Pharmaceutical preparations

Abstract

The present invention relates to a membrane comprising an alginate of a monovalent cation or a mixture of alginate containing at least one alginate of a monovalent cation, and a compound of formula (I), such as epinephrine or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for producing such a membrane, and to the use of such a membrane in treating a human patient, in particular the use of such a membrane in treating a condition selected from anaphylaxis, superficial bleeding and cardiac arrest.

Description

Technical Field

[0001] The present invention relates to a membrane comprising a monovalent cationic alginate or a mixture of alginate containing at least one monovalent cationic alginate, and a compound of formula (I), such as epinephrine or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for producing such a membrane, and the use of such a membrane in the treatment of diseases, in particular in the treatment of allergic reactions, superficial bleeding and cardiac arrest. Background Art

[0002] Epinephrine is a hormone and neurotransmitter that is normally produced in the human body by the adrenal glands and certain neurons. It plays an important role in the "fight or fight" response by, for example, increasing muscle blood flow, heart rate, cardiac output, respiratory rate, bronchial dilation, pupil dilation, and blood sugar levels. At the molecular level, epinephrine acts on alpha- and beta-adrenergic receptors.

[0003] Epinephrine can also be used as a drug for treating many conditions. In particular, it is used to treat conditions including anaphylaxis, superficial hemorrhage and cardiac arrest. In anaphylaxis, which is a serious, life-threatening systemic reaction, epinephrine is indicated in the emergency treatment of anaphylaxis, including anaphylaxis to bites, contrast media, drugs or in people with a history of anaphylaxis to known triggers. It is believed that epinephrine (a) stimulates α-adrenaline receptors, increases peripheral vascular resistance, thereby improving blood pressure and coronary perfusion, reverses peripheral vasodilation, and reduces angioedema, (b) stimulates β1 adrenaline receptors, produces positive inotropic and chronotropic cardiac effects, and (c) stimulates β2 adrenaline receptors, causes bronchodilation and increases intracellular cyclic adenosine monophosphate production in mast cells and basophils, reduces the release of inflammatory mediators, and mediates the effects of anaphylaxis. [1] In the treatment of allergic reactions, the recommended dose of epinephrine is about 0.3-1.0 mg for adults and about 0.01 mg / kg for infants and children. [1] Epinephrine is also used to treat superficial bleeding, including abrasions and nosebleeds. Epinephrine reduces blood flow to the skin by constricting small blood vessels, so topical or systemic application of epinephrine can be used to divert blood flow away from the site of injury and thereby reduce bleeding from a wound. Epinephrine has also been used as a suppository to constrict blood vessels and thereby shrink hemorrhoids. In a related application, epinephrine can also be mixed with a local anesthetic (such as lignocaine) to prevent the anesthetic from spreading away from the site of action, prolong its numbing effect, and reduce toxicity and stop bleeding by constricting small blood vessels. [2]

[0004] The only currently available epinephrine preparations for use in, for example, anaphylaxis treatment are injectable formulations; intramuscular injection is particularly recommended. However, intramuscular injection is invasive and carries a risk of needle stick injury for first responders and caregivers. In addition, intramuscular injection can be difficult due to the varying depth of subcutaneous fat between patients and may result in subcutaneous or intravenous injections. Subcutaneous injections are thought to be associated with a significant delay in peak plasma concentrations of epinephrine compared to intramuscular injections. [3] Also, intravenous administration of epinephrine can be associated with adverse side effects in many patients, sometimes severe or fatal, and should be reserved only for those patients with unresponsive anaphylaxis. [1]

[0005] Furthermore, solution formulations of epinephrine are known to have low stability, resulting in a low shelf life of the formulation. In particular, oxidation is the major pathway for the degradation of epinephrine in aqueous solution. This process is accelerated by exposure to light, oxygen, neutral or alkaline pH, or elevated temperature. The effect of pH is believed to be the major determinant of epinephrine stability. The stability of epinephrine is optimal around pH 3-4 and is acceptable below pH 5.5.[4]

[0006] In summary, there is currently no available formulation of epinephrine that can be administered in a non-invasive manner, that is needle-free, that results in acceptable bioavailability and plasma concentrations of epinephrine with low variability between patients, and that is sufficiently stable to have an acceptable shelf life as a pharmaceutical product. Summary of the invention

[0007] The present invention is based on the unexpected discovery that a formulation of a compound of formula (I) such as epinephrine or a pharmaceutically acceptable salt thereof in a film suitable for oral administration can provide a favorable balance of properties. This balance of properties is desirable for use in treating conditions such as allergic reactions, superficial bleeding, and cardiac arrest. In particular, in the case where the film comprises epinephrine or a pharmaceutically acceptable salt thereof, the properties of the film are advantageous compared to the properties of a formulation containing epinephrine intramuscularly. The film formulation of epinephrine can potentially provide a needle-free alternative to intramuscular formulations while enabling acceptable plasma levels of epinephrine to be delivered to patients, wherein the variability between patients is low. In addition, it was found that the film formulation of epinephrine was substantially stable for 83 days at room temperature.

[0008] Thus, the present invention provides for the first time a film comprising a compound of formula (I), such as epinephrine, suitable for oral administration, its use in treating patients suffering from conditions such as anaphylaxis, superficial bleeding and cardiac arrest, and a process for its preparation.

[0009] In one aspect, the present invention provides a film suitable for oral administration, comprising:

[0010] (i) a monovalent cationic alginate or an alginate mixture comprising at least one monovalent cationic alginate; and

[0011] (ii) an active pharmaceutical ingredient (API) which is a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0012]

[0013] in:

[0014] X is selected from hydrogen and OH;

[0015] R 1 is selected from hydrogen, OH and CH2OH;

[0016] R 2 and R 3 independently selected from hydrogen and OH;

[0017] R 4 is selected from hydrogen and methyl; and

[0018] R 5 Selected from hydrogen and C 1-4 alkyl;

[0019] Furthermore, the monovalent cation alginate (a) comprises 25 to 35% by weight of β-D-mannuronate and / or 65 to 75% by weight of α-L-guluronate, and (b) has an average molecular weight of 30,000 to 90,000 g / mol.

[0020] In another aspect, the present invention provides a membrane according to the present invention for use in treating a human patient.

[0021] In another aspect, the present invention provides a membrane according to the present invention for use in treating anaphylaxis, superficial bleeding or cardiac arrest in a human patient.

[0022] In another aspect, the present invention provides a method of treating an allergic reaction, superficial bleeding, or cardiac arrest in a human patient, wherein the method comprises administering to the human patient at least one membrane according to the present invention.

[0023] In another aspect, the present invention provides the use of a membrane according to the present invention for the manufacture of a medicament for treating an allergic reaction, superficial bleeding or cardiac arrest in a human patient.

[0024] In another aspect, the present invention provides a method for producing the membrane of the present invention, the method comprising the steps of:

[0025] (a) Any of the following:

[0026] (i) optionally, mixing at least one antioxidant in water;

[0027] (ii) mixing the API in water, or in the solution obtained in step (i), and optionally subsequently adjusting the pH of the solution to the desired level by adding a suitable acid or base, typically a dilute aqueous acid or base solution, more typically a dilute aqueous base solution, and preferably adjusting the pH of the solution to a level between 3.8 and 5.5;

[0028] (iii) optionally, mixing one or more excipients into the solution obtained in step (ii); and

[0029] (iv) adding monovalent cation alginate under appropriate conditions to produce a viscous slurry (cast);

[0030] Or the following steps:

[0031] (i) mixing one or more excipients in water;

[0032] (ii) separately, dissolving the API in water or an aqueous solution containing one or more antioxidants, and optionally adjusting the pH of the solution to the desired level by adding a suitable acid or base, typically a diluted aqueous acid or base solution, more typically a diluted aqueous base solution, and preferably adjusting the pH of the solution to a level between 3.8 and 5.5;

[0033] (iii) mixing the solution obtained in step (i) with a monovalent cationic alginate; and

[0034] (iv) adding monovalent cationic alginate under appropriate conditions to produce a viscous slurry;

[0035] (b) optionally, degassing the slurry;

[0036] (c) pouring the slurry onto a surface and spreading the slurry to a desired thickness;

[0037] (d) drying the slurry layer, usually at a temperature of 30-60° C., until the residual water content of the film is 0-20% by weight and a solid film is formed; and

[0038] (e) optionally cutting the solid film into small pieces of desired size, further optionally placing the small pieces in a pouch, preferably wherein the pouch is made of PET-lined aluminum, sealing the pouch, and further optionally labeling it. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1Shown is the amount of epinephrine (in mg / dose) present in a film dosage also containing ascorbic acid at various time points when stored at room temperature (25°C; bars on the left hand side of each pair) or 40°C (bars on the right hand side of each pair) for a period of 83 days.

[0040] Figure 2 The relative material areas (%) of impurities with relative retention times (RRT) of 0.89, 1.14, 1.68, 2.32, 2.86 and 3.16 are shown for formulations #50, #51, #52 and #53 as the molar ratio of ascorbic acid to the molar ratio of epinephrine increases. The membranes were stored at 40°C / 75% relative humidity for 8 weeks.

[0041] Figure 3 The relative mass area (%) of impurities with RRT of 0.89, 1.14, 1.68, 2.32, 2.86 and 3.16 for formulations #54, #55, #56 and #57 is shown with increasing molar ratio of sodium bisulfite to epinephrine. The membranes were stored at 40°C / 75% relative humidity for 8 weeks.

[0042] Figure 4 The relative material area (%) of impurities with RRT of 0.89, 1.14, 1.68, 2.32, 2.86 and 3.16 for formulations #50, #51, #52 and #53 are shown, with increasing molar ratios of ascorbic acid to epinephrine. The membranes were stored at 40°C / 75% relative humidity for 12 weeks.

[0043] Figure 5 The relative material area (%) of impurities with RRT of 0.89, 1.14, 1.68, 2.32, 2.86 and 3.16 for formulations #54, #55, #56 and #57 is shown with increasing molar ratio of sodium bisulfite to epinephrine. The membranes were stored at 40°C / 75% relative humidity for 12 weeks.

[0044] Figure 6 The relative material area (%) of impurities with RRT of 1.14, 1.68, 2.32, 2.86 and 3.16 for formulations #81, #82, #83 and #84 are shown, with increasing molar ratios of ascorbic acid to epinephrine. The membranes were stored at 40°C / 75% relative humidity for 4 weeks.

[0045] Figure 7Shown are (A) the relative material area (%) of impurities with RRT of 0.89, 1.14, 1.68, 2.32, 2.86 and 3.16 for formulations #83, #88 and #90 with increasing EDTA content after storage at 40°C / relative humidity of 75% for 4 weeks, and (B) the relative material area (%) of impurities with RRT of 1.14, 1.68, 2.32, 2.86 and 3.16 for formulations #87, #89 and #91 with increasing EDTA content after storage at 40°C / relative humidity of 75% for 4 weeks.

[0046] Figure 8 The relative material area (%) of impurities with RRT of 1.14, 1.68, 2.32, 2.86 and 3.16 for formulations #81, #82, #83 and #84 are shown, with increasing molar ratios of ascorbic acid to epinephrine. The membranes were stored at 40°C / 75% relative humidity for 8 weeks.

[0047] Fig. 9 Shown are (A) the relative material area (%) of impurities with RRT of 0.89, 1.14, 1.68 and 3.16 for formulations #83, #88 and #90 with increasing EDTA content after storage at 40°C / relative humidity of 75% for 8 weeks, and (B) the relative material area (%) of impurities with RRT of 1.14, 1.68 and 3.16 for formulations #87, #89 and #91 with increasing EDTA content after storage at 40°C / relative humidity of 75% for 8 weeks.

[0048] Fig.10 The relative material areas (%) of impurities with RRT of 1.14, 1.68, 2.86, 3.16 and 3.9 are shown with increasing molar ratio of ascorbic acid to molar ratio of epinephrine in formulations #81, #82, #83 and #84. The films were stored at 40°C / 75% relative humidity for 12 weeks.

[0049] Fig.11 Shown are (A) the relative material area (%) of impurities with RRT of 1.14, 1.68 and 3.16 for formulations #83, #88 and #90 with increasing EDTA content after storage at 40°C / 75% relative humidity for 12 weeks, and (B) the relative material area (%) of impurities with RRT of 1.14, 1.68 and 3.16 for formulations #87, #89 and #91 with increasing EDTA content after storage at 40°C / 75% relative humidity for 12 weeks.

[0050] Fig.12Shown are (A) the content of impurity C (RRT 1.15) with increasing ascorbic acid content (in terms of molar ratio to epinephrine); note that the x-axis is disconnected between 0.01 and 0.05, and (B) the content of impurity C (RRT 1.15) with increasing EDTA concentration (%). AA = ascorbic acid; BS = sodium metabisulfite.

[0051] Fig.13 The contents (in terms of molar ratio to epinephrine) of (A) RRT 1.11 impurities, (B) impurity C (RRT 1.15), (C) RRT 1.28 impurities, (D) RRT 1.31 impurities, (E) RRT 1.33 impurities, and (F) RRT 1.56 impurities are shown with increasing ascorbic acid content; note that the x-axis is broken between 0.01 and 0.05. AA = ascorbic acid; BS = sodium metabisulfite.

[0052] Fig.14 The contents of (A) impurities of RRT 1.11, (B) impurity C (RRT 1.15), (C) impurities of RRT 1.31 are shown with increasing EDTA concentration. AA = ascorbic acid; BS = sodium metabisulfite. DETAILED DESCRIPTION

[0053] The present invention relates to a film suitable for oral administration, which can be used for delivering a compound of formula (I), such as epinephrine, or a pharmaceutically acceptable salt thereof, to a human patient. This film can also be referred to as an orally dissolvable film (ODF) and / or an oral transmucosal film (OTF). The film is typically an alginate film, which is applied to the oral mucosa by the patient himself or other people, such as a physician, a nurse, a nursing staff, a social worker, a patient's colleague or a patient's family member. The film has bioadhesive properties and adheres to the oral surface after application. After application, the alginate film begins to dissolve, releasing active pharmaceutical ingredients. The present invention is particularly useful for the treatment of allergic reactions, superficial bleeding and cardiac arrest.

[0054] For the avoidance of doubt, all alternative and preferred features relating to the membrane itself apply equally to the use of said membrane in the treatment of human patients.

[0055] definition

[0056] As defined herein, the term "alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix. 1-4 "Alkyl" refers to a straight chain saturated monovalent hydrocarbon group of one to four carbon atoms or a branched chain saturated monovalent hydrocarbon group of three or four carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

[0057] As defined herein, the term "acyl" refers to a -COR group, wherein R is alkyl, haloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, each as defined herein, or poly(ethylene glycol), and wherein R is optionally further substituted with one, two, three, four or more substituents independently selected from alkyl, alkoxy, halo, haloalkoxy, -OH, -NH2, alkylamino, -COOH or alkoxycarbonyl.

[0058] As defined herein, the term "alkoxy" refers to a -OR group, wherein R is alkyl as defined above, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butyl, isobutyl, tert-butyl, and the like.

[0059] As defined herein, the term "alkoxycarbonyl" refers to a -C(O)OR group wherein R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl, each as defined herein, or poly(ethylene glycol), and wherein R is optionally further substituted with one, two, three, four or more substituents independently selected from alkyl, alkoxy, halo, haloalkoxy, -OH, -NH2, alkylamino, -COOH or alkoxycarbonyl.

[0060] As defined herein, the term "alkylamino" refers to a -NHR group, wherein R is alkyl as defined above, for example, methylamino, ethylamino, n-propylamino, isopropylamino, and the like.

[0061] As defined herein, the term "aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, such as phenyl or naphthyl, and the like.

[0062] As defined herein, the term "aralkyl" refers to a -(alkylene)-R group, where R is aryl as defined above.

[0063] As defined herein, the term "carbamate" refers to -C(O)NR x R y Group, where R x and R y are independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkanealkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocycloalkyl, each as defined herein, or poly(ethylene glycol), and wherein R x and R y Optionally further substituted with one, two, three, four or more substituents independently selected from alkyl, alkoxy, halogen, haloalkoxy, OH, -NH2, alkylamino, -COOH or alkoxycarbonyl.

[0064] As defined herein, the term "cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon group of three to ten carbon atoms, wherein one or two carbon atoms may be replaced by an oxo group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0065] As defined herein, the term "cycloalkanealkyl" refers to a -(alkylene)-R group, wherein R is a cycloalkyl group as defined above, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl, and the like.

[0066] As defined herein, the term "halo" refers to fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

[0067] As defined herein, the term "haloalkyl" refers to an alkyl group as defined above, which is substituted by one or more halogen atoms, preferably one to five halogen atoms, preferably fluorine or chlorine, including those substituted by different halogens, for example CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc.

[0068] As defined herein, the term "haloalkoxy" refers to a -OR group, wherein R is a haloalkyl group as defined above, for example, -OCF3, -OCHF2, and the like.

[0069] As defined herein, the term "heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic group of 5 to 10 ring atoms, wherein one or more, preferably one, two or three, ring atoms are heteroatoms selected from N, O or S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.

[0070] As defined herein, the term "heteroaralkyl" refers to a -(alkylene)-R group, where R is heteroaryl as defined above.

[0071] As defined herein, the term "heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms, wherein one or two of the ring atoms are selected from N, O or S(O). nThe heteroatom of wherein n is an integer from 0 to 2, and the remaining ring atoms are C. The heterocyclyl ring is optionally fused to (one) aryl or heteroaryl ring as defined herein, provided that the aryl and heteroaryl rings are monocyclic. In addition, one or two ring carbon atoms on the heterocyclyl ring may be optionally replaced by -CO- groups. More specifically, the term heterocyclyl includes but is not limited to pyrrolidinyl, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, etc. When the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not aromatic.

[0072] As defined herein, the term "heterocycloalkyl" refers to a -(alkylene)-R group, wherein R is a heterocyclyl ring as defined above, for example, tetrahydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.

[0073] As defined herein, "room temperature" refers to a temperature of 25°C.

[0074] As defined herein, the term "oral cavity" is understood to refer to the oral cavity, including the inner upper and lower lips, all parts of the inner cheeks, the sublingual area, the tongue itself, and the upper and lower gums and hard and soft palates.

[0075] As defined herein, the term "oral mucosa" is understood to refer to the mucosal lining of the interior of the oral cavity and includes, but is not exclusive to, mucosa in the cheeks, labia, sublingual, gingival or labial areas, soft palate, and hard palate.

[0076] The film of the present invention

[0077] The present invention provides a film suitable for oral administration, comprising:

[0078] (i) a monovalent cationic alginate or an alginate mixture comprising at least one monovalent cationic alginate; and

[0079] (ii) an active pharmaceutical ingredient (API) which is a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0080]

[0081] in:

[0082] X is selected from hydrogen and OH;

[0083] R 1 is selected from hydrogen, OH and CH2OH;

[0084] R 2 and R 3 independently selected from hydrogen and OH;

[0085] R 4 is selected from hydrogen and methyl; and

[0086] R 5 Selected from hydrogen and C 1-4 alkyl.

[0087] Preferably, the compound of formula (I) is epinephrine. More preferably, the compound of formula (I) is (-)-epinephrine. Alternatively, the compound of formula (I) is a racemic mixture of (-)-epinephrine and (+)-epinephrine.

[0088] The monovalent cationic alginate or alginate mixture containing at least one monovalent cationic alginate functions as a film former in the film. As used herein, the term "film former" refers to a chemical or a group of chemicals that form a tough, cohesive and continuous coating when applied to a surface.

[0089] Alginate is a salt of alginic acid, a linear polysaccharide naturally produced by brown algae (Phaeophyceae, mainly Laminaria). The alginate used in the present invention generally comprises 100 to 3000 monomer residues linked together in a flexible chain. There are two types of these residues, namely β-(1,4)-linked D-mannuronic acid (M) residues and α-(1,4)-linked L-guluronic acid (G) residues. Typically, the carboxylic acid group of each residue in the polymer is usually ionized at physiological pH. The two types of residues are diastereomers of each other, differing only in the stereochemistry at their C5 position, with the D-mannuronic acid residues being converted to L-guluronic acid residues by enzymes after polymerization. However, in the polymer chain, the two types of residues will produce very different configurations: as shown in the following formula (II), any two adjacent D-mannuronic acid residues are 4 C1-bilateral bond connection, while any two adjacent L-guluronic acid residues are 4 C1-Dual upright key connection.

[0090]

[0091] Typically in alginate polymers, the residues are organized in repeating or strictly alternating blocks of residues, such as MMMMM..., GGGGG... or GMGMGM... Different monovalent and polyvalent cations can exist as counterions to the negatively charged carboxylate groups of the D-mannuronic acid and L-guluronic acid residues of the alginate polymer. Typically, the membrane comprises alginate, wherein the counterions of the alginate polymer are monovalent cations. The cations that serve as counterions of individual alginate polymer molecules may all be identical to one another, or may be different from one another. Preferably, the counterions of the alginate polymer are selected from the group consisting of Na + , K + and NH4 +More preferably, the counter ion of the alginate polymer is Na + Alternatively, the membrane may comprise an alginate mixture comprising at least one monovalent cation alginate. The alginate mixture may comprise a cation selected from the group consisting of Na + , K + and NH4 + The group consisting of alginate.

[0092] Typically, the film comprises an alginate composition having a dynamic viscosity of 100-1000 mPa·s, or 200-800 mPa·s, or 300-700 mPa·s, as measured using a Brookfield LVF viscometer (obtained from Brookfield Engineering Laboratories, Inc.) using a No. 2 spindle on a 10% aqueous solution (w / w) thereof at a temperature of 20° C. and a shear rate of 20 rpm.

[0093] Preferably, the film comprises an alginate composition having an average guluronate (G) content of 50% to 85% by weight, more preferably 60% to 80% by weight, most preferably 65% ​​to 75% by weight. Preferably, the film comprises an alginate composition having an average mannuronate (M) content of 15% to 50% by weight, more preferably 20% to 40% by weight, most preferably 25% to 35% by weight. Preferably, the film comprises an alginate composition having an average molecular weight of 30,000 g / mol to 90,000 g / mol, for example 35,000 g / mol to 85,000 g / mol, or 40,000 g / mol to 70,000 g / mol, or 40,000 g / mol to 50,000 g / mol. Preferably, the film comprises an alginate composition having an average guluronate (G) content of 50% to 85%, an average mannuronate (M) content of 15% to 50%, and an average molecular weight of 30,000 g / mol to 90,000 g / mol. More preferably, the film comprises an alginate composition having an average guluronate (G) content of 60 to 80%, an average maluronate (M) content of 20 to 40%, and an average molecular weight range of 30,000 g / mol to 90,000 g / mol. Most preferably, the film comprises an alginate composition having an average guluronate (G) content of 65% to 75%, an average mannuronate (M) content of 25% to 35%, and an average molecular weight of 30,000 g / mol to 90,000 g / mol. Without wishing to be bound by any particular theory, the combination of (a) a specific average relative ratio of melosuronate to guluronate in the alginate composition and (b) a specific average molecular weight of the alginate composition is believed to impart the desired bioadhesive properties to the film.

[0094] The monovalent cationic alginate or a mixture of alginate containing at least one monovalent cationic alginate may be the only film former present in the film. Alternatively, the film may comprise one or more further film formers in addition to the monovalent cationic alginate or a mixture of alginate containing at least one monovalent cationic alginate.

[0095] The film preferably comprises LFR5 / 60 or LF10 / 60 (both are sodium alginate products commercially available from FMC BioPolymer) were used as alginate. LFR5 / 60 is a low molecular weight, low viscosity sodium alginate extracted from the stem of the kelp Laminariahyperborea. LF10 / 60 is a sodium alginate with a G / M% ratio of 65-75 / 25-35 and a viscosity of 20-70 mPa·s as measured using a Brookfield LVF viscometer using a No. 2 spindle on a 1% aqueous solution thereof at a temperature of 20° C. at a shear rate of 20 rpm. LF10 / 60 has a LFR5 / 60 has higher average molecular weight and higher viscosity.

[0096] Without wishing to be bound by any particular theory, after being applied to the oral cavity by adhering to the mucous membranes of the oral cavity, films comprising a higher viscosity alginate are believed to have a longer residence time (i.e., dissolution time) than films comprising a lower viscosity alginate of similar thickness. It is contemplated that the viscosity of the alginate composition within the film may be adjusted by mixing any number of alginates having different viscosities. Typically, the alginate composition comprising A film of about 1 mm thick with LFR5 / 60 as the only alginate component had a residence time of about 3-10 minutes after adhering to the oral mucosa. An approximately 1 mm thick film of LF10 / 60 as the only alginate component had a residence time of approximately 30 minutes after adhering to the oral mucosa.

[0097] Therefore, if it is desired that the film have a longer residence time in the oral cavity, then the film generally preferably comprises LF10 / 60 as alginate. However, LFR5 / 60 as alginate membrane, including LF10 / 60 as an alginate film will generally exhibit poor adhesion properties when applied to the oral mucosa. More generally, it is believed that film formers with longer average chain lengths will exhibit poorer mucoadhesion than film formers with shorter average chain lengths. Without wishing to be bound by any particular theory, better mucoadhesion of the film to the oral mucosa is believed to enable any active ingredient contained in the film to be more effectively delivered to its site of action. Therefore, if a longer residence time of the film in the oral cavity is not particularly desired, it may be preferred to use LFR5 / 60 was used as alginate.

[0098] The membrane particularly preferably comprises LFR5 / 60 was used as alginate.

[0099] The film may also include a film former other than the monovalent cation alginate or a mixture of alginate containing at least one monovalent cation alginate. These other film formers include agents such as poly(vinyl pyrrolidone) (PVP), hydroxypropyl methylcellulose (HPMC), pullulan, etc. However, if any other film former is present in the film in addition to the monovalent cation alginate or a mixture of alginate containing at least one monovalent cation alginate, the monovalent cation alginate or a mixture of alginate containing at least one monovalent cation alginate will generally be present in the film in an amount greater than any other film former present. Preferably, the ratio (by weight) of monovalent cationic alginate or a mixture of alginate containing at least one monovalent cationic alginate to the combined sum of all other film formers (e.g. PVP, HPMC and / or pullulan) present in the film is 1:1 or higher, or 2:1 or higher, or 3:1 or higher, or 4:1 or higher, or 5:1 or higher, or 10:1 or higher, or 20:1 or higher, or 50:1 or higher, or 100:1 or higher, or 500:1 or higher, or 1000:1 or higher, or 10000:1 or higher. Preferably, the monovalent cationic alginate or a mixture of alginate containing at least one monovalent cationic alginate will constitute at least 50% by weight of all film formers present in the film, more preferably at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, at least 95% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.9% by weight, at least 99.95% by weight, or at least 99.99% by weight of all film formers present in the film.

[0100] Preferably, monovalent cation alginate or alginate mixture containing at least one monovalent cation alginate is substantially the only film former present in the film. More preferably, alginate of monovalent cation or alginate mixture containing at least one monovalent cation is the only film former present in the film. Or, the film preferably does not include any or substantially any poly (vinyl pyrrolidone). Or, the film preferably does not include any or substantially any pullulan. Or, the film preferably does not include any or substantially any hydroxypropyl methylcellulose.

[0101] As used herein, reference to a film that does not contain "substantially any" of a particular component means that the film may contain trace amounts of the particular component, as long as the particular component does not substantially affect the basic characteristics of the film. Typically, therefore, a film that does not contain substantially any particular component typically contains less than 5% by weight of the particular component, preferably less than 1% by weight of the particular component, and most preferably less than 0.1% by weight of the particular component.

[0102] The discovery of the present invention is that, using alginate of monovalent cation or alginate mixture containing at least one monovalent cation as film former, compared with using other film formers such as PVP, HPMC and / or pullulan, there is benefit. In particular, using alginate as the main film former will ensure that the film of the present invention has better viscosity characteristics than the film mainly comprising other film formers (such as PVP, HPMC and / or pullulan). The film of the present invention has bioadhesion; that is, the film of the present invention can be firmly adhered to the moist surface (i.e. mucosa) in the oral cavity of a mammalian object before it is completely dissolved. The film that alginate is not the main film former generally does not have this desired characteristic. A further advantageous discovery of the present invention is that selecting alginate as the main film former enables the active pharmaceutical ingredient (such as epinephrine) of a therapeutically effective dose to be loaded into the film, while maintaining the uniformity of the film and other desired physical properties.

[0103] Without wishing to be bound by any particular theory, it is believed that one of the reasons that alginate is a preferred film former over, for example, PVP, HPMC and pullulan is that the negatively charged alginate can act as a counter ion to the positively charged amine salt of the compound of formula (I) (i.e., the API), thereby producing a solid amorphous dispersion during film preparation (i.e., enabling the preparation of a transparent film with desired physical properties).

[0104] Typically, the film comprises 25% to 99% by weight of a monovalent cationic alginate or a mixture of alginate containing at least one monovalent cationic alginate, preferably 27% to 95% by weight, more preferably 29% to 93% by weight, even more preferably 30% to 91% by weight, most preferably 35% to 90% by weight of a monovalent cationic alginate or a mixture of alginate containing at least one monovalent cationic alginate.

[0105] The membranes of the present invention may also contain a residual water content. Typically, the membranes contain 0% to 20% residual water by weight. More typically, the membranes contain 5% to 15% residual water by weight. Preferably, the membranes contain 9% to 11% residual water by weight. Most preferably, the membranes contain about 10% residual water by weight.

[0106] The film of the present invention further comprises an active pharmaceutical ingredient (API), which is a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0107]

[0108] in:

[0109] X is selected from hydrogen and OH;

[0110] R 1 is selected from hydrogen, OH and CH2OH;

[0111] R 2 and R 3 independently selected from hydrogen and OH;

[0112] R 4 is selected from hydrogen and methyl; and

[0113] R 5 Selected from hydrogen and C 1-4 alkyl.

[0114] Therefore, R 2 is selected from hydrogen and OH. 3 Selected from hydrogen and OH.

[0115] Preferably, in the compound of formula (I), X is OH. Preferably, in the compound of formula (I), R 1 Preferably, in the compound of formula (I), R 2 Preferably, in the compound of formula (I), R 3 Preferably, in the compound of formula (I), R 4 Preferably, in the compound of formula (I), R 5 It is hydrogen or methyl, more preferably methyl.

[0116] Preferably, the compound of formula (I) is selected from the group consisting of epinephrine, norepinephrine, ephedrine, pseudoephedrine, amphetamine, salbutamol, terbutaline, metaproterenol, isoproterenol and tyramine.

[0117] More preferably, the compound of formula (I) is adrenaline. The structure of adrenaline is shown in the following general formula (III).

[0118]

[0119] The compound of formula (I) may contain one or more stereocenters. For example, when the substituent X in formula (I) is OH, the carbon atom to which X is bonded is the stereocenter. Similarly, when the substituent R in formula (I) is 4 When it is methyl, R 4The bonded carbon atom is a stereocenter. Therefore, some compounds of formula (I) can be separated in optically active or racemic forms. How to prepare optically active forms, such as by resolution of materials, is well known in the art. For the avoidance of doubt, formula (I) includes all enantiomers, diastereomers and racemic forms of its compounds, as well as all mixtures of enantiomers and diastereomers of its compounds.

[0120] Thus, for example, when the compound of formula (I) is epinephrine, this means that the compound of formula (I) can be (+)-epinephrine, (-)-epinephrine, or a mixture of (+)-epinephrine and (-)-epinephrine.

[0121] Most preferably, the compound of formula (I) is (-)-epinephrine. The structure of (-)-epinephrine is shown in the following general formula (IV).

[0122]

[0123] Adrenaline may also be referred to as epinephrine. For the avoidance of doubt, as used herein, the terms "adrenaline" and "epinephrine" may be used interchangeably. (-)-Adrenaline may also be referred to as (-)-epinephrine, L-adrenaline, L-epinephrine, L-(-)-adrenaline, L-(-)-epinephrine, or (R)-(-)-3,4-dihydroxy-α-(methylaminomethyl)benzyl alcohol. These terms, as used herein, are interchangeable for the avoidance of doubt.

[0124] The API may be a pharmaceutically acceptable polymorph, co-crystal, hydrate or solvate of a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably a pharmaceutically acceptable polymorph, co-crystal, hydrate or solvate of adrenaline or a pharmaceutically acceptable salt thereof, more preferably a pharmaceutically acceptable polymorph, co-crystal, hydrate or solvate of (-)-adrenaline or a pharmaceutically acceptable salt thereof.

[0125] Alternatively, the API may be a prodrug of a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably a prodrug of epinephrine, more preferably a prodrug of (-)-epinephrine. The term "prodrug" of a compound of formula (I) as used herein refers to any compound or a pharmaceutically acceptable salt thereof that can be metabolized in vivo to a compound of formula (I) after administration to a human body. Typical prodrugs include acyl, ester, alkoxycarbonyl and carbamate derivatives of a compound of formula (I). For example, prodrugs of epinephrine include dipivefrine.

[0126] Thus, the API may be a compound of formula (V)

[0127]

[0128] in:

[0129] R a , R b and R c are independently hydrogen or a biolabile linker such as acyl, alkoxycarbonyl, carbamate, phosphate, diphosphate or triphosphate; and

[0130] R d is hydrogen or a biolabile linker such as acyl, alkoxycarbonyl, or carbamate;

[0131] The condition is R a , R b , R c and R d Not all hydrogen.

[0132] Therefore, R a is hydrogen or a biolabile linker such as acyl, alkoxycarbonyl, carbamate, phosphate, diphosphate or triphosphate. b is hydrogen or a biolabile linker such as acyl, alkoxycarbonyl, carbamate, phosphate, diphosphate or triphosphate. c is hydrogen or a biolabile linker such as acyl, alkoxycarbonyl, carbamate, phosphate, diphosphate or triphosphate.

[0133] Preferably, when the API is a compound of formula (V), R c and R d It's hydrogen.

[0134] Typically, the API is a pharmaceutically acceptable salt of a compound of formula (I). Typically, the pharmaceutically acceptable salt of each compound of formula (I) is selected from its acetate, propionate, isobutyrate, benzoate, succinate, suberate, tartrate, citrate, fumarate, malonate, maleate, adipate, dimethanesulfonate, sulfate, benzenesulfonate, nitrate, carbonate, hydrochloride, hydrobromide, phosphate, aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, The preferred salt forms of the compound of formula (I) include acetate, propionate, isobutyrate, benzoate, succinate, suberate, tartrate, citrate, fumarate, malonate, maleate, adipate, dimethanesulfonate, sulfate, benzenesulfonate, nitrate, carbonate, hydrochloride, hydrobromide and phosphate of the compound of formula (I). More preferred salt forms of the compound of formula (I) include tartrate, dicarboxylate, hydrochloride, phosphate, sulfate or benzenesulfonate salts of the compound of formula (I).

[0135] As defined herein, the term "compound of formula (I)" refers to a form of the compound of formula (I) in which the molecule exists in a neutral (i.e., unionized) form. The term "pharmaceutically acceptable salt of a compound of formula (I)" refers to any salt of a compound of formula (I). For example, when the compound of formula (I) is adrenaline, the term "pharmaceutically acceptable salt of adrenaline" refers to any salt of adrenaline in which the secondary amine group of adrenaline is protonated or one or both of the hydroxyl (phenol) groups in adrenaline are deprotonated. Preferably, the term "pharmaceutically acceptable salt of adrenaline" refers to any salt of adrenaline in which the secondary amine group is protonated.

[0136] Typically, the API is a pharmaceutically acceptable salt of adrenaline selected from the group consisting of acetate, propionate, isobutyrate, benzoate, succinate, suberate, tartrate, citrate, fumarate, malonate, maleate, adipate, dimethanesulfonate, sulfate, benzenesulfonate, nitrate, carbonate, hydrochloride, hydrobromide and phosphate of adrenaline. Preferred salt forms of adrenaline include dicarboxylates, hydrochlorides, phosphates, sulfates, benzenesulfonates or tartrates of adrenaline. More preferably, the pharmaceutically acceptable salt of adrenaline is a dicarboxylate or tartrate of adrenaline, most preferably tartrate of adrenaline.

[0137] Typically, the API is a pharmaceutically acceptable salt of (-)-adrenaline, wherein the pharmaceutically acceptable salt of (-)-adrenaline is selected from the group consisting of acetate, propionate, isobutyrate, benzoate, succinate, suberate, tartrate, citrate, fumarate, malonate, maleate, adipate, dimethanesulfonate, sulfate, benzenesulfonate, nitrate, carbonate, hydrochloride, hydrobromide and phosphate of (-)-adrenaline. Preferred salt forms of (-)-adrenaline include dicarboxylates, hydrochlorides, phosphates, sulfates, benzenesulfonates or tartrates of (-)-adrenaline. More preferably, the pharmaceutically acceptable salt of (-)-adrenaline is a dicarboxylate or tartrate of (-)-adrenaline, most preferably the tartrate of (-)-adrenaline.

[0138] Typically, the API is a pharmaceutically acceptable salt of a racemic mixture of (-)-epinephrine and (+)-epinephrine selected from the group consisting of acetate, propionate, isobutyrate, benzoate, succinate, suberate, tartrate, citrate, fumarate, malonate, maleate, adipate, dimethanesulfonate, sulfate, benzenesulfonate, nitrate, carbonate, hydrochloride, hydrobromide and phosphate of a racemic mixture of (-)-epinephrine and (+)-epinephrine. Preferred salt forms of the racemic mixture of (-)-epinephrine and (+)-epinephrine include dicarboxylate, hydrochloride, phosphate, sulfate, benzenesulfonate or tartrate of a racemic mixture of (-)-epinephrine and (+)-epinephrine. More preferably, the pharmaceutically acceptable salt of the racemic mixture of (-)-epinephrine and (+)-epinephrine is a dicarboxylate or tartrate of the racemic mixture of (-)-epinephrine and (+)-epinephrine, most preferably a tartrate of the racemic mixture of (-)-epinephrine and (+)-epinephrine.

[0139] The API may be present in the film in varying amounts. Typically, the film comprises 0.001% to 75% API by weight, preferably 0.01% to 60% API by weight, more preferably 0.15% to 50% API by weight, still more preferably 0.2% to 45% API by weight, and most preferably 0.25% to 40% API by weight.

[0140] Typically, the compound of formula (I) or a pharmaceutically acceptable salt thereof is the only API present in the film. However, the film may optionally contain one or more other active pharmaceutical ingredients in addition to the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0141] Preferably, the film comprises 25% to 99% by weight of a monovalent cationic alginate or a mixture of alginate containing at least one monovalent cationic alginate, 0% to 20% by weight of water, and 0.001% to 75% by weight of API. More preferably, the film comprises 29% to 93% by weight of a monovalent cationic alginate or a mixture of alginate containing at least one monovalent cationic alginate, 5% to 15% by weight of water, and 0.15% to 50% by weight of API. Even more preferably, the film comprises 35% to 91% by weight of a monovalent cationic alginate or a mixture of alginate containing at least one monovalent cationic alginate, 9% to 11% by weight of water, and 0.2% to 45% by weight of API.

[0142] The membrane of the present invention may optionally contain other components in addition to the API, water and film former. Typically, the membrane of the present invention further comprises one or more of the following:

[0143] (i) at least one antioxidant;

[0144] (ii) at least one pharmaceutically acceptable solvent;

[0145] (iii) at least one buffer component;

[0146] (iv) at least one excipient, such as one or more plasticizers, fillers, taste masking agents or flavoring agents;

[0147] (v) at least one acidifying agent or alkalizing agent;

[0148] (vi) at least one penetration enhancer;

[0149] (vii) self-emulsifying drug delivery systems (SEDDS), such as self-microemulsifying drug delivery systems (SMEDDS) or self-nanoemulsifying drug delivery systems (SNEDDS);

[0150] (viii) at least one chelating agent;

[0151] (ix) at least one antimicrobial agent; and

[0152] (x) at least one inorganic salt.

[0153] The film may additionally comprise any suitable antioxidant. As defined herein, an "antioxidant" is any compound that inhibits the oxidation of other chemicals. Examples of suitable antioxidants include, but are not limited to: ascorbic acid; citric acid; sodium bisulfite; sodium metabisulfite; ethylenediaminetetraacetic acid (EDTA); butylated hydroxytoluene; and combinations thereof. Preferably, if an antioxidant is present, it is ascorbic acid, sodium bisulfite, sodium metabisulfite, EDTA, or a combination thereof. Thus, typically, at least one antioxidant is present in the film of the present invention. Preferably, the film comprises at least two antioxidants. More preferably, the film comprises at least three antioxidants. Most preferably, the antioxidant is selected from ascorbic acid, citric acid, sodium bisulfite, sodium metabisulfite, EDTA, and butylated hydroxytoluene.

[0154] More preferably, if an antioxidant is present, it is ascorbic acid. Still more preferably, ascorbic acid and sodium bisulfite are both present as antioxidants. Alternatively, ascorbic acid and sodium pyrosulfite are both present as antioxidants. Even more preferably, ascorbic acid, sodium bisulfite and EDTA are all present as antioxidants. Alternatively, ascorbic acid, sodium pyrosulfite and EDTA are all present as antioxidants.

[0155] Thus, in particularly preferred films of the invention, the film comprises (i) ascorbic acid and (ii) sodium bisulfite or sodium metabisulfite. Alternatively, the film may comprise (i) ascorbic acid and (ii) EDTA. Alternatively, the film may comprise (i) sodium bisulfite or sodium metabisulfite and (ii) EDTA. In even more preferred films of the invention, the film comprises (i) ascorbic acid, (ii) sodium bisulfite or sodium metabisulfite, and (iii) EDTA.

[0156] The film may contain 0.01% to 10% by weight of each antioxidant present. Preferably, the film may contain 0.1% to 8% by weight of each antioxidant present, more preferably 0.25% to 6% by weight of each antioxidant present, and more preferably 0.5% to 5% by weight of each antioxidant present. The ratio (by weight) of the total antioxidant present in the film to the API present in the film is typically 0.01:1 to 10:1, preferably 0.05:1 to 10:1, more preferably 0.1:1 to 10:1, still more preferably 0.25:1 to 10:1, still more preferably 0.5:1 to 10:1, even more preferably 1:1 to 3:1, and most preferably about 2:1. The ratio of total antioxidant present in the film to API present in the film (on a molar basis) is typically from 0.01:1 to 5:1, preferably from 0.02:1 to 2:1, more preferably from 0.03:1 to 1:1, still more preferably from 0.05:1 to 0.5:1, even more preferably from 0.08:1 to 0.3:1, and most preferably from 0.1:1 to 0.2:1.

[0157] If ascorbic acid is present as the antioxidant, it is typically present in a molar amount of 0.0005 to 0.5 per mole of API present in the film, preferably 0.001 to 0.1, more preferably 0.005 to 0.05, still more preferably 0.008 to 0.02, most preferably 0.01 or less.

[0158] If sodium bisulfite or sodium metabisulfite is present as the antioxidant, it is typically present at 0.001 to 1.0 per mole of API in the film, preferably 0.005 to 0.5, more preferably 0.01 to 0.2, still more preferably 0.025 to 0.1, most preferably about 0.05.

[0159] If EDTA is present as an antioxidant, it is typically present in a molar amount of 0.001 to 1.0 per mole of API present in the film, preferably 0.005 to 0.5, more preferably 0.01 to 0.3, still more preferably 0.02 to 0.2, most preferably 0.03 or more. If EDTA is present as an antioxidant, it is typically present in the film in an amount by weight of 0.01% to 5%, preferably 0.03% to 1%, more preferably 0.06% to 0.5%, most preferably 0.12 to 0.25%.

[0160] The film can comprise any pharmaceutically acceptable solvent in addition. This solvent can be a non-aqueous solvent, or a combination of water and a non-aqueous solvent. The example of a non-aqueous solvent should be nontoxic, and includes but is not limited to ethanol, acetone, benzyl alcohol, diethylene glycol monoethyl ether, glycerol, hexylene glycol, isopropyl alcohol, polyethylene glycol, methoxypolyethylene glycol, diethyl sebacate, dimethyl isosorbide, propylene carbonate, dimethyl sulfoxide, transcutol, triacetin, fatty acid esters and oils, for example soybean oil, peanut oil, olive oil, palm oil, rapeseed oil, corn oil, coconut oil, other vegetable oils etc.

[0161] The film may additionally include any suitable buffer component. As defined herein, "buffer component" refers to any chemical entity that, when dissolved in a solution, causes the solution to prevent its pH from changing after the subsequent addition of an acid or base. Suitable buffer components for the film of the present invention are buffer components that are effective buffers in the pH range of 3.0 to 5.5. Preferably, the buffer component is an effective buffer in the pH range of 3.8 to 5.5. Examples of suitable buffer components include, but are not limited to, phosphates, sulfates, citrates, and acetates. Buffers can be salts of monovalent cations, such as sodium, potassium, or ammonium salts. Particularly preferred buffer components include citric acid and sodium dihydrogen phosphate. Without wishing to be bound by any particular theory, it is believed that epinephrine has low stability to oxidation at a pH greater than 5.5. In addition, without wishing to be bound by any particular theory, it is believed that alginate tends to gel at a pH less than 3.8.

[0162] The membrane may comprise 0.1% to 10% by weight of a buffer component, typically 0.2% to 8% by weight, typically 0.3% to 6% by weight, typically 0.5% to 5% by weight. Alternatively, the membrane may not additionally comprise a buffer component.

[0163] The film may additionally comprise any suitable excipient, such as one or more fillers or plasticizers. The film may comprise both a plasticizer and a filler. Alternatively, the film may comprise only one of a plasticizer or a filler. The film preferably comprises a plasticizer. In some cases, it may be desirable that the film does not comprise a filler. The film particularly preferably comprises a plasticizer but does not comprise a filler. The film may additionally comprise a taste masking agent or a flavoring agent. The taste masking agent may be a sweetener.

[0164] Plasticizers can be selected from the group consisting of polyethylene glycol, glycerol, sorbitol, xylitol and combinations thereof when present. Typically, the film comprises a plasticizer selected from the group consisting of glycerol, sorbitol and combinations thereof. Preferably, the film comprises a plasticizer selected from glycerol, sorbitol and combinations thereof. More preferably, the film comprises glycerol and sorbitol as plasticizers. Most preferably, the film comprises glycerol, sorbitol and xylitol. The film may comprise 0% to 40% by weight of each plasticizer, preferably 5% to 35% by weight of each plasticizer, more preferably 5% to 30% by weight of each plasticizer, most preferably 3% to 25% by weight of each plasticizer. Without wishing to be bound by any particular theory, adding a plasticizer, such as a combination of glycerol, sorbitol and xylitol, is considered to increase the flexibility and toughness of the film and reduce brittleness. This is considered to make the film easier to handle and use.

[0165] Fillers, when present, may be, for example, microcrystalline cellulose or titanium dioxide.Suitable filler amounts may be 0% to 20% by weight of the total pharmaceutical composition, for example 0.1% to 10% by weight of the total pharmaceutical composition.

[0166] Flavoring agents, when present, may for example be selected from gum arabic, anise oil, caraway oil, cardamom, cherry syrup, cinnamon, citric acid syrup, clove oil, cocoa, coriander oil, ethyl vanillin, anise oil, ginger, glycerine, liquorice, honey, lavender oil, lemon oil, mannitol, nutmeg oil, orange oil, orange flower water, peppermint oil, raspberry, rose oil, rose water, rosemary oil, sarsaparilla syrup, spearmint oil, thyme oil, toluoyl balsamic syrup, vanilla, wild cherry syrup and mixtures thereof. The film may contain 0.001% to 10% by weight of each flavoring agent present, preferably 0.01% to 5% by weight of each flavoring agent, and most preferably 0.1% to 3% by weight of each flavoring agent.

[0167] The film may further comprise an acidifying agent or an alkalizing agent. As defined herein, an "acidifying agent" refers to a compound that can be used alone or in combination with other compounds to acidify a pharmaceutical composition. As defined herein, an "alkalizing agent" refers to a compound that can be used alone or in combination with other compounds to alkalize a pharmaceutical composition.

[0168] Typically, the membrane comprises an alkalizing agent. Typically, the alkalizing agent is an alkali. Examples of suitable alkalizing agents include, but are not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide. A preferred alkalizing agent is sodium hydroxide. Alternatively, the membrane may comprise an acidulant. Examples of suitable acidulants include, but are not limited to, acetic acid, dehydroacetic acid, ascorbic acid, benzoic acid, boric acid, citric acid, edetic acid, hydrochloric acid, isostearic acid, lactic acid, nitric acid, oleic acid, phosphoric acid, sorbic acid, stearic acid, sulfuric acid, tartaric acid, and undecylenic acid. A preferred acidulant is phosphoric acid.

[0169] The membrane of the invention is prepared by drying the membrane-forming solution (see below). Typically, a sufficient amount of an acidifying agent or alkalizing agent is added to adjust the pH of the membrane-forming solution (before it is dried to form a membrane) to pH 3.0 to 5.5, preferably pH 3.8 to 5.5.

[0170] The membrane may additionally comprise any suitable penetration enhancer. As defined herein, "penetration enhancer" refers to a compound that can be used to help absorb other substances through the epithelium or other biological membranes alone or in combination with other compounds. In particular, the term "penetration enhancer" is used herein to refer to a compound that can be used to help absorb other substances through the buccal mucosa alone or in combination with other compounds. Penetration enhancers can be generally divided into two different types, paracellular (para) or transcellular (trans) penetration enhancers according to their mechanism of action. Paracellular penetration enhancers are enhancers that help absorb other substances through the intercellular spaces in the epithelium or other biological membranes. Transcellular penetration enhancers are enhancers that help absorb other substances through the cells in the epithelium or other biological membranes, wherein the other substances pass through the top and basolateral cell membranes in the epithelium or other biological membranes.

[0171] Typically, the membrane may comprise one or more paracellular permeation enhancers. Alternatively, the membrane may comprise one or more transcellular permeation enhancers. Alternatively, the membrane may comprise at least one paracellular permeation enhancer and at least one transcellular permeation enhancer.

[0172] Typically, the penetration enhancer, if present, is one or more compounds selected from the group consisting of nonionic, cationic, anionic or zwitterionic surfactants (e.g., caprylocaproylpolyoxyethylene-8-glyceride, sodium lauryl sulfate, cetyltrimethylammonium bromide, decyldimethylammonium propane sulfonate); bile salts (e.g., sodium deoxycholate); fatty acids (e.g., caproic acid, heptanoic acid, oleic acid); fatty amines; fatty ureas; fatty acid esters (e.g., methyl laurate, methyl palmitate); substituted or unsubstituted nitrogen-containing heterocyclic compounds (e.g., methylpyrrolidone, methylpiperazine, azone); terpenes (e.g., limonene, fenchone, menthone, eucalyptol); sulfoxides (e.g., dimethyl sulfoxide (DMSO)); ethylenediaminetetraacetic acid (EDTA); and combinations thereof. Preferably, the penetration enhancer, if present, is selected from the group consisting of EDTA, oleic acid, and combinations thereof.

[0173] Typically, the membrane may comprise EDTA. Without wishing to be bound by any particular theory, EDTA is thought to act as a paracellular permeation enhancer by transiently affecting the tight junctions interconnecting membrane cells, followed by increased paracellular or pore transport. EDTA is also thought to act as a transcellular permeation enhancer by interacting with phospholipid head groups and increasing membrane fluidity [5]. Alternatively, the membrane may comprise oleic acid. Without wishing to be bound by any particular theory, oleic acid is thought to act as a transcellular permeation enhancer by interacting with the polar head groups of phospholipids in or on the cell membrane and increasing cell membrane flexibility, thereby promoting transcellular drug permeability. Oleic acid has been shown to exhibit enhanced permeability to porcine cheek epithelium at concentrations of 1-10% [6].

[0174] The film may further comprise a self-emulsifying drug delivery system (SEDDS) or an emulsion thereof. Such a system is preferably a self-microemulsifying drug delivery system (SMEDDS) or an emulsion thereof, or a self-nanoemulsifying drug delivery system (SNEDDS) or an emulsion thereof. A self-microemulsifying drug delivery system is a microemulsion preconcentrate or an anhydrous form of a microemulsion. A self-nanoemulsifying drug delivery system is a nanoemulsion preconcentrate or an anhydrous form of a nanoemulsion. These systems are typically an oil (e.g., a triglyceride, a diglyceride, or a monoglyceride or a mixture thereof) and at least one surfactant (e.g., Twain ) which, when introduced into an aqueous phase under mild stirring, spontaneously form oil-in-water (O / W) microemulsions or nanoemulsions (respectively). SNEDDS systems typically form emulsions with globule sizes less than 200 nm [7]. SEDDS (e.g., SMEDDS or SNEDDS) may also contain co-emulsifiers or co-surfactants and / or solubilizers to facilitate emulsification (e.g., microemulsions or nanoemulsions) or to improve the incorporation of drugs into the SEDDS (e.g., SMEDDS or SNEDDS). Typically, the SEDDS (e.g., SMEDDS or SNEDDS) component is selected from: a mixture of Tween with one or more glycerides and a hydrophilic cosolvent; a mixture of Tween with a low HLB co-surfactant and a hydrophilic cosolvent; a mixture of polyethylene glycol (PEG), Labrasol and Chremophore EL; a mixture of polyethylene glycol (PEG), Labrasol and Kollihorse EL; and a mixture of polyethylene glycol (PEG), Labrasol, Chremophore EL and Chremophore RH40. PEG can be any suitable polyethylene glycol, such as PEG with an average molecular weight of 100 to >1000 Da, preferably 200 to 800 Da, more preferably 300 to 600 Da, and most preferably about 400.

[0175] As defined herein, the term "glyceride" refers to any ester formed between glycerol and one or more fatty acids. The term "glyceride" can be used interchangeably with the term "acylglycerol". Typically, a glyceride is a monoglyceride, a diglyceride or a triglyceride. Preferably, a glyceride is a triglyceride. Typically, a glyceride is a simple glyceride. The term "simple glyceride" refers to a diglyceride in which two fatty acids are identical to each other, or a triglyceride in which three fatty acids are identical to each other. Alternatively, a glyceride is a mixed glyceride. The term "mixed glyceride" refers to a diglyceride in which two fatty acids are different from each other, or a triglyceride in which any of the three fatty acids is different from the other two or all three fatty acids are different from each other. Therefore, a glyceride is typically a monoglyceride, a simple diglyceride, a simple triglyceride, a mixed diglyceride or a mixed triglyceride. Preferably, a glyceride is a simple triglyceride or a mixed triglyceride.

[0176] As defined herein, a "hydrophilic co-solvent" is any solvent that is miscible with water. Examples of suitable hydrophilic co-solvents include, but are not limited to, glycerol, ethanol, 2-(2-ethoxyethanol), PEG-400, and propylene glycol.

[0177] As defined herein, the term "low HLB co-surfactant" refers to any lipid that falls into Class IIIA, IIIB or IV of the lipid formulation classification system described by CW Puton [8], the contents of which are incorporated herein by reference in their entirety.

[0178] Typically, the membrane may additionally contain any suitable chelating agent. Chelating agents may be added to the membrane as preservatives. "Chelating agent" as defined herein refers to a compound that is a multidentate ligand capable of forming two or more separate bonds with a single central atom, typically a metal ion. Examples of suitable chelating agents include, but are not limited to: ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), citric acid, phosphonic acid, glutamic acid, histidine, malate and derivatives thereof. Preferably, the chelating agent, if present, is ethylenediaminetetraacetic acid (EDTA). The membrane may contain 0.001% to 4% by weight of each chelating agent present. Preferably, the membrane may contain 0.001% to 0.1% by weight of each chelating agent present.

[0179] Typically, the film may additionally comprise any suitable antimicrobial agent. As defined herein, an "antimicrobial agent" is any compound that kills or prevents the growth of microorganisms. Examples of suitable antimicrobial agents include, but are not limited to: benzyl alcohol; benzalkonium chloride; benzoic acid; methyl, ethyl or propyl parabens; and quaternary ammonium compounds. The film may comprise from 0.001% to 4% by weight of each antimicrobial agent present. Preferably, the film may comprise from 0.001% to 0.1% by weight of each antimicrobial agent present.

[0180] Therefore EDTA can be present in the film of the present invention as an antioxidant, a penetration enhancer or a chelating agent. Generally, if EDTA is present, EDTA acts as all antioxidants, penetration enhancers and chelating agents. Alternatively, if EDTA is present, EDTA may only act as an antioxidant. Alternatively, if EDTA is present, EDTA may only act as a penetration enhancer. Alternatively, if EDTA is present, EDTA may only act as a chelating agent.

[0181] Alternatively, the film may additionally comprise at least one inorganic salt. The inorganic salt may be any salt suitable for preparing medicines. Examples of these salts include, but are not limited to, halides, oxides, hydroxides, sulfates, carbonates, phosphates, nitrates, acetates and oxamate of alkali metals, alkaline earth metals, aluminum, zinc and ammonium. Typically, the inorganic salt may be selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, calcium chloride and ammonium chloride. Preferably, the inorganic salt is sodium chloride. Typically, the total concentration of the inorganic salt in the film is at least 0.05 weight %, preferably 0.1 to 5 weight %, more preferably 0.2 to 2 weight %, even more preferably 0.25 to 1 weight %, most preferably about 0.5 weight %. Alternatively, the film does not comprise any inorganic salt. In such an embodiment, the film typically comprises API in a neutral (i.e., non-ionized) form.

[0182] Typically, the film may additionally comprise at least one antioxidant, at least one excipient, optionally at least one alkalizer or acidifier, optionally at least one penetration enhancer, optionally at least one pharmaceutically acceptable solvent, optionally at least one buffer component, and optionally SEDDS (e.g., SMEDDS or SNEDDS). For example, the film may comprise at least one antioxidant, at least one excipient, optionally at least one alkalizer or acidifier, optionally at least one penetration enhancer, and optionally at least one buffer component. Preferably, the film may comprise at least one antioxidant, glycerol, sorbitol, optionally at least one alkalizer or acidifier, optionally at least one penetration enhancer, and optionally at least one buffer component. More preferably, the film may comprise at least one antioxidant, glycerol, sorbitol, and optionally at least one alkalizer. Even more preferably, the film may comprise: an antioxidant selected from ascorbic acid, sodium bisulfite, and combinations thereof; glycerol; sorbitol; and optionally at least one alkalizer, preferably sodium hydroxide. Still more preferably, the film may comprise: ascorbic acid; glycerol; sorbitol; and optionally at least one alkalizing agent, preferably sodium hydroxide. Most preferably, the film may comprise: ascorbic acid; sodium bisulfite; glycerol; sorbitol; and optionally at least one alkalizing agent, preferably sodium hydroxide.

[0183] Preferably, the membrane according to the invention comprises 25 to 99% by weight of a monovalent cationic alginate or a mixture containing at least one monovalent cationic alginate, 0 to 20% by weight of water, 0.001 to 75% by weight of API, 0.01 to 10% by weight of at least one antioxidant, 0 to 40% by weight of glycerol, 0 to 40% by weight of sorbitol, optionally 0 to 40% by weight of xylitol, optionally an alkalizer or acidifier, optionally 0.01 to 5% by weight of a permeation enhancer, optionally 0.1 to 10% by weight of SEDDS (e.g. SMEDDS or SNEDDS) and optionally 0.001 to 4% by weight of a chelating agent. More preferably, the film according to the invention comprises 30% to 91% by weight of a monovalent cationic alginate or a mixture containing at least one monovalent cationic alginate, 9% to 11% by weight of water, 0.2% to 45% by weight of API, 0.01% to 10% by weight of at least one antioxidant, 10% to 20% by weight of glycerol, 10% to 20% by weight of sorbitol, optionally 10% to 20% by weight of xylitol and optionally an alkalizing agent or an acidulant, and wherein the ratio (by weight) of total antioxidant present in the film to API present in the film is from 0.5:1 to 10:1.

[0184] Alternatively, the membrane of the present invention is composed of 25% to 99% by weight of a monovalent cation alginate or a mixture containing at least one monovalent cation alginate, 0% to 20% by weight of water, 0.001% to 75% by weight of API, 0.1% to 10% by weight of at least one antioxidant, 0% to 40% by weight of glycerol, 0% to 40% by weight of sorbitol, optionally 0% to 40% by weight of xylitol, optionally an alkalizer or acidifier, optionally 0.01% to 5% by weight of a permeation enhancer, optionally 0.1% to 10% by weight of SEDDS (e.g. SMEDDS or SNEDDS) and optionally 0.001% to 4% by weight of a chelating agent. Alternatively, the film of the present invention consists of 30% to 91% by weight of a monovalent cationic alginate or a mixture containing at least one monovalent cationic alginate, 9% to 11% by weight of water, 0.2% to 45% by weight of API, 0.1% to 10% by weight of at least one antioxidant, 10% to 20% by weight of glycerol, 10% to 20% by weight of sorbitol, optionally 10% to 20% by weight of xylitol and optionally an alkalizer or acidifier, and wherein the ratio (by weight) of total antioxidant present in the film to API present in the film is 0.5:1 to 10:1.

[0185] The film according to the present invention has a thickness before drying of preferably 200 to 2000 μm, more preferably 300 to 1750 μm, even more preferably 400 to 1500 μm, most preferably about 1000 μm.

[0186] The membrane according to the invention preferably has a thickness of 0.1 to 20 cm on each of its two largest surfaces. 2 , more preferably 0.5 to 15 cm 2 , even more preferably 1 to 10 cm 2 , most preferably 2 to 6 cm 2 Preferably, the surface area of ​​each of the two largest surfaces of the membrane is about 3 cm 2 .

[0187] One skilled in the art will be able to select an appropriate film thickness and surface area by simply preparing a series of films of varying thicknesses and surface areas and testing the resulting films to measure the dissolution time, taking into account the desired dissolution time for a given application.

[0188] The mechanical properties of the film of the present invention are very satisfactory. Especially, the film is flexible (i.e. it allows bending and folding without breaking), and has high tensile strength. Importantly, the film of the present invention is not a gel, because the alginate polymer chains are not cross-linked to each other. The film of the present invention has bioadhesion; that is, the film comprises a natural polymeric material (alginate) that can serve as an adhesive. The film has viscosity for a wet surface like a mucosa. Especially, the film is viscous to the oral mucosa, such as the mucosa of the cheek, lip, sublingual, gum or lip region, soft palate and hard palate.

[0189] The film according to the invention may be provided with printed textual content or printed images thereon, such as a brand name, a trademark, dosage instructions or symbols.

[0190] Drug delivery and therapeutic use of membranes

[0191] Typically, the films of the present invention are administered to a human patient in order to deliver to the patient a therapeutically effective amount of an active pharmaceutical ingredient (API), preferably (-)-epinephrine or a pharmaceutically acceptable salt thereof, contained therein.

[0192] As used herein, the term "therapeutically effective amount" refers to an amount of the API sufficient to reduce or alleviate the severity, duration, progression, or onset of the disease being treated, prevent the progression of the disease being treated, cause regression of symptoms associated with the disease being treated, prevent the recurrence, generation, onset or progression of symptoms associated with the disease being treated, or enhance or improve the preventive or therapeutic effect of another therapy. The exact amount of the API administered to the patient will depend on the type and severity of the disease or condition, and also on the patient's characteristics, such as general health, age, sex, weight, and resistance to drugs. It will also depend on the extent, severity, and type of the disease being treated. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors.

[0193] As used herein, the terms "treat," "treatment," and "treating" refer to a reduction or improvement in the progression, severity, and / or duration of a disease being treated, or an improvement in one or more symptoms (preferably one or more identifiable symptoms) of a disease being treated by administering a film of the present invention to a patient.

[0194] Typically, the membranes of the present invention are provided for use in treating human patients. Typically, the membranes of the present invention are provided for use in treating a condition selected from the group consisting of: anaphylaxis, superficial bleeding, cardiac arrest, hypotension, septic shock, neurogenic shock, asthma, narcolepsy, obesity, nasal congestion, sinus congestion, eustachian tube congestion, vasomotor rhinitis, allergic rhinitis, croup, sinusitis, otitis media, tracheobronchitis, congestion, edema, priapism, attention deficit hyperactivity disorder (ADHD), depression, chronic pain, bronchoconstriction, chronic obstructive pulmonary disease (COPD), hyperkalemia, premature labor, bradycardia, and heart blockage.

[0195] Typically, the compound of formula (I) is adrenaline and the membranes of the present invention are provided for use in treating a condition selected from the group consisting of anaphylaxis, superficial bleeding and cardiac arrest.

[0196] Alternatively, the compound of formula (I) is norepinephrine and the membrane of the present invention is provided for use in treating a condition selected from the group consisting of hypotension, septic shock and neurological shock.

[0197] Alternatively, the compound of formula (I) is ephedrine and the film of the present invention is provided for use in treating a condition selected from the group consisting of hypotension, asthma, narcolepsy, obesity and nasal congestion.

[0198] Alternatively, the compound of formula (I) is pseudoephedrine and the film of the invention is provided for use in treating a condition selected from the group consisting of nasal congestion, sinus congestion, Eustachian tube congestion, vasomotor rhinitis, allergic rhinitis, croup, sinusitis, otitis media, tracheobronchitis, congestion, edema and priapism.

[0199] Alternatively, the compound of formula (I) is amphetamine, and the film of the present invention is provided for use in treating a condition selected from the group consisting of attention deficit hyperactivity disorder (ADHD), narcolepsy, obesity, depression and chronic pain.

[0200] Alternatively, the compound of formula (I) is salbutamol, and the membrane of the present invention is provided for use in treating a condition selected from the group consisting of asthma, bronchoconstriction, chronic obstructive pulmonary disease (COPD) and hyperkalemia.

[0201] Alternatively, the compound of formula (I) is terbutaline and the film of the present invention is provided for use in treating a condition selected from the group consisting of asthma, bronchoconstriction and premature labour.

[0202] Alternatively, the compound of formula (I) is metaproterenol and the film of the present invention is provided for use in treating a condition selected from the group consisting of asthma and bronchoconstriction.

[0203] Alternatively, the compound of formula (I) is isoproterenol and the membrane of the present invention is provided for use in treating a condition selected from the group consisting of bradycardia, cardiac arrest and asthma.

[0204] Preferably, the membrane according to the invention is provided for the treatment of anaphylaxis, superficial bleeding and / or cardiac arrest. Thus, typically, the membrane according to the invention is used for the treatment of anaphylaxis. Alternatively, the membrane according to the invention is provided for the treatment of superficial bleeding. Alternatively, the membrane according to the invention is provided for the treatment of cardiac arrest.

[0205] The present invention provides a film of the present invention for use in treating an allergic reaction. The effects of an allergic reaction in a patient can be severe. The effects of an allergic reaction can include one or more of the following: an itchy rash; swelling of the throat or tongue; shortness of breath; vomiting; dizziness; and low blood pressure. These symptoms typically develop over a period of minutes to hours. In the most severe cases, the effects of an allergic reaction can result in the death of the patient.

[0206] The present invention provides a membrane of the present invention for use in treating superficial bleeding. Superficial bleeding is caused by superficial wounds. These are small cuts, abrasions and punctures that affect one or both of the outer two layers of the skin, the epidermis and the dermis.

[0207] The present invention provides a membrane of the present invention for use in treating cardiac arrest. Cardiac arrest is a sudden loss of blood flow due to the heart's inability to effectively pump blood. The effects of cardiac arrest are often severe. The effects of cardiac arrest may include one or more of the following: loss of consciousness; abnormal or absent breathing; chest pain; shortness of breath; and nausea. If not treated within a few minutes, cardiac arrest often results in the death of the patient.

[0208] Therefore, the present invention provides a film according to the present invention for treating or ameliorating symptoms selected from the group consisting of: itchy rash; swelling of the throat or tongue; shortness of breath; vomiting; dizziness; hypotension; bleeding from superficial wounds; loss of consciousness; abnormal or lack of breathing; chest pain; shortness of breath; nausea; and combinations thereof.

[0209] Typically, the patient to be treated is an adult. Alternatively, the patient to be treated may be a child. The patient to be treated may be an elderly patient. The patient to be treated may be a child suffering from allergies.

[0210] Typically, the film is applied to the patient's oral cavity. The film is preferably applied to the oral mucosa in the cheeks or lips or the sublingual area or the soft palate. The film is typically applied by the patient himself. Alternatively, the film is applied to the patient by another person, such as a medical practitioner, a nurse, a caregiver, a social worker, a colleague of the patient, or a family member of the patient.

[0211] The film has bioadhesive properties and adheres to the oral cavity surface after application. After application, the alginate film begins to dissolve, releasing the active pharmaceutical ingredient. Typically, the film is completely dissolved in a time period of 0.1 to 60 minutes or longer after being applied to the oral mucosa. Preferably, after being applied to the oral mucosa, the film is completely dissolved in a time period of 0.5 to 30 minutes, more preferably 1 to 20 minutes, even more preferably 3 to 10 minutes, and most preferably 3 to 5 minutes.

[0212] Without wishing to be bound by any particular theory, as the film dissolves in the oral cavity, it is believed that the accompanying released active pharmaceutical ingredient can enter the bloodstream via one or both of two different pathways: (a) direct absorption into the bloodstream through the oral mucosa ("oral transmucosal route"); and (b) swallowing into the stomach and subsequent absorption into the bloodstream through the intestinal epithelium. Typically, the peak plasma concentration of the API in a patient exceeds 1 ng / mL. Peak plasma concentrations can be achieved within 120 minutes after the film is adhered to the oral mucosa, preferably within 60 minutes after adhesion, more preferably within 45 minutes after adhesion, even more preferably within 30 minutes or 20 minutes after adhesion, and most preferably within 10 minutes after adhesion.

[0213] Typically, a single film is applied to a patient at a given time, typically to the oral mucosa. However, in some cases, it may be desirable to apply two films simultaneously to achieve the correct dose for an individual patient. When the API is epinephrine and it is used to treat acute allergic reactions, the recommended dose for adults is 0.6 to 3 mg epinephrine per allergic event. When the API is epinephrine and it is used to treat acute allergic reactions, the recommended dose for infants and children is 0.3 to 1.5 mg epinephrine per allergic event. [1] In some cases, it may be desirable to apply more than two films simultaneously to achieve the correct dose for an individual patient, for example three, four, five, six, seven, eight, nine, ten or more.

[0214] Thus, the present invention also provides a method of treating a condition in a human patient, wherein the method comprises applying at least one film according to the present invention to the oral cavity of the human patient, optionally wherein the condition to be treated is an allergic reaction, superficial bleeding or cardiac arrest.

[0215] The present invention also provides the use of a membrane according to the present invention for the manufacture of a medicament for treating a condition in a human patient, optionally wherein the condition to be treated is an allergic reaction, superficial bleeding or cardiac arrest.

[0216] The present invention also provides a product comprising one or more films of the present invention, and packaging. Each film can be wrapped in a pouch individually, or a plurality of films can be wrapped together in the same pouch. Optionally, the pouch is made of aluminum lined with PET. The product may further comprise instructions for using the film. These instructions may contain information about the recommended frequency or time of use of the film by the patient, how to remove the film from its pouch or packaging, how to adhere the film to the mucosa, and at which position in the oral cavity to adhere the film to the mucosa.

[0217] Any one or more of the films of the present invention may also be used in combination with one or more other drugs or pharmaceutical compositions to treat a disease or condition, and the films of the present invention and / or other drugs or pharmaceutical compositions may be used in the treatment of the disease or condition for which they are useful.

[0218] One or more other drugs or pharmaceutical compositions may be administered to a patient by any one or more of the following routes: oral, systemic (e.g., transdermal, intranasal, transmucosal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous). The composition of one or more other drugs or pharmaceutical compositions may be in the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, transdermal patches, bioadhesive films, or may be any other suitable composition. The selection of preparations depends on various factors, such as the mode of drug administration (e.g., for oral administration, the preparations are preferably in the form of tablets, pills or capsules) and the bioavailability of the drug substance.

[0219] Membrane manufacturing

[0220] The membrane of the present invention can be made as follows: prepare a membrane-forming solution by adding and mixing the constituent components of the membrane, distribute the solution onto a solid surface, and allow the solution to dry on the surface to form a membrane. To distribute the solution or composition onto a solid surface, the solution or composition can be simply poured onto and / or evenly spread onto the surface, for example, using a draw-down blade or similar device to pour and / or evenly spread onto the surface.

[0221] A typical method includes the following process steps:

[0222] (a) optionally, mixing at least one antioxidant in water;

[0223] (b) mixing the API in water, or in the solution obtained in step (a), and optionally subsequently adjusting the pH of the solution to the desired level by adding a suitable acid or base, typically a dilute aqueous acid or base solution, more typically a dilute aqueous base solution, and preferably adjusting the pH of the solution to a level between 3.8 and 5.5;

[0224] (c) optionally, mixing one or more excipients into the solution obtained in step (b);

[0225] (d) adding monovalent cationic alginate under appropriate conditions to form a viscous slurry;

[0226] (e) optionally, degassing the slurry;

[0227] (f) pouring the slurry onto a surface and spreading the slurry to a desired thickness, e.g., about 1 mm;

[0228] (g) drying the slurry layer, usually at a temperature of 30-60° C., until the residual water content of the film is 0-20 wt % and a solid film is formed; and

[0229] (h) Optionally, cutting the solid film into small pieces of desired size, further optionally placing the small pieces in a pouch, preferably wherein the pouch is made of aluminum lined with PET, sealing the pouch, and further optionally labeling it.

[0230] Thus, an exemplary method for preparing the membrane of the present invention comprises the following process steps:

[0231] (a) mixing at least one antioxidant in water, optionally wherein the antioxidant is selected from the group consisting of ascorbic acid, citric acid, sodium bisulfite, sodium metabisulfite, butylated hydroxytoluene, and combinations thereof;

[0232] (b) mixing the API, preferably adrenaline or a pharmaceutically acceptable salt thereof, more preferably adrenaline tartrate, in the solution obtained in step (a), and optionally subsequently adjusting the pH of the solution to the desired level by adding a suitable acid or base, typically a diluted aqueous acid or base solution, more typically a diluted aqueous base solution, and preferably adjusting the pH of the solution to a range of 3.8 to 5.5;

[0233] (c) optionally, adding additional water and / or one or more plasticizers and / or one or more fillers to the solution obtained in step (b) under further mixing;

[0234] (d) adding the monovalent cationic alginate under suitable conditions, such as by mixing for about 30 minutes or until a lump-free dispersion is obtained, thereby forming a viscous slurry;

[0235] (e) optionally, degassing the slurry, typically for 5-14 hours;

[0236] (f) pouring the slurry onto a surface, for example onto a plate, preferably onto a glass plate, and spreading the slurry to a desired thickness, usually with the aid of a coater;

[0237] (g) drying the slurry layer, usually at a temperature of 30 to 60° C., preferably 35 to 45° C., until the residual water content of the film is 0 to 20% by weight, preferably 5 to 15% by weight, more preferably 9 to 11% by weight, and a solid film is formed; and

[0238] (h) Optionally, cutting the solid film into small pieces of desired size, further optionally placing the small pieces in a pouch, preferably wherein the pouch is made of aluminum lined with PET, sealing the pouch, and further optionally labeling it.

[0239] An alternative method for producing a membrane according to the invention comprises the following process steps:

[0240] (a) mixing one or more excipients in water;

[0241] (b) separately, dissolving the API in water or an aqueous solution containing one or more antioxidants, and optionally adjusting the pH of the solution to the desired level by adding a suitable acid or base, typically a diluted aqueous acid or base solution, more typically a diluted aqueous base solution, and preferably adjusting the pH of the solution to a level between 3.8 and 5.5;

[0242] (c) mixing the solution obtained in step (a) with a monovalent cationic alginate, e.g., for about 10 minutes;

[0243] (d) adding the solution obtained in step (b) to the solution obtained in step (c) under suitable conditions, for example by mixing for about 20 minutes or until a lump-free dispersion is obtained, thereby forming a viscous slurry;

[0244] (e) optionally, degassing the slurry, typically for 5-14 hours;

[0245] (f) pouring the slurry onto a surface, such as a plate, preferably a glass plate, and spreading the slurry to a desired thickness, such as about 1 mm, usually with the aid of a coater;

[0246] (g) drying the slurry layer, usually at a temperature of 30 to 60° C., preferably 35 to 45° C., until the residual water content of the film is 0 to 20% by weight, preferably 5 to 15% by weight, more preferably 9 to 11% by weight; and

[0247] (h) Optionally, cutting the solid film into small pieces of desired size, further optionally placing the small pieces in a pouch, preferably wherein the pouch is made of aluminum lined with PET, sealing the pouch, and further optionally labeling it.

[0248] Typically, in the method for preparing a membrane according to the present invention, when an antioxidant is present in the membrane, the antioxidant is dissolved in an aqueous solution before the addition of the API.

[0249] In any alternative variation of the above method, after pouring the viscous slurry onto the surface, the viscous slurry is first spread to a thickness of about 2 mm by an applicator having a slot height of about 2 mm, and then spread to a thickness of about 1 mm by an applicator having a slot height of about 1 mm.

[0250] Typically, alginate is added to an aqueous solution containing the API. Alternatively, the API and alginate are dissolved together in the solution. Alternatively, the API may be added to the alginate solution so as to obtain an emulsion or suspension of the API in the alginate solution. Alternatively, the film-forming composition of the present invention may contain dissolved and undissolved active ingredients. For example, the film-forming composition may contain a combination of active ingredients dissolved in the alginate solution and active ingredients suspended in the solution.

[0251] Further API can be applied to the surface of the film before or after drying, for example by applying the API as an aerosol spray to a dry or wet film. The active ingredient can also be applied to the surface of the film as a powder. Flavoring agents can additionally be applied in this manner.

[0252] Publications, patent publications and other patent documents mentioned herein are incorporated herein by reference as a whole. In this article, any reference to a singular term also includes its plural form. When using the term "comprising", "comprise" or "comprises", the term can be replaced by "consisting of", "consist of" or "consist of", or replaced by "consisting essentially of", "consisting essentially of" or "consisting essentially of". Any time a numerical range or a single numerical value is mentioned, it also includes a value of about the range or the single value. Any reference to a compound of formula (I) such as epinephrine also includes its physiologically acceptable salt, unless otherwise stated. Any content related to alginate includes any physiologically acceptable salt thereof, unless otherwise stated. Any % value is based on the relative weight of one or more components discussed, unless otherwise stated.

[0253] Example

[0254] The following are examples illustrating the present invention. However, these examples are in no way intended to limit the scope of the present invention. Unless otherwise stated, reference to "epinephrine" or a pharmaceutically acceptable salt thereof throughout the Examples section specifically refers to the (-) enantiomer of epinephrine, i.e., (-)-epinephrine or a pharmaceutically acceptable salt thereof. Unless otherwise stated, reference to "tartrate" in this Examples section specifically refers to the L-(+)-isomer of tartaric acid or a salt thereof.

[0255] Example 1: Preparation of membrane containing epinephrine

[0256] Two basic membrane formulation protocols were developed. One membrane formulation protocol prepared membranes containing epinephrine without pH adjustment. The other membrane formulation protocol produced membranes containing epinephrine in which the pH of the membrane formulation was adjusted to about 5 prior to coating and drying.

[0257] Preparation of adrenaline oral film adjusted to pH 5

[0258] The batch formulations containing 1 mg / dose of epinephrine tartrate as the API are listed in Table 1, and the batch formulations containing 10 mg / dose of epinephrine tartrate as the API are listed in Table 2. Each formulation contains ascorbic acid and / or sodium bisulfite. This component is believed to act as an antioxidant. The ratio of antioxidant to API is provided. The yield based on 1000 doses / batch is calculated (dose size = 3 cm 2 ).

[0259] Table 1 Batch formulation for preparing epinephrine film containing 1 mg / dose of epinephrine tartrate adjusted to pH 5. AA = ascorbic acid; Na-B = sodium bisulfite; AT = epinephrine tartrate; qs = quantum satis.

[0260]

[0261] Table 2 Batch formulation for preparing epinephrine film containing 10 mg / dose of epinephrine tartrate adjusted to pH 5. AA = ascorbic acid; Na-B = sodium bisulfite; AT = epinephrine tartrate; qs = quantum satis.

[0262]

[0263] Prepare the membrane according to the following procedure:

[0264] • Sodium bisulfite or ascorbic acid or a mixture of sodium bisulfite and ascorbic acid is dissolved in mostly purified water with mixing followed by the addition of epinephrine bitartrate.

[0265] • Add glycerin and sorbitol to the solution with mixing.

[0266] • Adjust the pH of the solution to 5 by adding the necessary amount of dilute sodium hydroxide.

[0267] • Increase batch volume to correct total by adding remaining purified water.

[0268] • Add sodium alginate with mixing for about 30 minutes or until a lump-free dispersion is obtained to give a viscous slurry.

[0269] • Allow the slurry to stand overnight to degas.

[0270] • Pour the slurry onto a glass plate and spread it with a coater to a thickness of 1 mm.

[0271] The slurry layer was dried in a drying oven heated to about 40°C until the residual water content reached about 10% by weight to form a solid film.

[0272] • Use a knife to cut the solid film into small pieces of 15 x 20 mm.

[0273] The resulting films were placed individually in aluminum / polyethylene terephthalate (PET) bags, sealed with a heat sealer and labeled.

[0274] A method for preparing an adrenaline oral film without pH adjustment

[0275] Table 3 lists the batch formulations containing 3 mg / dose of epinephrine tartrate as the API and no pH adjustment prior to coating and drying. Each formulation contained ascorbic acid and / or sodium bisulfite. This component is believed to act as an antioxidant. The ratio of antioxidant to API is provided. One of the formulations containing sodium bisulfite also included xylitol. The yield was calculated based on 1000 doses / batch (dose size = 3 cm 2 ).

[0276] Table 3 Batch formulation for preparing epinephrine film without pH adjustment, containing 3 mg / dose of epinephrine tartrate. AA = ascorbic acid; Na-B = sodium bisulfite; AT = epinephrine tartrate.

[0277]

[0278] Prepare the membrane according to the following procedure:

[0279] • Sodium bisulfite or ascorbic acid or a mixture of sodium bisulfite and ascorbic acid is dissolved in mostly purified water with mixing followed by the addition of epinephrine bitartrate.

[0280] - Add glycerin and sorbitol (xylitol if present) to the solution with mixing.

[0281] • Add sodium alginate with mixing for about 30 minutes or until a lump-free dispersion is obtained to give a viscous slurry.

[0282] • Allow the slurry to stand overnight to degas.

[0283] • Pour the slurry onto a glass plate and spread it with a coater to a thickness of 1 mm.

[0284] The slurry layer was dried in a drying oven heated to about 40°C until the residual water content reached about 10% by weight to form a solid film.

[0285] • Use a knife to cut the solid film into small pieces of 15 x 20 mm.

[0286] The obtained films were placed in aluminum bags, sealed with a heat sealer, and labeled.

[0287] Example 2: Physical Evaluation of Epinephrine-Containing Membranes

[0288] After manufacture, each of the epinephrine-containing membranes prepared as described above in Example 1 was evaluated according to the following criteria:

[0289]

[0290] *Target residual moisture: A combination of IR-induced water evaporation and real-time weight measurement. The percent weight change from the start is observed until no further change is observed as a measure of residual moisture.

[0291] **Epinephrine content and homogeneity: Separated by reverse phase high performance liquid chromatography (RP-HPLC) with detection at 220 nm. The amount of epinephrine per dose was calculated using an epinephrine standard curve. [9]

[0292] Evaluation of an epinephrine oral film adjusted to pH 5

[0293] Epinephrine was completely dissolved in the liquid (aqueous) phase and a uniform (yellowish) viscous slurry without lumps could be prepared with each individual batch formulation / protocol, wherein the pH adjustment was as described above in Example 1. Air bubbles generated during the preparation of the slurry, which introduced inhomogeneities in the film, were removed by passive degassing by leaving the slurry at room temperature overnight prior to coating.

[0294] All prepared films had a smooth and flat surface structure and were flexible when dried to a water content of 9–11%.

[0295] Quantitative determination of epinephrine in the membrane was performed on RP-HPLC in isocratic mode with ammonium acetate as mobile phase and UV detection at 280 nm.

[0296] Evaluation of an adrenaline oral film without pH adjustment

[0297] A non-lump (yellowish) viscous slurry was prepared using each individual batch formulation / protocol without pH adjustment as described above in Example 1. Most of the bubbles generated during the preparation of the slurry were removed by passively degassing the slurry by leaving it at room temperature overnight prior to coating.

[0298] Except for some bubbles, all prepared films had smooth and flat surface structures when dried to a moisture content of 9%-11% and were flexible. The flexibility could be further improved by adding xylitol as an additional plasticizer.

[0299] Example 3: Stability study of membranes containing epinephrine

[0300] Stability studies were also conducted to determine the stability of the epinephrine API within the oral film prepared in Example 1. As described above, epinephrine is susceptible to degradation by oxidation, and it is desirable to minimize such degradation (ie, optimize the stability of the oral film).

[0301] Study on the stability of adrenaline oral film adjusted to pH 5

[0302] Initial stability studies were conducted on 10 mg / dose epinephrine oral films adjusted to pH 5 and containing only ascorbic acid as the antioxidant (ie, the formulation listed in column 2 of Table 2 in Example 1 above) prior to coating and drying.

[0303] Figure 1 The effect of temperature on the oxidation process of the epinephrine film stabilized by ascorbic acid is shown. The epinephrine oral films to be tested were stored at room temperature (RT) and 40°C, respectively, and the epinephrine content per dose was analyzed after 0, 7, 18, 41 and 83 days. It is clear from these results that the oxidation process of the epinephrine film containing ascorbic acid can be accelerated by increased temperature. The epinephrine film is almost stable after 83 days at room temperature (RT), while the epinephrine film stored at 40°C undergoes a gradual degradation, wherein a loss of about 30% of the epinephrine content after 83 days is observed.

[0304] Study on the Stability of Epinephrine Oral Film without pH Adjustment

[0305] pH measurements and stability studies were performed on each of the four epinephrine oral film formulations prepared without pH adjustment (ie, the formulations listed in Table 3 in Example 1 above). The results of these studies are listed in Table 4 below.

[0306] Table 4 pH of slurries of batch formulations prepared without pH adjustment but with the addition of different antioxidants and plasticizers at the initial time point and after three weeks, and the amount of adrenaline API present in each formulation. Standard deviations are provided in parentheses (number of samples tested in each experiment = 5). AA = ascorbic acid; Na-B = sodium bisulfite; AT = adrenaline tartrate.

[0307]

[0308] It was observed that without any external pH adjustment, the pH of all prepared slurries (containing different stabilizers) was greater than 3.8. This is beneficial because sodium alginate can be converted to alginic acid and start gelling at a pH below 3.8. Therefore, acceptable slurries containing epinephrine as API can be prepared without the need for external pH adjustment.

[0309] Stability studies based on these multiple formulations were performed by evaluating the epinephrine content per dose in each formulation at the initial time point and after 3 weeks of storage at room temperature. As shown in Table 5, the stability studies showed that after 3 weeks at room temperature, the epinephrine film containing ascorbic acid as the sole antioxidant was more stable than the epinephrine film containing sodium bisulfite as the sole antioxidant. This may be due to the relatively low pH of the slurry containing ascorbic acid and / or the excellent antioxidant properties of ascorbic acid compared to sodium bisulfite. However, for the epinephrine film containing both ascorbic acid and sodium bisulfite, the greatest stabilizing effect on epinephrine was observed, which surprisingly showed that the synergistic effect originated from the combination of these two antioxidants in the film.

[0310] The dose-weight variations obtained in this study were considered acceptable for laboratory scale sample preparation, and the homogeneity data (mg epinephrine / mg film) showed good consistency within the batch.

[0311] in conclusion

[0312] The results in Examples 1 to 3 show the possibility of formulating a stable adrenaline oral film. The main conclusions of this study are summarized below.

[0313] • By degassing the slurry for more than 15 hours, a uniform viscous slurry without lumps with few bubbles was obtained.

[0314] • The films produced are uniform and have a smooth and flat surface. They are tough and flexible and are considered easy to handle and administer to patients.

[0315] • The dose weight variation obtained in this study was considered acceptable for laboratory scale sample preparation and the homogeneity data (mg epinephrine / mg membrane) showed good consistency within batches.

[0316] • For the membranes in which the pH in the pre-slurry solution was adjusted to 5, the adrenaline membranes were almost stable after 83 days at room temperature (RT), whereas the adrenaline membranes stored at 40°C underwent gradual degradation.

[0317] For membranes with a pH of about 4, membranes containing epinephrine with ascorbic acid were more stable at room temperature than membranes containing sodium bisulfite. However, the synergistic effect of using ascorbic acid and sodium bisulfite gave the best stabilization effect on epinephrine in the membrane.

[0318] Example 4: Effect of Ascorbic Acid:Sodium Bisulfite Ratio on Membrane Stability

[0319] The physical and chemical stability of twenty-five epinephrine alginate-based oral film formulations containing ascorbic acid and / or sodium bisulfite as antioxidants were followed under ambient conditions (room temperature and relative humidity) and accelerated conditions (40°C / 75% relative humidity and 50°C / 75% relative humidity).

[0320] The formulations prepared in this study are listed below in Table 5. The compositions tested in this study are described in Table 5. Formulations and compositions containing a combination of plasticizer and stabilizer were prepared at pH 4.1 ± 0.2.

[0321] Table 5 Composition of individual antioxidant-containing films tested in this study.

[0322]

[0323]

[0324] The films were packed in aluminum / PET bags immediately after preparation.All samples were protected from light and stored under ambient conditions (room temperature and humidity) and accelerated conditions (40°C / relative humidity 75% and 50°C / relative humidity 75%).

[0325] Analysis time and methods

[0326] The formulations were analyzed according to the stability procedure listed in Table 6. The stability of the epinephrine oral film phenotype was followed for 12 weeks. The analytical methods and specification limits used are described in Table 7.

[0327] Table 6 Stability procedures used in this study

[0328] Time date Room temperature and relative humidity 40℃ / RH 75% 50℃ / RH 75% Starting 2018 / 12 / 21 AD AD AD 2 weeks 2019 / 01 / 04 AB AB AB 4 weeks 2019 / 01 / 18 AD AD AD 8 weeks 2019 / 02 / 15 AD AD AD 12 weeks 2019 / 03 / 15 AD AD AD

[0329] Table 7 Stability analysis methods and specifications applied in this study.

[0330]

[0331]

[0332] The HPLC-RPC (High Performance Liquid Chromatography - Reversed Phase Chromatography) method used (developed by Klaria Pharma Holding AB, Uppsala, Sweden) is as follows:

[0333] • Prepare solvent mixture A by dissolving 5 g of potassium dihydrogen phosphate in 1000 mL of MilliQ water using a magnetic stirrer. Then adjust the pH to 5.5 with 1 mol / L sodium hydroxide.

[0334] Solvent mixture B was prepared by mixing solvent mixture A and acetonitrile in a ratio of 13:87 (volume ratio).

[0335] - Prepare a 300 μg / mL stock solution of bitartrate epinephrine by weighing 30 mg bitartrate epinephrine and dissolving in 100 g solvent mixture B.

[0336] Prepare the epinephrine bitartrate standard according to the dilution scheme of the stock solution shown in Table 8 below.

[0337] Table 8 Preparation of adrenaline bitartrate standard

[0338] Standards dilution Epinephrine bitartrate concentration (μg / mL) Epinephrine concentration (μg / mL) blank Mobile phase 0 0 1 Dilute the stock solution with diluent at a ratio of 1:4 60 33 2 Dilute the stock solution with diluent at a ratio of 1:2 100 55 3 Dilute the stock solution with diluent at a ratio of 1:1 150 82.5 4 Mother liquor 300 165

[0339] To prepare a test sample of 1 mg API dose / film, add 20 g of solvent mixture B to a 100 mL beaker. Weigh two test films and dissolve them in solvent mixture B for 10 minutes using a magnetic stirrer. Filter an aliquot of the sample solution through a 0.45 um HPLC grade filter. Discard the first 2-3 mL of solution and then collect approximately 1 mL of sample solution.

[0340] • To prepare the test samples of 3 mg API dose / film, the same protocol was used except that the amount of solvent mixture B used was 60 g.

[0341] HPLC was performed with the following settings: column used = ReproSil-Pur 120C18-AQ; flow rate = 1.0 mL / min; injection volume (sample loop) = 20 μL; run time = 15 minutes; detection wavelength = 210 nm; column temperature = 35°C.

[0342] The column was equilibrated with at least 5 column volumes in the mobile phase at a flow rate of 1 mL / min.

[0343] The gradient run analysis was performed as follows (mobile phase A = acetonitrile: solvent mixture A (5:95, by volume) and connected to pump A1; mobile phase B = acetonitrile: solvent mixture A (45:55, by volume) and connected to pump B2):

[0344] Time (minutes) % Mobile phase A % Mobile phase B 0 95 5 10 67 33 11 95 5 15 95 5

[0345] ·Samples were run through HPLC in the following order: (1) blank; (2) blank; (3) blank; (4) standard 1; (5) standard 2; (6) standard 3; (7) standard 4; (8) sample 1; (9) sample 2; (10) continue sampling until the last sample; (11) blank; (12) standard 1; (13) standard 2; (14) standard 3; (15) standard 4; (16) stop.

[0346] - Following data collection, a calibration curve is generated using the standard samples, and the sample data can then be measured against this calibration curve to determine the concentration of epinephrine and impurities in the sample.

[0347] The approximate relative retention times (RRTs) of known impurities using the current RP-HPLC method are provided in Table 9 below.

[0348] Table 9. Relative retention times of specific impurities. RRT was calculated compared to the retention time of the main peak.

[0349]

[0350] Results after 2 and 4 weeks of storage

[0351] Physical changes

[0352] Appearance and toughness were judged by visual inspection according to Table 7. All formulations initially passed the specifications for appearance and toughness.

[0353] After 4 weeks of storage at ambient and accelerated conditions, all formulations studied passed the toughness specification, with no signs of crystallization of epinephrine in any of the film formulations studied. However, the epinephrine film containing ascorbic acid turned a light yellow color after 4 weeks of storage at 50°C / 75% relative humidity. The color change is believed to be related to the ascorbic acid content and the storage temperature. After 4 weeks of storage at ambient temperature and 40°C / 75% relative humidity, no color change was observed in any of the formulations. A gradient of color change was observed with increasing ascorbic acid content (e.g., batches 57, 50, 51, 52, and 53 showed increasingly intense yellow color, respectively).

[0354] Chemical changes

[0355] The chemical stability of the investigated formulations was tested by HPLC after 2 and 4 weeks at ambient conditions of 40°C / 75% relative humidity and 50°C / 75% relative humidity.

[0356] No significant differences in chemical stability were observed between film formulations with and without stabilizers (i.e., antioxidants) after 2 weeks under ambient conditions. A slight increase in the level of impurity F was detected after 4 weeks in formulations containing either bisulfite or ascorbic acid, while less or even no impurity F was detected in film formulations containing both stabilizers. In general, all formulations studied were relatively stable under ambient conditions, with total impurities below 1.0% after 4 weeks of storage.

[0357] Under accelerated conditions (40°C / 75% RH and 50°C / 75% RH), the concentration of impurities increased with the concentration of stabilizer in the formulation. An increasing trend of impurity F can be seen in film formulations containing only bisulfite as a stabilizer, while the content of two unknown impurities at RRT 2.86 and 3.16 increased with the concentration of ascorbic acid in the film formulation. Adding ascorbic acid to bisulfite-containing films can inhibit the formation of impurities F (RRT 0.89) and C (RRT 1.14). Bisulfite mixed with ascorbic acid at low concentrations (e.g., a molar ratio of 0.05 to epinephrine) has an improved stabilizing effect. Fewer impurities and generally lower impurity levels were observed in these formulations. However, high concentrations of ascorbic acid (i.e., a molar ratio of 0.25 and 0.5 to epinephrine) have a suboptimal effect on chemical stability, resulting in higher levels of total impurities.

[0358] Results after 8 weeks

[0359] Physical changes

[0360] Under ambient conditions, all formulations studied passed the appearance and toughness specifications according to the limits listed in Table 7.

[0361] Under accelerated conditions (40°C / 75% relative humidity and 50°C / 75% relative humidity), a color change of the epinephrine film was noted. The color change was mainly related to the concentration of ascorbic acid in the formulation and the storage temperature. A gradient of color change was observed with increasing ascorbic acid content and was more pronounced after storage at higher temperatures.

[0362] Chemical changes

[0363] In general, all formulations studied were relatively stable under ambient conditions, with total impurity levels below 1.0% after 8 weeks of storage. Improved stabilization was achieved for formulations containing bisulfite (total impurity levels < 0.6%). Impurity F was observed in small amounts (RRT 0.89) in formulations containing bisulfite or ascorbic acid, whereas it was not observed in film formulations containing both stabilizers. In some formulations containing ascorbic acid, impurities were formed at RRT 3.16.

[0364] Under accelerated conditions (40°C / 75% RH and 50°C / 75% RH), the level of total impurities increased with the concentration of ascorbic acid in the formulation, while the effect of bisulfite concentration was not significant. High concentrations of ascorbic acid (e.g., a molar ratio of 0.5 to epinephrine) resulted in higher levels of total impurities than formulations without stabilizer (i.e., batch #74). The impurity levels of RRT 2.86 and 3.16 increased with increasing ascorbic acid concentration in the formulation, while the impurity levels of RRT 1.14, 1.68, and 2.32 decreased with increasing ascorbic acid concentration. In addition, the formation of impurity F (RRT 0.89) could be found in all formulations studied, but an increase in the amount of impurity F was seen in film formulations with increasing bisulfite content. The effect of ascorbic acid and sodium bisulfite concentrations on each of the measured impurities at 40°C / 75% RH can be seen in the Figures 2 and 3. Figure 2 and 3 It can be seen in.

[0365] Results after 12 weeks

[0366] Physical changes

[0367] At ambient conditions (room temperature), all formulations passed the appearance and toughness specifications according to the limits listed in Table 7. No color change was observed for any of the epinephrine-containing films.

[0368] Under accelerated conditions (40°C / 75% RH and 50°C / 75% RH), color change was noted for some films and was more severe than that observed after 8 weeks of storage. A gradient of color change was still observed with increasing ascorbic acid content and was more pronounced after storage at higher temperatures. The effect of bisulfite content on color change was not significant.

[0369] Chemical changes

[0370] All formulations studied were relatively stable under ambient conditions. In most of the formulations studied, the total impurity content was less than 1.0%, except for #56 (1.77%) and #57 (136%), which were mainly due to the formation of impurity F (RRT 0.89). In addition, a small amount of impurity with RRT 3.16 could be found in the formulation containing ascorbic acid.

[0371] Under accelerated conditions (40°C / 75% RH and 50°C / 75% RH), a similar trend was found compared to the results after 8 weeks of storage (for data on films stored at 40°C / 75% RH, see Figure 4 and Figure 5 ). All formulations stored at 40°C / 75% RH contained much higher levels of impurities than those stored at 50°C / 75% RH. The total impurity content increased with ascorbic acid concentration in the formulations, whereas no clear trend was observed with increasing sodium bisulfite content. For individual impurities, increasing ascorbic acid content in the formulations resulted in an increase in the content of impurities with RRT 2.86 and 3.16, whereas increasing ascorbic acid content resulted in a decrease in the content of impurities with RRT 1.14, 1.68, and 2.32 (see Figure 4 and 5 ). Increased levels of impurity F can be seen in film preparations with increased bisulfite content.

[0372] Example 5: Effect of adding EDTA on stability

[0373] In general, the epinephrine formulations investigated in Example 4 were stable after 4 weeks of storage under ambient conditions. Most formulations containing ascorbic acid and sodium bisulfite (at a molar ratio to epinephrine between 0.05 and 0.5) have shown a stabilizing effect compared to the control. However, it was noted that the formation of impurities with RRT 0.89 (impurity F) and 3.16 accelerated with increasing concentrations of stabilizer in the formulations after 4 weeks of storage. The formation of these impurities may be caused by the sulfonation reaction of epinephrine with sodium bisulfite, aided by the possible pro-oxidant activity of ascorbic acid at higher concentrations:

[0374]

[0375] Since the formation of these impurities is accelerated at higher molar ratios between stabilizer and epinephrine, formulations containing stabilizers at low molar ratios to epinephrine (less than or equal to 0.05) were investigated to further optimize film stability.

[0376] Therefore, in this example study, the molar ratio of sodium bisulfite and ascorbic acid to epinephrine in the formulation was reduced, and EDTA was added as an additional stabilizer. Sodium pyrosulfite was also used instead of sodium bisulfite as a more commonly used sulfite source in pharmaceuticals. Therefore, fourteen epinephrine oral formulations were studied under refrigerated conditions (5°C), ambient conditions (room temperature and humidity) and accelerated conditions (40°C / relative humidity 75% and 50°C / relative humidity 75%), with a pH of 4.1±0.2. Both 1 mg and 3 mg epinephrine films were studied. The formulations prepared in this study are listed in Table 10 below.

[0377] Table 10 Composition of the investigated formulations.

[0378]

[0379]

[0380] The films were packed in aluminum / PET bags immediately after preparation. All samples were protected from light and stored under refrigerated conditions (5°C), ambient conditions (room temperature and humidity) or accelerated conditions (40°C / 75% relative humidity and 50°C / 75% relative humidity).

[0381] Analysis timeline and methodology

[0382] The formulations were analyzed according to the stability procedure listed in Table 11. The stability of the epinephrine oral film phenotype was followed for 12 weeks. The analytical methods and specification limits used are described in Table 7 above.

[0383] Table 11 Stability procedures used in this study

[0384] Time date 5℃ environment 40℃ / RH 75% Starting 2019 / 01 / 17 AE AE AE 2 weeks 2019 / 01 / 31 AD AD AD 4 weeks 2019 / 02 / 14 AD AD AD 8 weeks 2019 / 03 / 14 AD AD AD 12 weeks 2019 / 04 / 11 AD AE AD

[0385] The approximate relative retention times (RRTs) of known impurities using the current RP-HPLC method are provided in Table 9 above.

[0386] Research results - initial membrane

[0387] Fourteen formulations with different stabilizer compositions and slurry pH were prepared. The viscosity was measured before coating. Although the viscosity of the slurry was generally higher at pH close to 4, all formulations could be easily coated and formed uniform films. The absence of reflection spots under polarizing microscopy indicated the absence of crystals in the freshly prepared films.

[0388] In most of the membrane preparations without ascorbic acid, the formation of impurity F (RRT 0.89) (#79, #81 and #87) was detected. It is presumed that the sulfonation reaction was delayed by the presence of ascorbic acid.

[0389] Results after 2 and 4 weeks of storage

[0390] Physical changes

[0391] All formulations passed the specifications for appearance and toughness according to the limits listed in Table 7.

[0392] Chemical changes

[0393] No impurity levels were found in most formulations after 4 weeks of storage under refrigerated conditions (+5°C). The only formulation containing impurities was #92, in which impurity F was detected. Although the formation of impurity F was related to the sodium bisulfite concentration, formulations with a sodium bisulfite molar ratio higher than #92 did not contain impurity F. It is presumed that the detected peaks were false positives due to errors in the analytical method.

[0394] No impurity levels were found in formulations containing low concentrations of stabilizers at ambient conditions (room temperature) after 4 weeks of storage. Impurities of RRT 2.32 and 3.16 were formed in formulations containing ascorbic acid with a molar ratio of ascorbic acid to epinephrine, i.e., #80, #84, #85, and #86, of ≥ 0.025. Impurity F was found to form in #87 and #88.

[0395] After 4 weeks of storage at 40°C / 75% RH, the impurity levels were high in all formulations. It was observed that the impurity levels of RRT3.16 increased with increasing ascorbic acid content in formulations #81-84 (see Figure 6 The impurities of RRT 2.86 increased slightly with increasing ascorbic acid content in formulations #81-84 ( Figure 6 ). However, as the ascorbic acid content increases, the formation of impurities C (RRT 1.14) and RRT 1.68 is hindered. Considering these two effects, it is expected that the combination of low levels of ascorbic acid and sodium metabisulfite should have the effect of reducing the total impurity content.

[0396] like Figure 7 As shown in A and B, it was observed that 0.06% EDTA content in the slurry delayed the formation of impurity C (RRT 1.14).

[0397] No clear trend in formulation stability was observed with increasing sodium metabisulfite content.

[0398] Results after 8 weeks

[0399] Physical changes

[0400] All formulations passed the specifications for appearance and toughness according to the limits listed in Table 7.

[0401] Chemical changes

[0402] Under refrigerated conditions (+5°C), no impurity levels were found in all formulations after 8 weeks of storage.

[0403] At ambient conditions (room temperature), low levels of Impurity F (0.05%-0.2%) were found in some formulations, namely #79, #80, #81, #82, #88, #89 and #92.

[0404] Under accelerated conditions (40°C / 75% relative humidity), the same trend as the results after 4 weeks of storage was observed. The impurity content of RRT2.86 and 3.16 increased with increasing amounts of ascorbic acid in formulations #81-84 ( Figure 8 ). 0.06% EDTA content in the slurry delayed the formation of impurity C (RRT 1.14) ( Fig. 9 A and B).

[0405] Results after 12 weeks

[0406] Physical changes

[0407] Formulations stored under refrigerated and ambient conditions passed the appearance and toughness specifications according to the limits listed in Table 7. After 12 weeks of storage under refrigerated and ambient conditions, no crystals were found in any formulation.

[0408] Crystallization has been noted in 3 mg epinephrine formulations (#79-#91) after 12 weeks of storage at 40°C / 75% relative humidity. However, no crystals were found in the 1 mg formulation (#92), suggesting that crystallization may be dose-dependent.

[0409] Chemical changes

[0410] Under refrigerated conditions (+5°C), no impurity levels were found in any of the formulations after 12 weeks of storage.

[0411] Under ambient conditions (room temperature), an unknown impurity (RRT 2.32) was found in most formulations at low levels (0.05%-0.14%). Another unknown impurity (RRT 3.16) was found in formulations with relatively high ascorbic acid concentrations, namely #80, #84, #86, #88, and #90.

[0412] Under accelerated conditions (40°C / 75% RH), some new unknown impurities of RRT 1.2, 2.06 and 3.9 appeared in some formulations. The impurity levels of RRT 2.86, 3.16 and 3.9 increased with increasing ascorbic acid content in formulations #81-84 (see Fig.10). The higher content of ascorbic acid in the formulation slightly hindered the formation of the unknown impurities of impurity C (RRT 1.14) and RRT 1.68. The formulation with 0.06% EDTA in the slurry showed slightly lower content of impurity C (RRT 1.14) and RRT 1.68 and 3.16 than the formulation with 0.0012% EDTA (see Fig.11 A&B) of unknown impurity content.

[0413] Example 6: Further optimization of membrane stability

[0414] In Example 4, it is noted that ascorbic acid and sodium bisulfite show a stabilizing effect in the epinephrine buccal formulation. However, some impurities are observed to increase in concentration at higher ascorbic acid concentrations (although still present in relatively low, i.e., acceptable, amounts). Furthermore, it is noted in Example 5 that reducing the total amount of antioxidant present in the film can lead to a reduction in the amount of these specific impurities, but also to an increase in the level of impurities resulting from the oxidation of epinephrine. In order to optimize the film formulation, it seems that a balance should be achieved between the antioxidant effect of the stabilizers used, i.e., the mixture of ascorbic acid, sodium pyrosulfite, and EDTA, and the formation of related impurities.

[0415] In this example study, the physical and chemical stability of ten 3 mg epinephrine buccal formulations under refrigerated conditions (5°C), long-term storage conditions (25°C / relative humidity 60%), intermediate storage conditions (30°C / relative humidity 65%), and accelerated storage conditions (40°C / relative humidity 75%) were further optimized. The study design was influenced by the results of Examples 4 and 5. The effects of each of the three stabilizer components that can be determined from Examples 4 and 5 are summarized as follows:

[0416] Sodium Metabisulfite: The formulations with the lowest total impurity levels after 4 weeks of storage under ambient and accelerated conditions were formulations containing no sodium bisulfite or sodium bisulfite at a molar ratio of 0.05 to epinephrine as in Example 4, i.e., #54 and #58. Therefore, in this study, the amount of bisulfite in the formulations was ≤ 0.05 molar ratio to epinephrine.

[0417] Ascorbic acid: Due to the pro-oxidant effect of ascorbic acid at higher concentrations, it is expected that lower concentrations of ascorbic acid may result in reduced amounts of impurities with RRTs of 2.86 and 3.16 (and therefore reduced overall levels of impurities). Lower concentrations of ascorbic acid (which may result in reduced antioxidant effects on epinephrine overall) should be mitigated by the inclusion of other stabilizers.

[0418] EDTA: In Example 5, 0.06% EDTA in the slurry had a positive effect on the delayed formation of impurity C (RRT 1.14). Therefore, a higher concentration of EDTA in the slurry, i.e. 0.12%, was also investigated in this study.

[0419] In Examples 4 and 5, three formulations with the lowest total impurity content under accelerated conditions were selected as the base formulations for this study, i.e., formulations #54, #58, and #81. Based on these formulations, different concentrations of ascorbic acid and EDTA were studied. Eighteen buccal formulations containing a combination of stabilizers at pH 3.9 ± 0.2 were prepared. The compositions of the formulations studied are given in Table 12.

[0420] Table 12 Composition of the investigated formulations.

[0421]

[0422]

[0423] The films were packed in aluminum / PET bags immediately after preparation. The films of batch #110 and batch #114 were packed in aluminum / PET bags purged with N2. All samples were protected from light and stored under refrigerated conditions (5°C), long-term storage conditions (25°C / relative humidity 60%), intermediate storage conditions (30°C / relative humidity 65%) and accelerated storage conditions (40°C / relative humidity 75%).

[0424] Analysis timeline and methodology

[0425] The formulations were analyzed according to the stability procedure listed in Table 13. The stability of the epinephrine buccal membrane phenotype was followed for 8 weeks. The analytical methods and specification limits used are described in Table 7 above.

[0426] Table 13 Stability procedures used in this study

[0427] Time date 5℃ 25℃ / RH 60% 30℃ / RH 65% 40℃ / RH 75% Starting 2019 / 02 / 21 AE AE AE AE 2 weeks 2019 / 03 / 07 AD AD AD AD 4 weeks 2019 / 03 / 21 AD AD AD AD 8 weeks 2019 / 04 / 17 AE AE AE AE

[0428] The HPLC method used to evaluate the samples was developed by Recipharm (Uppsala, Sweden) and was different from the method used to evaluate the samples in Examples 4 and 5 above. The HPLC-RPC method was as follows:

[0429] An Agilent 100 series liquid chromatography system was used, which consisted of a binary pump, a degasser, an autosampler, a thermostatic column chamber, and a diode array UV detector for analysis. The HPLC column was YMC-Triart PFP (150×3.0 mm, 3 μm) from YMC. The filter membrane was from Membrane Solutions. Nylon Syringe Filter, diameter 30 mm, pore size 0.45 μm. Vortex-Mix is ​​UK plug VWR.

[0430] Prepare buffer solution A by dissolving 5.0 g potassium dihydrogen phosphate and 2.6 g sodium octane sulfonate monohydrate in 1000 mL water using a magnetic stirrer. Stirring must be performed for at least 10 minutes to achieve complete dissolution. The pH is then adjusted to 4.0 with orthophosphoric acid solution.

[0431] Prepare stock solutions of epinephrine, impurities B, C, D, E, F, D, L-adrenochrome and excipients (E1, E2, E3, E4 and E5) at a concentration of 1 mg / mL. Dissolve all impurities and excipients in HCl 1M / buffer A / MeOH in a ratio of 1 / 8 / 1 (v / v / v). These three solutions must be added separately in the order of HCl 1M / buffer A / MeOH. Epinephrine is prepared directly in sample diluent. The stock solution is then diluted with sample diluent to concentrations of 50, 5 and 0.5 μg / mL. A mixture of all compounds is also prepared at a concentration of about 50 μg / ml.

[0432] Each compound was injected separately into the mixture solution. Retention time and relative retention time were determined and used to identify the API and impurities. Resolution between peaks was measured. Due to the low stability of D,L-adrenochrome, the impurity was prepared and injected immediately.

[0433] To prepare a test sample of 1 mg API dose / film, accurately weigh 2 test films and transfer to a 10 mL volumetric flask and add 5 mL of Buffer A. The solution is then vortexed for 5 minutes and 1.0 mL of MeOH is added. Mixing is continued for 2 minutes. Buffer A is added to a final volume of 10 mL. The solution is filtered through a 0.45 micron filter. The first 3 mL is discarded and the next 1 mL is collected in an amber 1 mL vial.

[0434] To prepare a test sample of 3 mg API dose / film, accurately weigh 2 test films and transfer to a 30 mL volumetric flask and add 18 mL of Buffer A. The solution is then vortexed for 5 minutes and 3 mL of MeOH is added. Mixing is continued for 2 minutes. Buffer A is added to a final volume of 30 mL. The solution is filtered through a 0.45 micron filter. The first 3 mL is discarded and the next 1 mL is collected in an amber 1 mL vial.

[0435] HPLC was performed with the following settings: flow rate = 0.8 mL / min; injection volume = 5.0 μL; run time = 30 minutes; detection wavelength = 210 ± 4 nm; column temperature = 50°C; injection temperature = 25°C; needle wash solvent = solvent mixture of buffer A (pH 4.0): MeOH 9:1 (v / v), 1x; dilution solvent = 90% mobile phase A: 10% mobile phase B (v / v).

[0436] The column was equilibrated and then analyzed by gradient run as follows (mobile phase A = buffer A; mobile phase B = MeOH):

[0437] Time (minutes) % Mobile phase A % Mobile phase B 0 100 0 2 100 0 16 45 55 20 45 55 21 100 0 30 100 0

[0438] - Following data collection, a calibration curve is generated using the standard samples, and the sample data can then be measured against this calibration curve to determine the concentration of epinephrine and impurities in the sample.

[0439] Using this method, the approximate relative retention times (RRTs) of the impurities identified are listed in Table 14 below.

[0440] Table 14. Relative retention times of specific impurities. RRT was calculated compared to the retention time of the main peak.

[0441]

[0442] Research results - initial membrane

[0443] Eighteen formulations were prepared at pH 3.9 ± 0.2 with different stabilizer compositions. The viscosity was measured before coating. All formulations could be easily coated and formed uniform films. The absence of reflection spots under polarizing microscopy indicated the absence of crystals in the freshly prepared films. No impurities were initially found in the formulations studied, except for batch #115. A high level of an unknown impurity (RRT 1.04) was found in batch #115, which may have been caused by unexpected degradation of epinephrine during sample preparation.

[0444] Results after 2 and 4 weeks of storage

[0445] Physical changes

[0446] All formulations passed the specifications for appearance and toughness according to the limits listed in Table 7.

[0447] Chemical changes

[0448] Low levels of total impurities (<0.5%) were found in most formulations under refrigerated conditions (+5°C) and long-term storage conditions (25°C / relative humidity 60%). Higher levels of total impurities were observed in formulations #112 and #115, which were mainly attributed to impurities of RRT 1.04. It is suspected that the detected peak in #112 is a false positive due to an error in the analytical method.

[0449] After 4 weeks of storage at intermediate storage conditions (30°C / relative humidity 65%), low total impurity levels (≤1%) were found in some formulations, namely #110, #114, #107, #108, #111. However, under accelerated storage conditions (40°C / relative humidity 75%), almost all formulations studied (except #113) showed higher total impurity levels (>3.5%). The total impurity content of #113 was 3.4% at 40°C, which is still within acceptable limits.

[0450] The formulation with a sodium metabisulfite content of 0.05 (molar ratio to epinephrine) showed a better stabilizing effect than 0.025. The combination of a higher amount of sodium metabisulfite with a lower concentration of ascorbic acid (molar ratio to epinephrine of ≤ 0.01) resulted in a lower total impurity content. Impurities of RRT 0.77 may be evident in films with ascorbic acid content > 0.01 in a molar ratio to epinephrine.

[0451] The addition of EDTA has a positive effect on delaying the formation of impurities in RRT 1.04. Based on the results of #110 and #110N2, #114 and #114N2, the effect of storage atmosphere (N2 or air) on chemical stability is not significant after 4 weeks of storage.

[0452] Results after 8 weeks

[0453] Physical changes

[0454] Formulations stored at refrigerated conditions (5°C), long term conditions (25°C / 60% RH), and intermediate conditions (30°C / 65% RH) passed the appearance and toughness specifications according to the limits listed in Table 7. Some crystals were observed in some formulations stored at 25°C / 60% RH or 30°C / 65% RH.

[0455] After storage for 8 weeks at 40°C / 75% relative humidity, all formulations became opaque and crystals were observed under a polarized light microscope.

[0456] Chemical changes

[0457] No impurities were detected in the formulations studied, except in batch #115 after 8 weeks of storage under refrigerated conditions (5° C.) Since impurities were initially detected for RRT 1.04 and 1.07, it was suspected that these impurities were the result of contamination during the membrane preparation process.

[0458] Low total impurity levels (<1%) were observed for most formulations after 8 weeks of storage under ambient conditions (25°C / 60% relative humidity). No impurities were detected in formulations #105, #107, #113, and #114.

[0459] Total impurities were < 2% in all formulations except batch #115 which was stored at intermediate conditions (30°C / 65% relative humidity). Impurity C (RRT 1.15) and an unknown impurity at RRT 1.56 were the main impurities found in the formulations. The levels of both impurities doubled since the previous time point (4 weeks). Increasing the levels of ascorbic acid (0 to 0.05 molar ratio to epinephrine) and EDTA (0 to 0.12%) slightly delayed the formation of impurity C (RRT 1.15) (see Fig.12 A and B).

[0460] More impurities and higher total impurity concentrations were observed in the formulations stored under accelerated conditions (40°C / 75% relative humidity). The growth of all impurities with RRTs of 1.11, 1.15, 1.28, 1.31, 1.33, and 1.56 was inhibited with higher ascorbic acid content in the film ( Fig.13 AF). However, in the formulations containing ascorbic acid at a molar ratio of 0.05 to epinephrine, i.e., #115, #116, and #117, impurities with RRTs of 0.72 and 0.77 were found. In the formulation containing a higher concentration of EDTA, 0.12%, impurity C (RRT 1.15) and unknown impurities RRTs 1.11 and 1.31 were found at lower levels than in the formulation without EDTA (see Fig.14 AC).

[0461] in conclusion

[0462] In summary, it has been observed that the presence of ascorbic acid, sodium metabisulfite, and EDTA can all improve the stability of oral films containing epinephrine. However, for an optimal film, a balance should be achieved between preventing oxidation of epinephrine and inhibiting the formation of impurities generated by the stabilizing additives themselves. In particular, it appears that limiting the concentration of ascorbic acid to 0.01 or less (molar ratio to epinephrine) in combination with higher concentrations of sodium metabisulfite (0.05 or more molar ratio to epinephrine) and EDTA (0.06 wt % or more; or 0.03 or more molar ratio to epinephrine) is particularly beneficial.

[0463] References

[0464] [1]McLean-Tooke AP, Bethune CA, FayAC, Spickett GP. Adrenaline in the treatment of anaphylaxis: what is the evidence? BMJ, 2003, 327(7427): 1332-1335.

[0465] [2]Upfal,J.The Australian Drug Guide.2007,7 th Ed.,pub.Black Inc.

[0466] [3]Simons EEpinephrine absorption in children with a history ofanaphylaxis.J Clin Immunol,1998,101:33-37.

[0467] [4]Tuleu,C.et al.Shortterm stability of pH-adjusted lidocaine-adrenaline epidural solution used for emergency caesareansectior.International Journal of obstetric anesthesia,17.2.118-122.

[0468] [5]Prachayasittikul,V.;Isarankura-Na-Ayudhya,C.;Tantimongcolwat,T.;Nantasenamat,C.;Galla,H.J.EDTA-induced Membrane Fluidization andDestabilization:Biophysical Studies on Artificial Lipid Membranes.Actabiochimica et biophysica Sinica,2007,39(11),901-913.

[0469] [6]Managaro,A.;Wertz,P.The effect of permeabilizer on the in vitropenetration of propranolol through porcine buccal epithelium.

[0470] [7]Date,A.A.;Desai,N.;Dixit,R;Nagarsenker,M.Self-nanoemulsifying DrugDelivery Systems:Formulation Insights,Applications andAdvances.Nanomedicine,2010,5(10),1595-1616.

[0471] [8]Pouton,C.W.Formation of poorly water-soluble drugs for oraladministration:Physicochemical and physiological issues and the lipidformulation classification system.European Journal of PharmaceuticalSciences,2006,29(3-4),278-287.

[0472] [9]European Pharmacopoeia Commission&European Directorate for theQuality of Medicines&Healthcare.European Pharmacopoeia,2013,Council ofEurope,Vol.1,1490-1492.

Claims

1. A film suitable for oral administration, comprising: (i) 29% to 93% by weight of a monovalent cationic alginate, or an alginate mixture containing at least one monovalent cationic alginate; (ii) 0.15% to 50% by weight of an active pharmaceutical ingredient (API) which is epinephrine or a pharmaceutically acceptable salt thereof; (iii) 0.01 to 10% by weight of an antioxidant selected from the group consisting of sodium bisulfite, sodium metabisulfite, ascorbic acid, EDTA, and combinations thereof; and (iv) at least one plasticizer selected from sorbitol, glycerol, xylitol or a combination thereof, wherein each plasticizer is present in an amount up to 40% by weight; Furthermore, wherein the monovalent cationic alginate (a) comprises 25 to 35% by weight of β-ᴅ-mannuronate and / or 65 to 75% by weight of α-ʟ-guluronate, and (b) has an average molecular weight of 30,000 to 90,000 g / mol; and wherein the weight ratio of total antioxidant present in the film to total API present in the film is from 0.01:1 to 10:

1.

2. The film according to claim 1, wherein the API is (−)-epinephrine or a pharmaceutically acceptable salt thereof.

3. The membrane of claim 1, wherein the API is tartrate of epinephrine.

4. The membrane of claim 3, wherein the API is the tartrate salt of (−)-epinephrine.

5. The membrane of claim 1, wherein the monovalent cationic alginate is selected from the group consisting of sodium alginate, potassium alginate, and ammonium alginate.

6. The membrane of claim 1, wherein the monovalent cationic alginate is sodium alginate.

7. The film of claim 1, wherein the film comprises 5 to 15% by weight water.

8. The film of claim 1, wherein the film comprises at least two antioxidants.

9. The film of claim 8, wherein the film comprises at least three antioxidants.

10. The film of claim 8, wherein the antioxidants are each independently selected from ascorbic acid, sodium bisulfite, sodium metabisulfite, and EDTA.

11. The film of claim 1 , wherein the weight ratio of total antioxidant present in the film to total API present in the film is from 0.5:1 to 10:

1.

12. The film of claim 8, wherein the film comprises (i) ascorbic acid and (ii) sodium bisulfite or sodium metabisulfite.

13. The film of claim 12, wherein the molar amount of ascorbic acid relative to the molar amount of total API is 0.01 or less.

14. The membrane of claim 12, wherein the molar amount of sodium bisulfite or sodium metabisulfite relative to the molar amount of total API is 0.025 or greater.

15. The membrane of claim 1, wherein the membrane comprises EDTA.

16. The film of claim 15, wherein the amount of EDTA present in the film is 0.03 wt% or greater.

17. The film of claim 1, wherein the film further comprises: Alkalizing agent.

18. The membrane of claim 17, wherein the alkalizing agent is an aqueous sodium hydroxide solution.

19. The film of claim 17, wherein the film comprises sorbitol and glycerol.

20. Use of the film according to any one of claims 1 to 19 in the preparation of a medicament.

21. Use of a membrane as claimed in any one of claims 1 to 19 for the preparation of a medicament for the treatment of anaphylaxis, superficial bleeding or cardiac arrest in a human patient.

22. The use according to claim 21, wherein the medicament is for the treatment of allergic reactions.

23. The use according to claim 21, wherein the film is applied to the oral cavity of the human patient.

24. A method of manufacturing a membrane according to any one of claims 1 to 19, the method comprising the steps of: (a) Either: (i) mixing at least one antioxidant in water; (ii) mixing epinephrine or a pharmaceutically acceptable salt thereof into the solution obtained in step (i); (iii) mixing one or more excipients into the solution obtained in step (ii); as well as (iv) adding monovalent cation alginate under appropriate conditions to form a viscous slurry; Or the following steps: (i) mixing one or more excipients in water; (ii) separately, dissolving epinephrine or a pharmaceutically acceptable salt thereof in an aqueous solution containing one or more antioxidants; (iii) mixing the solution obtained in step (i) with monovalent cationic alginate; as well as (iv) adding the solution obtained in step (ii) to the solution obtained in step (iii) under suitable conditions to form a viscous slurry; (b) pouring the slurry onto a surface and spreading the slurry to a desired thickness; and (c) drying the slurry layer until the residual water content of the film is 0-20% by weight and a solid film is formed.

25. The method according to claim 24, wherein: After pouring the viscous slurry onto the surface, the viscous slurry was first spread to a thickness of 2 mm by a coater having a slit height of 2 mm, and then spread to a thickness of 1 mm by a coater having a slit height of 1 mm.

26. The method according to claim 24, wherein the method comprises the following steps: (a) Either: (i) mixing at least one antioxidant in water; (ii) mixing epinephrine or a pharmaceutically acceptable salt thereof into the solution obtained in step (i), and then adjusting the pH of the solution to a desired level by adding an acid or a base; (iii) mixing one or more excipients into the solution obtained in step (ii); as well as (iv) adding monovalent cation alginate under appropriate conditions to form a viscous slurry; Or the following steps: (i) mixing one or more excipients in water; (ii) separately, dissolving adrenaline or a pharmaceutically acceptable salt thereof in an aqueous solution containing one or more antioxidants, followed by adjusting the pH of the solution to a desired level by adding an acid or a base; (iii) mixing the solution obtained in step (i) with monovalent cationic alginate; as well as (iv) adding the solution obtained in step (ii) to the solution obtained in step (iii) under suitable conditions to form a viscous slurry; (b) pouring the slurry onto a surface and spreading the slurry to a desired thickness; and (c) drying the slurry layer until the residual water content of the film is 0-20% by weight and a solid film is formed.

27. The method according to claim 24, wherein the method comprises the following steps: (a) Either: (i) mixing at least one antioxidant in water; (ii) mixing epinephrine or a pharmaceutically acceptable salt thereof into the solution obtained in step (i), and then adjusting the pH of the solution to a desired level by adding a diluted aqueous solution of an acid or a base; (iii) mixing one or more excipients into the solution obtained in step (ii); as well as (iv) adding monovalent cation alginate under appropriate conditions to form a viscous slurry; Or the following steps: (i) mixing one or more excipients in water; (ii) separately, dissolving adrenaline or a pharmaceutically acceptable salt thereof in an aqueous solution containing one or more antioxidants, followed by adjusting the pH of the solution to a desired level by adding a dilute aqueous solution of an acid or base; (iii) mixing the solution obtained in step (i) with monovalent cationic alginate; as well as (iv) adding the solution obtained in step (ii) to the solution obtained in step (iii) under suitable conditions to form a viscous slurry; (b) pouring the slurry onto a surface and spreading the slurry to a desired thickness; and (c) drying the slurry layer until the residual water content of the film is 0-20% by weight and a solid film is formed.

28. The method according to claim 24, wherein the method comprises the following steps: (a) Either: (i) mixing at least one antioxidant in water; (ii) mixing epinephrine or a pharmaceutically acceptable salt thereof into the solution obtained in step (i), and then adjusting the pH of the solution to a desired level by adding a diluted aqueous solution of a base; (iii) mixing one or more excipients into the solution obtained in step (ii); as well as (iv) adding monovalent cation alginate under appropriate conditions to form a viscous slurry; Or the following steps: (i) mixing one or more excipients in water; (ii) separately, dissolving adrenaline or a pharmaceutically acceptable salt thereof in an aqueous solution containing one or more antioxidants, followed by adjusting the pH of the solution to a desired level by adding a dilute aqueous solution of an acid or base; (iii) mixing the solution obtained in step (i) with monovalent cationic alginate; as well as (iv) adding the solution obtained in step (ii) to the solution obtained in step (iii) under suitable conditions to form a viscous slurry; (b) pouring the slurry onto a surface and spreading the slurry to a desired thickness; and (c) drying the slurry layer until the residual water content of the film is 0-20% by weight and a solid film is formed.

29. A method according to any one of claims 26 to 28, wherein the pH of the solution is adjusted to between 3.8 and 5.

5.

30. The method of claim 24, wherein between (a) and (b), the slurry is degassed.

31. The method of claim 24, wherein in (c), drying the slurry layer is at a temperature of 30-60 °C.

32. The method of claim 24, wherein after (c), the solid film is cut into pieces of desired size, the pieces are placed in pouches, and the pouches are sealed and labeled.

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