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    • 专利摘要:
    SUBLINGUAL AND MOUTH COMPOSITIONS IN MOVIE. The present invention relates to products and methods for treating narcotic addiction in a user. The invention, more particularly, relates to self-sustained dosage forms which provide an active agent to treat narcotic addiction while providing narcotic adherence while providing sufficient oral adherence to the dosage form.
    公开号:BR112012002817B1
    申请号:R112012002817-0
    申请日:2010-08-05
    公开日:2020-12-01
    发明作者:Garry L. Myers；Samuel D. Hilbert；Bill J. Boone；B. Arlie Bogue；Pradeep Sanghvi；Madhusudan Hariharan
    申请人:Indivior Uk Limite；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    The present invention relates to compositions, methods of manufacture, products and methods of use relating to films containing therapeutic active ingredients. More particularly, the invention relates to self-supporting film dosage forms that provide a therapeutically effective dosage, essentially corresponding to dosages of currently marketed tablets containing the same active substance. Such compositions are particularly useful for the treatment of narcotic addiction, providing sufficient adhesion to the oral dosage form. FIELD OF THE INVENTION
    The oral administration of two therapeutic active ingredients in a single dosage form can be complex if the intention is to have one asset absorbed by the body while the other asset remains substantially unabsorbed. For example, one active can be relatively soluble in the mouth, at a certain pH, and the other active can be relatively insoluble at the same pH. In addition, the absorption kinetics of each therapeutic agent can be substantially different due to the different absorption of charged and unloaded species. These factors represent some of the challenges of adequate co-administration of therapeutic agents.
    Co-administration of therapeutic agents has many applications. These areas of treatment include individuals who need treatment for narcotic addiction. Such individuals have a tendency to suffer from severe physical dependence on said narcotic, resulting in potentially dangerous withdrawal effects when the narcotic is not administered to the individual. In order to help people addicted to drugs, this type of treatment is known to provide a reduced level of a drug, which provides an effect to satisfy the body's drive for the narcotic, but does not provide the "high" concentration that is provided for the misuse of the narcotic. The drug can be supplied as an agonist or a partial agonist, which provides a reduced sensation and can help to decrease dependence on the drug. However, even if these drugs provide only a low level of euphoric effect, they will be able to incite individuals to use them. In such cases, it is desirable to provide a combination of the drug with a second drug, which can decrease the likelihood of drug diversion and abuse alone. For example, it is known that it is possible to provide a dosage of an antagonist in combination with an agonist or partial agonist. The narcotic antagonist binds to a receptor in the brain to block the receptor, thereby reducing the effect of the agonist.
    Such a combination of drugs has been marketed under the trade name Suboxone® and corresponds to an orally ingestible tablet. However, such tablet combinations have the potential for abuse. In some cases, the patient who has taken the drug may store the tablet in his mouth without swallowing the tablet, and then extract the agonist from the tablet and inject the drug into an individual's body. Although certain antagonists (such as highly water-soluble antagonists) can be used to help reduce the ability to separate the agonist, the potential for abuse continues to exist. It is desired to provide a dosage that cannot be easily removed from the mouth once it has been administered.
    There is currently a need for a dosage form orally dissolved in film that provides the desired levels of absorption of the agonist and antagonist, while providing an adhesive effect in the mouth, making it difficult to remove once placed in the mouth, thus making it difficult to abuse the agonist. SUMMARY OF THE INVENTION
    In an embodiment of the present invention, a film dosage composition is provided including: a polymeric carrier matrix; a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of naloxone or a pharmaceutically acceptable salt thereof, and a buffer in an amount that provides a pH of the composition in a sufficient amount to optimize the absorption of buprenorphine.
    In another embodiment of the present invention, a film dosage composition is provided including: a polymeric carrier matrix; a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of naloxone or a pharmaceutically acceptable salt thereof, and a buffer in an amount sufficient to inhibit the absorption of naloxone, when administered orally.
    In yet other embodiments, a film dosage composition may be provided including: a polymeric carrier matrix; a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of naloxone or a pharmaceutically acceptable salt thereof and a buffer system; where the
    Buffering system includes a buffer with sufficient capacity to maintain naloxone ionization, as long as the composition is in a user's oral cavity.
    In another embodiment of the invention, a method of treating a user's narcotic addiction is provided, including the steps of: providing a composition including: a polymeric carrier matrix; a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of naloxone or a pharmaceutically acceptable salt thereof and a buffer in an amount to provide a pH of the composition of a value sufficient to optimize the absorption of "buprenorphine; and the administration of the composition in a user's oral cavity.
    In yet another embodiment of the invention, a process for forming a film dosage composition is provided including the steps of: casting a film forming composition, the film forming composition, including: a polymeric carrier matrix; a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of naloxone or a pharmaceutically acceptable salt thereof and a buffer in an amount to provide a pH of the composition of a value sufficient to optimize the absorption of buprenorphine and drying the film-forming composition to form a self-dosing film composition supported.
    In another embodiment, there is provided a film dosage composition including a therapeutically sufficient amount of buprenorphine or a pharmaceutically acceptable salt thereof and a therapeutically sufficient amount of naloxone or a pharmaceutically acceptable salt thereof, the film dosage composition having a profile of release, in bioequivalent comparison with a Suboxone® tablet containing about 2 times the amount of buprenorphine or a pharmaceutically acceptable salt thereof.
    Still other embodiments of the present invention provide an oral dissolution film formulation including buprenorphine and naloxone, wherein the formulation provides a plasma profile in vivo having a Cmax of between about 0.624 ng / ml and about 5.638 ng / ml for buprenorphine and an in vivo plasma profile with a Cmax of between about 41.04 pg / ml to about 323.75 pg / ml for naloxone. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Definitions
    As used herein, the term Cmax refers to a maximum mean plasma concentration after administration of the composition to a human subject. As also used herein, the term AUC refers to an average area under the plasma concentration value curve for time after administration of the compositions formed in this document. As will be defined in more detail below and below, the term "optimize absorption" does not refer to reaching the maximum absorption of the composition, and instead refers to reaching the optimal level of absorption at a pH of about 2 to about 4. "Optimal" absorption can be, for example, a level that provides bioequivalent absorption like administration of the currently available Suboxone ® tablet. An "optimum" Cmax of buprenorphine is from about 0.67 to about 5.36 mg / ml in dosages of from 2-16 mg of buprenorphine at a given pH. Likewise, a "great" buprenorphine AUC can be from about 7.43 to about 59.46 hr * ng / ml in doses of 2-16 mg of buprenorphine at a given pH. As will be described in more detail below, it has been surprisingly determined that the absorption of a specific agonist, buprenorphine, can provide optimal absorption at a pH of about 2 to 4, as well as about 5.5 to 6.5. Thus, one can "optimize" the absorption of buprenorphine, providing a pH of about 2 to 4 or about
    The term "maximizing absorption" refers to the maximum in in vivo absorption values carried out at a pH of about 4 to about 9.
    The term "local pH" refers to the pH of the region of the carrier matrix that immediately surrounds the active agent such as matrix hydrates and / or dissolves, for example, in the user's mouth.
    By "inhibiting" the absorption of an asset, it must be understood that it is intended to complete an active state of ionization as possible, in such a way that little to no asset is measurable absorbable. For example, at a pH of 3 to 3.5, the Cmax of an active, such as naloxone for the dosage from 0.5 mg to 4.0 mg, ranges from 32.5 to 260 pg / ml, and an AUC of naloxone for the dosage of 0.5 mg to 4.0 mg ranging from 90.55 to 724.4 hr * pg / ml. It is understood that at a pH below 3.0, even more ionization would be expected and therefore would result in less absorption.
    The term "bioequivalent" means obtaining 80% to 125% of the Cmax and AUC values for an asset given in a different product. For example, assuming the Cmax and AUC values of buprenorphine for a commercially available Suboxone® c tablet (containing 2 mg buprenorphine and 0.5 mg naloxone) are 0.780 ng / ml and 6, 789 hr * ng / ml, respectively, a bioequivalent product would have a buprenorphine Cmax in the range of 0.624 to 0.975 ng / ml, and a buprenorphine AUC value of 5.431 to 8.486 hr * ng / ml.
    It will be understood that the term "film" includes thin films and sheets, in any shape, including rectangular, square or other desired shape. The films described here can be of any desired thickness and of such size that it can be placed in the oral cavity of the user. For example, the films can be relatively thin in thickness from about 0.1 to about 10 mm, or they can be slightly thicker in thickness from about 10 to about 30 mm. For some films, the thickness may be even greater, that is, greater than about 30 mm. Films can be on a single layer or can be multi-layer, including laminated films.
    Oral dissolution films generally fall into three main classes: fast dissolving, moderate dissolving and slow dissolving. Rapidly dissolving films usually dissolve in about 1 second to about 30 seconds in the mouth. Moderately dissolving films generally dissolve in about 1 to about 30 minutes in the mouth, and slow dissolving films generally dissolve in more than 30 minutes in the mouth. Rapidly dissolving films can consist of hydrophilic low molecular weight polymers (i.e., polymers with a molecular weight between about 1,000 to 9,000, or polymers having a molecular weight of up to 200,000). In contrast, slow dissolving films generally have high molecular weight polymers (i.e., having a molecular weight in the order of millions).
    Moderately dissolving films tend to fall between fast and slow dissolving films. Moderately dissolving films dissolve quickly, but also have a good level of mucoadhesion. Moderately dissolving films are also flexible, quickly wettable and are typically non-irritating to the user. For the present invention, it is preferable to use films that fall between the categories of rapid dissolution and moderate dissolution. Such moderately dissolving films provide a sufficiently rapid dissolution rate, most desirably between about 1 minute and about 20 minutes, while providing an acceptable level of mucoadhesion such that the film is not easily removable once it is placed in the oral cavity of the user.
    Inventive films described herein can include one or more agonists or partial agonists used for the treatment of drug addiction. As used herein, the term "agonist" refers to a chemical that is capable of providing a physiological response or activity in the user's body. The films described herein may also include one or more antagonists. As used herein, the term "antagonist" refers to any chemical substance that acts within the user's body to reduce the physiological activity of another chemical substance. In some modalities, an antagonist used here can act to reduce and / or block the agonist's physiological activity. The active ingredients may be soluble in water, or they may be insoluble in water. As used herein, the term "water-soluble" refers to substances that are at least partially soluble in a solvent, including but not limited to water. The term "water-soluble" does not necessarily mean that the substance is 100% soluble in the solvent. The term "water-insoluble" refers to substances that are not soluble in a solvent, including but not limited to water. The solvents can include water, or, alternatively, they can include other polar solvents alone or in combination with water.
    Inventive Films
    The present invention relates to methods of treating narcotic addiction in an individual. Most desirably, the invention relates to the treatment of an individual's opioid addiction, using a formulation and delivery that makes it difficult to use the narcotic. Currently, the treatment of opiate addiction is aided by the administration of Suboxone®, which is an oral dissolvable tablet. This tablet that provides a combination of buprenorphine (an opioid agonist) and naloxone (an opioid antagonist). Therefore, the present invention provides a method of treating narcotic addiction, providing an oral dosage of soluble film, which provides a bioequivalent effect to Suboxone® tablets. Film dosing preferably provides oral adhesion while in the user's mouth, making it difficult to remove after placement.
    The film dosage composition preferably includes a polymeric carrier matrix. Any desired polymeric carrier matrix can be used, as long as it is orally dissolvable. Desirably, the dosage should have sufficient bioadhesion to not be easily removed and should form a structured gel when administered. The films are preferably consumable orally and with moderate dissolution in the oral cavity and are particularly suitable for the delivery of active agents, although compositions of quick and sustained release are also among the various modalities contemplated.
    The films used in pharmaceutical products can be produced by a combination of at least one polymer and a solvent, optionally including other fillers known in the art. The solvent can be water, a polar organic solvent, including, but not limited to, ethanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent may be a non-polar organic solvent, such as methylene chloride. The film can be prepared by using a selected casting or deposition method and a controlled drying process. For example, the film can be prepared through controlled drying processes, which includes the application of heat and / or radiation energy to the wet film matrix to form a visco-elastic structure, thereby controlling the uniformity of the content. of the movie. Such processes are described in more detail in US patent application No. 10 / 074,272, filed on February 14, 2002, and published as US No. 2003/0107149 Al, the content of which is incorporated herein by reference in its entirety. .
    Alternatively, films can be extruded, as described in more detail in US patent application No. 10 / 856,176, filed on May 28, 2004, and published as US No. 2005/0037055 Al, whose content is incorporated herein by reference in its entirety.
    The polymer included in the films can be water-soluble, water-swellable, water-insoluble or a combination of one or more polymers or water-soluble, water-swellable or water-insoluble. The polymer can include cellulose or a cellulose derivative. Specific examples of useful water-soluble polymers include, but are not limited to, polyethylene oxide, pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, gum xanthan , tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl copolymers, starch, gelatin and combinations thereof. Specific examples of useful water-insoluble polymers can include, but are not limited to, ethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate compounds, methyl hydroxypropyl cellulose and combinations thereof. For specific doses, a desirable polymer can be incorporated which provides a high level of mp viscosity compared to lower dosages.
    As used herein the term "water-soluble polymer" and its variants refer to a polymer that is at least partially soluble in water, and desirably wholly or predominantly soluble in water, or that absorbs water. Water-absorbing polymers are often referred to as water-swellable polymers. The materials useful for the present invention can be soluble in water or expandable by water at room temperature and other temperatures, such as temperatures above room temperature. In addition, the materials can be water-soluble or expandable by water at pressures below atmospheric pressure. Desirably, water-soluble polymers are water-soluble or water-expandable, having at least 20 weight percent water absorption. Water-expandable polymers having 25 percent or more water absorption by weight are also useful. In some embodiments, films formed from such water-soluble polymers may be sufficiently soluble in water to be soluble in contact with body fluids.
    Other polymers useful for incorporation in films include biodegradable polymers, copolymers, block polymers and combinations thereof. It is understood that the term "biodegradable" is intended to include materials that degrade chemically, as opposed to materials that physically break (ie, bioerodable materials). Among the known useful polymers, or classes of polymers, that meet the above criteria are: poly (glycolic acid) (PGA), poly (lactic acid) (PLA), polydioxanes and polyoxalates, poly (ct-esters), polyanhydrides, polyacetates and polycaprolactones, poly (orthoesters), polyamino acids, polyamino carbonates, polyurethanes, polycarbonates, polyamides, poly (alkyl cyanoacrylates) and mixtures and their copolymers. Additional useful polymers include, D- and L-lactic acid stereopolymers, bis (p-carboxyphenoxy) propane and sebacic acid copolymers, sebacic acid copolymers, caprolactone copolymers, poly (lactic acid) / poly (glycolic acid) / polyethylene glycol copolymers, polyurethane and (poly (lactic acid) copolymers, polyurethane and poly (lactic acid) copolymers, copolymers of a-amino acids, copolymers of amino acids and caprylic acid, copolymers of a-benzyl glutamate and polyethylene glycol, copolymers of succinate and poly (glycols), polyphosphazene, polyhydroxy-alkanoates and their mixtures Binary and ternary systems are contemplated.
    Other specific polymers useful include those marketed under the Medisorb and Biodel brands. Medisorb materials are marketed by the Dupont Company of Wilmington, Delaware, and are generically identified as a "lactide / glycolide copolymer" containing "propanoic acid, 2-hydroxy-polymer with hydroxy-polymer with hydroxyacetic acid." Four of such polymers include 100L lactide / glycolide, which is believed to be 100% lactide having a melting point within the range of 338 to 347 ° F (170 to 175 ° C); lactide / glycolide 100L, which is believed to be 100% glycolide having a melting point within the range of 437 to 455 ° F (225 to 235 ° C); lactide / glycolide 85/15, believed to be 85% lactide and 15% glycolide with a melting point within the range of 338 to 347 ° F (170 to 175 ° C), and lactide / glycolide 50/50 , which is believed to be a copolymer with 50% lactide and 50% glycolide with a melting point within the range of 338 to 347 ° F (170 to 175 ° C).
    Biodel materials represent a family of several polyanhydrides that differ chemically.
    Although a variety of different polymers can be used, it is desired to select the polymers that provide mucoadhesive properties to the film, as well as a desired dissolution and / or disintegration rate. In particular, the length of time for which it is desired to keep the film in contact with the mucosal tissue depends on the type of asset contained in the composition. Some assets may only require a few minutes for delivery through mucosal tissue, while other assets may require several hours or even longer. Therefore, in some embodiments, one or more water-soluble polymers, such as those described above, can be used to form the film. In other embodiments, however, it may be desirable to use combinations of water-soluble polymers and polymers that are water-expandable, water-insoluble and / or biodegradable, as provided above. The inclusion of one or more polymers that are water-expandable, water-insoluble and / or biodegradable can provide films with slower dissolution or slower disintegration rates than films formed from water-soluble polymers alone. As such, the film can adhere to mucosal tissue for longer periods of time, such as up to several hours, which may be desirable for the delivery of certain active components.
    Desirably, the individual film dosage has a small size, which is between about 0.5 to 1 cm by about 0.5 to 1 cm. Most preferably, the film dosage is about 0.75 inches by 0.5 inches. The film dosage should have good adherence when placed in the user's oral cavity or sublingual region. In addition, the film dosage should disperse and dissolve at a moderate rate, most desirably, dispersion within about 1 minute and dissolving within about 3 minutes. In some embodiments, film dosing may be capable of dispersion and dissolution, at a rate of between about 1 to about 1.5 minutes.
    For example, in some embodiments, the films may include polyethylene oxide alone or in combination with a second polymer component. The second polymer can be another water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer or any combination thereof. Suitable water-soluble pymers include, without limitation, any of the above. In some embodiments, the water-soluble polymer may include hydrophilic cellulosic polymers, such as hydroxypropyl cellulose and / or hydroxypropyl methyl cellulose. According to some embodiments, polyethylene oxide can vary from about 20% to 100% by weight, in the polymer component, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight. In some embodiments, one or more water-expandable, water-insoluble and / or biodegradable polymers can also be included in the film based on polyethylene oxide. Any of the water-expandable, water-insoluble or biodegradable polymers provided above can be used. The second polymer component can be employed in amounts of about 0% to about 80% by weight, in the polymer component, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight.
    The molecular weight of polyethylene oxide can also be varied. In some embodiments, high molecular weight polyethylene oxide, such as about 4 million, may be desired to increase mucoadhesion of the film. In some other embodiments, the molecular weight can vary from about 100,000 to 900,000, more specifically from about 100,000 to 600,000, and even more specifically from about 100,000 to 300,000. In some embodiments, it may be desirable to combine high molecular weight (600,000 to 900,000) with low molecular weight (100,000 to 300,000) of polyethylene oxide in the polymer component.
    A variety of optional components and fillers can also be added to the films. These can include, without limitation: surfactants; plasticizers; polyalcohols; silicone antifoaming agents, such as containing compounds, that promote a smoother surface of the film by releasing oxygen from the film; gel-defining agents such as pectin, carrageenan and gelatin, which help maintain the dispersion of components; inclusion compounds, such as cyclodextrins and caged molecules; coloring agents, and flavors. In some embodiments, more than one active component can be included in the film.
    Additives can be included in the films. Examples of additive classes include excipients, lubricants, buffering agents, stabilizers, blowing agents, pigments, coloring agents, fillers, thickening agents, sweetening agents, flavoring agents, fragrances, release modifiers, adjuvants, plasticizers, flow accelerators, agents release agents, polyols, granulating agents, diluents, binders, buffers and absorbents, glidants, adhesives, non-stick, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers and mixtures thereof. These additives can be added with the active ingredient.
    Useful additives include, for example, gelatin, vegetable proteins such as sunflower protein, soy protein, cotton seed protein, peanut protein, grape seed protein, whey protein, whey protein isolate whey, blood proteins, egg proteins, acrylated proteins, water-soluble polysaccharides such as alginates, carrageenans, guar gum, agar-agar, xanthan gum, gellan gum, arabic gum and related gums (ghatti gum, gum karaya, gum tragancanth), pectin, water soluble cellulose derivatives: hydroxyalkylcelluloses alkylcelluloses and hydroxyalkylalkylcelluloses and similar methylcelluloses, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose (CAP), hydroxypropylmethylcellulose (HPMC); carboxyalkylcelluloses, carboxyalkylalkylcelluloses, esters such as carboxyalkylcellulose carboxymethylcellulose and its alkali metal salts; synthetic water-soluble polymers, such as polyacrylic acids and esters of polyacrylic acids, polymethacrylic acids and esters of polymethacrylic acid, polyvinylacetates and polyvinylalcohols and polyvinylacetatephthalates (PVAP), polyvinylpyrrolidone and PVP; also suitable are phthalate succinates, gelatin, cross-linked gelatin, shellac, water-soluble chemical starch derivatives, cationically modified acrylates and methacrylates having, for example, a tertiary or quaternary amino group, such as the diethylaminoethyl group, which can be quaternized, if desired and other similar polymers.
    Such diluents can optionally be added in any desired amount desirably within the range of up to about 80%, desirably about 3% to 50% and most desirably within the range of 3% to 20% based on the weight of all components of the movie.
    Other additives can flow opacifying agents and, such as aluminum and magnesium oxides, silicon, titanium, etc., desirably, in a concentration range of about 0.02% to about 3% by weight, and desirably about 0 , 02% to about 1% based on the weight of all film components.
    Other examples of additives are plasticizers that include polyalkylene oxides, such as polyethylene glycols, polypropylene glycols, polyethylene-propylene glycols, low molecular weight organic plasticizers, such as glycerol, glycerol monoacetate diacetate or triacetate, triacetin, polysorbate, glycolic alcohol , propylene, sodium diethylsulfosuccinate sorbitol, triethyl citrate, tributyl citrate and the like, added in concentrations ranging from about 0.5% to about 30%, and desirably from about 0.5% to about 20 % based on the weight of the polymer.
    Compounds can also be added to improve the texture properties of the starch material, such as animal or vegetable fats, desirably in its hydrogenated form, especially those that are solid at room temperature. These fats desirably have a melting point of 50 ° C or higher. Triglycerides with Ci2c Ci4, Cig, Cig, C20 θ 022- fatty acids are preferred
    These fats can be added alone without the addition of diluents or plasticizers and can be advantageously added alone or together with mono- and / or di-glycerides or phosphatides, especially lecithin. The mono- and di-glycerides are desirably derived from the types of fats described above, that is, with C12, C14, 016/018 / C20 fatty acids θ 022-
    The total amounts used of the fats, mono-, di-glycerides and / or lecithins are up to about 5% and preferably within the range of about 0.5% to about 2% by weight of the total composition of the film.
    It may still be useful to add silicon dioxide, calcium silicate or titanium dioxide in a concentration of about 0.02% to about 1% by weight of the total composition. These compounds act as flow and opacifying agents.
    Lecithin is a surfactant for use in the films described here. Lecithin can be included in the raw material in an amount of about 0.25% to about 2.00% by weight. Other surfactants, i.e. surfactants, include, but are not limited to, sodium cetyl sulfate, lauryl alcohol, gaps ™ and Tweens ™ that are commercially available from ICT Americas Inc., ethoxylated oils, including ethoxylated castor, such as Cremophor ® EL, which is commercially available from BASF, are also useful. Carbowax ™ is yet another modifier that is very useful in the present invention. Tweens ™ or combinations of surfactants can be used to achieve the desired hydrophilic-lipophilic balance ("HLB"). The present invention, however, does not require the use of a film surfactant or film-forming agent and the compositions of the present invention can be essentially free of a surfactant while still providing the desirable uniformity characteristics of the present invention.
    Other ingredients include binders that contribute to the ease of formation and the overall quality of the films. Non-limiting examples of binding agents include starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols.
    Other potential additives include solubility enhancing agents, such as substances that form inclusion compounds with active components. Such agents can be useful for improving the properties of very insoluble and / or unstable active ingredients. In general, these substances are in the form of a ring with hydrophobic molecules with hydrophilic inner and outer cavities. Insoluble and / or unstable active ingredients can fit inside the hydrophobic cavity, thus producing an inclusion complex, which is soluble in water. Consequently, the formation of the inclusion complex allows very insoluble and / or unstable assets to be dissolved in water. A particularly desirable example of such agents are cyclodextrins, which are cyclic carbohydrates derived from starch. Other similar substances, however, are also considered within the scope of the present invention.
    Suitable dyes include medication, food and cosmetic dyes (FD & C), drug dyes and cosmetic dyes (D & C), or drug exterior dyes and cosmetic dyes (ext. D & C). These dyes are synthetic dyes, their corresponding sets, and certain natural dyes and their derivatives. Sets are dyes absorbed in aluminum hydroxide.
    Other examples of coloring agents include known azo dyes, organic or inorganic pigments, or coloring agents of natural origin. Inorganic pigments are preferred, such as iron or titanium oxides, these oxides being added in concentrations ranging from about 0.001 to about 10% and, preferably, from about 0.5 to about 3%, with based on the weight of all components.
    Flavors can be chosen from synthetic and natural flavoring liquids. An illustrative list of such agents includes volatile oils, synthetic flavoring and aromatic flavoring oils, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A representative non-limiting list of examples includes mint, cocoa, and citrus oils such as lemon, orange, lime, grapefruit and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum , pineapple, apricot or other fruit aromas.
    Other useful flavorings include aldehydes and esters, such as benzaldehyde (cherry, almonds), citral ie alpacitral (lemon, lime), neral, ie beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), C-9 aldehyde (citrus fruits), C-12 aldehyde (citrus fruits), para-iyi aldehyde (cherry, almonds), 2,6-dimethyloctanol (green fruits), and 2-dodecenal (citrus, mandarin), their combinations and the like.
    Sweeteners can be chosen from the non-limiting list which comprises: glucose (corn syrup), dextrose, inverted sugar, fructose, and their combinations; saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrocalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevioside); chlorinated sucrose derivatives, such as sucralose, sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also contemplated are starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-1-1-1,2,3-oxatiazin-4-one-2, 2-dioxide, in particular the potassium salt (acesulfame -K), sodium and calcium salts and the same, and natural intensive sweeteners, such as Lo Han Kuo. Other sweeteners can also be used.
    Anti-foam and / or foaming components can also be used with the films. These components assist in the removal of air, such as air trapped from film-forming compositions. Such trapped air can lead to non-uniform films.
    Dimethicone is particularly useful as an anti-foaming agent and / or defoaming agent. The present invention, however, is not limited and other defoaming and / or foaming agents can be used appropriately.
    For a related matter, dimethicone agents and the like can be used for densification purposes. More specifically, such agents can facilitate the removal of voids, air, moisture, and unwanted analogous components, thus providing denser material and therefore more uniform films. Agents or components that perform this function can be called densifiers or densifying agents. As described above, trapped air or unwanted components can lead to non-uniform films.
    Dimethicone is generally used in the medical field as a treatment for gas or colic in babies. Dimethicone is a mixture of linear, fully methylated siloxane polymers containing polydimethylsiloxane repeat units that are stabilized with bonded and blocked trimethylsiloxy termination and silicon dioxide. This usually contains polydimethylsiloxane 90.5 to 99% and silicon dioxide 4 to 7%. The mixture is a gray, translucent, viscous fluid that is insoluble in water.
    When dispersed in water, dimethicone will spread over the entire surface, forming a thin film of low surface tension. In this way, dimethicone reduces the surface tension of air bubbles located in the solution, such as foam bubbles, causing it to collapse. Dimethicone's function mimics the double action of oil and alcohol in water. For example, in an oily solution, any trapped air bubbles will rise to the surface and dissipate more quickly and easily, because an oily liquid has a lighter density compared to a water solution. On the other hand, an alcohol / water mixture is known to have a lower density than water, as well as having a lower surface tension than water. Thus, any air bubbles trapped inside this mixing solution will also be easily dissipated.
    A dimethicone solution provides both of these advantages. It reduces the surface energy of any air bubbles that are trapped inside the aqueous solution, as well as reducing the surface tension of the aqueous solution. As a result of this unique functionality, dimethicone has an excellent anti-foaming property, which can be used in physiological processes (anti-gas in the stomach), as well as for any external processes that require the removal of air bubbles from a product.
    In order to prevent air bubbles from forming in the films, the mixing step can be carried out under vacuum. However, as soon as the mixing step is completed and the film solution is returned to the normal atmosphere condition, air will be reintroduced or in contact with the mixture. In many cases, small air bubbles will be trapped again within this viscous polymeric solution. The incorporation of dimethicone in the film-forming composition substantially reduces or eliminates the formation of air bubbles.
    Dimethicone can be added to the film-forming mixture as an anti-foaming agent in an amount of about 0.01 weight percent to about 5.0 weight percent, most desirably between about 0.05 weight percent to about 2.5 weight percent and, more desirably, from about 0.1 weight percent to about 1.0 weight percent.
    Any other optional components described in U.S. Patent Document No. 7,425,292 and US Patent Application No. 10 / 856,176, referred to above, can also be included in the films described herein.
    When the dosage form includes at least one antagonist, it may be desirable to control the release of the antagonist, in order to delay or prevent the total release of the antagonist in the dose when taken orally. Desirably, the dosage form is a self-supporting film composition, which is placed in the user's oral cavity. In a dosage form that will be placed in the oral cavity, it is desired to absorb the agonist orally, in order to provide rapid integration of the agonist into the user's body. At the same time, it may be desired to prevent or reduce the absorption of any buccal antagonist, thereby allowing the antagonist to be swallowed and destroyed in the stomach. Reducing the absorption of an antagonist can be achieved by physical means, such as by encapsulating the antagonist in a material that blocks absorption. It is desired, however, to reduce the absorption of the antagonist by chemical means, such as by controlling the local pH of the dosage.
    It was found that, by controlling the local pH of the dosage form, the release and / or absorption of the active agents of the same can be controlled. For example, at a dosage that includes an amount of an agonist, the local pH can be controlled to a level that maximizes its release and / or absorption into the user's oral cavity. In dosages that incorporate an amount of an agonist and an amount of an antagonist, the local pH can be controlled to a level that maximizes the release and / or absorption of the agonist, while simultaneously minimizing the release and / or absorption of the antagonist.
    The dosage form preferably includes a combination of a partial agonist and an antagonist, while the dosage has a controlled pH. In one embodiment, the partial agonist may include buprenorphine or a pharmaceutically acceptable salt thereof, while the antagonist includes naloxone or a therapeutically acceptable salt thereof. It is to be understood that the present invention is not limited to the use of buprenorphine and naloxone and that any agonist (or partial agonist) and any antagonist can be incorporated into the present invention for use in the treatment of drug addiction. The agonist and optional antagonist should be selected from those agonists and antagonists that are useful in treating the particular addiction to the narcotic being treated.
    As discussed above, the pH of the dosing site is preferably controlled to provide the desired release and / or absorption of the agonist and antagonist.
    Buprenorphine is known to have a pKa of about 8.42, while naloxone has a pKa of about 7.94. According to the pH partition theory, it would be expected that saliva (which has a pH of about 6.5) would maximize the absorption of both active ingredients. However, it has been surprisingly determined by applicants that through buffering the dosage goes to a particular pH level, at which optimal levels of absorption of the agonist and antagonist can be achieved. Desirably, the local pH of a composition including an agonist and an antagonist is between about 2 to about 4, and most desirably it is from 3 to 4. At this local pH level, optimal absorption of the agonist and antagonist is achieved. As will be described in more detail in the Examples below, controlling the local pH of the film compositions of the present invention provides a system in which the release is desired and / or the absorption of the components is bioequivalent to that presented by a similar Suboxone® tablet.
    In one embodiment, the dosage form is a self-supporting film. In this embodiment, the film dosage includes a polymer-bearing matrix, a therapeutically effective amount of buprenorphine and an agonist. The buffer is preferably capable of providing a local pH of the composition within a range that provides the desired level of absorption of buprenorphine. The resulting dosage is a film composition that allows a quick and effective release of buprenorphine into the user's oral cavity. At the same time, the film composition preferably has a sufficient adhesion profile, such that the film cannot be easily removed from the oral cavity of the user once it has been placed in said cavity, the complete release of buprenorphine it preferably takes place in less than about 30 minutes and preferably remains in the oral cavity for at least 1 minute.
    As explained above, providing a pharmaceutically acceptable level of an agonist is useful in treating those addicted to narcotics, and it may be desirable to provide buprenorphine in combination with naloxone (an antagonist) in order to reduce the effect of the agonist and therefore , helps in reducing dependence on the narcotic. Therefore, it may be desirable to combine the opioid agonist (or a partial agonist) in the film composition with an opioid antagonist or a pharmaceutically acceptable salt. The active ingredients can be dispersed throughout the dosage separately or they can be combined together and dispersed in the dosage. Most desirably the antagonist includes naloxone, but any suitable base antagonist can be selected, as desired. The antagonist can optionally be soluble in water, in order to make the separation of the antagonist and agonist difficult, thereby decreasing the potential for abuse of the agonist.
    As with a film including an agonist, a film including an agonist and an antagonist is desirably pH-controlled, through the inclusion of a buffer. In the films of such a set, it has been found that the local pH of the film composition should preferably be in the range of about 2 to about 4, and more preferably about 3 to about 4, in order to provide a bioequivalent product such as the commercially available tablet, Suboxone®. Most preferably, the local pH of the film composition is about 3.5. At this local pH level, the absorption of buprenorphine is optimized while the absorption of naloxone is inhibited.
    The film can contain any desired level of self-supporting film-forming polymer, such that a self-supporting film composition is provided. In one embodiment, the composition contains a film-forming polymer film, in an amount of at least 25% by weight of the composition. The film-forming polymer film may alternatively be present in an amount of at least 50% by weight of the composition. As explained above, the film of any film forming polymer that provides mucoadhesion and the desired film dissolution rate can be used, as desired.
    Any desired level of optional agonist and antagonist can be included in the dosage, in order to provide the desired effect. In a particular embodiment, the film composition includes about 2 mg to about 16 mg agonist per dosage. Most desirably, the film composition includes about 4 mg to about 12 mg agonist per dosage. If desired, the film composition can include about 0.5 mg to about 5 mg of antagonist per dosage. Most desirably, the film composition includes about 1 mg to about 3 mg of antagonist per dosage. If an antagonist is incorporated into the film, the film composition can include the antagonist in a ratio of about 6: 1 to 2: 1 agonist to antagonist. Most desirably, the film composition contains about 4: 1 agonist to antagonist per dosage. For example, in one embodiment, the dosage includes an agonist in an amount of about 12 mg and includes an antagonist in an amount of about 3 mg.
    The film compositions, more desirably, contain a buffer, in order to control the local pH of the film composition. Any desired level of buffer can be incorporated into the film composition to provide the desired local pH level. The buffer is preferably provided in an amount sufficient to control release from the film and / or absorption in the body of the agonist and optional antagonist. In a desired embodiment, the film composition includes a buffer in a ratio of buffer to agonist in an amount from about 2: 1 to about 1: 5 (agonist buffer). The buffer may alternatively be provided in a 1: 1 ratio of buffer to agonist. As stated above, the film composition preferably has a local pH of about 2 to about 4, and more preferably has a local pH of about 3.5. Any buffer system can be used, as desired. In some embodiments, the buffer may include sodium citrate, citric acid and combinations thereof.
    In this embodiment, the resulting film composition includes a polymer matrix, an agonist and an optional antagonist, while the film composition has a local pH controlled to the desired level. The buffer is preferably present in an amount to provide therapeutically adequate absorption of the agonist, while simultaneously limiting the absorption of the antagonist. Controlling the local pH allows the desired release and / or absorption of the components, thus providing a more useful and effective dosage.
    The film dosage composition can include a polymer carrier matrix, a therapeutically effective amount of agonist, a therapeutically effective amount of antagonist and a buffering system. The buffering system can include a buffer in addition to a solvent. The buffering system desirably includes a sufficient level of buffer to provide a desired local pH level of the film dosing composition.
    In addition, at a desired local pH level, the buffer preferably has sufficient buffering capacity to maintain ionization of the optional antagonist for as long as the composition is in a user's oral cavity. Maintaining ionization of the antagonist can limit the absorption of the antagonist, and thus provide the desired control of the antagonist. While the ionization of the antagonist is limited, the ionization of the agonist may not be as limited. As such, the resulting dosage form provides absorption of the agonist to sufficiently reduce and / or prevent absorption of the antagonist. By maintaining the ionized antagonist and the local pH at the optimum pH, the antagonist has any type of limited absorption, but makes the product that is abused or taken present through a different route of administration. However, when taken in the administered form, the antagonist has little or no effect on blocking the agonist.
    The film dosage composition including an agonist can be configured to provide an in vivo plasma profile with an average maximum plasma concentration (Cmax) in a desired range. It was determined by the applicants that the Cmax control of the film composition allows the absorption of the active substance (such as an agonist) in the user to be controlled. The resulting film composition is more effective and suitable for delivery to a user.
    As explained, the film dosage composition provides a bioequivalent result to a commercially available Suboxone® product. As will be explained in more detail in the Examples below, the commercially available Suboxone® product provides different levels of absorption, depending on the amount of buprenorphine and naloxone administered. The present invention provides a product desirably on film providing bioequivalent release to one of the Suboxone® product. As with the Suboxone® product, buprenorphine can be present in an amount of about 2 mg to about 16 mg per dose or, if desired, about 4 mg to about 12 mg per dose. In addition, naloxone can be present in any desired amount, preferably at about 25% the level of buprenorphine. For example, an inventive film product can have 2 mg of buprenorphine and 0.5 mg of naloxone, 4 mg of buprenorphine and naloxone 1 mg, 8 mg of buprenorphine and naloxone 2 mg, 12 mg of buprenorphine and naloxone 3 mg, 16 mg of buprenorphine and 4 mg of naloxone or any similar amounts.
    It was further determined that by controlling the value of the average area under the curve (AUC) of the film composition, a more effective dosage form can be provided. As will be described in more detail in the examples below, the film composition of the present invention preferably provides an AUC value in order to provide a bioequivalent result like that provided for commercially available Suboxone® tablets. In one embodiment, the film composition may include an average AUCinf value of about 6.8 hr.ng/ml or greater. Alternatively, the film composition can include an average value of AUCinf from about 6.8 hr.ng/ml to about 66 hr.ng/ml.
    As explained above, film compositions can include naloxone, an antagonist. When the film composition includes a combination of agonist and antagonist, the film composition can be configured to provide a certain Cmax and / or AUCinf to the antagonist. For example, when a buprenorphine agonist and a naloxone antagonist are incorporated into the film composition, naloxone can be configured to provide a Cmax of less than about 400 pg / ml, less than about 318 pg / ml, less than about 235 pg / ml, less than about 92 pg / ml or less than about 64 pg / ml. In such films, naloxone can provide an average AUCinf value of less than about 1030 hr.ng/ml.
    In formulations that include an agonist in combination with an antagonist, the film composition can be prepared to provide a desired Cmax and / or AUCinf value for each of the agonists and antagonists. In one embodiment, film composition provides a plasma profile in vivo having a Cmax of less than about 6.4 ng / ml for the agonist and a plasma profile in vivo having a Cmax of less than about 400 pg / ml for the antagonist. In such embodiments, the formulation can provide an AUCinf value of more than about 6.8 hr.ng/ml for the agonist. If desired, the formulation can provide an AUCinf value of less than about 1030 hs.pg/ml for the antagonist. Such compositions can include the agonist and antagonist in any desired amount, and in a preferred embodiment, the composition includes from about 2 mg to about 16 mg of the agonist per dose and about 0.5 mg to about 4 mg of the antagonist by dosage.
    The present invention provides a method of treating narcotic addiction in a patient. In one embodiment, the patient is dependent on opioid narcotics, but the patient may have a dependency on non-opioid narcotics. Desirably, the patient is treated by providing a dose to the patient, which provides an effective release of active agents but, at the same time, provides adequate adherence so that the dosage cannot be easily removed. In a treatment method, an orally dissolvable film composition is provided to a patient.
    Depending on the particular narcotic, on which the patient is dependent, the film composition may include one or more particular active components. In one embodiment, the film composition includes a polymer-bearing matrix and a therapeutically effective amount of an agonist. Desirably, the agonist is a partial agonist. For opiate addiction, the agonist can be an opioid agonist, such as buprenorphine or a pharmaceutically acceptable salt thereof. The film composition preferably includes a buffer in an amount sufficient to control the local pH of the film composition. Any buffer system can be used, including sodium citrate, citric acid, and combinations thereof. In compositions solely including an agonist, the local pH of the film composition is desirably about 5 to about 6.5, and most desirably the local pH is about 5.5. At this level, the absorption of the agonist is more effective. To treat addiction, the film composition is administered to the patient, most desirably within the patient's oral cavity.
    If desired, the composition can include a therapeutically effective amount of an antagonist, to prevent abuse of the agonist. An "therapeutically effective amount" of an antagonist is intended to refer to an amount of the antagonist that may be useful in deflecting abuse of the agonist by a user. The antagonist can be any desired antagonist, and in one embodiment it includes naloxone or a pharmaceutically acceptable salt thereof. The film composition is preferably administered to a patient through the patient's oral cavity, but can be administered in any desired medium. The orally dissolvable film composition is then left to dissolve in the patient's oral cavity long enough to release the active substance therein. In some embodiments, the film composition can remain in the oral cavity for at least 30 seconds and in some embodiments it can remain in the oral cavity for at least 1 minute. After the film composition is placed in the patient's oral cavity, the film preferably becomes sufficiently adhered to make removal difficult. After the film composition has been administered to the patient, the active substance is sufficiently released from the composition and left to have an effect on the patient.
    The film compositions of the present invention can be formed by any desired process. The appropriate processes are presented in US patent documents US N 0 7,425,292 and 7,357,891, the contents of which are incorporated herein by reference in their entirety. In one embodiment, the film dosage composition is formed by preparing a first wet composition, the wet composition, including a polymeric vehicle matrix, a therapeutically effective amount of an agonist and a buffer in an amount sufficient to control the pH composition site at a desired level. The wet composition is converted into a film and then dried sufficiently to form a self-supporting film composition. The wet composition can be converted into individual dosages, or can be converted to a sheet, where the sheet is then cut into individual dosages. The agonist can be a partial agonist. If desired, the wet composition can include a therapeutically effective amount of an antagonist.
    The agonist and optional antagonist are preferably selected to treat an addiction to a particular narcotic. For opioid dependence, for example, the agonist may include buprenorphine or a pharmaceutically acceptable salt thereof, while the antagonist may include naloxone or a pharmaceutically acceptable salt thereof. The local pH of the film composition is desirably maintained at about 2 to about 4. EXAMPLES Example 1 - Buprenorphine / naloxone film composition in different dosages

    Example 2 - Absorption studies for Suboxone® products

    Using the data in Table 2, the absorption data for Suboxone® tablets for other levels of buprenorphine and naloxone are shown in Table 2A, below. 5 Table 2A - extrapolated absorption data for Suboxone® products
    Example 3 - Suboxone® Tablets Bioequivalence Assessment
    Using the data generated for the Suboxone® tablets in Table 2, above, acceptable bioequivalence ranges are generated to provide an equivalent level of treatment, as per the Suboxone® tablet. As is currently understood, a product provides a bioequivalent effect if it provides levels of absorption of between about 80% to about 125% of the reference Suboxone® tablet. Absorption in this range is considered to be bioequivalent. Table 3 - Acceptable range of bioequivalence for
    Thus, to be considered bioequivalent to the Suboxone® tablet, buprenorphine Cmax must be between about 0, 624 and 5, 638 and buprenorphine AUCs should be between about 5.431 to about 56.238. Similarly, to be considered bioequivalent to the Suboxone® tablet, the Cmax of naloxone must be between about 41.04 to about 323.75 and the AUC of naloxone must be between about 102.88 to about 812, 00. Example 4 - absorption studies of film products at 10 pH 3.5
    Various film products were prepared and tested for absorption data, including Cmax and AUC absorption levels. The tested products included film strips of the present invention, film strips having either 2 mg or 16 mg of buprenorphine, as well as 0.5 mg or 4.0 mg of naloxone. These products were tested for absorption levels, with the amounts listed in Table 4, below. Table 4 - absorption data for the film products of the present invention, at pH 3.5.


    As can be seen, in this experiment, the absorbance values for buprenorphine were placed in the bioequivalence range evaluated above. The films of the invention were therefore determined to have provided a bioequivalent absorption of buprenorphine at a local pH of 3.5 - like commercially available Suboxone® tablets. Values for naloxone absorption were found very close to the bioequivalent range of Suboxone®. A slightly higher absorption of naloxone was not due to the local pH, 10 but to an amount of buffer (buffer capacity, as discussed earlier). This is confirmed by the fact that the lowest dose of 2 / 0.4 mg is in the range for naloxone; and this is due to the greater buffer capacity, compared to the 2 / 0.4 dose as noted in the buffer capacity graph. Example 5 - Preparation of films for in vivo study
    Film dosages were prepared for use in an in vivo study to determine the bioavailability of buprenorphine / naloxone in tablets and film formulations. Specifically, the films were tested to determine whether the film provides a bioequivalent effect to that of a tablet formulation. 5 Three film formulations, including 8 mg of buprenorphine and 2 mg of naloxone, were prepared, each being buffered at a different pH. The first film did not include any buffer, providing a local pH of about 6.5. The second was buffered at a local pH level of about 3 to 3.5. The third was buffered at a local pH value of about 5 to 5.5. The formulations are shown in Table 5, below. Table 5 - Test film formulations at various pH levels.

    Example 6 - In vivo absorption analysis of film having a pH of 6.5
    The film dosing composition with film having a local pH 5 of 6.5 was analyzed. Specifically, test formulation 1, as prepared in Example 5, was analyzed in vivo to determine the absorption of buprenorphine and naloxone. The comparative film was compared to the absorption of buprenorphine and naloxone provided by a unit dose tablet (Suboxone®). The test film was compared to determine whether it can have a bioequivalent effect as the product in tablet form. 5 Results for test formulation 1, which had a local pH of about 6.5, compared to the unit dose tablet, are shown in Tables 6 and 7, below. Table 6 - Buprenorphine absorption data in vivo for test formulation 1.
    Table 7 - In vivo absorption data for naloxone for test formulation 1

    As can be seen, the in vivo data indicates that buprenorphine is absorbed very well from the film formulation at a local pH of 6.5, when combined closely with 5 absorption data seen for Suboxone®, unit dose tablet. However, absorption was also maximized for naloxone, which was undesirable. It was determined that a film with a combination of buprenorphine and naloxone and a local pH of 6.5 does not provide a bioequivalent effect like the Suboxone® tablet for buprenorphine and naloxone. Example 7 - In vivo absorption analysis of film having a pH of 5 to 5.5
    Once the absorption of buprenorphine and naloxone on film having a local pH of 6.5 was determined, a film film dosage composition having a local pH of 5 to 5.5 was analyzed. Specifically, test formulation 3, as prepared in Example 5, was analyzed in vivo to determine the absorption of buprenorphine and naloxone. The comparative films were compared with the absorption of buprenorphine and naloxone provided by the Suboxone® unit dose tablet. The test film was compared to determine whether it can have a bioequivalent effect to that of the Suboxone® tablet. 10 Results for test formulation 3, which had a local pH of about 5 to 5.5, compared to the Suboxone® tablet, are shown in Tables 8 and 9, below. Table 8 - Buprenorphine in vivo absorption data for test formulation 3

    Table 9 - In vivo absorption data for naloxone for test formulation 3

    As can be seen, in vivo data indicated that the absorption of buprenorphine increased as the local pH level decreased. It was found that by decreasing the local pH from 6.5 to 5.5, the absorption of buprenorphine moved to a level further than the unit dose tablet. In addition, naloxone values do not provide a bioequivalent result like the unit dose tablet. Thus, it was determined that the film having a local pH of 5.5 does not provide a bioequivalent result to that of the Suboxone® tablet for buprenorphine and naloxone.
    It was noted that by lowering the film's local pH to a level of 5.5, an increase in the level of buprenorphine absorption would be provided. Thus, it may be desirable to buffer a film composition incorporating buprenorphine at a pH level of about 5.5 to provide increased absorption. Example 8 - In vivo absorption analysis of the film having a pH of 3 to 3.5
    Having determined the absorption of buprenorphine and naloxone in films having a local pH of 6.5 and 5.5, a film dosing composition film having a local pH of about 3 to 3.5 was analyzed. It was assumed that the absorption of buprenorphine would continue to be increased, as it had been shown to be at a local pH of 5.5. Thus, it was assumed that at a local pH of 3.5, the film would not be bioequivalent to the tablet.
    Specifically, a test formulation 2, as prepared in Example 5, was analyzed in vivo to determine the absorption of buprenorphine and naloxone. The comparative films were compared with the absorption of buprenorphine and naloxone provided by the Suboxone® unit dose tablet. The test film was compared to determine whether it can have a bioequivalent effect as the product in the form of a tablet. 5 Results for test formulation 2, which had a local pH of about 3 to 3.5, compared to the Suboxone® tablet, are shown in Tables 10 and 11, below. Table 10 - Buprenorphine in vivo absorption data for test formulation 2.
    Table 11 - In vivo absorption data for naloxone for test formulation 2.

    As can be seen, the in vivo data indicated that the absorption of buprenorphine was substantially bioequivalent to that of the unit dose tablet when the film composition with local pH was reduced to about 3 to 3.5. This result was surprising, since it does not seem to follow the pH partition theory. In addition, at a local pH of about 3 to 3.5, the absorption of naloxone was found to be substantially bioequivalent to that of the unit dose tablet. 10 Thus, it was determined that the film product, including buprenorphine and naloxone, at a local pH of 3 to 3.5 is substantially bioequivalent to the Suboxone® unit dose tablet. Example 9 - normalized values for naloxone in films and tablets
    Several film compositions, including buprenorphine and naloxone in dosages 8/2 mg and 2 / 0.4 mg, and having different local pH values from 6.5 to 3.5, were prepared and analyzed. The data were normalized and compared with the unit dose tablet. The results are shown 10 in Table 12, below. Table 12 - normalized values of naloxone film compared to tablet

    The data indicate that not only is the local pH of significant importance, but the amount of buffer present in the formula is also important. The improvement of the 8/2 dose to the 2 / 0.4 dose (at a local pH of 3.5) demonstrates this importance. The 8/2 dose has a buffer / naloxone ratio of 0.67, and this dose provided acceptable limits on bioequivalent results. In contrast, the 2 / 0.4 dose has a buffer / naloxone ratio of 2.68, and provides an absorption value of more than the 8/2 bioequivalent dose.
    In fact, the data show that the dose 2 / 0.4 at a local pH of 3.5 has an even lower absorption than the buccal unit dose tablet 10, as seen from the normalized values for AUC and Cmax. This demonstrates that even less absorption of naloxone occurs for the film formulation at a local pH of 3.5 when compared to a tablet formulation. Given the goal of reducing naloxone absorption, it appears that the film product buffered to a local pH of 3.5 with a buffer buffer / naloxone ratio of 2.68 provides even better results than the Suboxone tablet formulation. ®.
    权利要求:
    Claims (19)
    [0001]
    1. Film dosage composition characterized by the fact that it comprises: a. a polymeric carrier matrix; B. a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt thereof; ç. a therapeutically effective amount of naloxone or a pharmaceutically acceptable salt thereof; and d. a buffer in quantity to provide a local pH of said composition in a value sufficient to optimize the absorption of said buprenorphine; wherein the composition has a local pH of 2 to 4; wherein said buprenorphine is present in an amount of about 2 mg to about 16 mg per dosage; wherein the weight ratio of buprenorphine to naloxone is about 4: 1; and wherein said buffer is present in an amount of about 2: 1 to about 1: 5 by weight of buffer for buprenorphine or a pharmaceutically acceptable salt thereof.
    [0002]
    2. Composition according to claim 1, characterized by the fact that said local pH is about 3 to about 4.
    [0003]
    3. Composition, according to claim 2, characterized by the fact that the local pH of said composition is about 3.5.
    [0004]
    Composition according to claim 1, characterized in that said polymeric carrier matrix comprises at least one polymer in an amount of at least 25%, by weight, of said composition.
    [0005]
    5. Composition according to claim 1, characterized in that said buffer is present in an amount of about 2: 1 to about 1: 5 by weight, of buffer for buprenorphine.
    [0006]
    6. Composition according to claim 1, characterized by the fact that said polymeric carrier matrix comprises at least one self-supporting film-forming polymer.
    [0007]
    Composition according to claim 1, characterized in that the polymeric carrier matrix comprises polyethylene oxide alone or in combination with a second polymeric component.
    [0008]
    8. Composition according to claim 1, characterized in that the second polymeric component comprises a hydrophilic cellulosic polymer, for example, hydroxypropyl cellulose and / or hydroxypropylmethyl cellulose.
    [0009]
    9. Composition, according to claim 1, characterized by the fact that the molecular weight of polyethylene oxide is in the range of 100.00 to 900,000, more specifically, from about 100,000 to 600.00, and more specifically, from about 100,000 to 300,000.
    [0010]
    10. Composition according to claim 1, characterized by the fact that buprenorphine is present in an amount of about 2 mg to about 16 mg per dosage; and, where naloxone is present in an amount of about 25% of the level of buprenorphine, for example, 2 mg of buprenorphine and 0.5 mg of naloxone; 4 mg of buprenorphine and 1 mg of naloxone; 4 mg of buprenorphine and 2 mg of naloxone; 12 mg buprenorphine and 3 mg naloxone or 16 mg buprenorphine and 4 mg naloxone.
    [0011]
    11. Composition according to claim 1, characterized by the fact that said buffer comprises sodium citrate, citric acid and combinations thereof.
    [0012]
    12. Composition according to claim 1, characterized by the fact that said buffer comprises acetic acid, sodium acetate and combinations thereof.
    [0013]
    13. Composition, according to claim 1, characterized by the fact that the composition is a self-supporting film comprising: a. a polymeric carrier matrix; B. a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of naloxone or a pharmaceutically acceptable salt thereof; and c. a buffer in quantity to provide a local pH of said composition in a value sufficient to optimize the absorption of said buprenorphine; where: where the composition has a local pH of 2 to 4; optionally about 3.5; the polymeric matrix comprises a film-forming polymer in an amount of at least 25% by weight of the composition; the buffer comprises sodium citrate, citric acid and combinations thereof; the weight ratio of buprenorphine to naloxone is about 4: 1; said buprenorphine is present in an amount of about 2 mg to about 16 mg per dosage, and wherein said buffer is present in an amount of about 2: 1 to about 1: 5 by weight of buffer for buprenorphine or a pharmaceutically acceptable salt thereof.
    [0014]
    14. Composition according to claim 1, characterized by the fact that said composition comprises: (i) a combination of buprenorphine and naloxone in the ratio of 16: 4, comprising: - 17.28 mg of buprenorphine hydrochloride; - 4.88 mg of naloxone hydrochloride dihydrate; - 27.09 mg of Polyethylene Oxide, NF (MW 200,000); - 12.04 mg of Polyethylene Oxide, NF (MW 100,000); - 4.82 mg of Polyethylene Oxide, NF (MW 900,000); - 12.04 mg of maltitol; - 6.0 mg of flavoring agent - 5.92 mg of citric acid, USP; - 4.22 mg of HPMC; - 3.0 mg Ace-K; - 2.68 mg of sodium citrate, anhydrous; and - 0.03 mg of dye; wherein the composition has a total weight of 100 mg; or (ii) a combination of buprenorphine and naloxone in a 12: 3 ratio, comprising: - 12.96 mg buprenorphine hydrochloride; - 3.66 mg of naloxone hydrochloride dihydrate; - 20.32 mg of Polyethylene Oxide, NF (MW 200,000); - 9.03 mg of Polyethylene Oxide, NF (MW 100,000); - 3.62 mg of Polyethylene Oxide, NF (MW 900,000); - 9.03 mg of maltitol; - 4.5 mg of flavoring - 4.44 mg of citric acid, USP; - 3.16 mg of HPMC; - 2.25 mg Ace-K; - 2.01 mg of sodium citrate, anhydrous; and - 0.02 mg of dye; wherein the composition has a total weight of 75 mg; or (iii) a combination of buprenorphine and naloxone in an 8: 2 ratio, comprising: - 8.64 mg buprenorphine hydrochloride; - 2.44 mg of naloxone hydrochloride dihydrate; - 13.55 mg of Polyethylene Oxide, NF (MW 200,000); - 6.02 mg of Polyethylene Oxide, NF (MW 100,000); - 2.41 mg of Polyethylene Oxide, NF (MW 900,000); - 56.02 mg of maltitol; - 3.0 mg of flavoring agent - 2.96 mg of citric acid, USP; - 2.11 mg of HPMC; - 1.5 mg Ace-K; - 1.34 mg of sodium citrate, anhydrous; and - 0.01 mg of dye; wherein the composition has a total weight of 50 mg; or (iv) a combination of buprenorphine and naloxone in a 2: 0.5 ratio, comprising: - 2.16 mg buprenorphine hydrochloride; - 0.61 mg of naloxone hydrochloride dihydrate; - 19.06 mg of Polyethylene Oxide, NF (MW 100,000); - 2.05 mg of Polyethylene Oxide, NF (MW 900,000); - 5.87 mg of maltitol; - 2.4 mg of flavoring - 2.96 mg of citric acid, USP; - 2.34 mg of HPMC; -1.2 mg Ace-K; - 1.34 mg of sodium citrate, anhydrous; and - 0.01 mg of dye; wherein the composition has a total weight of 40 mg.
    [0015]
    15. Composition according to claims 1 to 14, characterized by the fact that it is for use in the treatment of narcotic addiction in a user.
    [0016]
    16. Composition, according to claim 15, characterized by the fact that said composition is administered by oral administration, sublingual administration and their combinations.
    [0017]
    17. Composition, according to claim 15, characterized by the fact that said composition remains in the oral cavity of the user for a period of at least 1 minute.
    [0018]
    18. Composition, according to claim 15, characterized by the fact that said composition remains in the oral cavity of the user for a period of at least up to 3 minutes.
    [0019]
    19. Composition according to claims 15 to 18, characterized by the fact that addiction to narcotics and addiction to opioids.
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    法律状态:
    2017-10-10| B25A| Requested transfer of rights approved|Owner name: RB PHAMACEUTICALS LIMITED (UK) |
    2017-10-24| B25D| Requested change of name of applicant approved|Owner name: INDIVIOR UK LIMITED (GB) |
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2019-01-29| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-03-19| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2020-06-02| B25G| Requested change of headquarter approved|Owner name: INDIVIOR UK LIMITED (GB) |
    2020-08-04| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-12-01| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 10 (DEZ) ANOS CONTADOS A PARTIR DE 01/12/2020, OBSERVADAS AS CONDICOES LEGAIS. |
    2021-05-25| B16C| Correction of notification of the grant [chapter 16.3 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 05/08/2010 OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |
    优先权:
    申请号 | 申请日 | 专利标题
    US12/537,571|US8475832B2|2009-08-07|2009-08-07|Sublingual and buccal film compositions|
    US12/537,571|2009-08-07|
    PCT/US2010/044488|WO2011017483A2|2009-08-07|2010-08-05|Sublingual and buccal film compositions|
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