TITLE

SUBLINGUAL FILM COMPOSITIONS FIELD OF THE INVENTION

The present invention relates to sublingual film compositions of buprenorphine and naloxone. BACKGROUND

Oral administration of two therapeutic actives in a single dosage form can be complex if the intention is to have one active absorbed into the body and the other active remain substantially unabsorbed. For example, one active may be relatively soluble in the mouth at one pH, and the other active may be relatively insoluble at the same pH. Moreover, the absorption kinetics of each therapeutic agent may be substantially different due to differing absorption of the charged and uncharged species. These factors represent some of the challenges in appropriately coadministering therapeutic agents.

Co-administration of therapeutic agents has many applications. Among such areas of treatment include treating individuals who suffer from narcotic dependence. Such individuals have a tendency to suffer from serious physical dependence on the narcotic, resulting in potentially dangerous withdrawal effects when the narcotic is not administered to the individual. In order to help individuals addicted to narcotics, it is known to provide a reduced level of a drug, which provides an effect of satisfying the body's urge for the narcotic, but does not provide the "high" that is provided by the misuse of the narcotic. The drug provided may be an agonist or a partial agonist, which provides a reduced sensation and may help lower dependence on the drug. However, even though these drugs provide only a low level of euphoric effect, they are capable of being abused by the individuals parenterally. In such cases, it is desirable to provide a combination of the drug with a second drug, which may decrease the likelihood of diversion and abuse of the first drug. For example, it is known to provide a dosage of an antagonist in combination with the agonist or partial agonist. The narcotic antagonist binds to a receptor in the brain to block the receptor, thus reducing the effect of the agonist.

There is currently a need for an orally dissolvable film dosage form that provides the desired absorption levels of the agonist and antagonist, while providing an adhesive effect in the mouth, rendering it difficult to remove once placed in the mouth, thereby making abuse of the agonist difficult.

U.S. Pat. No. 8,475,832 describes a film dosage 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 local pH of about 3 to about 3.5 for said composition of a value sufficient to optimize absorption of the buprenorphine; and administering the composition to the oral cavity of a user.

U.S. Pat. No. 8,603,514 describes films containing coated particles that include an active agent and a taste-masking and/or controlled-release coating. Accordingly, there is provided a drug delivery composition that includes (i) a flowable water-soluble film forming matrix; (ii) a particulate bioeffecting agent uniformly stationed therein; and (iii) a taste-masking agent or controlled-release agent coated or intimately associated with the particulate to provide taste- masking of the bioeffecting agent. In some embodiments, the combined particulate and taste- masking agent have a particle size of 200 microns or less and the flowable water-soluble film forming matrix is capable of being dried without loss of uniformity in the stationing of the particulate bioeffecting agent therein. U.S. Pat. No. 8,603,514 exemplifies water and combination of water and ethanol as a solvent.

We have surprisingly found that stable film of buprenorphine and naloxone can be made in spite of using non-aqueous solvent and the said buprenorphine and naloxone are solubilized during formation of the film which provide uniform distribution of components. Moreover the stable film of invention also does not use any buffer. It can be understood from prior art that making a stable sublingual film which does not contain buffer is difficult as the buffer in an particular amount is needed to provide a local pH of the composition within a range that provides the desired level of absorption of the buprenorphine. OBJECT AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide stable sublingual film comprising 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 non-aqueous solvent, wherein the formulation does not use water and buffer, wherein the said buprenorphine and naloxone are solubilized during formation of the film, and wherein the film is stable at accelerated condition; 40 °C/75% RH .

It is a further object of the present invention to provide stable sublingual film comprising buprenorphine, naloxone and non-aqueous solvent wherein the formulation does not use water and buffer, wherein the said buprenorphine and naloxone are solubilized during formation of the film and the film is stable for at least 6 months at 40 °C/75% RH.

It is a further object of the present invention to provide stable sublingual film comprising buprenorphine, naloxone, and methanol, wherein buprenorphine and naloxone are solubilized during formation of the film and the film is stable at 40°C/75% RH.

All percentages of ingredients reported herein are expressed as weight by weight, unless otherwise indicated.

The term "stable" or "stability" as used herein with respect to buprenorphine and naloxone refers to a film formulation with at least about 90% of buprenorphine and naloxone in undegraded form and having not more than 2% of total impurities after exposure of the formulation at 40 °C/75% RH; for at least 6 months.

The invention may be summarized as given below:

A. A stable sublingual film comprising 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 non-aqueous solvent, wherein the formulation does not use water and buffer, wherein the said buprenorphine and naloxone are solubilized during formation of the film, and wherein the film is stable for at least 6 months at 40°C/75% RH condition. B. A stable sublingual film according to A, wherein the non-aqueous solvent is methanol.

DETAILED DESCRIPTION

Buprenorphine is insoluble in water resulting in particulate and uneven distribution of Active pharmaceutical ingredient (API) during process. Additionally, to achieve absorption of buprenorphine a particular amount of buffer is needed to maintain the desired pH. Issues associated with maintaining an optimum pH range without using any buffer system makes formulating buprenorphine into a stable film challenging.

Buprenorphine in general is insoluble in water. The formulations of the present invention is a non-aqueous - based sublingual film of buprenorphine and naloxone combination wherein said sublingual film is stable at 40°C/75% RH. Additionally the composition is free from any buffer.

Buprenorphine is an opioid used to treat opioid addiction, moderate acute pain and moderate chronic pain. Naloxone is a medication used to block the effects of opioids. The combination buprenorphine/naloxone is also used for opioid addiction.

The films used in the pharmaceutical products may be produced by a combination of at least one polymer and a solvent, optionally including other fillers known in the art. The composition of the present invention does not use water. The solvent may be a polar organic solvent including, but not limited to, ethanol, methanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent may be a non-polar organic solvent, such as methylene chloride. The amount of solvent in the formulations of the present invention can range from about 30% to about 90% by weight. In preferred embodiments, the formulation uses methanol as a solvent.

The polymer included in the films may be water-soluble, water-swellable, water-insoluble, or a combination of one or more either water-soluble, water-swellable or water-insoluble polymers. The polymer may 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, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin, and combinations thereof. Specific examples of useful water-insoluble polymers include, but are not limited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate and combinations thereof. In accordance with some embodiments, polymer may range from about 5% to about 90% by weight, more specifically from about 20% to about 80% by weight, and even more specifically from about 40% to about 70% by weight. In certain embodiments, the formulation of the present invention uses Hydroxypropyl cellulose (HPC) SSL as a polymer.

A variety of optional components and fillers also may be added to the films. These may include, without limitation: surfactants; plasticizers; polyalcohols; anti-foaming agents, such as silicone-containing compounds, which promote a smoother film surface by releasing oxygen from the film; thermo-setting gels such as pectin, carageenan, and gelatin, which help in maintaining the dispersion of components; inclusion compounds, such as cyclodextrins and caged molecules; coloring agents; and flavors. In some embodiments, more than one active components may be included in the film.

Additives may be included in the films. Examples of classes of additives include excipients, lubricants, stabilizers, anti-oxidant, blowing agents, pigments, coloring agents, fillers, bulking agents, sweetening agents, flavoring agents, fragrances, release modifiers, adjuvants, plasticizers, flow accelerators, mold release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, glidants, adhesives, anti-adherents, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers and mixtures thereof. These additives may be added with the active ingredient(s). Further examples of additives are plasticizers which include polyalkylene oxides, such as polyethylene glycols, polypropylene glycols, polyethylene-propylene glycols, organic plasticizers with low molecular weights, such as glycerol, glycerol monoacetate, diacetate or triacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, and the like, added in concentrations ranging from about 0.5% to about 30%, and desirably ranging from about 0.5% to about 20%) based on the weight of the polymer. In preferred embodiments, the formulation uses polyethylene glycol as a plastisizer.

It further may be useful to add silicon dioxide, calcium silicate, or titanium dioxide in a concentration of about 0.02% to about 3% by weight of the total composition. These compounds act as flow agents and opacifiers.

An anti-oxidant may also be added to the film to prevent the degradation of an active. The composition of the present invention uses butylated hydroxy toluene as an antioxidant.

The sweeteners may be chosen from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof, saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also contemplated are hydrogenated starch hydroly sates and the synthetic sweetener 3,6- dihydro-6-methyl-l-l-l,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof, and natural intensive sweeteners, such as Lo Han Kuo. Other sweeteners may also be used.

Suitable coloring agents include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors are dyes, their corresponding lakes, and certain natural and derived colorants. Lakes are dyes absorbed on aluminum hydroxide.

Flavors may be chosen from natural and synthetic flavoring liquids. Suitable flavoring agents may include An illustrative list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A non-limiting representative list of examples includes mint oils, cocoa, and citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavors.

The stable sublingual film of buprenorphine and naloxone is formulated by dissolving both drugs; buprenorphine and naloxone in non-aqueous solvent and adding other excipients one by one. Then the blend is coated on release liner and dried. Buprenorphine and Naloxone are in soluble state during blend preparation and coating. Then the roll is slit to specified width and separate release liner. The roll is then print, die cut with specified film size and the films are pouched in specified unit pouch.

The following examples illustrate various aspects of the present invention, and are set forth to assist in understanding the invention. These examples should not be construed as specifically limiting the invention described herein. Variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are considered to fall within the scope of the invention.

[Example follows on the next page]

Example 1

One exemplary formulation of the sublingual film of the present invention is as follows:

Table 1

"Methanol is removed during drying process

Manufacturing procedure for non-aqueous - based buprenorphine and naloxone sublingual film

Buprenorphine and naloxone were added to methanol in SS container and mixed till both drugs solubilize in methanol. Sweetener, color, opacifier and flavor were added one by one and mixed till homogeneous mixture formed. HPC was added to above mixture and mixed till it dissolves. PEG 400 was added and mixed till homogeneous mixture formed. After releasing the blend, blend was coated on release liner. Matrix was dried at 50 -80°C for 20- 60 min at blower speed of 700 RPM. Roll was slit to specified width and separate release liner. Roll size was then print, die cut with specified film size. Then the sublingual films of the present invention were packaged in specified unit pouches.

Stability data of the said sublingual film formulation is shown in Table 2 below. The microscopy of said formulation is depicted in Fig 2, and XRD data in Fig 3. The microscopy of Suboxone film (reference product) is depicted in Fig 1, and XRD data in Fig 4. Stability Data

Table 2 includes stability data for the sublingual film of the present invention. The sublingual buprenorphine and naloxone film of the present invention was stored at 40°C/75% RH and assay and impurities were measured for six months. As can be seen from the results, the sublingual film of the present invention remains within 90% of buprenorphine and naloxone, and total impurities were less than 2 %.

Table 2

Microscopy Data

Fig. 1 shows the microscopy of Suboxone film (reference product) while Fig. 2 shows the microscopy of test product. Buprenorphine and naloxone were solubilized during blending and coating stage as it is solubilized in methanol and polyethylene glycol. However particles may appear in film during long term storage.

[Continued]

XRD Data

Fig. 3 shows the XRD of the test product while Fig. 4 shows the XRD of the Suboxone film (reference product). Based on XRD data, it can be seen that the reference product has more crystal forms than test product. A typical diffraction spectrum consists of a plot of reflected intensities versus the detector angle 2-THETA or THETA. Based on XRD data, the X-ray diffraction pattern of Suboxone film (reference product) has distinct diffraction peaks in XRD pattern, however test product has less distinct diffraction peaks, which infer that Suboxone has comparatively more crystals then test product (test product has less distinct diffraction peaks).

[Continued]

Figure 3:XRD of test product

Figure 4: XRD of reference product

Other Exemplary Formulations

Table 3 contains other exemplary formulations of the sublingual film of the present invention

Table 3

Poly Ethylene Glycol 7.5 10 14.8

Titanium dioxide 0.8 0.8 2

Butylated Hydroxy Toluene 0.08 0.08 0.08

Saccharin 0 0 1

Ascesulfame K 2.8 2.8 2.8 colour 0.1 0.1 0.1

Flavor 3.56 3.56 3.56

Sum 100 100 100

Manufacturing procedure for non-aqueous - based sublingual film:

Manufacturing process is same as above mentioned in example 1

The present invention has been described by reference to some of its preferred embodiments. This description is, however, in no way meant to limit the scope of the invention. Other embodiments that do not depart from the spirit of the invention should be similarly encompassed and addressed by the aforementioned description.