Oral disintegrating film formulations

Abstract

A composition suitable for preparing an orally soluble film having improved properties, particularly good elasticity (low brittleness), rapid disintegration, and low tackiness, is disclosed. Orally soluble films prepared from such compositions, as well as medical uses and therapeutic methods using such orally soluble films, are also disclosed.

Description

[Technical Field]

[0001] The present invention relates to a drug delivery system, particularly a drug delivery system in the form of an orally disintegrating film. [Background technology]

[0002] Many medical and / or pathological conditions require the administration of chemical and / or medicinal substances or drugs to the subject. A common example of an application requiring drug delivery is the treatment of pain.

[0003] A known method of administering a substance orally to a patient is by the use of orally disintegrating films ("OTFs"). The term "orally disintegrating films" is a term known in the art, and the term "thin" will be understood not as a relative term, but as merely part of the recognized phrase "orally disintegrating films," which is widely understood by those skilled in the art to have a recognized meaning and refers to a type of product. Other synonyms for the same type of product are "orally soluble films," "thin soluble films," "orally dispersible films," "orally disposable films," "orally drug strips," or "orally films."

[0004] OTFs are film formulations composed primarily of water-soluble film-forming polymers that can rapidly dissolve in the mouth of the target individual. Initially developed as breath fresheners, OTFs have evolved for the oral delivery of active pharmaceutical ingredients (APIs). Roughly the size of a postage stamp, they dissolve rapidly in saliva once placed in the mouth of the target individual, without the need for chewing or drinking water. These film formulations are formulated using minimal food- or pharmaceutical-grade excipients and are relatively inexpensive to manufacture. As an alternative solid platform for drug delivery, they can be formulated without the need for preservatives or solvents, making them an attractive option for pediatric drug delivery where the administration of liquid formulations can result in exposure to potentially harmful excipients.

[0005] Typically, 5-30% drug loading can be achieved with orally disintegrating film agents, and the target drug content can be easily controlled by adjusting the dimensions of the film agent (R.P. Dixit, S.P. Puthli, Oral strip technology: overview and future potential, J Control Release, 139 (2009) 94-107). Generally, the target surface area of orally disintegrating film agents is in the range of 5-20 cm 2 to enable practical dose administration (A. Arya, A. Chandra, V. Sharma, K. Pathak, Fast dissolving oral films: an innovative drug delivery system and dosage form, Int J ChemTech Res, 2 (2010) 576-583). The thickness of the film agent can also be easily controlled. A number of different film-forming polymers are available with different disintegration and release rates or even mucoadhesive properties. Many taste masking techniques as well as sweeteners and flavoring agents can be included to produce an acceptable, good-tasting drug delivery system.

[0006] Typical OTF formulations - Film-forming polymers (binders) such as xanthan gum, pullulan or HPMC, - Disintegrants such as polyvinylpyrrolidone (PVP), - Emulsifiers such as sucrose esters, for example Sisterna™, - Thickening agents such as starch or chitosan, - Plasticizers such as glycerol, - Water are included.

[0007] Typical OTF formulations may also include other excipients including sweeteners, flavoring agents, etc.

[0008] However, there are some problems associated with conventional OTF formulations. These are, in particular, - Brittleness, - Adhesiveness after introduction into the oral cavity of interest (which is particularly problematic for infants or elderly patients), and - Slow disintegration are included.

[0009] Examples of OTF formulations having one or more of these problems are disclosed in CN102160858A, CN107823191A, CN113712940A, CN110755412A, US2015038594A1, CN103720676A, CN108785280A, US2015 / 328125A1, WO2022 / 152883A1, US2012 / 009260A1, US2015 / 125495A1, US2007 / 0281003A1, and US2019 / 380973A1.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Patent Document 9

Patent Document 10

Patent Document 11

Patent Document 12

[0011] [Non-Patent Document 1] RP Dixit, SP Puthli, Oral strip technology: overview and future potential, J Control Release, 139 (2009) pp. 94-107 [Non-Patent Document 2] A. Arya, A. Chandra, V. Sharma, K. Pathak, Fast dissolving oral films: an innovative drug delivery system and dosage form, Int J ChemTech Res, 2 (2010) pp. 576-583. [Non-Patent Document 3] IUPAC Compendium of Chemical Terminology (Gold Book) [Overview of the Initiative] [Problems that the invention aims to solve]

[0012] The object of the present invention is to address and / or mitigate one or more problems related to the prior art.

[0013] The object of the present invention is to provide an intraoral disintegrating film agent having improved properties. [Means for solving the problem]

[0014] The present invention is based on the discovery that it is possible to provide an OTF having improved properties, and in particular one or more of the following properties: good elasticity (low brittleness), fast collapse, and low adhesion, preferably exhibiting all of these properties. This has been found to be achievable by the following non-obvious choices: - Select a film-forming polymer with high viscosity (but not so high as to hinder the casting of OTF). - Thickeners and emulsifiers found in conventional formulations are thought to have an adverse effect on disintegration, but are typically considered necessary in the art, so they should be removed, and / or - To mitigate the absence of thickeners and emulsifiers, increase the proportion of disintegrants and / or plasticizers in the formulation.

[0015] According to the first embodiment, a composition suitable for an intraoral disintegrating film agent, (i) Polyvinyl alcohol (PVA), (ii) Glycerol, and (iii) Polyethylene glycol (PEG) Includes, A composition is provided in which the combined amount of glycerol and polyethylene glycol is about 12-24 wt% in the dry formulation, and the mass ratio of glycerol and polyethylene glycol is about 1:2.1-1:4. In certain embodiments, PEG is about 1100-2900 g.mol -1 Or approximately 1,300 to 2,000 g.mol -1 It has an average molecular weight within the range.

[0016] Therefore, in the composition, polyvinyl alcohol may constitute a film-forming agent or act as a film-forming agent. In some embodiments, polyvinyl alcohol may constitute a film-forming agent or act as a film-forming agent, i.e., no further film-forming agent is required.

[0017] Glycerol and polyethylene glycol may constitute or act as plasticizers.

[0018] The inventors have surprisingly found that a formulation comprising polyvinyl alcohol (PVA) as a film-forming agent and a combination of glycerol and polyethylene glycol as plasticizers, wherein the combined amount of glycerol and polyethylene glycol is about 12-24 wt% in the dry formulation and the mass ratio of glycerol to polyethylene glycol is about 1:2.1-1:4, provides an intraoral disintegrating film agent with good elasticity (low brittleness), rapid disintegration, and low tackiness.

[0019] The inventors of this invention have found that PEG is present in amounts of approximately 1100 to 2900 g.mol. -1 More precisely, approximately 1,300 to 2,000 g.mol. -1 The range, for example, approximately 1,500 g.mol -1 We found that when the average molecular weight is such that the physical properties of the film agent (e.g., elasticity, rapid disintegration, and low tackiness) are particularly advantageous. Furthermore, surprisingly, we found that this composition does not require the inclusion of thickeners and emulsifiers to achieve these properties in the OTF.

[0020] Typically, the composition may contain about 30 to about 50 wt% polyvinyl alcohol by dry mass. Typically, the composition may contain about 10 to about 18 wt% polyvinyl alcohol by wet mass.

[0021] The term "dry mass" will be understood herein as the amount or ratio of a component to the total mass of a composition without a solvent. The term "wet mass" will be understood herein as the amount or ratio of a component to the total mass of a composition containing a solvent.

[0022] Typically, the composition may contain about 3 to about 17 wt% glycerol by dry mass. Typically, the composition may contain about 1 to about 6 wt% glycerol by wet mass.

[0023] Typically, the composition may contain from about 3 to about 17 wt% of polyethylene glycol on a dry mass basis. Typically, the composition may contain from about 1.1 to about 6.3 wt% of polyethylene glycol on a wet mass basis.

[0024] Typically, the polyvinyl alcohol may have a viscosity, for example, a kinematic viscosity of about 3.0 to about 3.8 mm 2 / s in a 4% aqueous solution at 20°C. Advantageously, this provides a composition having a viscosity that is high enough to avoid the need to use a thickening agent but not so high as to prevent casting of the composition into OTF.

[0025] In some embodiments, the combined amount of glycerol and polyethylene glycol is from about 12 to about 20 wt% in the dry formulation or from about 4 to about 8 wt% in the wet formulation. In some embodiments, the combined amount of glycerol and polyethylene glycol is from about 13 to about 18 wt% in the dry formulation or from about 4.5 to about 7.5 wt% in the wet formulation. In some embodiments, the combined amount of glycerol and polyethylene glycol is from about 14 to about 17 wt% in the dry formulation or from about 5 to about 7 wt% in the wet formulation.

[0026] In certain embodiments, glycerol and polyethylene glycol are in a mass ratio of about 1:2.1 to 1:3.5, about 1:2.4 to 1:3.2, or about 1:2.7 to 1:2.9.

[0027] The polyvinyl alcohol may have a degree of hydrolysis of about 86.5 to about 89.0 mol%.

[0028] In some embodiments, the polyethylene glycol has an average molecular weight, for example, from about 1100 to about 2900 daltons or g.mol -1 For example, from about 1100 to about 2700 daltons or g.mol -1 From about 1100 to about 2500 daltons or g.mol -1 Or from about 1100 to about 2300 daltons or g.mol -1Polyethylene glycol has a molecular weight of several daltons or g.mol, for example, 1,000 to 2,000, or 1,300 to 1,600 daltons or g.mol. -1 It may have several molecular weights in the range of [number]. In some embodiments, polyethylene glycol has an average molecular weight, for example, about 1,300 to about 2,000 daltons or g.mol. -1 Approximately 1,300 to 1,700 Daltons or g.mol -1 , or approximately 1500 Daltons or g.mol -1 It has a molecular weight in the range of several molecules.

[0029] The composition may further contain hydroxypropyl methylcellulose (HPMC). In such cases, the HPMC may constitute a film-forming agent or act as a film-forming agent. Therefore, the composition may contain two or more forming agents, at least PVA and HPMC. In some embodiments, the composition may contain two forming agents, at least PVA and HPMC, and no further film-forming agents may be present.

[0030] The composition may contain approximately 10 to 15 wt% HPMC by dry mass. The composition may also contain approximately 3.1 to 4.7 wt% HPMC by wet mass.

[0031] In some embodiments, the combined amount of polyvinyl alcohol and hydroxypropyl methylcellulose is about 40 to 65 wt% in the dry formulation or about 13 to 21 wt% in the wet formulation. In some embodiments, the combined amount of polyvinyl alcohol and hydroxypropyl methylcellulose is about 45 to 60 wt% in the dry formulation or about 15 to 19 wt% in the wet formulation. For example, the combined amount of polyvinyl alcohol and hydroxypropyl methylcellulose may be about 50 to 55 wt% in the dry formulation or about 16 to 18 wt% in the wet formulation.

[0032] According to the second aspect, (i) Hydroxypropyl methylcellulose (HPMC), (ii) Polyvinylpyrrolidone (PVP), (iii) Glycerol, and (iv) Polyethylene glycol (PEG) A composition suitable for an intraoral disintegrating film agent is provided, which includes [a specific ingredient / component].

[0033] Therefore, in the composition, HPMC may constitute a film-forming agent or act as a film-forming agent. In some embodiments, HPMC may constitute a film-forming agent or act as a film-forming agent, i.e., no further film-forming agent may be present.

[0034] Polyvinylpyrrolidone (PVP) may constitute a disintegrant or act as a disintegrant. In some embodiments, PVP may constitute a disintegrant or act as a disintegrant, i.e., no further disintegrants may be present.

[0035] Glycerol and polyethylene glycol may constitute or act as plasticizers.

[0036] The inventors have surprisingly discovered that a formulation containing HPMC as a film-forming agent, PVP as a disintegrant, and a combination of glycerol and polyethylene glycol as plasticizers provides an intraoral disintegrating film agent with good elasticity (low brittleness), rapid disintegration, and low tackiness.

[0037] Furthermore, surprisingly, it was found that this composition does not require the inclusion of thickeners and emulsifiers to achieve those properties in OTF.

[0038] Typically, hydroxypropyl methylcellulose may contain about 19 to about 24 wt% methoxy groups and about 7 to about 12 wt% hydroxypropyl groups.

[0039] Typically, hydroxypropyl methylcellulose may have a viscosity of about 3500 to about 5600 cPs in a 2% aqueous solution at 20°C.

[0040] In some embodiments, hydroxypropyl methylcellulose may contain, be essentially, or be derived from METHOCEL® K4M.

[0041] The composition may contain approximately 60 to 66 wt% of hydroxypropyl methylcellulose by dry weight. The composition may also contain approximately 4.1 to 4.5 wt% of hydroxypropyl methylcellulose by wet weight.

[0042] The composition may contain approximately 4 to 8 wt% polyvinylpyrrolidone by dry mass. The composition may also contain approximately 0.27 to 0.54 wt% polyvinylpyrrolidone by wet mass.

[0043] The composition may contain approximately 4 to 20 wt% glycerol by dry mass. The composition may also contain approximately 0.2 to 1.4 wt% glycerol by wet mass.

[0044] The composition may contain approximately 4 to 20 wt% polyethylene glycol by dry weight. The composition may also contain approximately 0.2 to 1.4 wt% polyethylene glycol by wet weight.

[0045] In some embodiments, polyethylene glycol has an average molecular weight, for example, about 1100 to about 2900 daltons or g.mol. -1 For example, approximately 1100 to 2700 daltons or g.mol. -1 Approximately 1100 to 2500 Daltons or g.mol -1 , or approximately 1100 to 2300 Daltons or g.mol -1 Polyethylene glycol has a molecular weight of several daltons or g.mol, for example, 1,000 to 2,000, or 1,300 to 1,600 daltons or g.mol. -1It may have several molecular weights in the range of [number]. In some embodiments, polyethylene glycol has an average molecular weight, for example, about 1,300 to about 2,000 daltons or g.mol. -1 Approximately 1,300 to 1,700 Daltons or g.mol -1 , or approximately 1500 Daltons or g.mol -1 It has a molecular weight in the range of several molecules.

[0046] The composition may contain a combined amount of glycerol and polyethylene glycol in the dry formulation, amounting to about 12 to about 24 wt%. The composition may also contain a combined amount of glycerol and polyethylene glycol in the wet formulation, amounting to about 0.5 to about 1.5 wt%.

[0047] The composition may contain polyethylene glycol and glycerol in a mass ratio of about 1:1.5 to about 1:4, for example, 1:2.1 to about 1:4.

[0048] The composition may contain polyvinylpyrrolidone having a viscosity of about 5.5 to about 8.5 cPs in a 10% aqueous solution at 20°C. PVP may be commercially known as "K30". PVP may be defined as a water-soluble homopolymer of N-vinyl-2-pyrrolidone.

[0049] According to the third aspect, (i) Hydroxypropyl methylcellulose (HPMC) containing approximately 19-24 wt% methoxy groups and approximately 7-12 wt% hydroxypropyl groups, (ii) Polyvinylpyrrolidone (PVP), and (iii) Glycerol and / or polyethylene glycol (PEG) A composition suitable for an intraoral disintegrating film agent is provided, which includes [a specific ingredient / component].

[0050] Therefore, in the composition, HPMC may constitute a film-forming agent or act as a film-forming agent. In some embodiments, HPMC may constitute a film-forming agent or act as a film-forming agent, i.e., no further film-forming agent may be present.

[0051] Polyvinylpyrrolidone (PVP) may constitute a disintegrant or act as a disintegrant. In some embodiments, PVP may constitute a disintegrant or act as a disintegrant, i.e., no further disintegrants may be present.

[0052] Glycerol and / or polyethylene glycol may constitute a plasticizer or act as a plasticizer.

[0053] The inventors have surprisingly found that a formulation comprising a combination of HPMC as a film-forming agent, PVP as a disintegrant, and glycerol and / or polyethylene glycol as a plasticizer provides an intraoral disintegrating film agent with good elasticity (low brittleness), rapid disintegration, and low tackiness.

[0054] Furthermore, surprisingly, it was found that this composition does not require the inclusion of thickeners and emulsifiers to achieve those properties in OTF.

[0055] The composition may also contain glycerol and polyethylene glycol.

[0056] Typically, hydroxypropyl methylcellulose may have a viscosity of about 3500 to about 5600 cPs in a 2% aqueous solution at 20°C.

[0057] In some embodiments, hydroxypropyl methylcellulose may contain, be essentially, or be derived from METHOCEL® K4M.

[0058] The composition may contain approximately 60 to 66 wt% of hydroxypropyl methylcellulose by dry weight. The composition may also contain approximately 4.1 to 4.5 wt% of hydroxypropyl methylcellulose by wet weight.

[0059] The composition may contain approximately 4 to 8 wt% polyvinylpyrrolidone by dry mass. The composition may also contain approximately 0.27 to 0.54 wt% polyvinylpyrrolidone by wet mass.

[0060] The composition may contain approximately 4 to 20 wt% glycerol by dry mass. The composition may also contain approximately 0.2 to 1.4 wt% glycerol by wet mass.

[0061] The composition may contain approximately 4 to 20 wt% polyethylene glycol by dry weight. The composition may also contain approximately 0.2 to 1.4 wt% polyethylene glycol by wet weight.

[0062] In some embodiments, polyethylene glycol has an average molecular weight, for example, about 1100 to about 2900 daltons or g.mol. -1 For example, approximately 1100 to 2700 daltons or g.mol. -1 Approximately 1100 to 2500 Daltons or g.mol -1 , or approximately 1100 to 2300 Daltons or g.mol -1 Polyethylene glycol has a molecular weight of several daltons or g.mol, for example, 1,000 to 2,000, or 1,300 to 1,600 daltons or g.mol. -1 It may have several molecular weights in the range of [number]. In some embodiments, polyethylene glycol has an average molecular weight, for example, about 1,300 to about 2,000 daltons or g.mol. -1 Approximately 1,300 to 1,700 Daltons or g.mol -1 , or approximately 1500 Daltons or g.mol -1 It has a molecular weight in the range of several molecules.

[0063] The composition may contain a combined amount of glycerol and polyethylene glycol in the dry formulation, amounting to about 12 to about 24 wt%. The composition may also contain a combined amount of glycerol and polyethylene glycol in the wet formulation, amounting to about 0.5 to about 1.5 wt%.

[0064] The composition may contain polyethylene glycol and glycerol in a mass ratio of about 1:1.5 to about 1:4, for example, 1:2.1 to about 1:4.

[0065] The composition may contain polyvinylpyrrolidone having a viscosity of about 5.5 to about 8.5 cPs in a 10% aqueous solution at 20°C. PVP may be commercially known as "K30". PVP may be defined as a water-soluble homopolymer of N-vinyl-2-pyrrolidone.

[0066] According to the fourth aspect, a composition suitable for an intraoral disintegrating film agent, (i) Hydroxypropyl methylcellulose (HPMC), (ii) Polyvinylpyrrolidone (PVP), and (iii) Glycerol and / or polyethylene glycol (PEG) Includes, The dry preparation contains approximately 60-66 wt% hydroxypropyl methylcellulose and / or approximately 4-8 wt% polyvinylpyrrolidone. A composition that does not contain emulsifiers is provided.

[0067] Therefore, in the composition, HPMC may constitute a film-forming agent or act as a film-forming agent. In some embodiments, HPMC may constitute a film-forming agent or act as a film-forming agent, i.e., no further film-forming agent may be present.

[0068] Polyvinylpyrrolidone (PVP) may constitute a disintegrant or act as a disintegrant. In some embodiments, PVP may constitute a disintegrant or act as a disintegrant, i.e., no further disintegrants may be present.

[0069] Glycerol and / or polyethylene glycol may constitute a plasticizer or act as a plasticizer.

[0070] The inventors have surprisingly found that a formulation comprising a combination of HPMC as a film-forming agent, PVP as a disintegrant, and glycerol and / or polyethylene glycol as a plasticizer, wherein the composition contains about 60 to about 66 wt% hydroxypropyl methylcellulose and / or about 4 to about 8 wt% polyvinylpyrrolidone in the dry formulation, and the composition is emulsifier-free, provides an intraoral disintegrating film agent having good elasticity (low brittleness), rapid disintegration, and low tackiness.

[0071] Furthermore, surprisingly, it was found that this composition does not require the inclusion of thickeners and emulsifiers to achieve those properties in OTF.

[0072] The composition may contain approximately 4.1 to 4.5 wt% hydroxypropyl methylcellulose by wet mass.

[0073] The composition may contain approximately 0.27 to 0.54 wt% polyvinylpyrrolidone by wet mass.

[0074] The composition may also contain glycerol and polyethylene glycol.

[0075] Typically, hydroxypropyl methylcellulose may contain about 19 to about 24 wt% methoxy groups and about 7 to about 12 wt% hydroxypropyl groups.

[0076] Typically, hydroxypropyl methylcellulose may have a viscosity of about 3500 to about 5600 cPs in a 2% aqueous solution at 20°C.

[0077] In some embodiments, hydroxypropyl methylcellulose may contain, be essentially, or be derived from METHOCEL® K4M.

[0078] The composition may contain approximately 4 to 20 wt% glycerol by dry mass. The composition may also contain approximately 0.2 to 1.4 wt% glycerol by wet mass.

[0079] The composition may contain approximately 4 to 20 wt% polyethylene glycol by dry weight. The composition may also contain approximately 0.2 to 1.4 wt% polyethylene glycol by wet weight.

[0080] In some embodiments, polyethylene glycol has an average molecular weight, for example, about 1100 to about 2900 daltons or g.mol. -1 For example, approximately 1100 to 2700 daltons or g.mol. -1 Approximately 1100 to 2500 Daltons or g.mol -1 , or approximately 1100 to 2300 Daltons or g.mol -1 Polyethylene glycol has a molecular weight of several daltons or g.mol, for example, 1,000 to 2,000, or 1,300 to 1,600 daltons or g.mol. -1 It may have several molecular weights in the range of [number]. In some embodiments, polyethylene glycol has an average molecular weight, for example, about 1,300 to about 2,000 daltons or g.mol. -1 Approximately 1,300 to 1,700 Daltons or g.mol -1 , or approximately 1500 Daltons or g.mol -1 It has a molecular weight in the range of several molecules.

[0081] The composition may contain a combined amount of glycerol and / or polyethylene glycol in the dry formulation, amounting to about 12 to about 24 wt%. The composition may also contain a combined amount of glycerol and / or polyethylene glycol in the wet formulation, amounting to about 0.5 to about 1.5 wt%.

[0082] The composition may contain a combined amount of glycerol and polyethylene glycol in the dry formulation, amounting to about 12 to about 24 wt%. The composition may also contain a combined amount of glycerol and polyethylene glycol in the wet formulation, amounting to about 0.5 to about 1.5 wt%.

[0083] The composition may contain polyethylene glycol and glycerol in a mass ratio of about 1:1.5 to about 1:4, for example, 1:2.1 to about 1:4.

[0084] The composition may contain polyvinylpyrrolidone having a viscosity of about 5.5 to about 8.5 cPs in a 10% aqueous solution at 20°C. PVP may be commercially known as "K30". PVP may be defined as a water-soluble homopolymer of N-vinyl-2-pyrrolidone.

[0085] The following may apply to any earlier embodiment.

[0086] Preferably, the composition does not contain a thickening agent. Typical thickening agents may include starch, gelatin, chitosan, agar, carrageenan, xanthan gum, guar gum, pectin, alginate, etc.

[0087] Preferably, the composition does not contain an emulsifier. Typical emulsifiers may include polysorbates such as polysorbate 80 (also known as polyoxyethylene (20) sorbitan monooleate, commercially available as Tween® 80), mono- and diglycerides, sucrose esters, lecithin, etc.

[0088] The composition may further contain one or more optional additives, such as fillers, flavoring agents, sweeteners, colorants, antioxidants, and microbial preservatives.

[0089] The composition may contain a pharmaceutically acceptable solvent.

[0090] The composition may contain approximately 50 to 98 wt% of the solvent, for example, approximately 60 to 95 wt%.

[0091] The solvent may contain water, be essentially composed of it, or consist of it. The solvent may also contain an organic solvent, such as ethanol, or further contain it. In some embodiments, the solvent may contain water and ethanol, be essentially composed of them, or consist of them.

[0092] The composition may contain a salivary stimulant. The salivary stimulant may contain, essentially contain, or be derived from citric acid.

[0093] The composition may contain a salivary stimulant in a dry mass of 0 to about 20 wt%, for example, about 1 to about 20 wt%, or for example, about 2 to about 18 wt%. The composition may also contain a salivary stimulant in a wet mass of 0 to about 7.5 wt%, for example, about 0.1 to about 7.5 wt%, or for example, about 0.2 to about 7 wt%.

[0094] The composition may contain a sweetener. The sweetener may include, essentially, or consist of a natural sweetener such as sucrose, or an artificial sweetener such as sucralose, saccharin, aspartame, or isomalt. In some embodiments, the sweetener may act as a salivary stimulant.

[0095] The composition may contain sweeteners in an amount of about 0 to about 20 wt% by dry mass, for example, about 1 to about 20 wt%, or for example, about 2 to about 15 wt%. The composition may also contain sweeteners in an amount of about 0 to about 8 wt% by wet mass, for example, about 0.1 to about 8 wt%, or for example, about 0.2 to about 5 wt%.

[0096] The composition may contain flavoring agents. The flavoring agents may include, essentially consist of, or be derived from, natural or artificial flavoring agents such as spearmint oil or lemon flavoring. Any suitable flavoring agent such as orange, passion fruit, tutti frutti, strawberry, lime, raspberry, or cherry flavoring may be used.

[0097] The composition may contain flavoring agents in a dry mass of approximately 0 to approximately 20 wt%, for example, approximately 1 to approximately 15 wt%, or for example, approximately 2 to approximately 12 wt%. The composition may also contain flavoring agents in a wet mass of approximately 0 to approximately 8 wt%, for example, approximately 0.1 to approximately 8 wt%, or for example, approximately 0.2 to approximately 5 wt%.

[0098] The composition may further contain a pharmaceutically active ingredient. The pharmaceutically active ingredient may include or may not include a therapeutic agent. In other words, the term “pharmaceutically active ingredient” may be understood herein to mean an active ingredient that can have a therapeutic effect on a patient, that is, an active ingredient that can treat a disease and / or medical condition.

[0099] In one embodiment, the pharmaceutically active ingredient may include or be a drug or substance capable of reducing pain in a subject, such as an analgesic.

[0100] The pharmaceutically active ingredient may include or consist of opioid drugs and / or their derivatives. The pharmaceutically active ingredient may include or consist of any other drug class. The pharmaceutically active ingredient is alfentanil, allylprozin, alphaprozin, amphepramone, amphetamine, amphetaminil, anirelizine, apocodeine, apomorphine, acimadrine, axomadol, benzylmorphine, vegitramide, bremazosin, brifentanil, buprenorphine, butorphanol, carfentanil, clonitazen, codeine, cyclazosin, cyclorphan, cyprenorphine, cyprodim, deltorphine, desomorphine, dextromethorphan, dex Stromoramide, Dextropropoxyfen, Dezosin, Diamorphine, Diamorphone, Diampromide, Diacetylmorphine, Dihydrocodeine, Dihydrocodeinone, Dihydroethorphine, Dihydromorphine, Dimenoxadol, Dimephetamol, Dimefeptanol, Dimethylthiambutene, Dioxafetyl butyrate, Diphenoxylate, Dipipanone, Dyprenorphine, Dronabinol, Met-Enkephalin, Leu-Enkephalin, Dynorphin A, Dynorphin B, β- Endorphins, Eptazosin, Elidolphin, Ethheptadine, 14-Ethoxymethopone, Ethylketocyclazosin, Ethylmethylthiambutene, Ethylmorphine, Etonitazene, Etorphine, Extromoramide, Fencamfamine, Phenethine, Fenproporex, Fentanyl, α-Methylfentanyl, Beta-Funaltrexamine, P-Hydroxy-3-Methylfentanyl, Heroin, Hydrocodone, Hydromorphone, Hydromorphodone, Hydroxymethylmorphinan, Hydro Xypetidine, isometadone, ketobemidone, kyotorphin, levo-α-acetylmetadol, levacetylmetadol, levallorphan, levometadone, levometazylate, levallorphan, levofenacilmorphan, lofentanyl, lofexidine, loperamide, malbufine, mazindol, melatonin, mephenorex, meperidine, meprobamate, meptazinol, metazosine, methadone, methopone, methyldihydromorphine, methyldihydromorphinone,Methylmorphine, methylnaltrexone, methylphenidate (and stereoisomers), metiprilone, methopone, milfentanil, modafinil, morphiceptin, morphinan, morphine, mirofin, nabilone, nalbufine, nalmefene, nalolphine, naloxone, naloxone benzoylhydrazone, naltrexone, naltribene, naltrindol, naltrindol isothiocyanate, narcein, natubuffine, nicomorphine, nornaltolfimine, norlevoluphanol, normethandone, nalolphine, normorphine, norpipanone, noscapine, omefentanil, o-methylnaltrexone, opium, onitazen, oxycodone, oxymorphone, papaveretam, papaverine, palegoric, pemoline, pentazocine, pethidine, fendimethrazine, fendimethrazone, fenmetrazine, fe Nadoxone, phenomorphan, phenazosin, phenoperidine, forcozine, piminozine, piperadrol, pyritramide, prenorphine, profadol, properidine, propeptadine, promedol, properidine, propyram, propoxyphene, propylhexedrine, remifentanil, spiradrine, sufentanil, sufentanyl, tapentadol, thebaine, tramadol, trefentanil, tyridine, viminol or salts thereof, or one or more opioids such as phenanthrene, morphinan, benzomorphan, methadone, phenylpiperidine, propionanilide, 4-anilidepiperidine, 4-arylpiperidine, 4-heteroarylpiperidine class, and / or salts and derivatives thereof.

[0101] In one embodiment, the pharmaceutically active ingredient may be morphine, or a salt or derivative thereof. In another embodiment, the pharmaceutically active ingredient may be apomorphine.

[0102] The pharmaceutically active ingredient may include, be essentially, or be derived from, a drug or substance capable of treating and / or preventing metabolic bone disorders in infants, such as hypophosphatemia, a condition common in low birth weight infants and associated with osteopenia in premature infants. The pharmaceutically active ingredient may include, be essentially, or be derived from, a potassium salt, such as acidic potassium phosphate.

[0103] The pharmaceutically active ingredient may include, be essentially, or be derived from, drugs or substances that can treat and / or prevent pathological conditions of the stomach and / or esophagus, such as vomiting, nausea, reflux, etc. The pharmaceutically active ingredient may include, be essentially, or be derived from, metoclopramide and / or its derivatives, such as metoclopramide hydrochloride. The pharmaceutically active ingredient may include, be essentially, or be derived from, cyclidine, ondansetron and / or granisetron, which are typically used to treat nausea.

[0104] The pharmaceutically active ingredient may include, be essentially, or be derived from, a drug or substance capable of treating and / or preventing progressive neurological disorders that may affect spontaneous movement, such as erectile dysfunction or Parkinson's disease.

[0105] The pharmaceutically active ingredient may contain, be essentially, or be essentially a cannabis derivative such as cannabis or cannabidiol and / or other cannabinoids.

[0106] The pharmaceutical active ingredient may contain melatonin, be essentially derived from it, or be derived from it.

[0107] The formulations described herein may be applied, for example, in the treatment of humans, particularly in pediatrics and / or geriatrics, where swallowing pills may be problematic. Another area is veterinary medicine, where administering pills to animals can be difficult.

[0108] The composition contains approximately 0.01 to 10 wt% of a pharmaceutically active ingredient by dry mass, for example, approximately 0.1 to 1 wt%, or approximately 1 × 10⁻⁶ wt% by wet mass. -5 ~Approximately 0.01 wt%, for example, approximately 1 × 10⁻⁶ -4 Contains approximately 0.001 wt% of the pharmaceutically active ingredient.

[0109] In one embodiment of the first aspect, a composition suitable for an intraoral disintegrating film agent is provided, (i) Polyvinyl alcohol (PVA) in an amount of approximately 30 to approximately 50 wt% of the dry weight of the composition, (ii) Glycerol in an amount of about 3 to about 17 wt% of the dry mass of the composition, (iii) The composition contains polyethylene glycol (PEG) in an amount of approximately 3 to approximately 17 wt% of the dry mass of the composition. A composition is provided in which the combined amount of glycerol and polyethylene glycol is approximately 12-24 wt% in the dry formulation, and the mass ratio of glycerol to polyethylene glycol is approximately 1:2.1-1:4. Typically, the polyethylene glycol is approximately 1100-2900 g.mol. -1 Or approximately 1,300 to 2,000 g.mol -1 It has an average molecular weight within the range.

[0110] The composition may contain polyvinyl alcohol in a wet mass of approximately 10 to approximately 18 wt%.

[0111] The composition may contain approximately 1 to 6 wt% glycerol by wet mass.

[0112] The composition may contain approximately 1.1 to 6.3 wt% polyethylene glycol by dry weight.

[0113] The composition may contain water in an amount of about 50 to about 80 wt%, for example, about 60 to about 70 wt%, of the total (wet) composition.

[0114] The composition may contain approximately 10 to 18 wt% of a salivary stimulant by dry weight. The composition may also contain approximately 3 to 7 wt% of a salivary stimulant by wet weight.

[0115] The composition may contain a sweetener in an amount of approximately 5 to 15 wt% by dry mass, for example, approximately 10 to 15 wt%. The composition may also contain a sweetener in an amount of approximately 1 to 6 wt% by wet mass, for example, approximately 4 to 6 wt%.

[0116] The composition may contain a flavoring agent in a dry mass of approximately 5 to approximately 15 wt%, for example, approximately 10 to approximately 15 wt%. The composition may also contain a flavoring agent in a wet mass of approximately 1 to approximately 6 wt%, for example, approximately 4 to approximately 6 wt%.

[0117] In one embodiment of the second aspect, (i) Hydroxypropyl methylcellulose (HPMC) in an amount of approximately 60 to 66 wt% of the dry mass of the composition, (ii) Polyvinylpyrrolidone (PVP) in an amount of approximately 4 to approximately 8 wt% of the dry mass of the composition, (iii) Glycerol in an amount of about 4 to about 20 wt% of the dry mass of the composition, (iv) Polyethylene glycol (PEG) in an amount of approximately 4 to 20 wt% of the dry weight of the composition. A composition suitable for an intraoral disintegrating film agent is provided, which includes [a specific ingredient / component].

[0118] The composition may contain water in an amount of about 70 to about 95 wt% of the total (wet) composition, for example, about 80 to about 95 wt%.

[0119] The composition may contain approximately 1 to 10 wt% of a salivary stimulant by dry weight. The composition may also contain approximately 0.1 to 1 wt% of a salivary stimulant by wet weight.

[0120] The composition may contain a sweetener in an amount of approximately 2 to 10 wt% by dry weight. The composition may also contain a sweetener in an amount of approximately 0.1 to 7 wt% by wet weight.

[0121] The composition may contain flavorings in an amount of approximately 1 to 12 wt% by dry weight. The composition may also contain flavorings in an amount of approximately 0.1 to 1 wt% by wet weight.

[0122] In one embodiment of the third aspect, (i) Hydroxypropyl methylcellulose (HPMC) containing about 19 to about 24 wt% methoxy groups and about 7 to about 12 wt% hydroxypropyl groups in an amount of about 60 to about 66 wt% of the dry weight of the composition, (ii) Polyvinylpyrrolidone (PVP) in an amount of about 4 to about 8 wt% of the dry mass of the composition, (iii) Glycerol and / or polyethylene glycol (PEG) in an amount of about 4 to about 20 wt% of the dry mass of each composition. A composition suitable for an intraoral disintegrating film agent is provided, which includes [a specific ingredient / component].

[0123] The composition may contain water in an amount of about 70 to about 95 wt% of the total (wet) composition, for example, about 80 to about 95 wt%.

[0124] The composition may contain approximately 1 to 10 wt% of a salivary stimulant by dry weight. The composition may also contain approximately 0.1 to 1 wt% of a salivary stimulant by wet weight.

[0125] The composition may contain a sweetener in an amount of approximately 2 to 10 wt% by dry weight. The composition may also contain a sweetener in an amount of approximately 0.1 to 7 wt% by wet weight.

[0126] The composition may contain flavorings in an amount of approximately 1 to 12 wt% by dry weight. The composition may also contain flavorings in an amount of approximately 0.1 to 1 wt% by wet weight.

[0127] In one embodiment of the fourth aspect, a composition suitable for an intraoral disintegrating film agent is provided, (i) Hydroxypropyl methylcellulose (HPMC) in an amount of approximately 60 to 66 wt% of the dry mass of the composition, (ii) Polyvinylpyrrolidone (PVP) in an amount of about 4 to about 8 wt% of the dry mass of the composition, (iii) Glycerol and / or polyethylene glycol (PEG) in an amount of about 4 to about 20 wt% of the dry mass of each composition. Includes, The dry preparation contains approximately 60-66 wt% hydroxypropyl methylcellulose and / or approximately 4-8 wt% polyvinylpyrrolidone. A composition that does not contain emulsifiers is provided.

[0128] The composition may contain water in an amount of about 70 to about 95 wt% of the total (wet) composition, for example, about 80 to about 95 wt%.

[0129] The composition may contain approximately 1 to 10 wt% of a salivary stimulant by dry weight. The composition may also contain approximately 0.1 to 1 wt% of a salivary stimulant by wet weight.

[0130] The composition may contain a sweetener in an amount of approximately 2 to 10 wt% by dry weight. The composition may also contain a sweetener in an amount of approximately 0.1 to 7 wt% by wet weight.

[0131] The composition may contain flavorings in an amount of approximately 1 to 12 wt% by dry weight. The composition may also contain flavorings in an amount of approximately 0.1 to 1 wt% by wet weight.

[0132] According to a fifth aspect, an oral dissolving film agent is provided which comprises or is prepared from a composition according to any of the above aspects.

[0133] According to the sixth aspect, a composition according to any of the first to fourth aspects or an orally dissolving film according to the fifth aspect is provided for use as a pharmaceutical.

[0134] According to the seventh aspect, a composition according to any of the first to fourth aspects or an orally soluble film according to the fifth aspect is provided for use in the treatment of one or more conditions or diseases selected from pain, migraine, headache, inflammation, metabolic bone disease, hypophosphatemia, nausea, vomiting, gastroesophageal reflux disease, anxiety, dyspnea, sleep disorders, erectile dysfunction, anxiety, and / or motor disorders, such as Parkinson's disease.

[0135] The composition or OTF may be intended for use in the treatment of pain.

[0136] According to the eighth aspect, a method is provided for treating one or more conditions or diseases selected from pain, migraine, headache, inflammation, metabolic bone disease, hypophosphatemia, nausea, vomiting, gastroesophageal reflux disease, anxiety, dyspnea, sleep disorders, erectile dysfunction, anxiety and / or motor disorders, such as Parkinson's disease, comprising the step of administering an orally soluble film according to the fifth aspect to a patient in need thereof.

[0137] The method may include a step for treating pain.

[0138] According to the ninth aspect, a method for preparing an oral dissolving film is provided, comprising the step of casting a composition according to any of the first to fourth aspects onto a support.

[0139] The method may include a step of preparing an oral dissolving film preparation according to the fifth embodiment, or a method for preparing such preparation.

[0140] The method may include a step of evaporating at least a portion of the solvent.

[0141] It will be understood that the final intraoral dissolving film may contain some residual solvent, such as water. Therefore, the method may include a step of evaporating some of the solvent present in the composition. It will be understood that the amount of residual solvent, such as water, in the OTF may depend on the type and amount of components used in the composition.

[0142] Features described in relation to any aspect of the present invention may be equally applicable to any other aspect and are not repeated merely for the sake of brevity. For example, features described in relation to a composition may be applied in relation to a method, and vice versa.

[0143] The present invention may be further described by reference to the following non-limiting clauses.

[0144] 1. A composition suitable for an intraoral disintegrating film agent, (i) Polyvinyl alcohol, (ii) Glycerol, and (iii) polyethylene glycol Includes, A composition in which the combined amount of glycerol and polyethylene glycol is approximately 12-24 wt% in the dry formulation, and the mass ratio of glycerol and polyethylene glycol is approximately 1:2.1-1:4.

[0145] 2. Polyethylene glycol is approximately 1100 to 2900 daltons or g.mol. -1 Approximately 1100 to 2700 Daltons or g.mol -1 Approximately 1100 to 2500 Daltons or g.mol -1 Approximately 1100 to 2300 Daltons or g.mol -1 , about 1,300~2,000g.mol -1 , about 1,300 to about 1,700g.mol -1 , or approximately 1500 g.mol -1 The composition according to Clause 1, having an average molecular weight in the range of [range].

[0146] 3. The composition according to Clause 1 or Clause 2, wherein the combined amount of glycerol and polyethylene glycol is about 12 to about 20 wt%, about 13 to about 18 wt%, or about 14 to about 17 wt% in the dry formulation.

[0147] 4. The composition according to any one of clauses 1 to 3, wherein glycerol and polyethylene glycol are in a mass ratio of about 1:2.1 to 1:3.5, about 1:2.4 to 1:3.2, or about 1:2.7 to 1:2.9.

[0148] 5. A composition according to any one of clauses 1 to 4, which does not contain a thickening agent.

[0149] 6. A composition according to any one of clauses 1 to 5, which does not contain an emulsifier.

[0150] 7. A composition according to any one of the preceding clauses, comprising approximately 30 to 50 wt% polyvinyl alcohol by dry mass or approximately 10 to 18 wt% polyvinyl alcohol by wet mass.

[0151] 8. A composition according to any one of the preceding clauses, comprising approximately 3 to approximately 7 wt% dry weight of glycerol or approximately 1 to approximately 6 wt% wet weight of glycerol.

[0152] 9. The composition according to any one of the preceding clauses, comprising approximately 3 to approximately 17 wt% by dry weight of polyethylene glycol or approximately 1.1 to approximately 6.3 wt% by wet weight of polyethylene glycol.

[0153] 10. Any one of the compositions described in the preceding clause, comprising a pharmaceutically acceptable solvent.

[0154] 11. The composition according to Clause 10, wherein the solvent is water.

[0155] 12. The composition according to Clause 10 or Clause 11, comprising about 60 to about 70 wt% of the total (wet) composition of the solvent.

[0156] 13. The composition according to any one of the preceding clauses, further comprising a salivary stimulant.

[0157] 14. The composition according to Clause 13, comprising approximately 10 to 18 wt% by dry weight of a salivary stimulant or approximately 3 to 7 wt% by wet weight of a salivary stimulant.

[0158] 15. The composition according to any one of the preceding clauses, further comprising a sweetener.

[0159] 16. The composition according to Clause 15, comprising a sweetener in a dry mass of about 10 to about 15 wt% or a wet mass of about 1 to about 6 wt%, for example, about 4 to about 6 wt%.

[0160] 17. A composition according to any one of the preceding clauses, further comprising a flavoring agent.

[0161] 18. The composition according to Clause 17, comprising approximately 10 to 15 wt% of a flavoring agent by dry mass or approximately 4 to 6 wt% of a flavoring agent by wet mass.

[0162] 19. The composition according to any one of the preceding clauses, further comprising hydroxypropyl methylcellulose.

[0163] 20. The composition according to Clause 19, comprising approximately 10 to 15 wt% dry weight of hydroxypropyl methylcellulose or approximately 3.1 to 4.7 wt% wet weight of HPMC.

[0164] 21. The composition according to Clause 19 or Clause 20, wherein the combined amount of polyvinyl alcohol and hydroxypropyl methylcellulose is about 40 to about 65 wt%, about 45 to about 60 wt%, or about 50 to about 55 wt% in the dry formulation.

[0165] 22. Polyvinyl alcohol yields approximately 3.0 to 3.8 mm in a 4% aqueous solution at 20°C. 2 A composition according to any one of the preceding clauses, having a kinematic viscosity of / s.

[0166] 23. (i) Hydroxypropyl methylcellulose, (ii) Polyvinylpyrrolidone, (iii) Glycerol, and (iv) Polyethylene glycol A composition suitable for oral disintegration film agents, containing [a specific ingredient / component].

[0167] 24. The composition according to Clause 23, wherein hydroxypropyl methylcellulose comprises about 19 to about 24 wt% methoxy groups and about 7 to about 12 wt% hydroxypropyl groups.

[0168] 25. The composition according to Clause 23 or Clause 24, wherein hydroxypropyl methylcellulose has a viscosity of about 3500 to about 5600 cPs in a 2% aqueous solution at 20°C.

[0169] 26. (i) Hydroxypropyl methylcellulose containing approximately 19 to 24 wt% methoxy groups and approximately 7 to 12 wt% hydroxypropyl groups, (ii) polyvinylpyrrolidone, and (iii) Glycerol and / or polyethylene glycol A composition suitable for oral disintegration film agents, containing [a specific ingredient / component].

[0170] 27. The composition according to Clause 26, wherein hydroxypropyl methylcellulose has a viscosity of about 3500 to about 5600 cPs in a 2% aqueous solution at 20°C.

[0171] 28. The composition according to any one of the clauses 23 to 27, comprising approximately 60 to 66 wt% by dry weight of hydroxypropyl methylcellulose or approximately 4.1 to 4.5 wt% by wet weight of hydroxypropyl methylcellulose.

[0172] 29. The composition according to any one of the clauses 23 to 28, comprising approximately 4 to approximately 8 wt% of polyvinylpyrrolidone by dry mass or approximately 0.27 to approximately 0.54 wt% of polyvinylpyrrolidone by wet mass.

[0173] 30. A composition according to any one of clauses 23 to 29, which does not contain an emulsifier.

[0174] 31. A composition suitable for an intraoral disintegrating film agent, (i) Hydroxypropyl methylcellulose, (ii) polyvinylpyrrolidone, and (iii) Glycerol and / or polyethylene glycol Includes, A composition containing approximately 60-66 wt% hydroxypropyl methylcellulose and / or approximately 4-8 wt% polyvinylpyrrolidone in a dry formulation, and free of emulsifiers.

[0175] 32. The composition according to Clause 31, comprising glycerol and polyethylene glycol.

[0176] 33. The composition according to Clause 31 or Clause 32, wherein hydroxypropyl methylcellulose comprises about 19 to about 24 wt% methoxy groups and about 7 to about 12 wt% hydroxypropyl groups.

[0177] 34. The composition according to any one of claims 31 to 33, wherein hydroxypropyl methylcellulose has a viscosity of about 3500 to about 5600 cPs in a 2% aqueous solution at 20°C.

[0178] 35. A composition according to any one of clauses 23 to 34, comprising approximately 4 to 20% glycerol by dry mass or approximately 0.2 to 1.4 wt% glycerol by wet mass.

[0179] 36. A composition according to any one of clauses 23 to 35, comprising approximately 4 to 20% polyethylene glycol by dry weight or approximately 0.2 to 1.4 wt% polyethylene glycol by wet weight.

[0180] 37.1,300~1,600 gmol -1 A composition according to any one of the clauses 23 to 36, comprising polyethylene glycol having an average molecular weight in the range of 23 to 36.

[0181] 38. The composition according to any one of clauses 23 to 37, comprising a combined amount of glycerol and polyethylene glycol in a dry formulation of about 12 to about 24 wt% or in a wet formulation of about 0.5 to about 1.5 wt%.

[0182] 39. A composition according to any one of the clauses 23 to 38, comprising polyethylene glycol and glycerol in a mass ratio of about 1:1.5 to about 1:4, for example, 1:2.1 to about 1:4.

[0183] A composition according to any one of claims 23 to 39, comprising polyvinylpyrrolidone having a viscosity of about 5.5 to about 8.5 cPs at 20°C in a 40.10% aqueous solution.

[0184] 41. A composition according to any one of clauses 23 to 40, comprising a pharmaceutically acceptable solvent.

[0185] 42. The composition according to Clause 41, wherein the solvent is water.

[0186] 43. The composition according to Clause 41 or Clause 42, comprising approximately 80 to approximately 95 wt% of the solvent.

[0187] 44. The composition according to any one of clauses 23 to 43, further comprising a sweetener.

[0188] 45. The composition according to Clause 44, comprising a sweetener in a dry mass of approximately 2 to approximately 10 wt% or a sweetener in a wet mass of approximately 0.1 to approximately 7 wt%.

[0189] 46. ​​The composition according to any one of the clauses 23 to 45, further comprising a flavoring agent.

[0190] 47. The composition according to Clause 46, comprising a flavoring agent in a dry mass of approximately 1 to approximately 12 wt% or a flavoring agent in a wet mass of approximately 0.1 to approximately 1 wt%.

[0191] 48. The composition according to any one of the clauses 23 to 47, further comprising a salivary stimulant.

[0192] 49. The composition according to Clause 48, comprising approximately 1 to approximately 10 wt% by dry weight of a salivary stimulant or approximately 0.1 to approximately 1 wt% by wet weight of a salivary stimulant.

[0193] 50. The composition according to any one of the preceding clauses, further comprising a pharmaceutically active ingredient.

[0194] 51. Dry mass of approximately 0.01 to approximately 10 wt%, for example, approximately 0.1 to approximately 1 wt%, of the pharmaceutically active ingredient or wet mass of approximately 1 × 10⁻⁶ -5 ~Approximately 0.01 wt%, for example, approximately 1 × 10⁻⁶ -4 The composition according to Clause 50, comprising approximately 0.001 wt% of the pharmaceutically active ingredient.

[0195] 52. The composition according to Clause 50 or Clause 51, wherein the pharmaceutically active ingredient is an opioid.

[0196] 53. An oral dissolving film preparation comprising or prepared from any of the compositions described in the preceding clause.

[0197] 54. A composition according to any one of clauses 50 to 52 or an orally dissolving film according to clause 53, for use as a pharmaceutical.

[0198] 55. A composition according to any one of clauses 50 to 52 or an orally dissolving film according to clause 53, for use in the treatment or prevention of pain.

[0199] 56. A method for treating pain, comprising the step of administering an orally dissolving film preparation described in Clause 53 to a patient in need thereof.

[0200] 57. A method for preparing an oral dissolving film, comprising the step of casting a composition described in any of the clauses 1 to 52 onto a support. [Modes for carrying out the invention]

[0201] In this disclosure, unless the context indicates otherwise, certain terms have the meanings set forth below. The nomenclature used herein to define compounds, and in particular compounds according to the present invention, is generally based on the rules of the IUPAC organization for compounds, in particular the "IUPAC Compendium of Chemical Terminology (Gold Book)". To avoid misunderstanding, if the rules of the IUPAC organization conflict with the definitions provided herein, the definitions herein shall prevail. Furthermore, if a compound structure conflicts with the name given to that structure, the structure shall prevail.

[0202] The term "includes" or its variation implies the inclusion of the elements, integers, or processes described, or groups of elements, integers, or processes, but does not imply the exclusion of any other elements, integers, or processes, or groups of elements, integers, or processes, as should be understood herein.

[0203] It should be understood that the term "consists of" or its variation implies the inclusion of any listed element, integer, or process, or group of elements, integers, or processes, as well as the exclusion of any other element, integer, or process, or group of elements, integers, or processes.

[0204] In this specification, the term "about" is used to modify a number or value, referring to a value within ±5% of the specified value. For example, if the temperature is specified as about 5 to about 13°C, it includes temperatures from 4.75 to 13.65°C.

[0205] Unless otherwise indicated by the context, references to the physical state of a substance (liquid, solid, etc.) refer to the state of the substance at 25°C and atmospheric pressure.

[0206] As described above, the inventors have found that it is possible to provide an oral dissolving film agent having improved properties, and in particular one or more of the following properties: good elasticity (low brittleness), rapid collapse, and low tackiness, preferably all of these properties. This has been found to be achievable by the following non-obvious choices: - Select a film-forming polymer with high viscosity (but not so high as to hinder the casting of OTF). - Thickeners and emulsifiers found in conventional formulations are thought to have an adverse effect on disintegration, but are typically considered necessary in the art, so they should be removed, and / or - To mitigate the absence of thickeners and emulsifiers, increase the proportion of disintegrants and / or plasticizers in the formulation.

[0207] Non-exclusive examples of formulations found to achieve such results are listed below. [Examples]

[0208] (Example 1)

[0209] [Table 1]

[0210] [Table 2]

[0211] [Table 3]

[0212] The formulations in Tables 1, 2, and 3 were based on hydroxypropyl methylcellulose (particularly Methocel® K4M) as a film-forming agent. This type of film-forming polymer was found to possess viscosity that enables the formation of OTFs with superior properties without the need for thickeners and emulsifiers.

[0213] The formulations in Tables 1, 2, and 3 also contained PVP as a disintegrant and further contained glycerol and / or polyethylene glycol as plasticizers. These formulations were found to provide oral disintegrating film agents with good elasticity (low brittleness), rapid disintegration, and low tackiness.

[0214] Furthermore, surprisingly, it was found that this composition does not require the inclusion of thickeners and emulsifiers to achieve those properties in OTF.

[0215] [Table 4]

[0216] [Table 5]

[0217] The formulations in Tables 4 and 5 were based on polyvinyl alcohol (PVA) as a film-forming agent. This type of film-forming polymer was found to possess viscosity that enables the formation of OTFs with superior properties without the need for thickeners and emulsifiers.

[0218] The formulations in Table 4 and Table 5 also contained glycerol and polyethylene glycol as plasticizers. These formulations were found to provide oral disintegration film agents with good elasticity (low brittleness), rapid disintegration, and low tackiness.

[0219] Surprisingly, the formulations in Table 4 and Table 5 were found not to require the use of PVP as a disintegrant.

[0220] Furthermore, surprisingly, it was found that this composition does not require the inclusion of thickeners and emulsifiers to achieve those properties in OTF.

[0221] The formulations in Table 4 used polyvinyl alcohol (PVA) as the sole film-forming polymer, while the formulations in Table 5 used a mixture of PVA and HPMC.

[0222] [Table 6]

[0223] The presence of active pharmaceutical ingredients (APIs) within the described range of formulations was not found to adversely affect the properties of the resulting orally disintegrating film. The presence of small amounts of water in the final "dried" film is understood to be due to some residual water remaining in the film after casting. The amount of residual water may depend on the combination and quantities of various components used in the formulation.

[0224] This embodiment is provided merely as an example, and it will be understood that various modifications can be made to this embodiment without departing from the scope of the invention.

Claims

1. A composition for an intraoral disintegrating film agent, (i) Polyvinyl alcohol, (ii) Glycerol, and (iii) Approximately 1100 to 2900 Daltons or g.mol -1 Or approximately 1,300 to 2,000 g.mol -1 Polyethylene glycol with an average molecular weight in the range of Includes, A composition in which the combined amount of glycerol and polyethylene glycol is approximately 12 to 24 wt% in the dry formulation, and the mass ratio of glycerol and polyethylene glycol is approximately 1:2.1 to 1:

4.

2. The composition according to claim 1, comprising approximately 30 to approximately 50 wt% of polyvinyl alcohol by dry mass or approximately 10 to approximately 18 wt% of polyvinyl alcohol by wet mass.

3. The composition according to claim 1 or 2, comprising approximately 3 to approximately 7 wt% dry weight of glycerol or approximately 1 to approximately 6 wt% wet weight of glycerol.

4. A composition according to any one of claims 1 to 3, comprising approximately 3 to approximately 17 wt% by dry weight of polyethylene glycol or approximately 1.1 to approximately 6.3 wt% by wet weight of polyethylene glycol.

5. It further contains hydroxypropyl methylcellulose, optionally, The composition according to any one of claims 1 to 4, comprising approximately 10 to approximately 15 wt% dry weight of hydroxypropyl methylcellulose or approximately 3.1 to approximately 4.7 wt% wet weight of HPMC.

6. A composition for an intraoral disintegrating film agent, (i) Hydroxypropyl methylcellulose, (ii) Polyvinylpyrrolidone, (iii) Glycerol, and (iv) Polyethylene glycol A composition containing the following:

7. A composition for an intraoral disintegrating film agent, (i) Hydroxypropyl methylcellulose containing approximately 19 to 24 wt% methoxy groups and approximately 7 to 12 wt% hydroxypropyl groups, (ii) polyvinylpyrrolidone, and (iii) Glycerol and / or polyethylene glycol A composition containing the following:

8. A composition for an intraoral disintegrating film agent, (i) Hydroxypropyl methylcellulose, (ii) polyvinylpyrrolidone, and (iii) Glycerol and / or polyethylene glycol Includes, A composition containing approximately 60 to 66 wt% hydroxypropyl methylcellulose and / or approximately 4 to 8 wt% polyvinylpyrrolidone in a dry formulation, and free of emulsifiers.

9. The composition according to claim 6 or claim 8, wherein the hydroxypropyl methylcellulose comprises about 19 to about 24 wt% of methoxy groups and about 7 to about 12 wt% of hydroxypropyl groups.

10. The composition according to any one of claims 6 to 9, wherein the hydroxypropyl methylcellulose has a viscosity of about 3500 to about 5600 cPs in a 2% aqueous solution at 20°C.

11. The composition according to any one of claims 6 to 10, comprising approximately 60 to 66 wt% by dry weight of hydroxypropyl methylcellulose or approximately 4.1 to 4.5 wt% by wet weight of hydroxypropyl methylcellulose.

12. The composition according to any one of claims 6 to 11, comprising approximately 4 to approximately 8 wt% of polyvinylpyrrolidone by dry mass or approximately 0.27 to approximately 0.54 wt% of polyvinylpyrrolidone by wet mass.

13. It contains approximately 4 to 20% glycerol by dry mass or approximately 0.2 to 1.4 wt% glycerol by wet mass, and / or The composition according to any one of claims 6 to 12, comprising approximately 4 to 20% polyethylene glycol by dry mass or approximately 0.2 to 1.4 wt% polyethylene glycol by wet mass.

14. The dry formulation contains a combined amount of glycerol and polyethylene glycol in an amount of approximately 12 to approximately 24 wt% or in a wet formulation of approximately 0.5 to approximately 1.5 wt%, and / or The composition according to any one of claims 6 to 13, comprising polyethylene glycol and glycerol in a mass ratio of about 1:1.5 to about 1:4, for example, 1:2.1 to about 1:

4.

15. The composition according to any one of claims 6 to 14, wherein polyvinylpyrrolidone has a viscosity of about 5.5 to about 8.5 cPs in a 10% aqueous solution at 20°C.

16. A composition according to any one of claims 1 to 15, which does not contain a thickening agent.

17. A composition according to any one of claims 1 to 16, which does not contain an emulsifier.

18. The composition according to any one of claims 1 to 17, wherein the composition comprises a pharmaceutically acceptable solvent, optionally the solvent being water, and optionally the composition comprising about 60 to about 95 wt% of the total (wet) composition of the solvent.

19. The composition according to any one of claims 1 to 18, further comprising one or more components selected from the list consisting of salivary stimulants, sweeteners, and flavoring agents.

20. The composition according to any one of claims 1 to 19, further comprising a pharmaceutically active ingredient, wherein the pharmaceutically active ingredient is optionally an opioid.

21. An intraoral dissolving film agent comprising or prepared from the composition described in any one of claims 1 to 20.

22. A composition according to any one of claims 1 to 20 or an orally dissolving film agent according to claim 21, for use as a pharmaceutical.

23. A composition according to any one of claims 1 to 20 or an orally soluble film according to claim 21 for use in the treatment of one or more conditions or diseases selected from pain, migraine, headache, inflammation, metabolic bone disease, hypophosphatemia, nausea, vomiting, gastroesophageal reflux disease, anxiety, dyspnea, sleep disorders, erectile dysfunction, anxiety, and / or motor disorders, such as Parkinson's disease.

24. A method for treating one or more conditions or diseases selected from pain, migraine, headache, inflammation, metabolic bone disease, hypophosphatemia, nausea, vomiting, gastroesophageal reflux disease, anxiety, dyspnea, sleep disorders, erectile dysfunction, anxiety, and / or motor disorders, such as Parkinson's disease, comprising the step of administering the orally soluble film preparation described in claim 21 to a patient in need thereof.

25. A method for preparing an oral dissolving film agent, comprising the step of casting a composition according to any one of claims 1 to 20 on a support.

Images