WO2016052960A1

WO2016052960A1 - Bitter taste-masked, ondansetron orally disintegrating film

Info

Publication number: WO2016052960A1
Application number: PCT/KR2015/010238
Authority: WO
Inventors: Jin Hoo Lee; Hyun Soo Kim; Jung Hoon Kim
Original assignee: Seoul Pharma. Co., Ltd.
Priority date: 2014-09-29
Filing date: 2015-09-25
Publication date: 2016-04-07
Also published as: KR101537263B1

Abstract

Disclosed herein are an orally disintegrating film composition comprising ondansetron, magnesium oxide or magnesium hydroxide, and a film forming agent, an orally disintegrating film made thereof, and a method for preparing the orally disintegrating film. The orally disintergrating film according to the present invention can be prepared without using an additional complicated process. Further, the ondansetron orally disintegrating film is provided with suitable physical properties, and effectively masks the bitter taste of ondansetron.

Description

BITTER TASTE-MASKED, ONDANSETRON ORALLY DISINTEGRATING FILM

The present invention relates to an orally disintegrating film composition comprising ondansetron, magnesium oxide or magnesium hydroxide, and a film forming agent, an orally disintegrating film made thereof, and a method for preparing the orally disintegrating film.

Ondansetron is a 5-HT3 receptor antagonist clinically used to prevent nausea and vomiting. Ondansetron was approved by the FDA in 1991, the first of the 5-HT3 receptor antagonists for use in the prevention of nausea and vomiting. This medicine is frequently prescribed as it ranks 6^thamongthemedicinesprescribedtopregnantwomenintheU.S.A.(2.78%in2004-2008)(JULY2011AmericanJournalofObstetrics&Gynecology,AllenAetal.),andaccountsfor99%of5-HT3receptorantagonistsfoundintheprescriptionsissuedintheU.S.A.(FDADrugUseReview2012).

Although various 5-HT3 antagonists including granisetron, dolasetron, palonosetron, tropisetron, and azasetron have been marketed, none of the 5-HT3 receptor antagonists are comparable to ondansetron in use diversity for preventing nausea and vomiting. These 5-HT3 receptor antagonist medicines are mainly used to prevent nausea vomiting caused by anticancer therapy and are generally administered as injections in hospitals whereas ondansetron can find wider applications in the prevention of general vomiting, such as post-operative vomiting, nausea due to the emesis gravidrum of pregnant women, etc. Accordingly, ondansetron needs to be formulated into oral dosage forms in addition to injections.

Among oral dosage forms are various orally soluble agents including tablets, chewable tablets, sublingual tablets, capsules, liquids, etc. Of them, general tablets or capsules may be problematic for patients who experience dysphagia (difficulty in swallowing) and liquids are poor in stability and difficult to accurately weigh. Accordingly, there is a need for novel formulations that are easy to ingest.

Recent extensive research has allowed formulations having novel drug delivery systems to appear in the market. One of the research results is an orally disintegrating tablet (ODT), which is designed to dissolve solid ingredients in the oral cavity. However, most of conventional ODTs are problematic in that not all of the ingredients are disintegrated, and water should be taken in many cases. Also, many ODTs comprising ondansetron have entered the market, but are inconvenient to carry along with the patients due to their large thicknesses, and are apt to be broken within the hand because of their low strength.

Newly suggested to solve the problems have been orally disintegrating film formulations in recent years. Over conventional solid formuations, liquids, and ODTs, the orally disintegrating films have some advantages. Able to be taken without water, orally disintegrating film formulations are advantageous for patients who experience difficulty in swallowing tablets or capsules, such as the elderly, children, the disabled, patients who must lie in their beds, and contemporary persons who are busy. Orally disintegrating film formulations are evaluated as further advanced forms than any other conventional formulations. Since drugs avoid hepatic first-pass upon absorption through the oral mucous membrane, orally disintegrating films have advantages that are applicable to drugs absorbed through the digestive duct, inter alia, drugs that are severely metabolized in the liver. Extensive attempts have been made to prepare orally disintegrating film formulations designed to improve film properties and drug compliance.

An orally disintegrating film formulation has a medication impregnated onto a film, and is convenient to carry along with the user. Since the user expects to carry many films in his or her wallet, the orally disintegrating film must be highly durable enough to endure friction and must be thin and light so as to provide convenience for carrying. Such properties of the orally disintegrating film limit the kind or weight of the additives available for preparing the films. Accordingly, it is very difficult to select additives that have no influences on the flexibility and durability of the film.

Thanks to the high solubility in water, ondansetron hydrochloride can guarantee content uniformity even by a simple process if water is used as a solvent to dissolve the drug. However, ondansetron hydrochloride tastes very bitter, and remains bitter for a long time in the mouth. Various studies have been thus directed toward masking the bitter taste of ondansetron hydrochloride.

WO 2001/070194 discloses the preparation of a fast dissolving orally consumable film containing an ion exchange resin to which an active ingredient is adsorbed. However, the ion exchange resin contained in a water soluble polymer scratches the film, lowering the marketability of the product, and makes the production process complicated, lowering the productivity.

In WO 2003/070227, a carbon dioxide-forming agent, such as sodium hydrogen carbonate, is used as a taste masking agent. However, sodium hydrogen carbonate cannot sufficiently mask the intensely bitter taste.

In US 2008/0044454, active components are coated using various coating techniques, and mixed with a film-forming agent to prepare a film throughout which the active components are uniformly dispersed as taste-masked coated particles. However, the coating process of the active components adds complexity to the preparation of the film.

Nowhere are orally disintegrating film formulations, which effectively mask the bitter taste of ondansteron and exhibit high marketability and productivity without negative influences on the properties of a film, known. Therefore, there is a need for developing such a formulation.

[Patent Document]

WO 2001/70194

US 2008/0044454

WO 2003/070227

Leading to the present invention, intensive and thorough research into an ondansetron orally disintegrating film formulation resulted in the finding that a proper alkalifying agent is useful for masking the bitter taste of ondansetron and for guaranteeing the film to exhibit superior properties, thus allowing for the production of highly marketable orally disintegrating films.

It is therefore an object of the present invention to provide an orally disintegrating film composition comprising ondansetron, magnesium oxide or magnesium hydroxide, and a film-forming agent, an orally disintegrating film prepared from the same, and a preparation method of the orally disintegrating film.

In order to accomplish the above object, the present invention provides an orally disintegrating film composition, comprising ondansetron or a pharmaceutically acceptable salt thereof, magnesium oxide or magnesium hydroxide, and a film-forming agent.

Also, the present invention provides an orally disintegrating film, comprising ondansetron or a pharmaceutically acceptable salt thereof, magnesium oxide or magnesium hydroxide, and a film-forming agent.

In addition, the present invention provides a method for preparing an orally disintegrating film, comprising: 1) mixing ondansetron or a pharmaceutically acceptable salt thereof, and magnesium oxide or magnesium hydroxide by stirring; 2) adding a film-forming agent to the mixture, followed by stirring, to give a film-forming liquid; and 3) drying the film-forming liquid.

Able to be prepared without using a complicated process, the ondansetron orally disintegrating film according to the present invention enjoys the advantage of process simplification. In addition, the ondansetron orally disintegrating film is provided with suitable physical properties, and effectively masks the bitter taste of ondansetron.

FIG. 1 shows images of orally disintegrating films containing magnesium oxide (Example 3) or magnesium hydroxide (Example 6), elucidating physical properties of the films.

FIG. 2 shows images of orally disintegrating film-forming liquids containing sodium hydroxide (Comparative Example 2) and an orally disintegrating film prepared therefrom, elucidating physical properties of the liquid and the film.

FIG. 3 shows images of orally disintegrating film-forming liquids containing sodium hydrogen carbonate (Comparative Examples 5 and 13) and orally disintegrating films prepared therefrom, elucidating physical properties of the liquids and the films.

In accordance with an aspect thereof, the present invention addresses an orally disintegrating film composition comprising ondansetron or a pharmaceutically acceptable salt thereof, magnesium oxide or magnesium hydroxide, and a film-forming agent.

The orally disintegrating film according to the present invention has a process advantage because it can be prepared without using an additional complicated process. Further, the ondansetron orally disintegrating film is provided with suitable physical properties while the bitter taste of ondansetron is effectively masked in the film.

As used herein, the term “orally disintegrating film composition” refers to a mixture comprising ingredients used to prepare an ondansetron orally disintegrating film, and may comprise any form of mixtures before a drying process for making an orally disintegrating film, without limitations.

Ondansetron, used in the present invention, is represented by the following Chemical Formula termed the IUPAC name (±)1,2,3,9-tetrahydro-9-methyl-3-[2-methyl-1h-imidazol-1-yl)methyl]-4h-carbazol-4-one, functioning as a selective 5-HT3 receptor antagonist.

For use in the present invention, ondansetron or a pharmaceutically acceptable salt thereof may be in any form of salt prepared from non-toxic, pharmaceutically acceptable acids or bases comprising organic or inorganic acids or bases. Preferably, ondansetron or a pharmaceutically acceptable salt thereof may be ondansetron hydrochloride or ondansetron hydrate, and most preferably ondansetron hydrochloride dihydrate.

Ondansetron hydrochloride may be administered to patients without irritation or causing side effects. Ondansetron hydrochloride dihydrate contains two water molecules bound within an ondansetron hydrochloride crystalline grid.

Ondansetron is a material that gives an intensely bitter taste in the mouth. To mask the bitter taste, an alkalifying agent may be used. However, alkalifying agents that can effectively mask the bitter taste of ondansetron without causing negative influences on the physical properties of orally disintegrating film are limited. Particularly when an alkalifying agent is used in a large amount, the physical properties of the polymer serving as a film-forming agent are affected. Therefore, further limited is an alkalifying agent that can effectively mask the bitter taste of ondansetron and can allow for the easy formation of the film even when it is used in a trace amount.

Accordingly, the present invention provides an orally disintegrating film composition comprising magnesium oxide or magnesium hydroxide as an alkalifying agent.

Even when contained in a trace amount in the orally disintegrating film composition, magnesium oxide or magnesium hydroxide can effectively mask the bitter taste of ondansetron. A trace amount of magnesium oxide or magnesium hydroxide has little influence on the physical properties of the film as well as the film-forming liquid. In the presence of a trace amount of magnesium oxide or magnesium hydroxide, the film-forming liquid is free of bubbles and layer separation at an upper portion, and does not allow for the appearance of coarse particles, scratches, discoloration, wave patterns, and brittleness upon film formation. In addition, the film prepared from the ondansetron film composition comprising magnesium oxide or magnesium hydroxide can maintain superior flexibility and durability.

Magnesium oxide or magnesium hydroxide may be used in an amount of 0.01 to 5.0 weight %, based on the total weight of the solid content of the orally disintegrating film composition, preferably in an amount of 0.1 to 3.0, more preferably in an amount of 0.2 to 3.0 weight %, and more preferably in an amount of 0.5 to 2.5 weight %.

Ondansetron or a pharmaceutically acceptable salt thereof may be used in an amount of 1.0 to 75 weight %, based on the total weight of the solid content of the orally disintegrating film composition, preferably in an amount of 5.0 to 20 weight %, and more preferably in an amount of 5.0 to 15 weight %. When formulated into a film, ondansetron or a pharmaceutically acceptable salt thereof may be contained in an amount of 1.0 to 25.0 weight % based on the total weight of the film.

As used herein, the term “film-forming agent” refers to a water-soluble polymer allowing for the formation of an ondansetron orally disintegrating film, and the water-soluble polymer may be at least one selected from the group consisting of pullulan, gelatin, pectin, low-viscosity pectin, hydroxypropylmethylcellulose, low-viscosity hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, polyvinylalcohol, polyacrylic acid, a methylmethacrylate copolymer, a carboxyvinyl polymer, polyethylene glycol, alginic acid, low-viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, a whey protein isolate, a soybean protein isolate, zein, levan, elsinan, gluten, acacia gum, carrageenan, Arabic gum, guar gum, locust bean gum, xanthan gum, gellan gum, and agar. In a more preferred embodiment, the film-forming agent may be a water-soluble polymer at least one selected from the group consisting of pullulan, gelatin, pectin, low-viscosity pectin, low-viscosity alginic acid, hydroxy propyl cellulose, and modified starch. Most preferably, the film-forming agent may be a water-soluble polymer consisting of pullulan alone or in combination with a trace amount of hydroxypropyl cellulose. In this regard, contents of pullulan and hydroxy propyl cellulose may range from 5.0 to 70.0 weight % and from 1.0 to 5.0 weight %, respectively, based on the total weight of the film.

The film-forming agent of the present invention may be contained in an amount of 5.0 to 75.0 weight % (w/w), based on the total weight of the orally disintegrating film, and preferably in an amount of 5.0 to 50 weight %.

The orally disintegrating film composition of the present invention may further include a sweetener to provide an orally disintegrating film with a taste more palatable to a consumer.

The sweetener may be a high-intensity sweetener at least one selected from the group consisting of sugar, glucose, maltose, oligosaccharide, galactose, starch syrup, sorbitol, maltitol, invert sugar, xylitol, erythritol, water-added starch syrup, mannitol, trehalose, aspartame, an acesulfame salt, sucralose, a saccharin salt, neotame, thaumatin, a thaumatin mixture, a cyclamate salt, thaumatin, a Siraitia grosvenori extract, a Glycyrrhiza extract, stevioside, enzyme-treated stevioside, neohesperidin and monellin, and preferably from the group consisting of aspartame, a thaumatin mixture, sucralose, neotame, and acesulfame.

The sweetener should not inhibit the formation of an orally disintegrating film, and may be contained in an amount of 0.1% to 10.0 weight %, based on the total weight of the film, and preferably in an amount of 0.1 to 8 weight %. In addition to the bitter taste-masking effect of the alkalifying agent, the sweetener may make the orally disintegrating film more palatable to a consumer.

Also, contemplated in accordance with another aspect of the present invention is an orally disintegrating film comprising ondansetron or a pharmaceutically acceptable salt thereof, magnesium oxide or magnesium hydroxide, and a film-forming agent.

The orally disintegrating film of the present invention may be prepared by drying, forming, aging and cutting the prepared orally disintegrating film composition. So long as it is typically used in the art, any process may be applied to the formation of the orally disintegrating film of the present invention.

The orally disintegrating film of the present invention, ondansetron or a pharmaceutically acceptable salt thereof may be contained in an amount of 1 to 50 weight % based on the total weight of the film, preferably in an amount of 1 to 30 weight %, and more preferably in an amount of 1 to 25 weight %.

The orally disintegrating film of the present invention may contain magnesium oxide or magnesium hydroxide in an amount of 0.01 to 5.0 weight %, based on the total weight thereof, preferably in an amount of 0.1 to 3.0 weight %, and more preferably in an amount of 0.2 to 3.0 weight %.

The orally disintegrating film of the present invention is characterized in that the bitter taste of ondansetron or a pharmaceutically acceptable salt thereof is masked.

In addition, the orally disintegrating film of the present invention may further comprise an additive, available for a typical orally disintegrating film, selected from among a filler, a plasticizer, an acidifier, a flavoring, a pigment, a mouth freshener, and a halitosis treating agent. The additives are exemplified as below.

Filler

The orally disintegrating film of the present invention may contain a filler. The filler functions to increase the density of the film and to maintain the morphology of the film, and also is used to control the decomposition rate of the film and the dissolution rate of the drug in the mouth by decreasing adhesion between films. The filler may be added in an amount of 0.5 ~ 10.0 weight % (w/w), based on the total weight of the orally disintegrating film. In one embodiment, the filler may be at least one selected form the group consisting of hydroxypropylcellulose, microcrystalline cellulose, a cellulose polymer, microcrystalline cellulose, carboxymethylcellulose sodium, magnesium carbonate, calcium carbonate, limestone powder, silicate, clay, talc, titanium dioxide, and calcium phosphate.

Plasticizer

The orally disintegrating film of the present invention may contain a plasticizer. The plasticizer can adjust the flexibility of the film, and may be added in an amount of 0.5 ~ 20.0 weight % (w/w), based on the total weight of the orally disintegrating film. The plasticizer may be at least one selected from the group consisting of glycerin fatty acid ester, sucrose fatty acid ester, lecithin, enzyme-treated lecithin, polysorbate, sorbitan fatty acid ester, sorbitol, maltitol, xylitol, glycerin, polyethylene glycol, propylene glycol, water-added starch syrup, starch syrup, glycerin, triacetin, glycerol oleate, fructose fatty acid ester, and a medium-chain fatty acid.

Acidifier

The orally disintegrating film of the present invention may further comprise an acidifier. The acidifier controls, together with the sweetener, the taste of the orally disintegrating film, and serves to stimulate the salivary glands to help the film dissolve well in the mouth. The acidifier may be contained in an amount of 0.5 ~ 10.0 weight % (w/w), based on the total weight of the orally disintegrating film, and may be at least one selected from the group consisting of citric acid, malic acid, fumaric acid, tartaric acid, ascorbic acid, succinic acid, adipic acid, and lactic acid.

Flavoring

The orally disintegrating film of the present invention may further comprise a flavor. The flavor may be a natural flavor, a synthetic flavor, or a mixture thereof. The natural flavor may be an extract obtained from leaves, flowers, and fruits of a plant, or a plant oil. Among the plant oil may be spearmint oil, cinnamon oil, peppermint oil, lemon oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, and almond oil. The synthetic flavor may mimic a flavor from fruits such as lemon, orange, grape, lime, strawberry, etc., and from other sources such as chocolate, coffee, cocoa, pine leaves, ginseng, red ginseng, citrus, etc. The content of the flavoring may vary depending on various factors including the flavoring’s form and type, and a desired degree of flavor. Typically, the flavoring may be contained in an amount of 0.1 to 10.0 weight % (w/w), based on the total weight of the orally disintegrating film. For an oily flavoring, an emulsifier may be used to increase miscibility with water-soluble materials. The content of the emulsifier may be adjusted depending on the type and amount of the flavoring, and typically ranges from 0.5 to 10 weight % (w/w), based on the total weight of the orally disintegrating film.

Pigment

The orally disintegrating film of the present invention may contain a pigment suitable for the product. As needed, a content of the pigment may be adjusted. Typically, a pigment may be added in an amount of 0.1 ~ 1.0 weight % (w/w), based on the total weight of the orally disintegrating film. The pigment may be natural or synthetic.

Mouth Freshener

The orally disintegrating film of the present invention may further contain a mouth freshener. The mouth freshener may be, for example, l-menthol, WS3, WS23, or Questice L. The content of the mouth freshener may be adjusted as needed, and may be 10.0 weight % (w/w) or less, based on the total weight of the orally disintegrating film.

Halitosis Treating Agent

The orally disintegrating film of the present invention may further contain a halitosis treating agent for reducing bad breath. The halitosis treating agent may be a metal salt. The metal salt may be at least one selected from the group consisting of metal salts of chlorite, copper gluconate, zinc chloride, zinc citrate, and zinc gluconate. In another embodiment, the halitosis treating agent may be at least one selected from the group consisting of triclosan, alexidine, hexetidine, benzalkonium chloride, salicylanilide, domiphen bromide, tetradecyl pyridium chloride, N-tetradecyl-4-ethylpyridinium chloride, octenidine, iodine, sulfonamide, bisbiguanide, phenols, delmopinol, octapinol, chlorhexidine, a nisin formulation, nystatin, sanguinarine, cetylpyridinium chloride, a red ginseng extract, a green tea extract, an algae extract, a herb extract, a grapefruit extract, an apple extract, thyme oil, thymol, an antibiotic, geraniol, carvacrol, citral, hinokitiol, eucalyptol, catechol, methyl salicylate, and hydrogen peroxide. This halitosis treating agent may be used alone or in combination with metal salt.

Preferably, the orally disintegrating film of the present invention may be very thin, with the maintenance of tensile strength and toughness in a suitable range. Accordingly, the orally disintegrating film formulation of the present invention ranges in thickness from 50 μm to 300 μm, preferably from 60 μm to 280 μm, and most preferably from 70 μm to 260 μm. The orally disintegrating film formulation of the present invention has a size of 0.5 cm to 10 cm, preferably 1 cm to 7 cm, and most preferably 1 cm to 5 cm.

A further aspect of the present invention provides a method for preparing an orally disintegrating film, comprising: 1) mixing ondansetron or a pharmaceutically acceptable salt thereof, and magnesium oxide or magnesium hydroxide by stirring; 2) adding a film-forming agent to the mixture, followed by stirring, to give a film-forming liquid; and 3) drying the film-forming liquid.

The method of the present invention may further comprise adding a sweetener to the film-forming liquid of step 2).

Without employing a complicated process, the method of the present invention can prepare an orally disintegrating film that retains excellent film properties while the bitter taste of ondansetron or a pharmaceutically acceptable salt thereof is effectively masked.

The term “film-forming liquid”, as used herein, is intended to a solution comprising the ingredients that are mixed and stirred in the processes used to prepare the orally disintegrating film.

In the preparation method of the present invention, stirring, film-forming liquid preparing, and drying processes, other than the process of adding and mixing magnesium oxide or magnesium hydroxide, may be carried out by using those known in the art.

Briefly, the method for preparing an orally disintegrating film in accordance with the present invention may be consisting of (1) a film-forming liquid preparing process (2) a film forming process (3) an aging process (4) a slitting and cutting process, and (5) a packaging process, but is not limited thereto.

The five processes are elucidated as below.

(1) Film-forming liquid preparing process: An active ingredient was homogeneously stirred, together with an alkalifying agent, a sweetener, a plasticizer, a surfactant, a flavoring, a colorant, a water-soluble polymer, a film-forming agent and etc. in a solvent to give a liquid for forming an orally disintegrating film. The solvent may be at least one selected from sterile distilled water and distilled water. As the active ingredient, ondansetron hydrochloride may be contained in an amount of 1 to 50 weight % of the total weight of the final product. As the alkalifying agent, magnesium oxide or magnesium hydroxide may be used in an amount of 0.01 to 5.0 weight % of the total amount of the final product. The sweetener, at least one selected from aspartame, thaumatin mixture, sucralose, neotame and acesulfame, may be used in an amount of 1.0~5.0 weight % of the total weight of the final product. Either or both of polyethylene glycol and glycerin may be used as the plasticizer in an amount of 3.0 ~ 20.0 weight % of the total weight of the final product. As the surfactant, polysorbate may be used in an amount of 1.0~5.0 weight % of the total weight of the final product. The film-forming agent, at least one selected from pullulan and hydroxypropylcellulose, may be used in an amount of 20.0%~60.0.weight % of the total weight of the final product. Other additives such as talc, titanium oxide, sodium chloride, etc. may be used in an amount of 1%~30 weight % of the total weight of the final product. The film-forming liquid thus obtained is subjected to the next process, film forming process.

(2) Film forming process: In a molding machine, the film-forming liquid is applied at a uniform thickness to a PET film, and then heated to obtain film. The final film is produced as a roll of the PET film coated with an orally disintegrating film. The thickness of the orally disintegrating film may be adjusted into 50 μm to 300 μm. In the molding machine, the drying temperature may be set to be 15 to 150°C, preferably 25 to 120°C, and more preferably 40 to 100°C.

(3) Aging process: The film may be, if necessary, aged at a relative humidity of 30 to 90% for 1 to 30 days. The aged film contains moisture suitable for slitting and cutting. In this regard, a water content of 20 % or less is preferred to carry out the next process.

(4) Slitting-cutting process: The aged film roll is slit into many small rolls. A slit width of 1 cm ~ 4 cm is proper. The slit rolls are cut into a suitable size, such as 1 cm ~ 4 cm, while the PET film is removed. The cut films are charged into a small container or an aluminum wrapper. Preferably, a sheet of the film has an area of 400 mm²to900mm².

(5) Packaging process: The small container or aluminum wrapper containing the films is packaged in a small box or the films are packaged in a blister to give products.

In accordance with still another aspect thereof, the present invention addresses a method for preventing or treating vomiting, using an orally disintegrating film prepared from an orally disintegrating film composition comprising ondansetron or a pharmaceutically acceptable salt thereof, magnesium oxide or magnesium hydroxide, and a film-forming agent.

Examples of the vomiting include, but are not limited to, those induced by anticancer agents, radiotherapy, narcotic analgesics, pregnancy, vestibule dysfunction, migraine, surgery, gastrointestinal obstruction, visceral pain, gastroesophageal reflux disease, heartburn, overeating, and dyspepsia.

The orally disintegrating film may be administered to a subject at a dose effective for preventing or treating vomiting.

In accordance with a still further object thereof, the present invention addresses the use of an orally disintegrating film composition comprising ondansetron or a pharmaceutically acceptable salt thereof, magnesium oxide or magnesium hydroxide, and a film-forming agent in preparing an orally disintegrating film for the prevention or treatment of vomiting.

In accordance with yet another object thereof, the present invention addresses the use of an orally disintegrating film prepared by drying orally disintegrating film composition comprising ondansetron or a pharmaceutically acceptable salt thereof, magnesium oxide or magnesium hydroxide, and a film-forming agent for the prevention or treatment of vomiting.

When the orally disintegrating film is prepared, available additives including a filler, a plasticizer, an acidifier, an favoring, a pigment, a mouth freshener, a halitosis treating agent, etc. may be further used.

Unless specified, the numerical values given in the specification should be understood to include their equivalent ranges.

A better understanding of the present invention may be obtained through the following examples that are set forth to illustrate, but are not to be construed as limiting the present invention.

EXAMPLES 1 TO 3: Preparation of Magnesium Oxide (MgO)-Containing Orally Disintegrating Film

Orally disintegrating films were prepared from compositions in which ondansetron hydrochloride dihydrate and other ingredients were constantly maintained in content percentage while the content of magnesium oxide varied from 0.31 to 1.25 weight %. Contents of the ingredients for orally disintegrating films are listed in Table 1, below.

[TABLE 1]

The preparation method of an ondansetron orally disintegrating film is described with the composition of Example 3 as below. First, 190 g of pure water was added with 1.2 g of magnesium oxide while being stirred at 400 rpm. After magnesium oxide was completely dispersed, the dispersion was stirred at 600 rpm for 30 min or longer during which 10 g of ondansetron hydrochloride was added and dispersed, followed by 6 g of hydroxypropylcellulose. When the hydroxypropylcellulose was completely dissolved, 5 g of polyethylene glycol 400, 3 g of polysorbate 20, and 3 g of glycerin were added to obtain a film-forming liquid. In a separate stainless container, 3 g of titanium oxide was pulverized along with 50 g of pure water, and then added to the film-forming liquid. As listed in Table 1, sucralose, sodium chloride, pullulan talc and etc. were added to the resulting film-forming liquid that was then stirred for 2 hrs/12 hrs. This stirred liquid was applied to a PET film using a film coater. The coated film was dried to remove water so that each film weighed 100 to 105 mg. Through the processes, approximately 1,000 sheets of the orally disintegrating film could be prepared, and the output can be scaled up by adjusting amounts of the ingredients.

.EXAMPLES 4 TO 6: Preparation of Magnesium Hydroxide-Containing Orally Disintegrating Film

Orally disintegrating films were prepared in the same manner as in Example 3, with the exception that magnesium hydroxide, instead of magnesium oxide, was used in respective amounts of 0.31, 0.625, and 1.25 weight %, based on the total weight of the solid content, for Examples 4 to 6. Concrete compositions are listed in Table 2, below.

[TABLE 2]

COMPARATIVE EXAMPLES 1 TO 3: Preparation of Orally Disintegrating Film

For use in comparison with magnesium oxide- or magnesium hydroxide-containing orally disintegrating films, an alkalifying agent-free orally disintegrating film (Comparative Example 1), and orally disintegrating films containing the strong alkalifying agents KOH (Comparative Example 2) and NaOH (Comparative Example 3) were prepared.

Compositions of the orally disintegrating films of Comparative Examples 1 to 3 are summarized in Table 3, below, and films were prepared in a similar manner to that of Example 3.

[TABLE 3]

COMAPRATIVE EXAMPLES 4 TO 11: Preparation of Orally Disintegrating Film

For use in comparison with magnesium oxide- or magnesium hydroxide-containing orally disintegrating films, orally disintegrating films were prepared in the same manner as in Example 3, with the exception that the weak alkalifying agents Na₂CO₃,MgCO₃,Na₂CO₃,NaHCO₃,K₂CO₃,KHCO₃,MgCO₃,NaH₂PO₄,KH₂PO₄,andCaCO₃wereused,insteadofmagnesiumoxideormagnesiumhydroxide. Compositions of the film formulations are listed in Table 4, below. In Comparative Examples 4 to 11, the weak alkalifying agents were used in an amount of as high as 13.13 weight % to obtain a bitter taste-masked effect.

[TABLE 4]

COMPRATIVE EXAMPLES 12 TO 19: Preparation of Orally Disintegrating Film

For use in comparison with magnesium oxide- or magnesium hydroxide-containing orally disintegrating films, orally disintegrating films were prepared in the same manner as in Example 3, with the exception that weak alkalifying agents, instead of magnesium oxide or magnesium hydroxide, were used in the same amount, that is, 1.25 weight %. Compositions of the orally disintegrating films are listed in Table 5, below.

[TABLE 5]

EXPERIMENTAL EXAMPLE 1: Comparison of Examples 1 to 6 and Comparative Example 1

The magnesium oxide- or magnesium hydroxide-containing orally disintegrating films of Examples 1 to 6 were compared to the alkalifying agent-free orally disintegrating film of Comparative Example 1 with regard to physical properties of film-forming liquid and film, folding endurance, and masking effect on the bitter taste of ondansetron.

Physical properties of film-forming liquid were regarded good when neither bubbles nor layer separation at an upper portion appeared. Physical properties of films were totally evaluated by observing the generation of large and coarse particles, scratches, discoloration, brittleness and wave patterns on the surface with the naked eye.

Also, physical properties of films were evaluated with regard to flexibility and durability such as folding endurance by a bending test. The bending test was conducted at 28°C and 30% RH 30 min after the packaged orally disintegrating films were opened. A film was repetitively folded into a half with two fingers and the number of times the film was folded was measured until the film was destroyed. When the number of bends was 10 or higher, it was recorded as 10. Larger numbers were evaluated to indicate the film had better flexibility and endurance.

The degree of masking the bitter taste of ondansetron containined in the film formulations of Examples 1 to 6 and Comparative Example 1 were scored as follows.

5: not tasted bitter at all.

4: insipid

3: bitter taste recognized

2: tasted a little bitter

1: tasted bitter

0: tasted intensely bitter

Test results of physical properties of film-forming liquid and film, film endurance (bending test), and bitter taste-masking degree are summarized in Table 6, and depicted in FIG. 1.

[TABLE 6]

As is apparent from data of Table 6 and FIG. 1, Examples 1 to 6 containing magnesium oxide or magnesium hydroxide were good in physical properties of both film-forming liquids and films, and exhibited excellent film endurance, flexibility, and degrees of bitter taste masking. In contrast, Comparative Example 1 lacking an alkalifying agent completely failed in masking the bitter taste of ondansetron as evaluated to be zero for the degree of bitter taste masking.

Therefore, magnesium oxide or magnesium hydroxide, used in Examples 1 to 6, was found to effectively achieve the bitter taste masking effect without affecting film properties.

EXPERIMENTAL EXAMPLE 2. Comparison of Examples 3, 6 and Comparative Examples 2, 3

Examination was made to see whether alkalifying agents, other than sodium hydroxide and magnesium oxide, could obtain the same effects. In this regard, the orally disintegrating films comprising the strong alkalifying agents sodium hydroxide and potassium hydroxide of Comparative Examples 2 and 3 were tested for physical properties, folding endurance, and bitter taste masking effect in the same manner as in Test Example 1.

The results are shown in Table 7 and FIG. 2.

[TABLE 7]

As can be seen in Table 7 and FIG. 2, Examples 3 and 6 using magnesium oxide and magnesium hydroxide, respectively, were good in physical properties of both film-forming liquids and films, and exhibited excellent film endurance, flexibility, and degrees of bitter taste masking. In contrast, the film-forming liquids of Comparative Examples 2 and 3 that used the strong alkalifying agents NaOH and KOH, respectively, were found to be unsuitable for mass film production because they did not flow, but became solidified. In addition, the liquids were unsuitable for use in forming films because they allowed for the generation of many bubbles and non-uniform particles. Even though prepared from the liquids, the films were observed to have many bubbles, coarse particles, and scratches on the surface thereof, and became brittle. Particularly, films of Comparative Examples 2 and 3 were very poor in flexibility as they were broken when bent once or more in the bending test. That is, the strong alkalifying agents, although expected to bring about a bitter taste masking effect, negatively affected physical properties of the polymer used as the film-forming agent, causing the film to be brittle and poor in flexibility. Further, the strong alkalifying agents raised a problem from the film-forming liquid preparing process, thus being unsuitable for use in preparing an orally disintegrating film.

From the data, it is understood that not all alkalifying agents can mask bitter tastes without affecting film properties, but magnesium oxide and magnesium hydroxide are the only materials that can effectively mask the bitter taste of ondanetron without negatively affecting ondansetron orally disintegrating films.

EXPERIMENTAL EXAMPLE 3: Comparison of Examples 3, 6 and Comparative Examples 4 to 11

Examination was made to see whether various weak alkalifying agents, other than sodium hydroxide and magnesium oxide, could obtain the same effects. In this regard, the orally disintegrating films comprising the compositions of Comparative Examples 4 to 11 were tested for physical property, folding endurance, and bitter taste masking effect in the same manner as in Test Example 1.

The results are shown in Table 7 and FIG. 3.

[TABLE 8]

As can be seen in Table 8 and FIG. 3, Examples 3 and 6 using magnesium oxide and magnesium hydroxide, respectively, were good in physical properties of both film-forming liquids and films, and exhibited excellent film endurance, flexibility, and degrees of bitter taste masking. In contrast, the film-forming liquids of Comparative Examples 4 to 11 that used weak alkalifying agents exhibited poor physical properties of both film-forming liquids and films although achieving a masking effect of bitter taste.

That is, an excess of weak alkalifying agents as in Comparative Examples 4 to 11, although expected to bring about a bitter taste masking effect, negatively affected physical properties of the polymer used as the film-forming agent, causing the films to be brittle and poor in flexibility. Further, the weak alkalifying agents raised a problem from the film-forming liquid preparing process, thus being unsuitable for use in preparing an orally disintegrating film.

EXPERIMENTAL EXAMPLE 4: Comparison of Examples 3, 6 and Comparative Examples 12 to 19

Orally disintegrating film compositions of Comparative Examples 4 to 11 in Test Example 3 contained weak alkalifying agents in an excessive amount, that is, 13.13 wt. % so as to mask the bitter taste of ondansetron. Thus, examination was made to see whether the same effect of bitter taste masking and film properties could be obtained when the weak alkalifying agents were used in the same amounts as in Examples 3 and 6. To this end, compositions of Comparative Examples 12 to 19 in which each of the weak alkalifying agents was used in an amount of 1.25% were tested for physical properties, folding endurance, and bitter taste masking effect in the same manner as in Test Example 1.

The results are shown in Table 9 and FIG. 3.

[TABLE 9]

As can be seen in Table 9 and FIG. 3, all of the compositions of Comparative Examples 12 to 19 in which the weak alkalifying agents were used in the same amount as in Examples 3 and 6 failed in masking the bitter taste of ondansetron. Although showing good bending test results, the compositions of Comparative Examples 12 to 19 in which the weak alkalifying agents had insufficient physical properties of film-forming liquids and films for producing marketable orally disintegrating film formulations.

Of various alkalifying agents, as described above, magnesium oxide or sodium hydroxide, when used in preparing ondansetron orally disintegrating films, is effective in masking the bitter taste of ondansetron and guarantees proper physical properties of the orally disintegrating film.

Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.

Claims

An orally disintegrating film composition comprising:

ondansetron or a pharmaceutically acceptable salt thereof;

magnesium oxide or magnesium hydroxide; and a film-forming agent.
The orally disintegrating film composition of claim 1, wherein the ondansetron is ondansetron hydrochloride.
The orally disintegrating film composition of claim 1, wherein the ondansetron is an ondansetron hydrate.
The orally disintegrating film composition of claim 3, wherein the ondansetron hydrate is ondansetron hydrochloride dihydrate.
The orally disintegrating film composition of any one of claims 1 to 4, further comprising a sweetener.
The orally disintegrating film composition of claim 5, wherein the sweetener is at least one selected from the group consisting of sugar, glucose, maltose, oligosaccharide, galactose, starch syrup, sorbitol, maltitol, invert sugar, xylitol, erythritol, water-added starch syrup, mannitol, trehalose, aspartame, an acesulfame salt, sucralose, a saccharin salt, neotame, thaumatin, a thaumatin mixture, a cyclamate salt, a Siraitia grosvenori extract, a Glycyrrhiza inflata extract, stevioside, enzyme-treated stevioside, neohesperidin and monellin.
An orally disintegrating film, comprising:

ondansetron or a pharmaceutically acceptable salt thereof;

magnesium oxide or magnesium hydroxide; and a film-forming agent.
The orally disintegrating film of claim 7, wherein the ondansetron or a pharmaceutically acceptable salt thereof is contained in an amount of 1 to 25 weight %, based on a total weight of the film.
The orally disintegrating film of claim 7, wherein the magnesium oxide or the magnesium hydroxide is contained in an amount of 0.2 to 3.0 weight %, based on a total weight of the film.
The orally disintegrating film of claim 7, wherein the film-forming agent is at least one selected from the group consisting of pullulan, gelatin, pectin, low-viscosity pectin, hydroxypropylmethylcellulose, low-viscosity hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, polyvinylalcohol, polyacrylic acid, a methylmethacrylate copolymer, a carboxyvinyl polymer, polyethylene glycol, alginic acid, low-viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, a whey protein isolate, a soybean protein isolate, zein, levan, elsinan, gluten, acacia gum, carrageenan, Arabic gum, guar gum, locust bean gum, xanthan gum, gellan gum, and agar.
The orally disintegrating film of any one of claims 7 to 10, wherein a bitter taste of the ondansetron or the pharmaceutically acceptable salt thereof is masked.
A method for preparing an orally disintegrating film, comprising:

1) mixing ondansetron or a pharmaceutically acceptable salt thereof, and magnesium oxide or magnesium hydroxide by stirring;

2) adding a film-forming agent to the mixture, followed by stirring, to give a film-forming liquid; and

3) drying the film-forming liquid.
The method of claim 12, further comprising adding a sweetener to the film-forming liquid of step 2).