3, wherein it contains :- between 4 and 6% w / w of hydroxypropylcellulose,- between 4 and 8% w / w of polyvinyl pyrrolidone,- between 1 and 1 .5 % w / w of glycerol,39- between 0.15 and 0.2% w / w of a mixture of glyceryl monolineate and polysorbate 80,- between 0.1 and 1% w / w of HMS and- water.

5. The ODF formulation of claim 1 or 3, wherein it contains :- between 4 and 6% w / w of hydroxypropylcellulose,- between 4 and 8% w / w of polyvinyl pyrrolidone,- between 1 and 1 .5 % w / w of glycerol,- between 0.15 and 0.2% w / w of a mixture of glyceryl monolineate and polysorbate 80,- between 0.1 and 1% w / w of a cyclodextrin-encapsulated hydrocortisone and- water.

6. The ODF formulation of any of claims 1-5, further containing a taste-masking agent, a sweetener, a flavor, a coloring agent and / or a saliva stimulator.

7. A method to manufacture a dry, thin, and flexible hydrocortisone-type corticosteroid (HTC)- releasing ODF, said process containing the steps of : a) mixing in water all the ingredients of the ODF gel formulation as defined in claims 1-6, until a gel is formed and complete solubilization of all the ingredients is achieved, b) degassing the ODF gel formulation obtained in step a), c) casting or 3D-printing the degassed gel formulation of step b) onto a silicon-coated surface, d) drying the casted or printed ODF gel formulation until less than 30% of water content is present in the ODF film, e) optionally, cutting the ODF film to obtain an appropriate size, and separating the ODF film from the surface.

8. The method of claim 7, wherein step a) is performed at a temperature comprised between 40°C and 50°C so as to facilitated the dispersion of the polymer agent before solubilization and gelation at a temperature below 40° C.

409. The method of claim 7 or 8, wherein the degassing step b) consists in letting the gel rest for a period of time comprised between 5 and 24 hours.

10. The method of any one of claim 7-9, wherein the drying step d) is performed at room temperature for at least 3 hours.

11. An HTC-releasing ODF obtained by the method of claims 7-10, said ODF preferably containing :Between 0.1 g / cm2and 1 g / cm2of a solubilized form of hydrocortisone-type corticosteroid (HTC), preferably between 0.1 g / cm2and 1 g / cm2of HMS or of a cyclodextrin-encapsulated hydrocortisone,Between 15 and 35% w / w of HPC,Between 20 and 45% w / w of polyvinyl pyrrolidone,Between 5 and 15% w / w of glycerol,Between 0.5 and 2% w / w of a mixture of glyceryl monolineate and polysorbate 80 (75% / 25% respectively),Less than 30% w / w of water.

12. An HTC-releasing ODF containing :Between 0.1 g / cm2and 1 g / cm2of a solubilized form of hydrocortisone-type corticosteroid (HTC), preferably between 0.1 g / cm2and 1 g / cm2of HMS or of a cyclodextrin-encapsulated hydrocortisone,Between 15 and 35% w / w of HPC,Between 20 and 45% w / w of polyvinyl pyrrolidone,Between 5 and 15% w / w of glycerol,Between 0.5 and 2% w / w of a mixture of glyceryl monolineate and polysorbate 80 (75% / 25% respectively),Less than 20% w / w of water.

13. The ODF of claim 11 or 12, wherein it has a thickness of less than 0.3mm, it is flexible, non-sticky, resistant to handling and remains stable for at least 84 days at room temperature.

14. The ODF of any of claims 11 to 13, wherein it contains 0.5g / cm2of HMS.

15. The ODF of any of claims 11 to 13, wherein it contains a HMS dose of 1 mg.

16. The ODF of any of claims 11-15, for use as a medicament.

17. The ODF of any of claims 11-16, for use as a medicament for treating patients suffering from adrenal insufficiency, allergic reactions, autoimmune conditions, multiple sclerosis, chronic inflammatory conditions, hypotension, or organ transplantation, preferably elderly or children patients suffering thereof.

18. The ODF of any of claims 11-16, for use as a medicament for treating children suffering from congenital adrenal hyperplasia.

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