High-load oral film formulations with improved bioavailability

Abstract

Oral film formulations are disclosed. The oral membrane formulation comprises: i. Suspended maropitant or a salt thereof; ii. An aqueous phase consisting of water and at least one surfactant; iii. At least one tackifier / suspending agent; and iv. At least one solubilizing agent.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 396,956, filed on August 10, 2022. This document is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to oral film dosage form formulations and methods for preparing oral film dosage forms, and more particularly to the preparation of high active content films suitable for use in both human and animal applications that exhibit improved bioavailability. Background Art

[0004] It is usually ideal to use oral film dosage forms to administer pharmaceutical ingredients. Compared with tablets and capsules, oral film dosage forms have multiple advantages. Many people have difficulty swallowing tablets and capsules, and there is a risk of choking when trying to swallow solid oral dosage forms, but they can voluntarily administer film dosage forms without difficulty. Similarly, administering drugs to animals (such as companion animals) through various dosage forms often faces unique challenges, especially when accurate administration is required. Animals may refuse to accept partial tablets, some of which need to be divided into several pieces, increasing the imprecision of administration.

[0005] Although it may be ideal to administer drugs in oral film dosage forms, it remains a challenge to design oral dosage forms that provide an ideal absorption profile. Oral film formulations have the potential to enhance the absorption rate of drugs or active pharmaceutical ingredients (APIs). Although oral film formulations have the desired advantages, the applicability of suitable oral film formulations is limited to date, which is partially attributed to the limited API loading capacity of oral films. The low API loading of oral films is due to several factors inherent to oral films, such as size limitations, which are determined by pharmacokinetics, but also by the size of the human or animal mouth. The mechanical properties of oral films also limit the API content to provide suitable flexibility parameters for oral film packaging processes. These unfortunate limitations of oral films make the potential of oral film formulations relatively undeveloped, which is evident by the limited number of approved drugs with oral film dosage forms.

[0006] The use of maropitant to treat vomiting and related ailments is not new in the art. WO2005 / 082416 describes the development of a pharmaceutical formulation of maropitant citrate, sulfobutyl ether beta-cyclodextrin and meta-cresol. The method of administration in this case is by skin injection, which may cause pain and adverse reactions in animal subjects. EP3173071A1 relates to a pharmaceutical composition comprising maropitant, a method for preparing the composition, the use of the composition as a drug, and the use of the composition in treating vomiting in mammals, particularly cats and dogs. The method of administration in this case improves the injection administration method, but also does not consider other dosage administration alternatives, such as oral films. CN110577522A relates to a new crystal form of maropitant citrate and its preparation method, without mentioning the use of a film as an administration method.

[0007] There are some oral administration methods in the art for therapeutic compositions for vomiting and related ailments in animals, such as CA2965524, where the oral form is a soft, chewable composition that does not bypass the liver circulation like an oral film, and generally employs different combination technologies and biological systems.

[0008] Oral films for veterinary use also exist in the art, for example US20040115253, US20060121096, US20140286876, US20160166511. There is a need for effective high-load animal health films with improved bioavailability.

[0009] Oral film technology can provide an alternative to injectable and tablet dosage forms and accommodate subjects or pet owners by providing easier-to-administer medications without requiring them to visit a clinic, experience pain, or embed the dosage form in food. There is also a need to improve the bioavailability of high concentrations of active agents in treatments and to increase treatment compliance by improving the administration and acceptability of the product.

[0010] These and other deficiencies and opportunities for improvement are addressed and / or overcome, at least in part, by the systems, assemblies, and methods of the present disclosure. Summary of the invention

[0011] Generally speaking, oral film dosage forms include dissolved API in a solubilizer, penetration enhancers, suspended API, surfactant system, suspending agents / viscosity increasing agents, plasticizers, flavoring agents, taste masking agents, and a polymeric film matrix.

[0012] According to some aspects of the present disclosure, an oral film dosage form comprises at least one API in a dual system: an API in a solubilizer and a suspended API in a polymeric mucoadhesive film matrix.

[0013] In certain aspects of the disclosure, the disclosed formulations and excipients are particularly suitable for use in humans.

[0014] In certain aspects of the present disclosure, the disclosed formulations and excipients are particularly suitable for use in animals.

[0015] These and other features, advantages and objects of the various embodiments will become better understood with reference to the following description and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 Permeation testing of three oral films of maropitant through porcine buccal mucosa is presented. The permeation testing used a FranzCell apparatus in which the donor medium was purified water and the receptor medium was purified water containing 30% hydroxypropyl-β-cyclodextrin. The results of the maropitant concentration (ug / cm2) in the receptor showed that the oral film in which maropitant was dissolved under acidic conditions (Batch 164-24-2) was superior to the oral film in which maropitant was partially dissolved in oleic acid and benzyl alcohol (Batch 164-28-3B), and finally the last profile of the oral film in which most of the maropitant was suspended (Batch 164-44). It is clear that the solubility of the API improves its permeability.

[0017] Figure 2 Shows how Figure 1 The permeation test in which the effect of permeation enhancers (glycerol in batch 164-28-3A and PEG 300 in batch 164-28-3B) on the permeation of maropitant oral films containing two solubilizers, oleic acid and benzyl alcohol, was compared.

[0018] Figure 3 Shows how Figure 1 The permeation test in , showed improved permeation within the first five hours when using the solubilizing agent oleic acid in batch 164-5E compared to benzyl acetate in batch 164-25-1 and benzyl alcohol in batch 164-15-2.

[0019] Figure 4 Shows how Figure 1 The penetration test described in. Figure 4 The improvement in maropitant permeability in batch 164-28-3A is shown when increasing the amount of surfactants tween 20 and labrafil and adding a water soluble solubilizer (benzyl alcohol) to the maropitant oral film (batch 164-28-6A) that already employs oleic acid as a solubilizer. Figure 4 It was shown that when the permeation enhancer glycerol (Batch 164-28-3A) was replaced with PEG 300, the permeation of maropitant in Batch 164-28-3B was improved and the lag time was reduced. Figure 4It is shown that when the penetration enhancer glycerol (batch 164-28-6A) is replaced with propylene glycol, the permeability of maropitant in batch 164-28-3B is improved, and the lag time is reduced. Batch 164-28-6A is optimized by adding more tween and labrafil and adding benzyl alcohol, and batch 164-28-3A is produced, wherein the latter gives a similar permeation curve as batch 164-28-6B, and batch 164-28-6B only replaces the penetration enhancer from glycerol (batch 164-28-6A) with propylene glycol (batch 164-28-6B). Therefore, the improvement of batch 164-28-3A to batch 164-28-3B produces a better permeation curve than batch 164-28-6B.

[0020] Figure 5 Shows how Figure 1 The penetration test described in. Figure 5 Improvements in the permeability of maropitant in batch 164-5E are shown when the amount of solubilizer (oleic acid) is increased compared to batch 164-28-6A. DETAILED DESCRIPTION

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0022] It is to be understood that the present disclosure is not limited to the particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0023] In this document, unless the context clearly indicates otherwise, the terms "a", "an" or "the" are used to include one or more than one. Unless otherwise indicated, the term "or" is used to refer to a non-exclusive "or". In addition, it should be understood that the words or terms used herein (not otherwise defined) are used for descriptive purposes only and not for limiting purposes. The use of any section headings is to assist in reading the document and should not be interpreted as limiting; information related to the section headings may appear within or outside the particular section described. In addition, all publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety, as if incorporated by reference individually. If there is an inconsistency in usage between this document and those documents incorporated by reference, the usage in the incorporated references should be considered to supplement the usage of this document; for irreconcilable inconsistencies, the usage in this document shall prevail.

[0024] Values ​​expressed in range format should be interpreted in a flexible manner to include not only the values ​​explicitly listed as range limits, but also all individual values ​​or subranges contained within the range, as if each value and subrange were explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also individual values ​​(e.g., 1%, 2%, 3% and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the specified range.

[0025] As used herein, the term "about" can allow for a degree of variability in values ​​or ranges, for example, within 10%, within 5%, or within 1% of a stated value or a stated range limit. When a range or list of ordinal values ​​is given, any value within the range or any value between the given ordinal values ​​is also disclosed unless otherwise stated.

[0026] As used herein, the term "substantially" refers to a majority or majority, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more.

[0027] Film systems embody a technical field with major advantages in the field of applying various active agents to individuals or subjects in need. The present disclosure relates to oral films (also referred to as films and film strips, sheets, discs, wafers, etc. in the art) of any shape (including rectangular, square or other desired shapes) and a method for forming a film product including at least one active agent. Specifically, the present disclosure provides a film and a method for forming a film. The terms "orally dissolving film", "orally dissolvable film", "orally disintegrating film", OSF, "orally dissolvable film", "OCF", "oral chewing film", "ODF", ​​"orally dissolving film", "OTF", "oral thin film", "oral strip" etc. refer to products for applying a predetermined amount of active ingredients by an oral route (e.g., oral mucosal absorption, sublingual delivery or buccal delivery), and will be referred to as "oral film" throughout.

[0028] The term "active agent" or "API" refers primarily to an active pharmaceutical ingredient, drug, medicine, but may also refer broadly to any agent that is intended to be incorporated into a finished drug product and is intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure or any function of a bodily subject.

[0029] The pharmaceutical composition may contain one or more active pharmaceutical ingredients. The active pharmaceutical ingredient may be a single pharmaceutical ingredient or a combination of pharmaceutical ingredients. The active pharmaceutical ingredient may be an anti-inflammatory analgesic, a steroidal anti-inflammatory agent, an antihistamine, a local anesthetic, a bactericide, a disinfectant, a vasoconstrictor, a hemostatic agent, a chemotherapeutic, an antibiotic, a keratolytic agent, a cauterizing agent, an antiviral, an anti-rheumatic, an antihypertensive, a bronchodilator, an anticholinergic, an anxiolytic, an antiemetic compound, a hormone, a peptide, a protein or a vaccine. The active pharmaceutical ingredient may be a compound of a drug, a pharmaceutically acceptable salt of a drug, a prodrug, a derivative, a drug complex or an analog. The term "prodrug" refers to a biologically inactive compound that can be metabolized in vivo to produce a biologically active drug.

[0030] In some embodiments, more than one active pharmaceutical ingredient may be included in the film. The active pharmaceutical ingredient may be an ACE inhibitor, an antianginal, an antiarrhythmic, an antiasthmatic, anticholesterolemia, analgesics, anesthetics, anticonvulsants, antidepressants, antidiabetics, antidiarrheal preparations, antidotes, antihistamines, antihypertensives, anti-inflammatory drugs, antilipidemics, antimanic drugs, antinausea drugs, anti-stroke drugs, antithyroid preparations, amphetamines, antitumor drugs, antiviral drugs, acne drugs, alkaloids, amino acid preparations, cough suppressants, anti-uricemia drugs, antiallergic drugs, viral drugs, synthetic Metabolic agents, systemic and non-systemic anti-infectives, antineoplastic agents, anti-Parkinson's disease agents, anti-rheumatic agents, appetite stimulants, blood regulators, bone metabolism regulators, cardiovascular drugs, central nervous system stimulants, cholinesterase inhibitors, contraceptives, decongestants, dietary supplements, dopamine receptor agonists, endometriosis therapeutics, enzymes, erectile dysfunction treatments, fertility agents, gastrointestinal agents, homeopathy, hormones, hypercalcemia and hypocalcemia management agents, immunomodulators, immunosuppressants, migraine treatments agents, motion sickness treatments, muscle relaxants, obesity management agents, osteoporosis preparations, oxytocics, parasympathomimetics, parasympathomimetics, prostaglandins, psychotropics, respiratory medications, sedatives, smoking cessation aids, sympathomimetics, tremor preparations, urinary tract medications, vasodilators, laxatives, antacids, ion exchange resins, antipyretics, appetite suppressants, expectorants, anxiolytics, antiulcer drugs, anti-inflammatory drugs, coronary artery dilators, cerebral dilators, peripheral vasodilators, psychotropic drugs, hallucinogens, Stimulants, antihypertensives, vasoconstrictors, migraine therapeutics, antibiotics, sedatives, antipsychotics, antineoplastics, anticoagulants, antithrombotics, hypnotics, antiemetics, antinauseants, anticonvulsants, neuromuscular drugs, hyperglycemic and hypoglycemic drugs, thyroid and antithyroid preparations, diuretics, antispasmodics, uterine relaxants, antiobesity drugs, erythropoiesis-stimulating drugs, antiasthmatics, antitussives, mucolytics, DNA and gene-modifying drugs, diagnostic agents, imaging agents, dyes or tracers, and combinations thereof.

[0031] The film product of the present disclosure comprises an active ingredient selected from pharmaceutical agents, bioactive agents, cosmetic agents and combinations thereof. The active ingredient may be present in any desired amount effective for the intended treatment. The particular expectation and advantage of the present disclosure is that the active component may be included in a high loading amount. The bioactive agent of the oral film is a substance having a specific biological effect when taken orally, and is generally used to achieve a therapeutic effect in pets or humans. These agents include drugs, vitamins, minerals, nutritional supplements, enzymes, probiotics, hormones, etc. They are incorporated into oral film preparations for conditions such as pain, inflammation, infection, or to support general health. Considerations include stability, bioavailability, and controlled release to optimize the effect of the agent while providing a convenient and effective method of application.

[0032] The various additives that can be incorporated into the film can provide a variety of different functions. Examples of categories of additives include excipients, lubricants, buffers, stabilizers, foaming agents, pigments, colorants, fillers, fillers, sweeteners, flavoring agents, fragrances, release modifiers, adjuvants, plasticizers, flow promoters, release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, glidants, adhesives, anti-adherents, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers, and mixtures thereof. These additives can be added together with the active ingredient".

[0033] The term "matrix" or "film matrix" refers to the polymer component or mixture of polymers that creates the "film-forming matrix" that supports the API within the oral film dosage form.

[0034] The term "amorphous" refers to the non-crystalline form of a solid, a state that lacks a regular crystalline organization of atoms. The amorphous content (amorphous degree) of a solid can be accurately and precisely assessed using a number of well-established methods, including isothermal calorimetry, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), continuous relative humidity perfusion, microcalorimetry (cRHp), and dynamic vapor sorption (DVS).

[0035] The term "stable" means that when the product is exposed to normal stability conditions (e.g., 25°C / 60% RH and 40°C / 75% RH) for an extended period of time, the product exhibits no change in dissolution profile or remains within established specifications and recovery, while also demonstrating no chemical degradation. The term "stable" may also refer to mechanical stability, for example, in the case of product recrystallization, flexibility and other mechanical properties will change. The term "stable" may also refer to chemical stability, and refers to a product for which the assay and impurity profiles show changes and remain within established specifications when the product is exposed to normal stability conditions (e.g., 24 months at 25°C / 60% RH and 6 months at 40°C / 75% RH), demonstrating that chemical degradation meets established specifications.

[0036] The term "non-dissolved" refers to a crystalline, solid amorphous powder or partially amorphous active agent suspended (insoluble) to form a homogeneous solution with another substance (solvent). By using an API in a partially / non-dissolved dispersion, the stability of the API in the final film product can be increased. Dissolved APIs, especially crystalline APIs, may recrystallize over time during time and storage conditions, which may have an adverse effect on the overall bioavailability of the product. The selection of partially / non-dissolved APIs can also be used to control the dissolution behavior and release of the API from the film dose to achieve systemic uptake by the patient. The uptake and absorption of the API are affected by the solubility and availability of the drug, so controlling its crystallinity and particle size affects the bioavailability of the API in humans or animals.

[0037] An average particle size diameter (D50) equal to or less than 250 μm refers to a size distribution of solid particles uniformly distributed in the matrix film. The size may be small enough to avoid a rough texture or unpleasant mouthfeel when orally ingested.

[0038] The term "suspended" (and variations thereof) refers to a dispersion of solid material (e.g., particles or powders) in a bulk liquid medium in which the solid material is not completely dissolved at the molecular level and will eventually settle out of the liquid in the absence of agitation or insufficient viscosity of the blend. In a suspension, the suspended material is not completely dissolved in the liquid.

[0039] The term "polymer" refers to a long molecular chain made of many repeating units."Film-forming polymer" refers to a polymer used to form and make a film matrix.

[0040] The term "water-soluble ingredient" refers to an ingredient that can be dissolved in water.

[0041] The term "water-insoluble component" refers to a component that is generally insoluble in water.

[0042] The term "suspending agent" (also called "viscosity enhancer") refers to a water-soluble or water-insoluble component or combination thereof that is used to prevent adjacent suspended particles from coming too close to bind to each other by sufficiently increasing the viscosity of the drug vehicle and to maintain the suspension (suspended entities) stably by steric stabilization. Certain suspending agents / viscosity enhancers also interact with biological mucosa to produce enhanced oral membrane mucoadhesion. Examples include polysaccharides in the form of one or a mixture of the following and derivatives thereof, such as hydroxypropyl methylcellulose (HPMC), in which the polymer structure incorporates a hydrophobic substituent (methoxy) and a hydrophilic substituent (hydroxypropoxy), wherein the 2% aqueous viscosity is between about 1298 and about 15000 millipascal seconds (mPas) (2%, 20C); hydroxypropyl cellulose (HPC), in which the 2% aqueous viscosity is above about 150 mPas (2%, 25C); hydroxyethyl cellulose (HEC); gums such as water-soluble carboxymethyl cellulose (CMC), gellan, propylene glycol alginate, water-soluble alginates, acacia, pectin, xanthan gum, guar gum, carrageenan and water-insoluble alginate derivatives, water-insoluble CMC derivatives, colloidal silicon dioxide, agar, locust bean gum, tragacanth gum. The definition also includes polyvinyl pyrrolidones with molecular weight (MW) of 1,000,000 MW and above (K values ​​of 85 and above) and aqueous viscosities of 300 m mPAs (10%, 20C) and above and higher molecular weight polyethylene oxides (PEO) (MW above 600,000). The definition of the term "suspending agent / viscosity increasing agent" does not include the following: one or a mixture of HPMC, wherein the polymer structure does not combine hydrophobic and hydrophilic substitutions and / or its aqueous viscosity is lower than 1298 mPas or higher than 15000 mPas (2%, 20C); methylcellulose (MC); microcrystalline cellulose (MCC); powdered cellulose; sodium starch glycolate; starch; polyvinyl pyrrolidone with a MW lower than 1000000 MW and a K value lower than 85 and an aqueous viscosity lower than 300 mPAs (10%, 20C); polyvinyl pyrrolidone-vinyl acetate copolymer; cross-linked polyvinylpyrrolidone (polyplasdone crospovidone); HPC, wherein the 2% aqueous solution viscosity is lower than 150 mPas (2%, 25C); water-insoluble bentonite.

[0043] The term "surfactant" or "surfactant system" refers to an amphiphilic structure having a polar hydrophilic head (ionic or nonionic) and a nonpolar hydrophobic tail. This balance between the hydrophilic and lipophilic parts of the amphiphilic molecule is expressed as the hydrophile-lipophile balance (HLB). Surfactants are used to dissipate the free surface energy of particles by reducing the interfacial tension and contact angle between the solid and the suspension vehicle, and include: PEG 300 oleylglycerol ( M-1944CS), PEG300 linoleic acid glyceride ( M-2125CS); hydroxylated lecithin; caprylocaproyl polyoxy-8 glyceride; polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate; sorbitan esters (sorbitan fatty acid esters), such as sorbitan monolaurate; polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene 20 sorbitan monooleate Esters, polyoxyethylene 20 monoisostearate; polyethylene glycol monostearate (Gelucire 48 / 16); poloxamers with a MW of 2200 to 14600 and a viscosity of 700 to 3100 mPAs (melt at 77°C), but excluding surfactants with an HLB lower than 7, such as propylene glycol monocaprylate type I, propylene glycol monocaprylate type II, propylene glycol monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate and sorbitan monooleate.

[0044] The term "co-surfactant" refers to a chemical substance used in addition to a surfactant specifically to improve its performance: thus, a secondary surfactant used in conjunction with a primary surfactant. Co-surfactants are typically alcohols, amines in the C4 to C10 range, or molecules with a polar hydrophilic head (ionic or nonionic) and a non-polar hydrophobic tail. Co-surfactants aid in the formation and stabilization of micelles / microemulsions.

[0045] The term "solubility enhancer" refers to an excipient used to dissolve a low solubility drug via non-covalent interactions and allow for enhanced dissolution and bioavailability of the drug. Non-covalent interactions include van der Waals forces, hydrogen bonds, dipole-dipole and ion-dipole interactions, and electromagnetic interactions that are favorable in certain circumstances. In the present disclosure, solubilizers refer to one or a combination of two types of excipients: type (I) having an amphiphilic structure with hydrophobic and hydrophilic components and type (II) having a non-amphiphilic structure with either a mostly hydrophilic component or a mostly hydrophobic component. Solubilizers are divided into two categories, the first of which is amphiphilic solubilizer type (I): A) cellulose derivatives such as, but not limited to, HPMC with an aqueous viscosity not exceeding (NMT) 500 mPas (2%, 25C) and low molecular weight (MW) hydroxypropyl cellulose (HPC) (up to 95,000) with an aqueous viscosity not exceeding (NMT) 150 mPas (5%, 25C), and B) surfactants with an HLB of 3 to 7 (type I) or with an HLB of 7 and above or a combination of two types: examples include, but are not limited to, sodium lauryl sulfate, copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), i.e., poloxamers, with a MW up to 14,600 and a viscosity up to 3,100 mPas (77C); PEG 300 oleyl glyceride, PEG 300 linoleic acid glyceride; sorbitan esters (sorbitan fatty acid esters), such as: sorbitan monoisostearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate; polyoxyethylene sorbitan fatty acid esters, such as: polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 Sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene 20 sorbitan monooleate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate, propylene glycol monocaprylate type I and II, caprylocaproyl polyoxy-8 glyceride, C) polyvinylpyrrolidone up to 1.500.000 MW, with an aqueous viscosity of NMT 700 mPAs (10%, 20C), D) polyethylene oxide (PEO) up to 300.000 MW, with an aqueous viscosity of NMT 1200 mPAs (5%, 25C), and E) cyclodextrins and their derivatives. The second type of non-amphiphilic solubilizing agent type (II): A) Mostly hydrophilic components: Examples include but are not limited to glycerol, propylene glycol and PEG.The PEG has a MW of up to 6600 and a viscosity of no more than (NMT) 390 mPas (at 98.98C+ / -0.3C); B) Most are hydrophobic ingredients, examples include but are not limited to oily surfactants and oily solubilizers with a hydrophilic-lipophilic balance (HLB) value below 3: medium chain triglycerides (MCT) and monolinoleic acid glyceride (Maisin CC TM), soybean oil, olive oil, trioleic acid sorbitan ester, tristearic acid sorbitan ester.

[0046] The term "solubilizer" also includes all excipients that act as "solubility enhancers" and solubilize a higher rate of the API than the "solubility enhancers" of the present invention. In the present disclosure, the solubilizer refers to one or a combination of the following: 1) non-volatile solubilizers of more lipophilic character with log p less than 8, such as surfactants with HLB up to 7 (class I), aliphatic surfactants, acids, oils or other lipid-based excipients, where non-limiting examples are α-linolenic acid, α-linoleic acid, oleic acid, olive oil, sesame oil, palm oil. 2) non-volatile solubilizers of hydrophilic character with log p less than 5, such as but not limited to surfactants with HLB equal to 7 and above (class II), benzene derivatives such as benzaldehyde, benzyl acetate, benzyl benzoate, pH adjusters such as but not limited to hydrochloric acid, citric acid, sodium hydroxide, sodium citrate, hydrophilic surfactants such as but not limited to polysorbates, sodium lauryl sulfate. Non-volatile solubilizers of hydrophilic nature also include PEO and its derivatives, cellulose derivatives, such as but not limited to HPMC and low molecular weight HPC with a water viscosity not exceeding (NMT) 500 mPas (2%, 25°C). Weight (MW) (up to 95.000), water viscosity not exceeding (NMT) 150 mPas (5%, 25°C). 3) Volatile solubilizers that evaporate at temperatures and pressures of normal indoor atmospheric conditions, non-limiting examples include ketone derivatives such as methyl ethyl ketone and acetone, alcohols such as methanol and ethanol, and alkanes such as hexane.

[0047] The term "solubilizing system" is used for the solubilizing system of oral films and refers to a combination of ingredients or components in the film preparation, which enhances the solubility and dissolution of hydrophobic or poorly water-soluble substances, such as active pharmaceutical ingredients (API) or bioactive agents. The solubilizing system is intended to improve the dispersion of these substances in the film matrix, ensuring effective release and bioavailability of the film when taken orally. In the context of pet or human oral films, the solubilizing system can include various excipients, surfactants, co-solvents and other additives that interact with the hydrophobic component, destroying its structure and making it easier to mix with the surrounding aqueous environment. This produces a uniform and stable preparation, allowing the active ingredient to be effectively absorbed after administration.

[0048] The purpose of solubilization systems in oral films is to overcome the challenges of delivering poorly water-soluble compounds, which can otherwise result in uneven distribution, reduced bioavailability, and compromised therapeutic efficacy. By using an effective solubilization system, oral films can enhance the solubility and dissolution of bioactive agents, thereby optimizing their absorption and ensuring consistent and reliable therapeutic outcomes.

[0049] The term "mucoadhesive" and variations thereof generally refer to a membrane matrix or drug dosage form that interacts with the mucus covering epithelial cells by adhesion.

[0050] The term "defoaming agent" refers to any substance added to prevent or counteract the generation of foam in a formulation. Typically, these agents have surface active properties and are insoluble in the foaming medium. Common defoaming agents include, but are not limited to, certain alcohols (cetostearyl alcohol), insoluble oils (castor oil), polydimethylsiloxanes and other silicone derivatives, ethers and glycols.

[0051] The term "mucoadhesive film-forming agent" refers to a polymer that forms a film matrix, a film strip, a film sheet, dissolves in an aqueous environment, and exerts bioadhesive properties on the mucosa. Non-limiting examples include the following and their derivatives: PEO, pullulan, CMC, HPC, HPMC, HEC, ethylcellulose (EC), polyvinyl alcohol (PVA), polymethacrylate polymers, including their derivatives. Examples of mucoadhesive materials that can be used to prepare mucoadhesive film matrices are not limited to the following and their derivatives: poly(ethylene oxide), polyvinyl pyrrolidone, poly(acrylic acid) derivatives (e.g., commercially available ), polycarbophil, polyoxyalkylene ether, polymethacrylate, copolymers based on polymethacrylate (e.g., commercially available ), biodegradable polymers such as poly(D,L-lactide-co-glycolide) (e.g., commercially available ), anionic biopolymers such as hyaluronic acid or sodium carboxymethylcellulose, cationic biopolymers such as chitosan or poly (L-lysine) and other cellulose derivatives. Other mucoadhesive polymers that can be used include methyl vinyl ether-maleic acid, mixed salts of methyl vinyl ether-sodium / calcium maleate, methyl vinyl ether-maleic anhydride and half esters (monoethyl ester, monobutyl ester and isopropyl ester) of methyl vinyl ether-maleic anhydride copolymers (e.g., commercially available ).

[0052] In the context of oral films, an agglomeration inhibitor refers to a substance or ingredient added to the film formulation to prevent or minimize the formation of agglomerates or clusters of particles. Agglomerates form when small particles stick together, which can negatively impact the quality, uniformity, and effectiveness of the oral film. Agglomeration inhibitors help maintain the desired properties of the film, such as its texture, appearance, and uniform distribution of the active ingredient. Examples include, but are not limited to, the following and their derivatives: polyvinylpyrrolidone and hydroxypropylmethylcellulose (HPMC), in which the polymer structure combines hydrophobic (methoxy) and hydrophilic substituents (hydroxypropoxy) and has an aqueous viscosity of up to 15000 mPas (2%, 20C), alone or in admixture with methylcellulose (MC) having an aqueous viscosity of up to 5040 mPas (2%, 20C).

[0053] The term "stabilizer" refers to a molecule that prevents chemical degradation, such as D-α-tocopheryl polyethylene glycol succinate (TPGS), citric acid, vitamin E, ascorbic acid, ethylenediaminetetraacetic acid (EDTA), glutathione, L-cysteine, tocopherol, BHT (butylated hydroxytoluene), BHA (beta hydroxy acid), or a combination thereof.

[0054] The term "crystal growth inhibitor" refers to a polymer that inhibits or delays crystal growth in the core, including but not limited to the following examples and their derivatives: poly(vinyl pyrrolidone) (PVP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMC, HPC, MC, poly(vinyl pyrrolidone) / vinyl acetate (PVP / VA) and poly(vinyl acetate) (PVAc).

[0055] The term "preservative" refers to an agent that prolongs the shelf life of food and non-food products by delaying or preventing flavor, odor, color, texture, appearance, nutritional value or safety from deteriorating. Preservatives do not need to provide fatal, irreversible effects that cause partial or complete microbial cell destruction or incapacity. Sterilizers, bactericides, disinfectants, sporicides, viricides and tuberculicides provide this irreversible mode of action, sometimes referred to as "bactericidal" effects. On the contrary, preservatives can provide reversible inhibition or bacteriostatic effects, because if the preservatives are removed, the target microorganisms can resume reproduction. The main difference between preservatives and disinfectants is mainly related to mode of action (preservatives prevent growth rather than killing microorganisms) and exposure time (preservatives have effects of several days to several months, while disinfectants have only a few minutes of effects at most). In a specific embodiment, preservatives include but are not limited to at least one of the following or its derivatives: for example sodium benzoate, methyl paraben, propyl paraben and sodium sorbate.

[0056] As used herein, the term "high loading" may describe a membrane with a high amount of API, for example a membrane above 50 mg API. High loading may also be described in terms of membrane composition, for example up to 40% of the membrane consists of API.

[0057] The term "bioavailability" shall have the meaning defined in the art, i.e., the ability of a drug or other substance to be absorbed and used by the body. Bioavailability is an important factor in oral film technology. The sublingual mucosa has a high membrane permeability due to its thin membrane structure and high degree of vascularization. Due to this rapid blood supply, it provides very good bioavailability. The enhanced systemic bioavailability is due to skipping the first-pass effect, and the better permeability is due to the high blood flow and lymphatic circulation. In addition, the oral mucosa is a very effective and selective systemic drug delivery route due to its large surface area and easy absorption. In studies, thin films have demonstrated their ability to, for example, improve the initial effect of drugs and the duration of effect, reduce the frequency of administration, and increase the effectiveness of drugs.

[0058] The term "plasticizer" as used herein refers to a material that produces or promotes plasticity and flexibility and reduces brittleness. As required, plasticizers can be advantageously used in film preparations to appropriately change the flexibility of the film, to promote processing and allow the film to easily conform to the shape of the oral mucosa to which the film is applied. Plasticizers can reduce the glass transition temperature of film-forming polymers (such as a water-soluble polymer or a variety of water-soluble polymers in the film). Examples of plasticizers that can be used for disclosed oral film dosage forms include, but are not limited to, the following materials and derivatives thereof: such as triacetin, triethyl citrate, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, trioctyl citrate, acetyl trioctyl citrate, trihexyl citrate, sorbitol, maltitol, dibutyl sebacate, PEG 300, PEG 400, glycerol, etc. Plasticizers may be added in amounts up to 25% of the total mass of the film oral dosage form, alone or as a combination, such as 0% to 25%, 1% to 20%, 2% to 15% or 5% to 10%.

[0059] The term "flavoring agent" or "flavoring agent" and its variations generally refer to concentrated preparations used to impart flavor, with or without flavor aids in their manufacture, except for salt, sweetness or sourness. Flavoring agents can be classified as natural, artificial, or natural and artificial (N&A) by combining all natural and synthetic flavoring agents or other forms known in the art. Flavoring agents are divided into solid flavoring agents and liquid flavoring agents according to their physical classification.

[0060] The term "natural flavor" and variations thereof generally refer to flavorings that come from natural sources such as spices, fruits, or vegetables. They can also come from herbs, barks, roots, or similar plant materials. Natural flavors also come from meat, seafood, poultry, eggs, and dairy products. Flavorings are used only to increase the taste of food; they are generally not nutritional by definition.

[0061] The term "artificial flavor" and its variations generally refer to flavoring agents that do not meet the definition of natural flavors. The chemical composition of natural and artificial flavors is usually not very different; the difference is the source. The active ingredients used to impart flavor in natural flavors are usually identified and recreated synthetically with reasonable accuracy.

[0062] The term "natural and artificial (N&A) flavors" and variations thereof generally refer to natural flavors combined with synthetic ingredients to enhance flavor balance and fullness. These flavors are often categorized by type and taste.

[0063] The term "liquid flavor" and variations thereof generally refer to flavors in a liquid phase with or without a liquid carrier. The texture generally depends on the solvent from which they are prepared. Liquid flavors are available in the form of oily (e.g., essential oils) or non-oily liquids. Examples of liquid flavors include, but are not limited to, essential oils, liquid extracts, tinctures, and distillates or other forms known in the art. The term "liquid" and variations thereof generally refer to viscous liquids, slurries, foams, pastes, gels, and the like.

[0064] Other known techniques for masking the unpleasant taste of active agents include the addition of taste masking agents, sweeteners, and flavor enhancers (sometimes referred to as "taste enhancers").

[0065] The term "flavor enhancer" and its variants generally refer to compounds that particularly enhance certain flavors or reduce undesirable flavors without having their own particularly strong flavors. They harmonize the flavor components and make food / pharmaceutical preparations more palatable. Examples include, but are not limited to, maltol, ethyl maltol, and monosodium glutamate, and most commonly glutamic acid, glutamate, purine-5-ribonucleotides, inosine, guanosine, adenosine 5-monophosphate, sugar, sweeteners, carboxylic acids (e.g., citric acid, malic acid, and tartaric acid), common salts (NaCl), amino acids, some amino acid derivatives (e.g., monosodium glutamate, MSG), and spices (e.g., pepper), yeast, yeast extract, dry yeast, etc., or mixtures thereof.

[0066] The term "taste masking agent" and its variations generally refer to ingredients that can cover unpleasant odors or tastes in food or medicines or at least make them more acceptable. Among the many flavors that must be covered in drugs, the most commonly encountered is bitterness; it is challenging to completely cover it. Examples of bitter masking agents include, but are not limited to, licorice, coffee, chocolate, mint, grapefruit, cherry, peach, raspberry, orange, lemon, lime, advantamin, etc. or mixtures thereof. Syrups of cinnamon, orange, citric acid, cherry, cocoa, wild cherry, raspberry or licorice elixir, raspberry and other fruit syrups can be used to effectively mask the salty and bitter tastes in many medicines. Metallic tastes (e.g., iron) in oral liquid products are usually masked by tropical fruit guarana extracts, but can also be masked by other extracts and agents.

[0067] The term "sweetener" and its variations generally refer to a solid or liquid ingredient used to impart sweetness to a food or drug product. Sweeteners are generally classified as nutritive (caloric) or non-nutritive (caloric-free), natural or synthetic. Examples of sweeteners include, but are not limited to, sucrose, dextrose, lactose, glucose, advantame, sorbitol, mannitol, liquid glucose, honey molasses, saccharin, sucralose, rebaudioside A stevioside, rebaudioside M stevioside, stevioside, mogroside IV, mogroside V, alitame, saccharin, neohesperidin dihydrochalcone, cyclamate, neotame, N-[3-(3-hydroxy-4-methoxybenzyl)propyl]- L-α-aspartyl]-L-phenylalanine 1-methyl ester, N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester, N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester, curculin, cyclamate, aspartame, acesulfame potassium, etc. or a mixture thereof.

[0068] The term "colorant" and its variations generally refers to any dye, pigment or other substance produced by synthetic processes or similar techniques, or extracted, isolated or otherwise derived from plants, animals, minerals or other sources, with or without intermediate or final changes in properties, and which, when added or applied, imparts color to foods, drugs, cosmetics or the human body. Color makes products attractive, interesting, appetizing and informative. Examples of colorants include, but are not limited to, Brilliant Blue FCF, Indigo, Seed Green FG, Indigo, Indanthrene Blue, Resorcinol Brown, Fast Green FCF, Alizarin Cyanine Green F, Quinizarin Green SS, Pyran, Dibromofluorescein, Diiodofluorescein, Erythrosine Yellow Na, Copper Phthalocyanine, Erythrosine, Ponceau SX, Lithol Ruby B, Lithol Ruby B Ca, Tony Red, Tetrabromofluorescein, Eosin, Tetrachlorotetrabromofluorescein, Yellow Iron Oxide, Ultramarine Blue, Zinc Ferrate, Chromium Oxide Green, Titanium Dioxide, Zinc Oxide, Phosphor, Herrington Pink CN, Brilliant Lake Red R, Acid Fuchsin, Bordeaux Lake B, Flame Red, Alba Red, Allura Red AC, Alizarin Violet SS, Alizarin Violet, Lemon Yellow, Sunset Yellow FCF, Fluorescein, Naphthol Yellow S, Uranium, Quinoline Yellow WS, Quinoline Yellow SS, etc. or mixtures thereof.

[0069] The term "penetration enhancer" and its variations generally refers to a chemical compound that is added to a formulation along with a target drug to improve the penetration of the active agent through biological membranes such as the skin, nasal, oral, and intestinal mucosa. Examples include, but are not limited to, bile salts, benzene derivatives, fatty acids and derivatives such as oleic acid and lauric acid, glycerides such as phospholipids and medium chain glycerides, surfactants such as sodium lauryl sulfate and polysorbates, inclusion compounds such as cyclodextrin derivatives, pH adjusters, chelating agents such as disodium ethylenediaminetetraacetate, D-α-tocopheryl polyethylene glycol succinate (TPGS), and mucoadhesive excipients such as chitosan and polycarbophil.

[0070] The term "penetration enhancer" and variations thereof generally refer to excipients used to enhance the action of a permeation enhancer and thereby improve API permeation by reducing the lag time between administration of the permeation enhancer and enhanced permeation. Examples include, but are not limited to, polyethylene glycol, propylene glycol, and glycerol.

[0071] "Surface pH" is the pH measured on the surface of the film, such as the top or bottom surface of a monolayer film or the exposed surface of a layer containing active substances in a multilayer oral film. The film is prepared for pH testing by slightly wetting the film (adding water, e.g., one to three drops, as needed for the pH test). The pH is then measured by contacting an electrode with the oral film surface. The surface pH measurement is preferably performed on several films of the same formulation.

[0072] The terms "blend" or "blending medium" and variations thereof generally refer to the combination of an oral film formulation in the presence of a solvent.

[0073] As used herein, the term "drug absorption" or "absorption" refers to the process of movement of a drug from a site of administration to the systemic circulation (eg, into a subject's bloodstream).

[0074] The term "residence time" as used in this specification refers to the time required for a film to disintegrate on the sublingual or buccal mucosa.

[0075] Preferred film dosage forms include sublingual and buccal oral dosage forms. Buccal and / or sublingual mucosal absorption allows the drug to be absorbed directly into the bloodstream, skipping liver metabolism. This is particularly challenging from a drug formulation perspective, as the transmucosal permeation process needs to be carefully optimized to obtain an acceptable pharmacokinetic profile. The use of long-acting oral films, which allow the dissolving film to direct the active agent across the mucosa directly into the bloodstream, can improve the absorption characteristics of the API, thereby increasing bioavailability.

[0076] Buccal or sublingual film dosage forms may comprise a single film layer or multiple layers. In some embodiments, a bilayer or multilayer film will include a mucoadhesive layer containing the API placed against the oral mucosa and a second layer directed outward from the mucosa, which acts as a protective barrier to prevent abrasion by the tongue or chewing or simply to prevent continuous washing by saliva. This protective layer also facilitates direct absorption of the API in the oral cavity, rather than ingestion by the intestine in the gastrointestinal (GI) tract.

[0077] As used herein, the term "animal" is intended to mean mammals, and does not include humans.

[0078] The present disclosure provides methods and products for topically administering one or more active agents by adhering the film to a mucous membrane, such as a mucous membrane contained in the oral cavity of a human or non-human mammal. A dissolving film containing the active agent is placed on the mucous membrane, such as a membrane in the oral cavity. The hydrophilicity of the dissolving film causes the film to adhere to the mucous membrane.

[0079] To enhance the acceptability of the delivery systems of the present disclosure to animal subjects, certain embodiments include flavorings such as, but not limited to, beef, chicken, liver, bacon, cheese, apple, smoke, fish, mint (e.g., spearmint or peppermint), combinations thereof, and the like.

[0080] Maropitant, a substituted quinuclidine, belongs to the class of organic compounds diphenylmethane, chemical name (2S,3S)-(diphenylmethyl)-N-[2-methoxy-5-(2-methyl-2-propyl)benzyl]quinuclidine-3-amine, systematic (IUPAC) name (2S,3S)-N-(5-tert-butyl-2-methoxybenzyl)-2-(diphenylmethyl)-1-azabicyclo[2.2.2]octane-3-amine, is a neurokinin (NK1) receptor antagonist that blocks the pharmacological effects of substance P in the central nervous system (CNS). Maropitant is used to prevent and treat vomiting in animals.

[0081] Maropitant also has mild analgesic, anxiolytic and anti-inflammatory effects. Maropitant and similar classes of compounds are useful pharmaceutically as antiemetics, autonomic agents, benzene derivatives, central nervous system agents, gastrointestinal agents and peripheral nervous system agents.

[0082] For injectable dosage forms, users (pet owners) or patients (pets) must consult professional health and veterinary care personnel for dosage administration. At the same time, injectable dosage forms are not the most preferred due to pain and local irritation, especially for chronic treatments that require repeated and more frequent administration. The preferred route for users and patients is the oral route because the gastrointestinal tract has a higher absorption surface area. However, some limitations, such as the first-pass mechanism of the liver and gastric degradation of drugs, have made emerging advances in this field challenge drug bioavailability.

[0083] It is known in the art that increasing the API load in an oral dosage form will improve bioavailability and will compensate for the portion of API lost through metabolism and excretion, however this approach may increase the potential risk of toxicity and the risk-benefit imbalance must be addressed.

[0084] Veterinary drugs may require higher doses depending on the animal's weight, which means a higher dose per tablet. Higher dose tablets mean taller tablet sizes to efficiently carry larger amounts of API and excipients.

[0085] Administering tablets to animals is challenging because the animal may attempt to expel the tablet from its mouth, so compliance becomes an issue. Often, pet owners will tear the tablet into pieces and hide it in the animal's food to mask the bad taste and try to ensure that the entire dose is consumed. While tablets can be broken into small pieces or even crushed as a means of overcoming swallowing difficulties or sticking, this is not a suitable solution for many tablet or pill forms. For example, crushing or disrupting a tablet or pill to facilitate ingestion alone or with food may destroy the controlled release properties of the dosage form, the taste masking properties, or otherwise affect the pharmacokinetic properties of the drug.

[0086] Oral film is an alternative dosage form to tablets, offering several advantages such as faster onset of action and better drug bioavailability. However, it cannot be easily adapted to higher drug loadings due to the limited size, weight, and thickness of the film. Larger sized films may not fit in the animal’s mouth, and thicker films will have unacceptable disintegration times or mouthfeel, all of which put the tablet back on track.

[0087] The use of mucoadhesive matrices will reduce the risk of animals spitting out the dosage form by creating an intimate contact with the absorption site to increase the likelihood of effective permeability, thereby improving the ease of administration and compliance with treatment. However, anionic mucoadhesive excipients are incompatible with the presence of cationic drugs because there is a risk of formation of ionic complexes leading to formulation failure. On the other hand, cationic mucoadhesive excipients require a more acidic microenvironment to dissolve, which may irritate the buccal mucosa and will be neutralized by saliva pH. The use of nonionic polymers with improved wettability facilitates adhesion through hydration and the formation of hydrogen bonds between the functional groups of the polymer and the mucosal layer.

[0088] Providing an oral film in which the API is suspended would have the advantage of being less susceptible to drug recrystallization, but may slow down the dissolution kinetics of the API and drug absorption due to the short residence time and limited amount of saliva available for dissolution. A combined suspension and dissolution approach would allow for a dual system - the dissolution portion would facilitate the system to cover the first portion of the drug to improve permeability, since drug absorption of the suspended API is slower (amorphous molecules are generally more readily absorbed than crystalline forms); the remaining portion of the suspended API and / or the dissolution portion would facilitate continuity of API absorption, even in the oral region and / or in a gastric tube.

[0089] Oral films containing dissolved API deliver active agents faster, thereby increasing oral and / or gastric absorption, however there is a risk of API recrystallization. The choice of excipients is very important to prevent this instability. However, in some embodiments, in order to maintain a soluble API, a ratio of API to solubilizer of less than 1:1 is generally required, and this results in a film with a higher weight and larger size.

[0090] The use of organic solvents to dissolve APIs is known in the art, but the choice of polymers is limited due to the limited solubility of film-forming polymers. Since the solvent cannot be retained at a high percentage after the film is dried for safety reasons (ICH guidelines), the API is more susceptible to recrystallization after drying.

[0091] For high API loadings, it is necessary to use higher ratios of crystal depressants such as poly(vinyl pyrrolidone) (PVP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), poly(vinyl pyrrolidone) / vinyl acetate (PVP / VA) and poly(vinyl acetate) (PVAc), resulting in higher percentages of solids in the film formulation.

[0092] Another alternative to volatile solubilizers for API is non-volatile solubilizers, which remain in the film after the drying step, but in addition to increasing the solid percentage, such solubilizers are generally liquids with more lipophilic properties, which results in formulations showing slower drug dissolution and lower API penetration in the absence of penetration enhancers. The use of liquid solubilizers (e.g., fatty acids, oils, or other lipid bases) can produce films with physical instability, oily aspects, longer disintegration times, drug precipitation, phase separation in the film mixture, and low permeability properties. In order to alleviate the low permeability problem, penetration enhancers can be used.

[0093] During permeation studies using the Franz Cell apparatus and buccal pig mucosa, suspended maropitant membrane prototypes prepared in neutral pH aqueous solution had long lag times and low permeation profiles. In vivo results with later membrane prototypes were not entirely satisfactory. Faster and more extensive absorption is desired.

[0094] Maropitant film prototypes with API dissolved in organic solvents crystallized, resulting in non-permeability of porcine mucosa even with the addition of crystal growth inhibitors (due to high API loading). Maropitant is a cationic drug at neutral pH that forms precipitates with polyacid polymers such as CMC, carbomer, and polycarbophil.

[0095] Membranes made with chitosan polymers do not disintegrate in aqueous solutions at neutral pH because chitosan is a polycationic biopolymer that can only be protonated in weak organic acid solutions at pH below its pKa (~6.3-6.5).

[0096] Maropitant oral films prepared with more than 10% oleic acid exhibited an oily aspect, longer disintegration time at neutral pH, and longer lag time during permeation studies.

[0097] Maropitant oral film prepared with MCT oil in MEK (methyl ethyl ketone) showed oily aspects and drug crystallization.

[0098] The present inventors have found that making the entire API of a high strength film permeable through the buccal mucosa would require a longer residence time of the dissolved API in the mucoadhesive matrix. It has been observed that there is a need for an oral film that improves the permeability of the oral mucosa by increasing the solubility or presence of an amorphous API to limit first liver passage and formulates a highly mucoadhesive dosage form to increase the contact of the API with the mucosa, thereby achieving better compliance, alternative administration procedures and repeatable dosing, thereby further improving bioavailability.

[0099] Further improvement of API solubility will give API a higher surface area, making API in an amorphous state, thereby increasing the absorption rate and degree of API in the oral microenvironment, thereby reducing the lag time of drug oral penetration. In addition, once the film is applied to the mucosa, the film will dissolve when it comes into contact with the wet surface of the mucosa. When the pH adjuster and / or other components of the oral film are hydrated, they will produce a microenvironmental pH, the pH of which can be predicted by measuring the membrane surface pH. The microenvironmental pH helps the API to ionize and form hydrogen bonds with water molecules, thereby promoting the dissolution of the API. Soluble ionic API will maintain a balance with the soluble non-ionic form of API, which is conducive to the absorption of API through the mucosa. Once the soluble non-ionic form is consumed by mucosal penetration, the balance will shift to the direction of providing more soluble non-ionic API. The favorable microenvironmental pH of alkaline API is lower than its pKa, while for acidic API, its favorable microenvironmental pH will be higher than its pKa.

[0100] In addition, it is important to provide a film matrix with optimal physical properties (e.g., physical appearance, folding resistance, tensile strength, and elongation) to maintain the performance of the product during its shelf life. Therefore, the combination of a matrix system that dissolves the API in a non-volatile solubilizer and a suspended API in a polymer mucoadhesive film matrix enables the concept of a high-load film with optimal permeability, film size, stability, and flexibility. The optimal film will contain a polymer with improved wettability that helps mucoadhesion by rapid hydration. When applied to the buccal mucosa, the easily soluble API portion improves permeability and reduces the lag time of penetration, while the suspended API portion and / or the remaining dissolved portion will promote the continuity of absorption, even in the oral cavity and / or the gastrointestinal tract.

[0101] The present disclosure provides a stable mucoadhesive flexible film with improved bioavailability, higher strength doses, and shorter permeation lag time.

[0102] Dual system: solubilization and suspension

[0103] Film matrices for high-strength APIs are only successful when two different approaches are combined: a solubilization system using an emulsion to provide the amorphous API, and a suspension system to provide finely dispersed crystals. When only one system (emulsion or suspension) is used, the properties required for high-strength APIs cannot be achieved or are not achievable.

[0104] In a preferred embodiment, the active pharmaceutical ingredient (API) is present in the film matrix in two ways, namely dissolved and suspended, to make the film of high-strength API feasible and successful. Dissolving the API increases the API surface area and prepares the API for release in an amorphous form; providing the highest dispersibility and providing the fastest onset of absorption while overcoming the dissolution rate limitation. This can have the fastest onset of action and improve bioavailability.

[0105] In order to dissolve poorly water soluble APIs, it is necessary to use at least one solubilizer. The solubilizer is preferably non-volatile and is intended to maintain the amorphous form available in the dry film.

[0106] When formulating high-load films with only dissolved API, many difficulties arise due to the required amounts of solubilizer and optional crystal growth inhibitor polymer resulting in higher film weight and unacceptable thickness. Using the suspended API only approach, less solids are used in the film because it does not require as much solubilizer and stabilizer as the dissolved prototype (crystal growth inhibitor polymer), but a small amount of viscosity enhancer / suspending agent, ranging from one-tenth to one-fifteenth of the amount of API, is required to maintain the stability of the dispersion. The permeability of the suspended API is reduced compared to the dissolved approach because the release of the API is limited by the dissolution rate, but the surface area of ​​the suspended API is increased compared to the physical mixture and the pure API, which facilitates the dispersibility and dissolution of the drug. The suspension approach prevents or at least mitigates uncontrolled, undesirable recrystallization of the API in the cast oral film, which may produce a different drug release profile and may lead to product failure.

[0107] Combining the two approaches of dissolving and suspending the API will allow for the use of less total solids, thereby allowing for the design of a stable oral membrane containing the dissolved portion of the API. The dissolved API, upon contact with the in vivo biological fluid, will promote rapid release and penetration of the drug close to the biomembrane, while the suspended API will provide a continuous concentration of the API close to the biomembrane to maintain a concentration gradient from the outer cells to the inner cells, promoting API absorption.

[0108] The higher the percentage of API in the matrix, the closer the API molecules are to each other, and the easier it is for the API to form recrystallization nuclei. Since the weight per unit surface area that can be coated is limited, the API should be limited to prevent the molecules from getting too close, unless there is a crystal growth inhibitor to prevent it, but the effect is limited and it will also increase the film weight.

[0109] In order to dissolve the API, a solubilizer / permeation enhancer with a log p of no more than 8 is selected for this embodiment because it provides better solubility according to the principle of "like dissolves like". This method allows the use of less than 6 parts of the solubilizer to 1 part of the low water soluble API. The lipophilic properties of the API and the solubilizer / permeation enhancer are proportional to their log p, and when it is higher (log p), a fatty membrane matrix will be produced, thereby offsetting the wettability of the membrane. The selected solubilizer has the property of enhancing penetration, which is crucial for drug absorption. By having a penetration enhancing property, it is beneficial to reduce the amount of solids in the membrane formulation.

[0110] Since the solubilizer / permeation enhancer is a lipid, its water solubility is relatively low, the wettability and hydration of the membrane decrease, resulting in a long permeation lag time, which is not conducive to drug release. In order to address these limitations, it is preferred that no more than 5% of the lipophilic solubilizer / permeation enhancer be used to limit the lipophilicity of the membrane matrix, convert the solubilizer / permeation enhancer to a low log p water-soluble solubilizer / permeation enhancer, or combine two types of solubilizers / permeation enhancers (one with lipophilic properties and one with water-soluble properties) to enhance membrane hydration and wettability and increase the amount of dissolved API in each membrane when using a higher ratio of combined solubilizers / permeation enhancers.

[0111] In addition, the addition of a surfactant system and a lipophilic solubilizer / permeation enhancer that meets the required HLB of the API will enhance the wettability of the membrane in aqueous media, aiding in drug dispensing, membrane dissolution, drug release, and permeation.

[0112] In addition, suspending agents (also called "viscosifiers") are added to prevent adjacent suspended particles from getting close enough to bind to each other and promote recrystallization. Sufficiently increasing the viscosity of the drug carrier (polymer matrix) can achieve steric stability of the dispersed drug. In addition to preventing drug crystallization, suspending agents can also thicken and stabilize emulsions containing APIs by increasing viscosity. In addition, the suspending agents interact with biological mucosa to generate and enhance oral membrane mucosal adhesion, thereby increasing drug penetration while keeping the API close to the absorption site.

[0113] To aid API penetration and reduce the lag time caused by lipophilic solubilizers / permeation enhancers, permeation enhancers are used to increase the aqueous solubility of the solubilizer / permeation enhancer, which allows it to leave the vehicle more easily, thereby allowing the solubilizer / permeation enhancer to enhance membrane fluidity and allow for a greater likelihood of drug penetration.

[0114] After the active drug phase (API, solubilizer with surfactant system, penetration enhancer and suspending agent / viscosity increasing agent) is prepared, a low viscosity polymer with solubility enhancing properties is added to the blend along with the phase to aid the incorporation of the organic API into the aqueous system, thereby preventing further precipitation of the API in the dry film.

[0115] To flavor the film, flavorants, flavor enhancers, and sweeteners are blended with the wet blend to produce an acceptable flavor profile upon final drying, thereby improving the palatability of the film and masking or eliminating any potential aftertaste, while also enhancing sweetness, prolonging sweetness, and enhancing other flavors.

[0116] In the last step of the blending process, polymers forming a film-forming matrix are added, at least one having fast wetting properties to form a mucoadhesive matrix together with another polymer that prevents the growth of API crystals in the final dry film.

[0117] The present invention is directed to providing a film forming matrix with a high load of drug substance, a substantial portion of which is intended to be released and absorbed orally to avoid the hepatic first pass and result in better API bioavailability.

[0118] In one embodiment, the film forming matrix includes API (amorphous) dissolved at a ratio of API to solubilizer ranging from 10:3 to 10:60 using a solubilizer with an appropriate Log P (log p no greater than 8), and suspending the API to increase the loading and keep the film weight low.

[0119] The high-load film has a portion of dissolved API, which accounts for more than one-tenth of the total dose, which is kept in an amorphous form in the surfactant system, which helps prevent the dissolution and dispersibility of the API. Another portion of the API is suspended to form a film-forming matrix of acceptable weight and size. The concept is to carry and release the uncharged and highly dispersible soluble API (amorphous) close to the absorption site of the biological mucosa, so as to act as early as possible, and then maintain the action by releasing and absorbing the API from the suspended portion of the API.

[0120] In a preferred embodiment, the film forming matrix comprises API (amorphous) dissolved using a solubilizing agent with an appropriate Log P (log p no greater than 8) at a ratio of API to solubilizing agent in the range of 1:1 to 1:2.5, and suspending the API to increase the loading and keep the film weight low.

[0121] Preferred embodiments also include the presence of a lipophilic solubilizer / permeation enhancer to help carry the amorphous form of the API, which is more soluble than the crystalline form of the API, through the membrane and thus enhance the hydration and wettability of the membrane.

[0122] Preferred embodiments also include suspending the API under conditions that may allow dissolution for additional oral absorption.

[0123] The preferred embodiment includes a permeation enhancer that pre-treats the mucosal cell membrane to help increase membrane fluidity, which will initially continuously feed the amorphous API, which has better solubility than the crystalline API. It also includes a mucoadhesive polymer that helps maintain close contact between the membrane and the biological mucosa for an acceptable period of time, and a suspending agent to prevent adjacent suspended particles from getting close enough to bind to each other and promote recrystallization, and a solubility enhancer is added to dissolve the API and prevent its recrystallization.

[0124] The concept herein is to induce high onset of action by allowing early release of the API in an amorphous state from a mucoadhesive film forming matrix. The API dissolves readily upon exposure to biological fluids and is introduced into an oral film close to the buccal mucosa to increase the fluidity of the cell membrane to facilitate its penetration. The matrix prevents crystallization and highly dispersible particles, wherein the film-forming polymer allows for a residence time in the oral cavity site that is favorable for increasing the chances of obtaining higher drug bioavailability. The oral film provides the API at a high load to cover a higher subject weight and maintain a concentration gradient to facilitate drug absorption. The high strength oral film has a second portion of the API provided as a suspended API to provide support for the continuity of drug release and the resulting drug action.

[0125] Generally speaking, oral film dosage forms include dissolved API in a solubilizer, penetration enhancers, suspended API, a surfactant system, a suspending agent / viscosity increasing agent, and a polymeric film matrix.

[0126] Generally speaking, oral film dosage forms include dissolved API in solubilizer, penetration enhancers, penetration enhancers, suspended API, surfactant system, suspending agent / viscosity enhancer, plasticizer, flavor system, chemical stabilizer and polymeric film matrix.

[0127] In certain embodiments, the oral film dosage form comprises a high strength API, a solubilizing agent, a penetration enhancer, a suspending agent / viscosity increasing agent, a mucoadhesive film-forming polymer, an amphiphilic dissolution enhancer, an agglomeration inhibitor, and a surfactant, wherein the portion of the dissolved API is less than the remaining suspended portion. The total API content per film is at least 50 mg, accounting for at least 22% of the total dry weight of the oral film.

[0128] According to some aspects of the present disclosure, an oral film dosage form comprises at least one API in a dual system: an API in a solubilizer and a suspended API in a polymeric mucoadhesive film matrix.

[0129] According to some aspects of the present disclosure, the dissolved API accounts for more than one tenth of the entire dose.

[0130] According to some aspects of the present disclosure, a multilayer oral film made from a portion of maropitant or a salt thereof is dissolved and made into a different film layer from the suspended maropitant or a salt thereof.

[0131] According to some aspects of the present disclosure, the oral film dosage form contains a solubilizer present in an amount of at least 4% and no more than 30% of the total oral film composition.

[0132] According to some aspects of the present disclosure, the solubilizer is lipid-based and present in an amount up to 10% of the total composition of the oral film dosage form and is made of one or more than one fatty acid, derivatives thereof, or combinations thereof, and preferably oleic acid or caprylic acid.

[0133] According to some aspects of the present disclosure, the solubilizing agent is lipid-based and is preferably made from one or a combination of: an oleic acid derivative or an octanoic acid derivative.

[0134] According to some aspects of the present disclosure, the solubilizer is a benzene derivative and is present in an amount up to 25% of the total composition of the oral film dosage form, and is preferably benzyl alcohol or benzyl acetate.

[0135] According to some aspects of the present disclosure, the solubilizing agent has a log p of no greater than 8.

[0136] According to some aspects of the present disclosure, oral film dosage forms contain a dissolved API in a solubilizer system.

[0137] According to some aspects of the present disclosure, an oral film dosage form contains a dissolved API in a solubilizer system. The solubilizer system comprises at least one solubilizer.

[0138] According to some aspects of the present disclosure, the oral film dosage form preferably contains a solubilizer system including a solubilizer having penetration enhancing properties.

[0139] According to some aspects of the disclosure, the ratio of dissolved API to solubilizer is 10:3 to 10:60. According to some aspects of the disclosure, the dissolved API in the solubilizer system is made of a combination of 10 parts lipid-based solubilizer and no more than 13 parts benzene derivative solubilizer.

[0140] According to some aspects of the present disclosure, the solubilized API in the solubilizer system is made from a combination of 1 part hydrophilic surfactant and no more than 4 parts benzene derivative solubilizer.

[0141] According to some aspects of the present disclosure, the solubilized API in the solubilizer system is made from a combination of 10 to 12 parts of a lipid-based solubilizer and 5 to 15 parts of a benzene derivative.

[0142] According to some aspects of the present disclosure, the solubilized API in the solubilizer system is made from a combination of 10 parts of a lipid-based solubilizer and no more than 15 parts of a non-volatile solubilizer that functions as a pH adjuster.

[0143] According to some aspects of the present disclosure, the solubilized API in the solubilizer system is made of a combination of 10 parts of a lipid-based solubilizer, no more than 12 parts of a non-volatile solubilizer that functions as a pH adjuster, and no more than 6 parts of a hydrophilic surfactant.

[0144] According to some aspects of the present disclosure, the solubilized API in the solubilizer system is made of a combination of 5 parts of a lipid-based solubilizer and no more than 7 parts of a benzene derivative and no more than 8 parts of a non-volatile solubilizer that functions as a pH adjuster.

[0145] According to some aspects of the present disclosure, the oral film dosage form comprises a water-soluble API.

[0146] According to some aspects of the present disclosure, the oral film dosage form has at least one API that does not contain ionizable groups.

[0147] According to some aspects of the present disclosure, the oral film dosage form has at least one API having at least one ionizable group.

[0148] According to some aspects of the present disclosure, the oral film dosage form has an API with an acidic character, such as aspirin or ascorbic acid.

[0149] According to some aspects of the present disclosure, the API has a basic character, such as, but not limited to, loxapine, maropitant, dimethyltryptamine (DMT), or rizatriptan.

[0150] According to some aspects of the present disclosure, the oral film dosage form has at least one API with amphiphilic characteristics, such as diclofenac.

[0151] According to some aspects of the present disclosure, the oral film comprises at least one pH adjusting agent.

[0152] According to some aspects of the present disclosure, the oral film has no more than 15% of the total dry weight of the oral film of a non-volatile solubilizer that functions as a pH adjuster.

[0153] According to some aspects of the present disclosure, the pH adjusting agent creates a pH that is favorable for dissolution of the API, keeping a portion of the drug un-ionized.

[0154] According to some aspects of the present disclosure, the pH adjuster is HCl, succinic acid, citric acid, sodium hydroxide, sodium citrate, sodium benzoate, or a combination thereof.

[0155] According to some aspects of the present disclosure, the pH adjuster includes a buffer system consisting of citric acid / sodium citrate or benzoic acid / sodium benzoate or a combination thereof.

[0156] According to some aspects of the present disclosure, the preferred pH adjuster is selected from the group consisting of: inorganic acids such as but not limited to hydrochloric acid, organic acids such as but not limited to citric acid, sodium citrate, succinic acid and sodium succinate, derivatives thereof, or combinations thereof.

[0157] According to some aspects of the present disclosure, the pH adjusting agent comprises no more than 12% of the total dry weight of the oral film.

[0158] According to some aspects of the present disclosure, the oral film comprises at least one penetration enhancer that does not exceed 20% of the total dry weight of the oral film.

[0159] According to some aspects of the present disclosure, the penetration enhancer is selected from the group consisting of PEG 300, PEG 400, glycerol, propylene glycol, derivatives thereof, or combinations thereof, and is preferably polyethylene glycol 300.

[0160] According to some aspects of the present disclosure, the penetration enhancer does not exceed 10% of the total dry weight of the oral film.

[0161] According to some aspects of the present disclosure, the solubility enhancer does not exceed 10% of the total dry weight of the oral film.

[0162] According to some aspects of the present disclosure, the solubility enhancer is amphiphilic and selected from the group consisting of: HPCSSL and poloxamer, derivatives thereof, or combinations thereof.

[0163] According to some aspects of the present disclosure, the solubility enhancer is non-amphiphilic and is selected from the group consisting of PEG, PEG derivatives, medium chain triglycerides, glyceride derivatives, or combinations thereof.

[0164] According to some aspects of the present disclosure, the solubility enhancer is preferably hydroxypropyl cellulose SSL.

[0165] According to some aspects of the present disclosure, the solubility enhancer does not exceed 6% of the total dry weight of the oral film.

[0166] According to some aspects of the present disclosure, the surfactant system does not exceed 14% of the total dry weight of the oral film and is composed of components selected from, but not limited to, polysorbate, labrafil M2125CS, labrafil, type I propylene glycol monocaprylate, type II propylene glycol monocaprylate, lecithin, hydroxylated lecithin, lecithin derivatives, and gelucire 44 / 14, derivatives thereof, or combinations thereof.

[0167] According to some aspects of the present disclosure, the surfactant system is preferably a combination of a low HLB surfactant (HLB up to 12) such as labrafil M2125CS and a high HLB surfactant (HLB equal to 12 and above) such as polysorbate 20.

[0168] According to some aspects of the present disclosure, the surfactant system preferably comprises a surfactant, such as lecithin, hydroxylated lecithin, or a lecithin derivative.

[0169] According to some aspects of the present disclosure, the surfactant system is preferably a combination of 8 to 9 parts of a lecithin derivative and 1 to 2 parts of a surfactant.

[0170] According to some aspects of the present disclosure, the surfactant system does not exceed 15% of the total dry weight of the oral film.

[0171] According to some aspects of the present disclosure, the surfactant system preferably does not exceed 11% of the total dry weight of the oral film.

[0172] According to some aspects of the present disclosure, the nonionic polymer is formulated with a basic API.

[0173] According to some aspects of the present disclosure, anionic polymers are formulated for mucoadhesion with an acidic API selected from the group consisting of cmc and carbomer, and the carbomer dissolves at neutral pH, as does the acidic API.

[0174] According to some aspects of the present disclosure, the oral film further comprises no more than 15%, preferably no more than 6%, of a suspending agent / viscosity increasing agent, based on the total dry weight of the oral film.

[0175] According to some aspects of the present disclosure, the oral film further comprises no more than 3% of a suspending agent / viscosity increasing agent.

[0176] According to some aspects of the present disclosure, the suspending agent / viscosity increasing agent is selected from the group consisting of propylene glycol alginate, hydroxypropyl methylcellulose 4000, gellan gum, hydroxyethyl cellulose, guar gum, hydrolyzed guar gum, derivatives thereof, polysaccharide derivatives, cellulose derivatives, or combinations thereof.

[0177] According to some aspects of the present disclosure, the suspending agent / viscosity increasing agent does not exceed 11% of the total dry weight of the oral film.

[0178] According to some aspects of the present disclosure, the oral film further comprises at least one plasticizer.

[0179] According to some aspects of the present disclosure, the plasticizer does not exceed 15%, preferably does not exceed 10% of the total dry weight of the oral film.

[0180] According to some aspects of the present disclosure, the plasticizer is selected from the group consisting of PEG 300, PEG 400, glycerol, propylene glycol, triacetin, and preferably polyethylene glycol and / or its derivatives.

[0181] According to some aspects of the present disclosure, the plasticizer is selected from the group consisting of PEG 300, PEG 400, glycerin, propylene glycol, triacetin, triethyl citrate, derivatives thereof, or combinations thereof.

[0182] According to certain aspects of the present disclosure, the film-forming matrix comprises at least one polymer selected from the group consisting of pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, gum arabic, gum arabic, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymer, starch, gelatin, ethylene oxide-propylene oxide copolymer, collagen, albumin, polyamino acids, polysaccharides, chitin, chitosan, carboxymethyl cellulose, derivatives thereof, or combinations thereof.

[0183] According to certain aspects of the present disclosure, the film-forming matrix preferably comprises at least one polymer selected from the group consisting of poly(ethylene oxide), MW 200,000 (PEO 200000), hydroxypropyl cellulose (HPC LF) and hydroxypropyl methyl cellulose (HPMCE50).

[0184] According to certain aspects of the present disclosure, the film-forming matrix comprises no more than 60% of the dry weight of the oral film, and preferably comprises 25% to 50% of the total dry weight of the oral film.

[0185] According to certain aspects of the present disclosure, the film-forming matrix preferably accounts for 30% to 45% of the total dry weight of the oral film.

[0186] In certain aspects of the present disclosure, the disclosed formulations and excipients are particularly suitable for use in animals.

[0187] In certain aspects of the present disclosure, the disclosed formulations and excipients are particularly suitable for use in animals, particularly for the treatment of antiemetics.

[0188] In certain aspects of the present disclosure, the disclosed formulations further comprise flavoring agents to improve palatability to humans and animals.

[0189] In certain aspects of the present disclosure, the disclosed formulations further comprise flavorants and flavor enhancers to improve palatability to humans and animals.

[0190] In certain aspects of the present disclosure, the disclosed formulations contain flavorants, flavor enhancers, bitterness masking agents, and taste masking agents to improve palatability in humans and animals.

[0191] According to some aspects of the present disclosure, the API delivered via the oral dosage form is maropitant.

[0192] According to some aspects of the present disclosure, the API delivered via the oral dosage form is maropitant citrate.

[0193] According to some aspects of the present disclosure, the API delivered via the oral dosage form is a maropitant salt.

[0194] According to some aspects of the present disclosure, the API delivered via the oral dosage form is ondansetron.

[0195] According to some aspects of the present disclosure, the API delivered via the oral dosage form is metoclopramide.

[0196] According to some aspects of the present disclosure, the API delivered via the oral dosage form is dolasetron.

[0197] According to some aspects of the present disclosure, the API delivered via the oral dosage form is aprepitant.

[0198] According to some aspects of the present disclosure, the API is delivered with ginger extract to further treat antiemetic effects.

[0199] According to some aspects of the present disclosure, each oral film has an API content of at least 50 mg, accounting for at least 22% and no more than 70% of the total dry weight of the oral film.

[0200] According to some aspects of the present disclosure, the oral film has a surface pH in the range of 2.95 to pH 9.0, and more preferably has a pH that is favorable for keeping a portion of the drug un-ionized.

[0201] According to some aspects of the present disclosure, the oral film further comprises a sweetener.

[0202] In certain aspects of the present disclosure, the disclosed formulations further comprise flavorants, flavor enhancers, taste masking agents, and sweeteners to improve palatability in humans and animals.

[0203] According to some aspects of the present disclosure, the oral film further comprises a colorant.

[0204] In specific embodiments, the orally dissolvable film is palatable to humans.

[0205] In particular embodiments, the orally dissolvable film is palatable to the animal.

[0206] In specific embodiments, the outer surface of the orally dissolvable film has a smooth texture.

[0207] In specific embodiments, the orally dissolvable film has a high tensile strength.

[0208] In particular embodiments, the orally dissolvable film is flexible.

[0209] In specific embodiments, the orally dissolvable film is non-sticky to the touch.

[0210] In specific embodiments, the orally dissolvable film does not readily adhere to another orally dissolvable film.

[0211] In particular embodiments, the orally dissolvable film is relatively soft to the touch.

[0212] In particular embodiments, the orally dissolvable film has a chewable configuration.

[0213] In specific embodiments, the orally dissolvable film has an elastic configuration.

[0214] In specific embodiments, the orally dissolvable film has an elastic or ductile configuration.

[0215] In specific embodiments, the orally dissolvable film has extensible properties.

[0216] In specific embodiments, the orally dissolvable film further comprises a bitter blocker.

[0217] In specific embodiments, the orally dissolvable film further comprises a powder coating present on at least one outer surface of the orally dissolvable film.

[0218] In a specific embodiment, the orally dissolvable film further comprises a powder coating present on two opposing outer surfaces of the orally dissolvable film.

[0219] In a specific embodiment, the method of making an orally dissolvable film is performed in the order shown.

[0220] In a specific embodiment, each step of the method of making an orally dissolvable film is performed in the order shown.

[0221] In specific embodiments, mixing includes blending.

[0222] In a specific embodiment, each of the plurality of orally dissolvable films of the system independently has a thickness of at least 2 cm 2 size.

[0223] In a specific embodiment, each of the plurality of orally dissolvable films of the system independently has a diameter of at most 18 cm 2 size.

[0224] In a specific embodiment, each of the plurality of orally dissolvable films of the system independently has a 9 cm 2 ±2 size

[0225] In a specific embodiment, each of the plurality of orally dissolvable films of the system independently has a 9 cm 2 ±1 size.

[0226] In specific embodiments, each of the plurality of orally dissolvable films of the system independently has a thickness of about 0.01 mm to about 2 mm.

[0227] In specific embodiments, each of the plurality of orally dissolvable films of the system independently has a thickness of at least about 0.01 mm.

[0228] In specific embodiments, each of the plurality of orally dissolvable films of the system independently has a thickness of at most about 2 mm.

[0229] In specific embodiments, each of the plurality of orally dissolvable films of the system independently has a thickness of about 0.03 mm to about 1 mm.

[0230] In specific embodiments, some excipients used in the orally dissolvable films of the present disclosure may have one or more functions. Therefore, the skilled artisan should not interpret the limitations of the excipients stated or illustrated in any aspect or embodiment or example of the oral film of the present disclosure as a single function.

[0231] According to some aspects of the present disclosure, the surfactant system is preferably at least one low HLB surfactant (HLB at most 12).

[0232] According to some aspects of the present disclosure, the surfactant system preferably comprises at least one high HLB surfactant (HLB equal to 12 and above).

[0233] According to some aspects of the present disclosure, the surfactant system is preferably a combination of at least one low HLB surfactant (HLB up to 12) and at least one high HLB surfactant (HLB equal to 12 and above).

[0234] The orally dissolvable film of any of the above embodiments, further comprising a powder coating present on at least one outer surface of the orally dissolvable film.

[0235] The orally dissolvable film of any of the above embodiments, further comprising a powder coating present on two opposing outer surfaces of the orally dissolvable film.

[0236] excipient

[0237]

[0238]

[0239]

[0240] Example

[0241] Example 1

[0242] In this example, the solubilized pharmaceutically active phase is prepared by dissolving a portion of the API (in our case, maropitant free base) which is combined and mixed in a solubilizing system consisting of at least one of the following: fatty acids, benzene derivatives, oils or mixtures thereof. In parallel, an aqueous phase is prepared by mixing water, a permeation enhancer, a surfactant and a co-surfactant to provide the required HLB of the solubilized pharmaceutically active phase or to promote the emulsification of the latter.

[0243] Next, the two phases (active drug phase and aqueous phase) are combined under mixing, followed by the addition of viscosity enhancer / suspending agent to stabilize the emulsion. Once the dispersion is formed, additional amount of API is added to form a suspended API component and mixing is continued.

[0244] Next, a solubility enhancer is added, followed by sweeteners, flavor enhancers, and flavoring agents.

[0245] Finally, the film-forming polymer is added and mixing is continued until the polymer is completely dissolved. The blend is degassed and then coated at a certain gap on the support liner, and finally the coated material is placed in an oven for drying.

[0246] 164-35A Weight(g) Dry% wet% Purified water 17.00 N / A 65.53 LABAFIL M 2125CS 0.05 0.56 0.19 Tween 20 0.48 5.32 1.84 Oleic acid 0.48 5.36 1.85 Benzyl alcohol 0.37 4.17 1.44 Maropitant base emulsion 0.39 4.35 1.50 Maropitant Matrix Extra 1.85 20.68 7.13 HPMC E4M 0.17 1.94 0.67 PEG 300 0.62 6.93 2.39 Hydroxypropyl Cellulose (NISSO HPC SSL) 0.40 4.48 1.54 Sucralose 0.24 2.69 0.93 Magnasweet MM100 0.24 2.69 0.93 SavorboostTM BK 0.06 0.67 0.23 Natural liver powder flavor (PF.Inc PC-0050) 0.35 3.92 1.35 HPMC E50 0.24 2.69 0.93 PEO WSR N80NF 3.00 33.54 11.56 Total dryness 8.94 100.00 N / A Total humidity 25.94 N / A 100.00 Membrane target weight (60mg API) 239.65mg N / A N / A

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253] Example 2

[0254] In this embodiment, the pharmaceutically active phase includes a benzene derivative as a solubilizer, such as but not limited to benzyl alcohol, benzyl acetate, benzaldehyde.

[0255]

[0256]

[0257] Example 3

[0258] In this embodiment, the pharmaceutically active phase includes an oil or a mixture of oils as a solubilizer, one or a mixture of esterified or free fatty acids of saturated or unsaturated fatty acids, such as but not limited to α-linolenic acid, α-linoleic acid, arachidonic acid, palmitoleic acid, gadoleic acid, caproic acid, heptanoic acid, 11-dodecenoic acid, caprylic acid, ricinoleic acid and caproic acid.

[0259]

[0260]

[0261] Example 4

[0262] In this example, the film-forming matrix contains a pH adjuster that aids in dissolving the API. The pH adjuster can be an acid (as shown in batches 164-24-2, 164-39, 164-33-3, and 164-24-1 below), or a basic excipient or buffer system that dissolves all or part of the total strength of the API and will provide a higher surface area for the API in an amorphous form, thereby triggering permeability through the buccal mucosa.

[0263] As an example of preparing the matrix with pH adjuster: first, a dissolved drug active phase is prepared by dissolving the entire API under acidic conditions, which is prepared by mixing water, acidifier, plasticizer, surfactant and co-surfactant to provide the required HLB for the dissolved drug active phase.

[0264] Then a viscosity enhancer / suspending agent is added to stabilize the solution and prevent nucleation, a low viscosity solubilizing polymer is added, followed by sweeteners, flavor enhancers, and flavoring agents.

[0265] Finally, add the film-forming polymer and keep mixing until the polymer is completely dissolved. Degas the blend and apply it to the support liner at a certain gap. Finally, put the coated material into an oven to dry.

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273] Example 5

[0274] The film-forming matrix combines the API dissolved with a pH modifier and a solubilizing system made of one of the following: fatty acids, benzene derivatives, oils or mixtures of the above. The matrix will have completely dissolved API.

[0275]

[0276] Example 6

[0277] In this example, the active drug phase used longer chain fatty acids or higher amounts of lipid-based excipients or benzene derivatives in the matrix and resulted in performance issues (longer disintegration time, low permeability, greasy surface).

[0278] 1- The pharmaceutically active phase includes two types of solubilizers, one is an organic solvent, and the other is oil or a mixture of oils, one or a mixture of saturated or unsaturated fatty acids (esterified or free fatty acids), such as but not limited to α-linolenic acid, α-linoleic acid, arachidonic acid, palmitoleic acid, gadoleic acid, caproic acid, heptanoic acid, 11-dodecenoic acid, caprylic acid, ricinoleic acid and caproic acid.

[0279] 2- The membrane matrix does not contain a permeation enhancer or contains a non-functional permeation enhancer.

[0280] 3-Pharmaceutically active phase, in which most of the solubilizers are essential oils, such as menthone, limonene, eucalyptol, and peppermint.

[0281] 4- Use a higher proportion of lipid excipients in the drug active phase.

[0282] 5- A membrane matrix, wherein the fatty acid or its derivative is not less than 10% and the surfactant is not less than 10%.

[0283] 6-The membrane matrix contains not less than 14% fatty acids.

[0284] 7- The pharmaceutically active phase uses at least an organic solvent to dissolve the API.

[0285] Example 7

[0286] In this example, the film-forming matrix of batch 164-5A was prepared under neutral conditions, where a portion of the API was dissolved in oleic acid and emulsified with Labrafil and Tween, and the remaining API (additional) was suspended. Glycerol was used as a permeation enhancer for penetration and a plasticizer for the film.

[0287]

[0288]

[0289] Example 8

[0290] In this example, the pH of the film-forming matrix of batch 164-5B was about 8 to increase the uncharged portion of the API, which is beneficial for penetration through the buccal mucosa. A portion of the API was dissolved in oleic acid and emulsified with Labrafil and Tween, and the remaining API (additional) was suspended. Glycerol was used as a penetration enhancer for penetration and a plasticizer for the film.

[0291]

[0292]

[0293] Example 9

[0294] In this example, the film-forming matrix of batch 164-5C, batch 164-5D, and batch 164-5B was prepared under neutral conditions, wherein a portion of the API was dissolved in oleic acid and emulsified with Labrafil and Tween, and the remaining API (extra) was suspended. Glycerol was used as a penetration enhancer for penetration and a plasticizer for the film. A penetration enhancer was added to each prototype.

[0295]

[0296]

[0297] Example 10

[0298] In this embodiment, the film-forming matrix of batch 164-6A is prepared under neutral conditions, while batch 164-6B is prepared under conditions of pH about 8 to increase the uncharged portion of the API, which is conducive to penetration through the buccal mucosa. Batch 164-6C is prepared under neutral conditions and a penetration enhancer is added. For the above three films, a portion of the API is dissolved in oleic acid and emulsified with Labrafil and poloxamer, and the remaining API (extra) is suspended. Glycerol is used as a penetration enhancer for penetration and a plasticizer for the film.

[0299]

[0300]

[0301] Embodiment 11

[0302] In this example, the film-forming matrix of batches 164-6D and 164-6E was prepared under neutral conditions, and a penetration enhancer was added to each prototype. For these two batches, a portion of the API was dissolved in oleic acid and emulsified with Labrafil and poloxamer, and the remaining API (extra) was suspended. Glycerol was used as a penetration enhancer for penetration and a plasticizer for the film.

[0303]

[0304]

[0305] Example 12

[0306] In this example, the film-forming matrix of batch 164-13 was prepared under neutral conditions of API suspension. The main film-forming polymer was pullulan.

[0307]

[0308]

[0309] Example 13

[0310] In this example, the film-forming matrix of batches 164-15-1 and 164-15-2 was prepared under neutral conditions, where benzyl alcohol was used to dissolve a portion of the API and emulsified with tween only (batch 164-15-1) or Labrafil and tween (batch 164-15-2). The rest of the API (additional) was suspended. Glycerol was used as a penetration enhancer for penetration and a plasticizer for the film.

[0311]

[0312]

[0313] Embodiment 14

[0314] In this example, the film-forming matrix of batch 164-16 was prepared under neutral conditions, where a portion of the API was dissolved in oleic acid and emulsified with Labrafil and Tween, while the remaining API (additional) was suspended. Glycerol was used as a penetration enhancer for penetration and a plasticizer for the film. The main film-forming polymer was polyacid (CMC).

[0315]

[0316] Embodiment 15

[0317] In this example, the film-forming matrix of batch 164-28-6A and batch 164-28-6A was prepared under neutral conditions, in which a portion of the API was dissolved in oleic acid and emulsified with Labrafil and Tween, and the remaining API (extra) was suspended. The total oleic acid was less than 5% dry, and glycerol and propylene glycol were used as penetration aids and membrane plasticizers.

[0318]

[0319]

[0320] Example 16

[0321] In the following example, the film matrix of batch 164-Ta was prepared under neutral conditions, in which a portion of the poorly soluble tadalafil was dissolved in propylene glycol monocaprylate, benzyl alcohol and PEG 300, and then emulsified with labrafil M2125CS and Tween 20, and the rest of the API was suspended. PEG 300 was used as a solubilizer, permeation enhancer and plasticizer for the film.

[0322] DescriptionBatch No. 164-Ta Weight(g) Dryness % humidity% Purified water 15.1 N / A 62.63 LABAFIL M 2125CS 0.14 1.554 0.58 Tween 20 0.89 9.878 3.69 Propylene glycol monocaprylate 0.39 4.329 1.62 Benzyl alcohol 0.39 4.329 1.62 Tadalafil Lotion 0.35 3.885 1.45 Tadalafil Extra 1.95 21.643 8.09 HPMC E4M 0.17 1.887 0.71 PEG 300 0.55 6.104 2.28 Hydroxypropyl Cellulose (NISSO HPC SSL) 0.4 4.440 1.66 Sucralose 0.24 2.664 1.00 Magnasweet MM100 0.24 2.664 1.00 HPMC E50 0.24 2.664 1.00 PEO WSR N80NF 3.06 33.962 12.69 Total dryness 9.01 100.000 N / A Total humidity 24.11 N / A 100.00 Membrane target weight (60mg API) 235.04 N / A N / A

[0323] Embodiment 17

[0324] In the following example, the film matrix of batch 164-Ap was made of poorly soluble API, in which a portion of apomorphine was dissolved under acidic conditions and the rest of the API was suspended. PEG 300 was used as a solubilizer, permeation enhancer and plasticizer for the film.

[0325]

[0326]

[0327] Embodiment 18

[0328] In the following example, the film matrix of batch 164-Bu was made of a poorly soluble API, in which a portion of the buprenorphine was dissolved under acidic conditions and the remainder was suspended. Propylene glycol was used as a solubilizer and permeation enhancer as well as a plasticizer for the film.

[0329]

[0330]

[0331] In the following examples, the membrane matrix of batch 164-Vi was made of a water-soluble API in which ascorbic acid was dissolved under neutral conditions. Glycerol was used as a permeation enhancer and plasticizer for the membrane.

[0332]

[0333]

[0334] Embodiment 19

[0335] The film matrix of batch 164-44 was prepared under neutral conditions where the API was kept completely suspended with the help of surfactants and viscosifiers to provide increased API surface area, but less than the dissolved prototype.

[0336]

[0337]

[0338] Embodiment 20

[0339] In this example, the solubilized pharmaceutically active phase is prepared by dissolving the combined and mixed API (DMT) in a solubilizing system consisting of at least one of the following: methanol or ethanol.

[0340] Next, the soluble excipients are added and mixed, followed by the viscosity enhancing agent / suspending agent / polymer matrix to create the blend.

[0341] The blend and coating are degassed at a certain gap on the support liner, and finally the coating material is placed in an oven for drying. Due to the size of the membrane, multiple layers of coating may be required to ensure good evaporation of the liquid.

[0342]

[0343]

[0344]

[0345]

[0346] Manufacturing process:

[0347] The oral film is prepared by dissolving all soluble and / or dispersible ingredients in the selected medium and mixing until all excipients are dissolved and / or dispersed, producing a uniform blend. The active ingredient is then added to the blend and dissolved or dispersed, depending on the formulation. The blend is mixed until uniform, and then the polymer is added to the blend and mixed until completely dissolved. Once dissolved and uniform, the mixing speed is reduced to degas the blend.

[0348] The preparation of film products generally involves casting or otherwise thinly spreading a liquid film formulation onto a substrate, drying (e.g., evaporating) all or most of the solvent in the film to produce a thin sheet of semisolid / solid film material, and cutting the film sheet into individual unit dosage forms for packaging or processing.

[0349] The above description is considered to be a description of a preferred embodiment only. Those skilled in the art and those who make or use the illustrated embodiments will appreciate modifications to these embodiments. Therefore, it should be understood that the embodiments described above are exemplary only and are not intended to limit the scope of the present disclosure, which is defined by the following claims interpreted in accordance with patent law principles (including the doctrine of equivalents).

Claims

1. An oral film preparation comprising: i. suspended maropitant or its salt; ii. an aqueous phase consisting of water and at least one surfactant; iii. at least one viscosity increasing / suspending agent, iv. at least one solubilizing agent.

2. The oral film formulation of claim 1, wherein the maropitant or a salt thereof is dissolved in a solubilizing system comprising at least one solubilizing agent.

3. The oral film preparation according to claim 2, wherein the ratio of maropitant or its salt to the solubilizer is 10:3 to 10:

60.

4. The oral film preparation of claim 1, wherein the maropitant or its salt is dissolved by at most 5%.

5. The oral film preparation of claim 1, wherein the maropitant or its salt is dissolved up to 40%.

6. The oral film formulation of claim 1, wherein the solubilizer is a benzene derivative selected from the group consisting of benzyl alcohol, benzyl acetate, benzaldehyde and other benzene derivatives.

7. The oral film formulation of claim 1, wherein the solubilizer is a fatty acid selected from the group consisting of α-linolenic acid, α-linoleic acid, arachidonic acid, palmitoleic acid, gadoleic acid, caproic acid, heptanoic acid, 11-dodecenoic acid, caprylic acid, ricinoleic acid and caprooleic acid, other fatty acids and other fatty acid derivatives.

8. The oral film formulation of claim 1, wherein the solubilizing agent is selected from the group consisting of a non-volatile excipient, a volatile excipient, and a combination of a volatile and a non-volatile excipient.

9. The oral film formulation of claim 1, wherein the solubilizing agent is a surfactant.

10. The oral film formulation of claim 1, wherein the solubilizing agent is a solubility enhancer.

11. The oral film formulation of claim 1, wherein the solubilizing agent comprises an oil, including the possibility of an essential oil.

12. The oral film formulation of claim 1, wherein the solubilizing agent is a pH adjusting agent.

13. The oral film formulation of claim 12, wherein the pH adjuster can be an acidic excipient, a basic excipient, or a buffered excipient.

14. The oral film preparation according to claim 1, wherein the film surface pH is not greater than 9, preferably not greater than 8.

5.

15. The oral film preparation according to claim 1, wherein the pH of the film blend mixture is not greater than 10, preferably not greater than 8.

5.

16. A method for preparing an oral film, comprising the steps of: a. Formulated into a film composition, the composition comprising: i. Maropitant or its salts ii. an aqueous phase consisting of water and at least one surfactant iii. at least one viscosity increasing / suspending agent, and b. dissolving a portion of maropitant or its salt in a solubilizing system consisting of at least one solubilizing agent. c. preparing an aqueous phase with at least one surfactant; d. merging the phases; e. adding a second amount of maropitant or a salt thereof; d. Adding viscosity enhancers / suspending agents to stabilize the emulsion; e. Optionally adding at least one low viscosity solubilizing polymer. f. optionally adding one or more acceptable excipients selected from the group consisting of: co-surfactants, penetration enhancers, flavoring agents, flavor enhancers, sweeteners, colorants, plasticizers, stabilizers, defoamers, antioxidants, preservatives and other excipients; g. Adding film-forming polymers; h. casting onto a substrate to form a film; i. drying the film to remove the solvent; and j. Cut the dried film into individual oral film units.

17. An oral film comprising a dissolved API in a solubilizer, a suspended API, a surfactant system, and a viscosity increasing / suspending agent, wherein the portion of the suspended API exceeds the portion of the API in the solubilizer, and wherein the oral film dosage form delivers up to 80 mg of the API or 120 mg of the API salt.

18. The oral film of claim 17, further comprising one or more acceptable excipients selected from the group consisting of co-surfactants, penetration enhancers, flavoring agents, flavor enhancers, sweeteners, colorants, plasticizers, stabilizers, antioxidants, anti-foaming agents, preservatives and other excipients.

19. The oral film of claim 17, wherein the solubilizing agent is selected from the group consisting of a non-volatile excipient, a volatile excipient, and a combination of a volatile and non-volatile excipient.

20. The oral film of any one of the preceding claims 1 to 19, wherein the oral film is suitable for use in animals.

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