TITLE HOT MELT EXTRUDED FILM CONTAINING SILICON DIOXIDE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 61/131,471, filed on June 9, 2008 which is expressly incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention relates generally to a single or multilayered laminated hot melt extruded film that may be applied to a mucosal surface to deliver a therapeutic agent. More specifically, the hot melt extruded film is based on silicon dioxide, polyethylene oxide, at least one additional polymer, at least one additive, and according to some embodiments, at least one therapeutic agent.

BACKGROUND OF THE INVENTION

[0003] Extrusion processing has been a preferred method of production in the plastics industry for nearly a century and is widely used today to produce films, sheets, and pipes cost effectively. The hot melt extrusion (HME) process has also become accepted in the pharmaceutical industry and the production of solid drug forms by hot melt extrusion is known. U.S. Patent No. 4,880,585, the content of which is hereby incorporated by reference, describes a drug form produced from a hot melt extrusion that contains a therapeutic agent with the aid of a molding calender that directly molds tablets from the melt. U.S. Patent No. 6,375,963, the content of which is hereby incorporated by reference, describes a process for preparing a hot melt extruded film for topical and mucosal adhesion and drug delivery.

[0004] Building on knowledge from the plastics industry, formulators can extrude combinations of drugs, polymers, and excipients into various final forms to achieve desired drug-release profiles. The benefits of using HME over traditional processing techniques such as granulation include: fewer unit operations, better content uniformity, an anhydrous process, a low energy alternative to high-shear granulation, and less processing time compared with conventional wet granulation. Further, HME allows the manufacture of a dispersion mechanism for poorly soluble drugs.

[0005] Oral dosage forms are designed to enable sufficient availability of the therapeutic agent at its site of action. The bioavailability of a drug depends on several parameters, such

as on the physiochemical nature of the active compound, the dosage form, as well as on physiological factors. Many substances obtained from modern drug discovery are problematic because of insufficient bioavailability. Such molecules often exhibit very low aqueous solubility and limited solubility in oils. Nucleoside derivatives, for instance, are often potent antiviral (e.g., HIV, HCV, Herpes simplex, CMV) and anticancer chemotherapeutic agents but their utility is often limited by poor pharmacokinetic properties that limit the absorption of the nucleoside from the gut and the intracellular concentration of the nucleoside derivatives. Furthermore, many substances exhibit significant food effects - i.e., when drugs and certain foods are taken at the same time they can interact in ways that diminish the effectiveness of the ingested drug or reduce the absorption of food nutrients. Some examples of how foods and drugs may interact include: increased or decreased rate of therapeutic action; impaired absorption of vitamins and minerals; stimulation or suppression of appetite; and alteration of how nutrients are used in the body. Additionally, vitamin and herbal supplements taken with prescribed medication can result in adverse reactions.

[0006] The production of thin films by HME for both drug delivery and/or wound care applications therefore offers numerous advantages, including increased efficiency of drug deliver to the patient, over other oral dosage forms including granules, pellets, and tablets also produced by HME. Thin films for transdermal/transmucosal drug delivery devices and wound care applications are known. U.S. Patent No. 6,375,963, the content of which is hereby incorporated by reference, describes a bioadhesive HME film for topical and mucosal adhesion applications and drug delivery.

[0007] However, the production of drug forms, particularly thin films, by HME is accompanied by persistent problems of buildup of the molten extrudate on the die head openings and adhesion to the calendering equipment during the extrusion process. In a typical process, the hot melt-processable polymers and ingredients are blended in an extruder. Through heat, shear, and pressure, the dry powders are fused to form a homogenous, molten material. Through the die head openings, the extruder feeds the molten material in a continuous process to the top of the calendering section in between the first and second heated calender rolls. The rolls rotate in opposite directions to help spread the extrudate across the width of the rolls. The extrudate winds between the first and second, second and third, third and fourth rolls, etc. After passing through the calender section, the material

moves through another series of rolls where it is stretched and gradually cooled forming a film or sheet then wound into master rolls.

[0008] Melt-processable cellulose derivatives such as hydroxypropyl cellulose (HPC) are, as water-soluble polymers, very suitable and frequently used for producing oral dosage forms by HME and calendering. It is also possible by an admixture of other excipients, e.g., hydroxypropylmethyl cellulose (HPMC) polymers that are swellable in water, to control the dissolution times of such drug forms resulting in increased efficiency of drug deliver to the patient, as is disclosed, for example, in DE-A 4226753, the content of which is hereby incorporated by reference. However, when HPC and/or HPMC are used in HME, although the resulting melts may be extruded satisfactorily, in the melted state, these polymers are "sticky" and will adhere to the machinery used in the manufacturing process. This buildup on the die head openings and adhesion to the calender rolls increases until it becomes necessary to routinely halt the extrusion operation to perform maintenance on the die head and calender rolls - frequently after only a few hours of operation. Considerable engineering goes into the design of die openings and calender rolls to minimize buildup and adhesion but no design completely eliminates it.

[0009] Clearly, an HME film composition with a reduced tendency to build up on die head opening and adhere during the calendering is a desirable goal. The present invention is directed to compositions and processes that permit extended operation run times without shutting down the extrusion line for clean-up due to extrudate adhesion and buildup.

SUMMARY OF THE INVENTION

[0010] According to some embodiments, a hot melt extrusion (HME) composition includes silicon dioxide, polyethylene oxide, at least one additional polymer, and at least one additive. According to some embodiments, an HME composition further includes at least one therapeutic agent.

[0011] According to some embodiments, a method of processing a mixture into a thin film includes the steps of: forming a mixture comprising silicon dioxide, polyethylene oxide, at least one additional polymer, and at least one additive; extruding said extrudate to the top of a calendering section; and winding the extrudate into master rolls of thin film. According to some embodiments, a method of processing a hot melt extruded composition into a thin film further includes blending at least one therapeutic agent into a molten extrudate.

[0012] According to some embodiments, a method of drug delivery includes applying to a mucosal surface an HME composition, wherein the extrusion composition includes silicon dioxide, polyethylene oxide, at least one additional polymer, at least one additive, and at least one therapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION

[0013] As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range.

[0014] In some embodiments, a hot melt extrusion (HME) composition includes: (A) at least one detackifier, (B) at least one polymer, and (C) at least one additive. In some embodiments, an HME composition further includes: (D) at least one therapeutic agent. In some embodiments, a method of processing an HME composition includes combining: (A) at least one detackifier, (B) at least one polymer, and (C) at least one additive. In some embodiments, a method of processing an HME composition further includes combining: (D) at least one therapeutic agent with (A), (B), and (C). In some embodiments, a method of drug delivery includes applying to a mucosal surface an HME composition, wherein the extrusion composition includes at least one detackifier, at least one polymer, at least one additive, and at least one therapeutic agent.

[0015] I. Hot Melt Extrusion (HME) Composition

[0016] A. Detackifier

[0017] Different detackifiers may be used in the preparation of an HME composition as known to those who are skilled in the art. Suitable detackifiers for use in the present invention should perform at least three primary functions. First, the detackifier should physically reduce intermolecular and intramolecular association of the polymer resin thereby reducing the adhesion of the molten extrudate to the extrusion/calendering equipment. The second primary function of the detackifier is to allow the extruded film to be wound into a roll and placed in a container without the film either adhering to itself or its container. Further, the detackifier should also act as a glidant, thereby improving the feeding of the powdered/granulated polymers into the extrusion/calendering equipment.

[0018] The detackifϊer may be any inorganic or organic species capable of physically restricting the intermolecular or intramolecular association of the polymer resin in the dry or molten state. Particulate matter such as diatamaceous earth and ground silica having a median particle size of about 6 to about 10 microns are examples of suitable detackifiers useful in the present invention. In one embodiment, the median particle size of a suitable detackifϊer is about 7 microns.

[0019] In preferred embodiments, silicon dioxide is used as a detackifϊer. It has been found, surprisingly, that the addition of even small amounts of silicon dioxide prevents adhesion of a composition of the invention to the processing equipment. One example of commercially available silicon dioxide suitable for use in some embodiments of the present invention includes SIPERNAT® 160PQ produced by Degussa AG. In some embodiments, the HME composition includes silicon dioxide in an amount of about 0.1% to about 30%, more preferably about 1% to about 20%, and most preferably about 1.50% to about 10% by weight.

[0020] B. Polymers

[0021] The term "polymer" as used herein shall include any thermoplastic matrix polymers suitable for use in the present invention. Polymer choice can be a critical factor to obtain the desired drug-release profile during formulation development for an HME composition. Suitable polymers for use in the present invention must facilitate processing in the extruder, generate an acceptable melt viscosity, torque, barrel pressure, drive-motor amperage for processing, and must not result in the degradation of any raw materials. Under a given set of processing conditions, higher viscosity materials generally result in higher values of torque, pressure, and drive-motor amperage. This is significant as all extrusion/calendering equipment have maximum values of these attributes that may not be exceeded without causing damage and degradation to both the equipment and the chemical components of an HME composition.

[0022] In some embodiments, where an HME composition is a pharmaceutical dosage form for use in the present invention, suitable polymers must not only facilitate processing in the extruder, but must also exhibit the desired drug-release profile.

[0023] In some embodiments, an HME composition includes at least one polymer. In some embodiments, an HME composition includes two or more polymers in combination. In

some embodiments, an HME composition includes three or more polymers in combination. In some embodiments, an HME composition includes at least one polymer in an amount of about 60% to about 99%, more preferably about 75% to about 98%, and most preferably about 90% to about 97% by weight. In some embodiments, an HME composition includes two or more polymers in a combined amount of about 60% to about 99%, more preferably about 75% to about 98%, and most preferably about 90% to about 97% by weight. In some embodiments, an HME composition includes three or more polymers in a combined amount of about 60% to about 99%, more preferably about 75% to about 98%, and most preferably about 90% to about 97% by weight.

[0024] Polymers that may be used in accordance with some embodiments of the present invention include, by way of example and without limitation, various hot melt-processable cellulose derivatives, hydroxypropyl cellulose (HPC), polyethylene oxide (PEO), acrylic acid polymers, hydroxyethyl cellulose, homopolymers and copolymers of these polymers and their pharmaceutically acceptable salts, and combinations thereof. In some embodiments, the following polymers may be used: polyacrylates, poly(meth)acrylates, copolymers of acryl and methacryl derivatives, and vinyl compounds (e.g., using the following monomers: acrylic acid, methacrylic acid, acrylic acid ethyl ester, acrylic acid butyl ester, acrylic acid octyl ester, 2-esthylhexylacrylate, 2-hydroxyethyl acrylate and vinyl acetate). Furthermore, polysiloxanes, preferably self-adhesive polysiloxanes; silicone rubbers; hydocarbon polymers, preferably polyisobutylene, polyisoprene, styrene-isoprene-styrene block copolymers and styrene butadiene-styrene block copolymers; pressure sensitive adhesive preparations based on cellulose derivatives (e.g., ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose) and adhesive resins (e.g., colophony and colophony derivatives) may be used in some embodiments. Using the above described polymers, it is possible to produce an HME film that has pressure-sensitive adhesive properties.

[0025] i. Polyethylene oxide

[0026] In some embodiments, suitable polymers for use in the present invention include low viscosity, water-soluble, thermoplastic polyethylene oxide (PEO). Polyethylene oxide is a white, free-flowing, hydrophilic, crystalline polymer powder available in 100,000- 7,000,000 Da molecular weights. PEO is suitable for use in the present invention due in part to its broad processing window. Using PEO in HME formulations also allows for a dry, continuous, efficient process; reduces processing steps; and no compressibility requirements

[0034] C. Additives

[0035] Suitable additives for use in the present invention include any compound that may by way of example and without limitation: improve the film composition, drug stability and solubility, control drug release, enhance bioadhesion, reduce or increase matrix erosion time, modify extrusion characteristics or physical properties of the extrudate and film, and does not otherwise interfere with the efficacy or results in the degradation of the other components of an HME composition. Suitable additives for use in the present invention include but are not limited to: pH modifying or buffering agents to improve drug stability and solubility; cross- linking agents to reduce matrix erosion time, control drug release, or enhance bioadhesion; antioxidants to inhibit oxidation and deterioration of preparations by oxidation; release rate modifiers; chelating agents; thickening agents (e.g., alginates, pectin); stabilizers (e.g., polyethoxylated sorbitan fatty acid esters such as TWEEN® or polyethoxylated fatty alcohols such as BRIJ®); surfactants; preservatives to prevent the growth of microorganisms (e.g., sorbic acid and its salts); paraben; fiavorants, sweeteners (e.g., aspartame, saccharine), colorants (e.g., quinoline yellow or TiO ₂ ), and/or fragrance to impart a pleasant flavor, color, and/or odor to a extrudated composition; skin-penetration enhancers; organic acids and bases; α-hydroxy and β-hydroxy acids; tartaric acid; citric acid; succinic acid and combinations thereof.

[0036] In some embodiments, an HME composition includes at least one additive. In some embodiments, an HME composition includes a pH modifying or buffering agent. In some embodiments, an HME composition includes citric acid. In some embodiments, an HME composition includes a pH modifying or buffering agent in an amount of about 0.01% to about 5%, more preferably 0.1% to about 2.5%, and most preferably 0.5% to about 1% by weight.

[0037] In some embodiments, an HME composition includes an antioxidant. In some embodiments, the antioxidant is butylated hydroxytoluene. In some embodiments, an HME composition includes an antioxidant in an amount of about 0.01% to about 2%, more preferably 0.05% to about 1%, most preferably about 0.1% to about 0.5% by weight.

[0038] D. Therapeutic agent

[0039] In some embodiments, an HME film includes and delivers a therapeutically effective amount of a therapeutic agent. Any molecular weight drug and its equivalent forms

- 8 -

may be used in the present invention. Suitable therapeutic agents for use in the present invention may be any drug or compound that can be administered through the skin or a mucosal surface and does not decompose under the conditions of melt extrusion. As used herein, "mucosal surface" means any moist anatomical membrane or surface on a mammal including but not limited to oral, buccal, vaginal, nasal, rectal, or ophthalmic surfaces.

[0040] The amount of the therapeutic agent component in the complete preparation can vary within wide limits depending on the activity and release rate. For most drugs, their passage through the skin or mucosa will be the rate-limiting step in delivery. Thus, the amount of drug and the rate of release are typically selected so as to provide delivery characterized by a pseudo-zero order time dependency for a prolonged period of time. The minimum amount of drug in the system is selected based on the amount of drug which passes through the skin or mucosa in the time span for which the device is to provide a therapeutically effective amount. Thus, the content of therapeutic agent in the present invention can be in the range from about 0% to about 45%, more preferably from about 2.5% to about 25%, and most preferably from about 5% to about 10%, of the total weight of the preparation. The only conditions are that the preparation is still HME-processable and the therapeutic agent may be administered through the skin or mucosal surface.

[0041] Preferred therapeutic agents are hydrophilic, not relatively volatile or reactive with the other extrusion components, and may be incorporated into an HME composition. In some embodiments, the therapeutic agent is a component integral to the molten extrudate. In some embodiments, therapeutic agents not stable under the temperature and shearing conditions of an HME process may be applied to the extruded films using techniques that are known to those skilled in the art. By way of example and without limitation, these therapeutic agents can be dissolved in a solvent and coated onto the extruded films.

[0042] Suitable therapeutic agents for use in the present invention by way of example and without limitation include: analgesics, androgens, anesthethics, anoretics, anti-acne agents, antibiotics, anticholinergics, anti-diabetic agents, anti-fungals, antihistamines, antiinflammatory agents, anti-malarials, anti-migraine agents, anti-Parkinson's and/or anti- Alzhiemers's agents, anti-psychotics and/or anti-anxiety agents, antiseptics, anti-ulcerative agents, anti-virals, anxiolytic agents, α- and β-adrenergic agonists, central nervous system stimulants and agents, chemotherapeutic agents, cholinergics, enzymes, estrogens, hormones, muscle relaxants, minerals, narcotic antagonist agents, peptides, progestational agents,

- 9 -

may be used in the present invention. Suitable therapeutic agents for use in the present invention may be any drug or compound that can be administered through the skin or a mucosal surface and does not decompose under the conditions of melt extrusion. As used herein, "mucosal surface" means any moist anatomical membrane or surface on a mammal including but not limited to oral, buccal, vaginal, nasal, rectal, or ophthalmic surfaces.

[0040] The amount of the therapeutic agent component in the complete preparation can vary within wide limits depending on the activity and release rate. For most drugs, their passage through the skin or mucosa will be the rate-limiting step in delivery. Thus, the amount of drug and the rate of release are typically selected so as to provide delivery characterized by a pseudo-zero order time dependency for a prolonged period of time. The minimum amount of drug in the system is selected based on the amount of drug which passes through the skin or mucosa in the time span for which the device is to provide a therapeutically effective amount. Thus, the content of therapeutic agent in the present invention can be in the range from about 0% to about 45%, more preferably from about 2.5% to about 25%, and most preferably from about 5% to about 10%, of the total weight of the preparation. The only conditions are that the preparation is still HME-processable and the therapeutic agent may be administered through the skin or mucosal surface.

[0041] Preferred therapeutic agents are hydrophilic, not relatively volatile or reactive with the other extrusion components, and may be incorporated into an HME composition. In some embodiments, the therapeutic agent is a component integral to the molten extrudate. In some embodiments, therapeutic agents not stable under the temperature and shearing conditions of an HME process may be applied to the extruded films using techniques that are known to those skilled in the art. By way of example and without limitation, these therapeutic agents can be dissolved in a solvent and coated onto the extruded films.

[0042] Suitable therapeutic agents for use in the present invention by way of example and without limitation include: analgesics, androgens, anesthethics, anoretics, anti-acne agents, antibiotics, anticholinergics, anti-diabetic agents, anti-fungals, antihistamines, anti- inflammatory agents, anti-malarials, anti-migraine agents, anti-Parkinson's and/or anti- Alzhiemers's agents, anti-psychotics and/or anti-anxiety agents, antiseptics, anti-ulcerative agents, anti-virals, anxiolytic agents, α- and β-adrenergic agonists, central nervous system stimulants and agents, chemotherapeutic agents, cholinergics, enzymes, estrogens, hormones, muscle relaxants, minerals, narcotic antagonist agents, peptides, progestational agents,

proteins, and others known to those of ordinary skill in the medical arts, and combinations thereof.

[0043] In some particular embodiments, the therapeutic agent is an opioid analgesic. In one embodiment, the opioid analgesic is fentanyl citrate. In one embodiment, the fentanyl citrate is present in an amount of about 0.01% to about 25%, more preferably from about 0.5% to about 10%, and most preferably from about 1% to about 5% by weight.

[0044] II. Method of Processing a Hot Melt Extrusion (HME) Composition

[0045] Processing conditions, equipment design, polymer selection, and the various uses of additives in the formulation are some of the factors that effect an HME composition. In the present invention, the components are processed in a conventional way in extruders, preferably in single or twin screw extruders at a temperature in the range of about 50°C to about 200 ⁰ C. Shaping the extrudate into the solid compositions according to the present invention can take place, for example, by calendering the extrudate and converting it into thin films.

[0046] In a calendering process line in accordance with the present invention, the polymer resin is blended with specific ingredients such as stabilizers to prevent thermal degradation; modifiers for clarity, heat stability or opacity characteristics; pigments; lubricants and processing aids; anti-static agents; UV inhibitors; and flame retardants. The mixed ingredients are blended in a kneader or extruder. Through heat, shear and pressure, the dry powders are fused to form a homogenous, molten material. The extruder feeds the molten material in a continuous process to the top of the calendering section of the calendering line in between first and second heated calender rolls. Typically, four rolls are used to form three nips or gaps. The rolls are configured in an "L" shape or an inverted "L" shape or they may be in other configurations. The rolls vary in size to accommodate different film widths. The rolls have separate temperature and speed controls.

[0047] The material proceeds through the nip between the first two rolls, referred to as the feed nip. The rolls rotate in opposite directions to help spread the material across the width of the rolls. The material winds between the first and second, second and third, third and fourth rolls, etc. The gap between rolls decreases in thickness between each of the rolls so that the material is thinned between the sets of rolls as it proceeds. After passing through the calender section, the material moves through another series of rolls where it is stretched and

gradually cooled forming a film or sheet. The cooled material is then wound into master rolls.

[0048] In one embodiment, a method of processing an HME composition into a thin film includes the continuous process steps of: (a) blending at least one detackifier (e.g., silicon dioxide), at least one hot melt processable polymer, polyethylene oxide, and at least one hot melt processable additive into a molten extrudate; (b) extruding said extrudate to the top of the calendering section; and (c) winding the extrudate into master rolls of thin film. In some embodiments, a method of processing an HME composition into a thin film further comprises blending at least one therapeutic agent into the molten extrudate.

[0049] III. Method of Drug Delivery

[0050] The present invention relates in particular to administration forms for application on the skin or mucosa. Generally, these transdermal/transmucosal administration forms are of a flat-shaped film structure and enable the administration of systemically active therapeutic agents via the skin or mucosa, it being possible to release said therapeutic agents to the skin or mucosa to be absorbed, continuously over a predetermined period of time and at a defined release rate. If the HME composition of the present invention is constituted so as to be disintegratable or degradable, the particles in the film can be released as such and subsequently the therapeutic agent contained in the particles can be released. If the particles are made of biodegradable material, the release may be influenced or accelerated by degradation of the particle material. In this way the present invention opens numerous possibilities of controlling the delivery of therapeutic agents. Furthermore, the release of the therapeutic agents may also take place in such manner that the particles migrate or diffuse from the HME film through the skin or mucosa, and subsequently deliver the therapeutic agent to the circulation.

[0051] In some embodiments of the present invention, a method of drug delivery includes applying to a mucosal surface a hot melt extruded film composition, wherein the film composition includes at least one detackifier (e.g., silicon dioxide), polyethylene oxide, at least one additional polymer, at least one additive, and at least one therapeutic agent.

[0052] III. Examples

[0053] The following examples further describe and demonstrate some embodiments within the scope of the present invention. These examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention as many variations thereof are possible without departing from the scope and spirit of the present invention.

Example 1: Hot melt extrusion composition (with silicon oxide)

[0054] Although the foregoing description is directed to the preferred embodiments of the invention, it is noted that other variations and modifications in the details, materials, steps and arrangement of parts, which have been herein described and illustrated in order to explain the nature of the preferred embodiments of the invention, will be apparent to those skilled in the art, and may be made without departing from the spirit or scope of the invention.