WO2015195605A1

WO2015195605A1 - Transmucosal delivery of glatiramer acetate by oral patches

Info

Publication number: WO2015195605A1
Application number: PCT/US2015/035933
Authority: WO
Inventors: Ursula GEISTER; Ralph Stefan; Stephan SCHWELZER; Gerald Huber; Martina BUERGER; Tanja PRIES
Original assignee: Teva Pharmaceutical Industries Ltd; Teva Pharmaceuticals USA Inc
Current assignee: Teva Pharmaceutical Industries Ltd; Teva Pharmaceuticals USA Inc
Priority date: 2014-06-17
Filing date: 2015-06-16
Publication date: 2015-12-23
Anticipated expiration: 2016-12-17

Abstract

The present invention provides an oral patch comprising: a) a liner; and b) film composition thereon, the film composition comprising: glatiramer acetate in an amount greater than 40 percent to about 80 percent by weight of the film composition; and one or more film forming agents in a total amount from about 20 percent to about 80 percent by weight of the film composition.

Description

TRA SMUCOSAL DELIVERY OF GLATIRAMER ACETATE BY ORAL PATCHES

This application claims priority of U.S. Provisional Application No. 62/013,310, filed June 17, 2014, the entire content of which is hereby incorporated by reference herein.

Throughout this application various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains .

BACKGROUND OF THE INVENTION Multiple Sclerosis

Multiple Sclerosis (MS) is a chronic, debilitating disease of the central nervous system (CNS) . MS has also been classified as an autoimmune disease. MS disease activity can be monitored by magnetic resonance imaging (MRI) of the brain, accumulation of disability, as well as rate and severity of relapses.

There are five main forms of multiple sclerosis: 1) Benign Multiple Sclerosis:

Benign multiple sclerosis is a retrospective diagnosis which is characterized by 1-2 exacerbations with complete recovery, no lasting disability and no disease progression for 10-15 years after the initial onset. Benign multiple sclerosis may, however, progress into other forms of multiple sclerosis.

2) Relapsing-Re itting Multiple Sclerosis (RRMS):

Patients suffering from RRMS experience sporadic exacerbations or relapses, as well as periods of remission. Lesions and evidence of axonal loss may or may not be visible on MRI for patients with RRMS.

3) Secondary Progressive Multiple Sclerosis (SPMS) :

SPMS may evolve from RRMS. Patients afflicted with SPMS have relapses, a diminishing degree of recovery during remissions, less frequent remissions and more pronounced neurological deficits than RRMS patients. Enlarged ventricles, which are markers for atrophy of the corpus callosum, midline center and spinal cord, are visible on MRI of patients with SPMS.

4) Primary Progressive Multiple Sclerosis (PPMS);

PPMS is characterized by a steady progression of increasing neurological deficits without distinct attacks or remissions. Cerebral lesions, diffuse spinal cord damage and evidence of axonal loss are evident on the MRI of patients with PPMS.

5) Progressive-Relapsing Multiple Sclerosis (PRMS):

PRMS has periods of acute exacerbations while proceeding along a course of increasing neurological deficits without remissions. Lesions are evident on MRI of patients suffering from PRMS (Multiple sclerosis: its diagnosis, symptoms, types and stages, 2003, albany.net/ . about . tjc/multiple-sclerosis.html; What are the Types of Multiple Sclerosis?, 2005, <imaginis.com/multiple- sclerosis/types-of-ms . asp? mode=l>) .

Chronic progressive multiple sclerosis is a term used to collectively refer to SPMS, PPMS, and PRMS (Types of Multiple Sclerosis (MS), 2005, <themcfox.com/multiple-sclerosis/types- of-ms/types-of-multi-ple-sclerosis .htm>) . The relapsing forms of multiple sclerosis are SPMS with superimposed relapses, RRMS and PRMS.

A clinically isolated syndrome (CIS) is a single monosymptomatic attack compatible with MS, such as optic neuritis, brain stem symptoms, and partial myelitis. Patients with CIS that experience a second clinical attack are generally considered to have clinically definite multiple sclerosis (CDMS) . Over 80 percent of patients with a CIS and MRI lesions go on to develop MS, while approximately 20 percent have a self-limited process (Frohman et al., The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology, Neurology 61(5):602-11 (2003)). Multiple sclerosis may present with optic neuritis, blurring of vision, diplopia, involuntary rapid eye movement, blindness, loss of balance, tremors, ataxia, vertigo, clumsiness of a limb, lack of co-ordination, weakness of one or more extremity, altered muscle tone, muscle stiffness, spasms, tingling, paraesthesia, burning sensations, muscle pains, facial pain, trigeminal neuralgia, stabbing sharp pains, burning tingling pain, slowing of speech, slurring of words, changes in rhythm of speech, dysphagia, fatigue, bladder problems (including urgency, frequency, incomplete emptying and incontinence) , bowel problems (including constipation and loss of bowel control) , impotence, diminished sexual arousal, loss of sensation, sensitivity to heat, loss of short term memory, loss of concentration, or loss of judgment or reasoning. Glatiramer Acetate

Glatiramer acetate (GA) , a mixture of polypeptides which do not all have the same amino acid sequence, is marketed under the tradename Copaxone®. GA comprises the acetate salts of polypeptides containing L-glutamic acid, L-alanine, L-tyrosine and L-lysine at average molar fractions of 0.141, 0.427, 0.095 and 0.338, respectively. The average molecular weight of Copaxone® is between 5,000 and 9,000 daltons. ("Copaxone", Physician's Desk Reference, (2005), Medical Economics Co., Inc., (Montvale, N.J.), 3115.) Chemically, glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L-lysine, L- tyrosine, acetate (salt) . Its structural formula is:

(Glu,Ala,Lys,Tyr) .xCH₃COOH

(C₅H₉N04.C₃H₇N0₂.C6H14 2O2. C9H11NO3) .XC2H4O2

CAS-147245-92-9

Copaxone® ("Copaxone", Full Prescribing Information, (February, 2009) , FDA Marketing Label) (20mg glatiramer acetate daily injection) is an approved therapy for patients with relapsing remitting multiple sclerosis (RRMS) , including patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis.

GA has also been disclosed for use in the treatment of other autoimmune diseases (U.S. Patent Publication No. 2002/0055466 Al (R. Aharoni et al . ) , inflammatory non-autoimmune diseases (U.S. Patent Publication No. 2005/0014694 Al (V. Wee Yong et al.); and U.S. Patent Application No. 2002/0077278 Al, published Jun. 20, 2002 (Young et al . ) ) and other diseases (U.S. Patent Publication Nos . 2003/0004099 Al and 2002/0037848 Al (Eisenbach- Schwartz, et al . ) ; U.S. Pat. No. 6,514,938 Bl, issued Feb. 4, 2003 (Gad et al . ) ; PCT International Publication No. WO 01/60392, published Aug. 23, 2001 (Gilbert et al . ) ; PCT International Publication No. WO 00/27417, published May 19, 2000 (Aharoni et al . ) ; and PCT International Publication No. WO 01/97846, published Dec. 27, 2001 (Moses et al . ) .

The 20mg/day subcutaneous (s.c.) dose has been shown to reduce the total number of enhancing lesions in MS patients as measured by MRI (G. Comi et al . , European/Canadian Multicenter, Double- Blind, Randomized, Placebo-Controlled Study of the Effects of Glatiramer Acetere on Magnetic Resonance Imaging-Measured Disease Activity and Burden in Patients with Relapsing Multiple Sclerosis, Ann. Neurol. 49:290-297 (2001)) .

Safety data accumulated for GA in clinical trials shows that the drug product is safe and well tolerated. However, reactions including Immediate Post-Injection Reaction (IPIR) consisting of one or more of the following symptoms: vasodilatation, chest pain, dyspnoea, palpitations or tachycardia was reported for 31% of the GA patients vs. 13% on placebo. Additional adverse reactions reported by patients treated with GA 20mg with at least 2% higher incidence than with placebo were pain, nausea, anxiety, rash, back pain, chills, face edema, local reaction, lymphadenopathy, vomiting, weight increase, tremor, skin disorder, eye disorder, vaginal candidiasis and injection site atrophy.

In all clinical trials, in ection-site reactions were seen to be the most frequent adverse reactions and were reported by the majority of patients receiving GA. In controlled studies, the proportion of patients reporting these reactions, at least once, was higher following treatment with GA (70%) than placebo injections (37%) . The most commonly reported injection-site reactions, which were more frequently reported in GA vs. placebo-treated patients, were erythema, pain, mass, pruritus, edema, inflammation and hypersensitivity.

In addition to the observed adverse events, administration by injection can be burdensome which can lead to poor patient compliance or suspension of therapy. Accordingly, there exists a need to develop alternative routes of glatiramer acetate delivery in which the glatiramer acetate is effective in treating a symptom of a form of multiple sclerosis. Alternatives to Glatiramer Acetate Injection

Glatiramer acetate administration through ingestion or inhalation has been disclosed (U.S. Patent 6,214,791); and compositions for oral, nasal and pulmonary administration also have been disclosed (U.S. Patent Application Publication No. 2001/0055568 Al) . Studies in mice showed that orally administered glatiramer acetate inhibited the induction of experimental autoimmune encephalomyelitis (EAE) in rats and mice and suggested that oral administration of glatiramer acetate may modulate multiple sclerosis as well (Teitelbaum et al . , Immunomodulation of experimental autoimmune encephalomyelitis by oral administration of copolymer 1, Immunology 96:3842-3847 (1999)). However, alternative routes of administration have yet to be demonstrated to be effective in the treatment of multiple sclerosis. For example, glatiramer acetate administered orally did not affect relapse rate or other clinical MRI parameters of disease activity in a recent clinical trial (Filippi et al, Effects of oral glatiramer acetate on clinical and MRI-monitored disease activity in patients with relapsing multiple sclerosis: a multicentre, double-blind, randomised, placebo-controlled study, Lancet Neurol. 5(3):213-220 (2006)).

Buccal administration avoids hepatic metabolism and gastrointestinal degradation which can hinder effectiveness of orally administered drugs and provides an attractive alternative to oral administration. However, the buccal mucosa is not an absorptive organ and permeation of the drug to be administered is problematic. Other problems to be overcome include drug stability and formulation palatability. Advantages of Mucoadhesive Buccal Drug Delivery System

Drugs administered via oral mucosa offers several ad-vantages

• Ease of administration.

• Termination of therapy is easy.

• Permits localization of drug to the oral cavity for a prolonged period of time.

• Can be administered to unconscious patients.

• Offers an excellent route, for the systemic delivery of drugs with high first pass metabolism, thereby offering a greater bioavailability.

• A significant reduction in dose can be achieved there by reducing dose related side effects.

• Drugs which are unstable in the acidic environment are destroyed by enzymatic or alkaline environment of intestine can be administered by this route.

• Drugs which show poor bioavailability via the oral route can be administered conveniently.

• It offers a passive system of drug absorption and does not require any activation.

• The presence of saliva ensures relatively large amount of water for drug dissolution unlike in case of rectal and transdermal routes .

• Systemic absorption is rapid.

• This route provides an alternative for the administration of various hormones, narcotic analgesic, steroids, enzymes , cardiovascular agents etc . The buccal mucosa is highly perfused with blood vessels and offers a greater permeability than the skin.

SUMMARY OF THE INVENTION

The present invention provides an oral patch comprising: a) a liner; and b) a film composition thereon, the film composition comprising: glatiramer acetate in an amount greater than 40 percent to about 80 percent by weight of the film composition; and one or more film forming agents in a total amount from about 20 percent to about 80 percent by weight of the film composition. The present invention also provides an oral patch comprising: a) a liner; and b) a film composition thereon, the film composition comprising: glatiramer acetate in an amount from about 10 percent to about 80 percent by weight of the film composition; and one or more film forming agents in a total amount from about 20 percent to about 80 percent by weight of the film composition, wherein the film forming agent is an acetate or acrylate polymer.

The present invention also provides an oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 14 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i. poly (ethyl acrylate-co-methyl methacrylate) 2:lpresent in the film composition in an amount of about 70 percent by weight of the film composition; and ii. l-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.4 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 7 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 7 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.4 percent by weight of the film composition, wherein the patch is about 10 cm2 , wherein the patch contains about 20mg glatiramer acetate.

The present invention also provides an oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 47 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i. poly(ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1:2:0.2 present in the film composition in an amount of about 28 percent by weight of the film composition; and ii. 1-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises an adhesion powder which comprises carbopol (sodium salt) present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the patch is about 10 cm2, wherein the patch contains about 50mg glatiramer acetate.

The present invention also provides an oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 47 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i. poly(ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1:2:0.1 present in the film composition in an amount of about 28 percent by weight of the film composition; and ii. l-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises an adhesion powder which comprises carbopol (sodium salt) present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the patch is about 10 cm2 , wherein the patch contains about 50mg glatiramer acetate. The present invention also provides an oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 47 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i. poly (ethyl acrylate-co-methyl methacrylate) 2 : lpresent in the film composition in an amount of about 28 percent by weight of the film composition; and ii. l-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises an adhesion powder which comprises carbopol (sodium salt) present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the patch is about 10 cm2, wherein the patch contains about 50mg glatiramer acetate. The present invention also provides an oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 47 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i. poly(ethyl acrylate-co-methyl methacrylate) 2 : lpresent in the film composition in an amount of about 28 percent by weight of the film composition; and ii. l-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises an adhesion powder which comprises carbopol (sodium salt) present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the patch is about 10 cm2, wherein the patch contains about 50mg glatiramer acetate.

The present invention also provides a method of treating an disease in a patient in need thereof comprising periodically contacting an oral patch of the present invention to the buccal tissue of the patient, so as thereby to treat the patient, wherein the disease is multiple sclerosis, relapsing remitting multiple sclerosis, clinically isolated syndrome, an autoimmune disease, an inflammatory non-autoimmune disease, an immune- mediated disease, an arthritic condition, a demyelinating disease, rheumatoid arthritis, osteoarthritis, autoimmune hemolytic anemia, autoimmune oophoritis, autoimmune thyroiditis, autoimmune uveoretinitis , Crohn's disease, chronic immune thrombbcytopenic purpura, colitis, contact sensitivity disease, diabetes mellitus, Graves disease, Guillain-Barre ' s syndrome, Hashimoto's disease, idiopathic myxedema, myasthenia gravis, psoriasis, pemphigus vulgaris, systemic lupus erythematosus, host-versus-graft disease (HVGD) , graft-versus- host disease (GVHD) , and delayed-type hypersensitivity (DTH) , injury or disease of the central or peripheral nervous system, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) , diabetic neuropathy, senile dementia, ischemia, acute disseminated encephalomyelitis, transverse myelitis, demyelinating genetic diseases, spinal cord injury, virus-induced demyelination, Progressive Multifocal Leucoencephalopathy, Human Lymphotrophic T-cell Virus I (HTLVI)- associated myelopathy and nutritional metabolic disorders. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. Schematic of the oral patch. The support layer is removed before packaging and is used for physical support during production. The insoluble layer represents the liner. The adhesion powder is sprinkled on the upper surface of the oral film in order to adhere the film to the buccal mucosa. The insoluble liner ensures that glatiramer acetate is not diluted in the mouth and defines the permeation direction.

Figure 2. Average permeation of glatiramer acetate across a porcine buccal membrane. Data series are presented as follows: glatiramer acetate solution without pre-incubated tissue (triangular markers, solid line) , glatiramer acetate oral patch (square markers, solid line) and glatiramer acetate solution with DMSO pre-incubated tissue (square markers, dotted line) .

DETAILED DESCRIPTION OF THE INVENTION Terms

As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below.

As used herein, an "amount" or "dose" of an agent measured in milligrams refers to the milligrams of agent present in a drug product, regardless of the form of the drug product.

Administration of different amounts of glatiramer acetate using oral patches of the present invention can be accomplished by applying one, two, three, four or five oral patches at the same time or consecutively or by applying a portion of an oral patch. For example ¼ of an oral patch can be obtained by cutting an oral patch once and ¾ of an oral patch can be obtained by cutting an oral patch twice.

Administration of an amount from about 5 to about 100 mg of glatiramer acetate can be achieved using the oral patches of the present invention. For Example, administration of 5 mg glatiramer acetate can be accomplished by applying ¾ of an oral patch containing 20 mg glatiramer acetate and administration of 10 mg glatiramer acetate can be accomplished by applying ½ of an oral patch containing 20 mg glatiramer acetate. Likewise, administration of 20, 40, 60, 80 or 100 mg glatiramer acetate can be accomplished, for example, by applying 1, 2, 3, 4 or 5 oral patches containing 20 mg glatiramer acetate, respectively. Similarly, administration of 100 mg glatiramer acetate can be accomplished, for example, by applying a single oral patch containing 100 mg glatiramer acetate, or by applying 2 oral patches containing 50 mg glatiramer acetate, etc. As used herein, the term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient (s) and the inert ingredient (s) that make up the carrier, as well as any product which results, directly or indirectly from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

As used herein, an "adhesion powder" is a powdered substance present on the surface of the oral film in order to adhere the film to the buccal mucosa. An example of an adhesion powder is carbomer (sodium salt) . A specific example is Carbopol®, available from The Lubrizol Corporation, Wickliffe, Ohio.

As used herein, a "liner layer" is an insoluble film which provides unidirectional drug delidelivery. An example of a liner layer is a neutral copolymer based on butyl methacrylate and methyl methacrylate in which the monomers are randomly distributed along the copolymer chain. A specific example is PLASTOID® B, available from Evonik Industries AG, Darmstadt, Germany. The weight average molar mass (Mw) of PLASTOID® B obtained by viscometry is approximately 150,000 g/mol.

As used herein, "film forming agents" are agents which form a matrix which allows for controlled release of an active ingredient. Film forming agents include, but are not limited to, polyethylene glycol, acrylate polymers and acetate polymers. Example acrylate polymers include poly(ethyl aerylate-co-methyl methacrylate), poly (ethyl acrylate-co-methyl methacrylate) 2:1 (such as Eudragit® NE, available from Evonik Industries AG, Darmstadt, Germany) , poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) , poly (ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1:2:0.2 (such as Eudragit® RL, available from Evonik Industries AG, Darmstadt, Germany) , poly(ethyl aerylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1:2:0.1 (such as Eudragit® RS, available from Evonik Industries AG, Darmstadt, Germany) and poly(ethyl acrylate-co-methyl methacrylate) 2:1 (such as Eudragit® NM, available from Evonik Industries AG, Darmstadt, Germany) . Examples of acetate polymers include polyvinal acetate and l-vinyl-2-pyrrolidone-vinyl acetate copolymer (such as Kollidon® VA 64, available from BASF Corporation, Florham Park, New Jersey. A specific example of a film forming agent comprising polyvinal acetate is a mixture of polyvinal acetate and povidone, such as Kollidon® SR, available from BASF Corporation, Florham Park, New Jersey.

As used herein, "softening agents" are agents which reduce rigidity of the film composition. Softening agents include alkyl citrates such as triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl triethyl citrate, and acetyl tributyl citrate; alkyl acetates such as triethyl acetate, acetyl triethyl acetate, tributyl acetate, acetyl triethyl acetate, and acetyl tributyl acetate; sucrose fatty acid esters; glycerin mono-, di- and tri-fatty acid esters such as triacetin, glycerin mono-fatty acid esters, glycerin monostearate and acetylated monoglyceride; polyglycerin fatty acid esters; polyethylene glycols such as PEG400, PEG600, PEG1500, PEG4000, PEG6000 dibutyl sebacate; tributyl sebacate; vinyl pyrrolidone; propylene glycol; castor oil; glycerin; phytosterol; alkyl phthalates such as diethyl phthalate, dibutyl phthalate and dioctyl phthalate; adipate polyesters; medium chain triglyceride; butyl phthalyl butyl glycolate; polyoxyethylene polyoxypropylene glycol; and combinations thereof. As used herein, "permeation enhancers" are agents which increase bioavailability of the active ingredient. Permeation enhancers include, but are not limited to, DMSO, n-Dodecyl nitrogen heterocyclic heptane-2-ketone, propylene glycol, isopropylmyristat, d, 1-alpha-toccopherol and oleic acid.

As used herein, "flavourant" include sweeteners including but not limited to acesulfam, saccharin-sodium, aspartame, and stevia. Other suitable flavourants can include, for example, flavors, which are known to those of skill in the art, such as, for example, natural flavors, artificial flavors, and combinations thereof. Flavourants are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Flavoring agents may be chosen, e.g., from synthetic flavor oils and flavoring aromatics and/or oils, oleoresins, extracts derived from plants, leaves, flowers, fruits, and the like, and combinations thereof. Non-limiting examples of flavor oils include spearmint oil, cinnamon oil, oil of wintergreen (methyl salicylate), peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, allspice, oil of sage, mace, oil of bitter almonds, and cassia oil. Suitable flavoring agents also include, for example, artificial, natural and synthetic flower derived or fruit flavors such as vanilla, ethyl vanillin, citrus oils (e.g., lemon, orange, tangerine, lime, and grapefruit), and fruit essences (e.g., natural and/or artificial flavor of apple, pear, peach, orange, grape, strawberry, raspberry, cherry, plum, pineapple, and apricot), and the like, and combinations thereof. The flavourants may be used in liquid or solid form and, as indicated above, may be used individually or in admixture. Other flavourants can include, for example, certain aldehydes and esters, e.g., cinnamyl acetate, cinnamaldehyde, citral diethylacetal, dihydrocarvyl acetate, eugenyl formate, p- methylamisol , and the like, and combinations thereof. They can be liquids or spray-dried, co-processed powders.

Pharmaceutical compositions of the present invention can optionally comprise one or more colorants, flavors, and/or fragrances to enhance the visual appeal, taste, and/or scent of the composition. Suitable colorants, flavors, or fragrances are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the chemical stability, the physical stability or the biological activity of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises a colorant, a flavor, and/or a fragrance. For example, the pharmaceutical composition comprises less than about 1 wt% (e.g., less than about 0.75 wt% or less than about 0.5 wt%) of each optionally ingredient, i.e., colorant, flavor and/or fragrance, by weight of the composition. In another example, the pharmaceutical composition comprises less than about 1 wt% (e.g., less than about 0.75 wt% or less than about 0.5 wt%) of a colorant. In still another example, the pharmaceutical composition comprises less than about 1 wt% (e.g., less than about 0.75 wt% or less than about 0.5 wt%) of a blue colorant (e.g., FD&C Blue #1 and/or FD&C Blue #2 Aluminum Lake, commercially available from Colorcon, Inc. of West Point, PA.)

As used herein, colorants can include, but are not limited to, Annatto extract, Dehydrated beets (beet powder) , Canthaxanthin, Caramel, β-Αρο-8 ' -carotenal, β-Carotene, Cochineal extract, Carmine, Sodium copper chlorophyllin, Toasted partially defatted cooked cottonseed flour, Ferrous gluconate, Ferrous lactate, Grape color extract, Grape skin extract (enocianina) , Synthetic iron oxide, Fruit juice, Vegetable juice, Carrot oil, Paprika, Paprika oleoresin, Mica-based pearlescent pigments, Riboflavin, Saffron, Titanium dioxide, Tomato lycopene extract; tomato lycopene concentrate, Turmeric, Turmeric oleoresin, FD&C Blue No. 1, FD&C Blue No. 2, FD&C Green No. 3, Orange B, Citrus Red No. 2, FD&C Red No. 3, FD&C Red No. 40, FD&C Yellow No. 5, FD&C Yellow No. 6, Alumina (dried aluminum hydroxide), Calcium carbonate, Canthaxanthin, Potassium sodium copper chlorophyllin (chlorophyllin-copper complex) , Dihydroxyacetone, Bismuth oxychloride, Synthetic iron oxide, Ferric ammonium ferrocyanide, Ferric ferrocyanide, Chromium hydroxide green, Chromium oxide greens, Guanine, Pyrophyllite, Mica, Talc, Aluminum powder, Bronze powder, Copper powder, Zinc oxide, D&C Blue No. 4, D&C Green No . 6, D&C Green No. 8, D&C Orange No. 4, D&C Orange No. 5, D&C Orange No. 10, D&C Orange No. 11, FD&C Red No. 4, D&C Red No. 6, D&C Red No. 7, D&C Red No. 17, D&C Red No. 21, D&C Red No. 22, D&C Red No. 27, D&C Red No. 28, D&C Red No. 30, D&C Red No. 31, D&C Red No. 33, D&C Red No. 34, D&C Red No. 36, D&C Red No. 39, D&C Violet No. 2, D&C Yellow No. 7, Ext. D&C Yellow No. 7, D&C Yellow No. 8, D&C Yellow No. 10 and D&C Yellow No. 11.

As used herein, a "perfusion enhancer" is an agent which increases blood flow to the capillary beds. Perfusion enhancers can include, but are not limited to, capsaicin and apitoxin and DMSO.

Acetic acid, as used herein, is an added in order to provoke a faster onset of an immune reaction. Relapsing Form of Multiple Sclerosis:

The term relapsing MS includes:

1) patients with RRMS;

2) patients with SPMS and superimposed relapses; and

3) patients with CIS who show lesion dissemination on subsequent MRI scans according to McDonald's criteria.^"

As used herein, relapsing forms of multiple sclerosis include: Relapsing-remitting multiple sclerosis (RRMS) , characterized by unpredictable acute episodes of neurological dysfunction (relapses) , followed by variable recovery and periods of clinical stability; Secondary Progressive MS (SPMS), wherein patients having RRMS develop sustained deterioration with or without relapses superimposed; and

Primary progressive-relapsing multiple sclerosis (PPRMS) or progressive-relapsing multiple sclerosis (PRMS) , an uncommon form wherein patients developing a progressive deterioration from the beginning can also develop relapses later on.

Embodiments o£ the Invention

The present invention provides an oral patch comprising: a) a liner; and b) a film composition thereon, the film composition comprising: glatiramer acetate in an amount greater than 40 percent to about 80 percent by weight of the film composition; and one or more film forming agents in a total amount from about 20 percent to about 80 percent by weight of the film composition. In one or more embodiments one of the one or more film forming agents is polyethylene glycol.

The present invention also provides an oral patch comprising: a) a liner; and b) a film composition thereon, the film composition comprising: glatiramer acetate in an amount from about 10 percent to about 80 percent by weight of the film composition; and one or more film forming agents in a total amount from about 20 percent to about 80 percent by weight of the film composition, wherein the film forming agent is an acetate or acrylate polymer.

In one or more embodiments the glatiramer acetate is present in the film composition in an amount from about 10 percent to about 20 percent by weight of the film composition.

In one or more embodiments the glatiramer acetate is present in the film composition in an amount from about 13 percent to about 14 percent by weight of the film composition. In one or more embodiments the glatiramer acetate is present in the film composition in an amount from about 20 percent to about 80 percent by weight of the film composition.

In one or more embodiments the glatiramer acetate is present in the film composition in an amount from about 45 percent to about 55 percent by weight of the film composition.

In one or more embodiments the glatiramer acetate is present in the film composition in an amount of about 47-48 percent by weight of the film composition. In one or more embodiments the film forming agents are present in the film composition in a total amount from about 25 percent to about 50 percent by weight of the film composition.

In one or more embodiments the film forming agents are present in the film composition in a total amount from about 25 percent to about 40 percent by weight of the film composition.

In one or more embodiments the film forming agents are present in the film composition in a total amount from about 25 percent to about 35 percent by weight of the film composition.

In one or more embodiments the film forming agents are present in the film composition in a total amount from about 30 percent to about 31 percent by weight of the film composition.

In one or more embodiments the film forming agents are present in the film composition in a total amount from about 60 percent to about 75 percent by weight of the film composition. In one or more embodiments the film forming agents are present in the film composition in a total amount from about 70 percent to about 71 percent by weight of the film composition.

In one or more embodiments the film composition further comprises an adhesion powder, wherein the adhesion powder is present in the film composition in a total amount up to about 10 percent by weight of the film composition.

In one or more embodiments the adhesion powder is present in the film composition in a total amount from about 0.5 percent to about 5 percent by weight of the film composition.

In one or more embodiments the adhesion powder is present in the film composition in a total amount from about 1 percent to about 2 percent by weight of the film composition.

In one or more embodiments the adhesion powder is present on the surface of the film composition which is opposite the surface of the liner and is the exposed surface of the film composition.

In one or more embodiments the film composition further comprises one or more softening agents, wherein the softening agents are present in the film composition in an amount up to about 30 percent by weight of the film composition.

In one or more embodiments the softening agents are present in the film composition in an amount from about 5 percent to about 20 percent by weight of the film composition.

In one or more embodiments the softening agents are present in the film composition in an amount from about 5 percent to about 10 percent by weight of the film composition.

In one or more embodiments the softening agents are present in the film composition in an amount from about 9 percent to about 10 percent by weight of the film composition. In one or more embodiments the softening agents are present in the film composition in an amount from about 6 percent to about 7 percent by weight of the film composition.

In one or more embodiments the film composition further comprises one or more fillers, wherein the fillers are present in the film composition in a total amount up to about 50 percent by weight of the film composition.

In one or more embodiments the fillers are present in the film composition in a total amount from about 5 percent to about 45 percent by weight of the film composition.

In one or more embodiments the fillers are present in the film composition in a total amount from about 5 percent to about 10 percent by weight of the film composition.

In one or more embodiments the fillers are present in the film composition in a total amount from about 9 percent to about 10 percent by weight of the film composition.

In one or more embodiments the fillers are present in the film composition in a total amount from about 6 percent to about 7 percent by weight of the film composition. In one or more embodiments the film composition further comprises one or more gel forming agents, wherein the gel forming agents are present in the film composition in a total amount up to about 5 percent by weight of the film composition.

In one or more embodiments the gel forming agents are present in the film composition in a total amount from about 0.5 percent to about 5 percent by weight of the film composition.

In one or more embodiments the gel forming agents are present in the film composition in a total amount from about 1 percent to about 2 percent by weight of the film composition. In one or more embodiments the film composition further comprises one or more permeation enhancers, wherein the permeation enhancers are present in the film composition in a total amount up to about 10 percent by weight of the film composition. In one or more embodiments the film composition further comprises one or more flavorant, wherein the flavorants are present in the film composition in a total amount up to about 10 percent by weight of the film composition. In one or more embodiments the film composition further comprises a pigment, wherein the pigment are present in the film composition in an amount up to about 5 percent by weight of the film composition.

In one or more embodiments the one or more film forming agents are selected from the group consisting of poly(ethyl acrylate- co-methyl methacrylate) , poly (ethyl acrylate-co-methyl methacrylate) 2:1, poly (ethyl acrylate-co-methyl methacrylate- co-trimethylammonioethyl methacrylate chloride) , poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1, poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2, polyvinal acetate, a mixture of polyvinal acetate and povidone, an 80:19 mixture of polyvinal acetate and povidone and l-vinyl-2-pyrrolidone-vinyl acetate copolymer. In one or more embodiments the adhesion powder is selected from the group consisting of carbomer (sodium salt) , xanthan gum, gum Arabic and carbophil.

In one or more embodiments the softening agent is selected from the group consisting of alkyl citrates such as triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl triethyl citrate, and acetyl tributyl citrate; alkyl acetates such as triethyl acetate, acetyl triethyl acetate, tributyl acetate, acetyl triethyl acetate, and acetyl tributyl acetate; sucrose fatty acid esters; glycerin mono-, di- and tri-fatty acid esters such as triacetin, glycerin mono-fatty acid esters, glycerin monostearate and acetylated monoglyceride; polyglycerin fatty acid esters; polyethylene glycols such as PEG400, PEG600, PEG1500, PEG4000, PEG6000 dibutyl sebacate; tributyl sebacate; vinyl pyrrolidone; propylene glycol; castor oil; glycerin; phytosterol; alkyl phthalates such as diethyl phthalate, dibutyl phthalate and dioctyl phthalate; adipate polyesters; medium chain triglyceride; butyl phthalyl butyl glycolate; polyoxyethylene polyoxypropylene glycol; and combinations thereof .

In one or more embodiments the one or more fillers are selected from the group consisting of sorbitol, mannitol and glycerol. In one or more embodiments the one or more gel forming agents are selected from the group consisting of hydroxyethyl cellulose, carbomer, hydroxypropyl cellulose and hydroxypropyl methylcellulose .

In one or more embodiments the one or more film forming agents comprises poly (ethyl acrylate-co-methyl methacrylate) 2:1, wherein the poly (ethyl acrylate-co-methyl methacrylate) 2:1 is present in the film composition in an amount from about from about 60 percent to about 80 percent by weight of the film composition. In one or more embodiments the poly (ethyl acrylate-co-methyl methacrylate) 2:1 is present in the film composition in an amount from about from about 69 percent to about 70 percent by weight of the film composition.

In one or more embodiments the one or more film forming agents comprises poly (ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1:2:0.2, wherein the poly (ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1:2:0.2 is present in the film composition in an amount from about from about 25 percent to about 50 percent by weight of the film composition.

In one or more embodiments the poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 is present in the film composition in an amount from about from about 28 percent to about 29 percent by weight of the film composition. In one or more embodiments the one or more film forming agents comprises poly(ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1:2:0.1, wherein the poly(ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1:2:0.1 is present in the film composition in an amount from about from about 25 percent to about 50 percent by weight of the film composition.

In one or more embodiments the poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl' methacrylate chloride) 1:2:0.1 is present in the film composition in an amount from about from about 28 percent to about 29 percent by weight of the film composition.

In one or more embodiments the one or more film forming agents comprises poly(ethyl acrylate-co-methyl methacrylate) 2:1, wherein the poly(ethyl acrylate-co-methyl methacrylate) 2:1 is present in the film composition in an amount from about from about 25 percent to about 50 percent by weight of the film composition.

In one or more embodiments the poly (ethyl acrylate-co-methyl methacrylate) 2 : 1 is present in the film composition in an amount from about from about 28 percent to about 29 percent by weight of the film composition.

In one or more embodiments the poly (ethyl aerylate-co-methyl methacrylate) 2:1 is present in the film composition in an amount from about from about 28 percent to about 29 percent by weight of the film composition.

In one or more embodiments the one or more film forming agents comprises 1-vinyl-2 -pyrrolidone-vinyl acetate copolymer, wherein the l-vinyl-2-pyrrolidone-vinyl acetate copolymer is present in the film composition in an amount from about from about 0.1 percent to about 45 percent by weight of the film composition.

In one or more embodiments the l-vinyl-2-pyrrolidone-vinyl acetate copolymer 64 is present in the film composition in an amount from about from about 1 percent to about 2 percent by weight of the film composition.

In one or more embodiments the adhesion powder comprises carbomer (sodium salt) , wherein the carbomer (sodium salt) is present in the film composition in an amount from about from about 1 percent to about 10 percent by weight of " the film composition.

In one or more embodiments the carbomer (sodium salt) is present in the film composition in an amount from about from about 1 percent to about 2 percent by weight of the film composition.

In one or more embodiments the one or more softening agents comprises polyethylene glycol, wherein the polyethylene glycol is present in the film composition in an amount from about from about 5 percent to about 20 percent by weight of the film composition.

In one or more embodiments the polyethylene glycol is present in the film composition in an amount of about 9 percent by weight of the film composition.

In one or more embodiments the polyethylene glycol is present in the film composition in an amount of about 7 percent by weight of the film composition. In one or more embodiments the one or more fillers comprises sorbitol, wherein the sorbitol is present in the ^ilm composition in an amount from about^' from about 5 percent to about 20 percent by weight of the film composition.

In one or more embodiments the sorbitol is present in the film composition in an amount of about 9 percent by weight of the film composition.

In one or more embodiments the sorbitol is present in the film composition in an amount of about 7 percent by weight of the film composition. In one or more embodiments the one or more gel forming agents comprises hydroxyethyl cellulose, wherein the hydroxyethyl cellulose is present in the film composition in an amount from about from about 0.5 percent to about 5 percent by weight of the film composition. In one or more embodiments the hydroxyethyl cellulose is present in the film composition in an amount from about from about 1 percent to about 2 percent by weight of the film composition.

In one or more embodiments the patch is about 5 to about 15 cm2.

In one or more embodiments the patch is about 10 cm2. In one or more embodiments the patch contains about lOmg to about lOOmg glatiramer acetate.

In one or more embodiments the patch contains about 20mg glatiramer acetate. In one or more embodiments the patch contains about 50mg glatiramer acetate.

In one or more embodiments the liner is a butyl methacrylate, methyl methacrylate copolymer liner. The present invention also provides an oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 14 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i. poly(ethyl acrylate-co-methyl methacrylate) 2:lpresent in the film composition in an amount of about 70 percent by weight of the film composition; and ii. 1-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.4 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 7 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 7 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.4 percent by weight of the film composition, wherein the patch is about 10 cm2, wherein the patch contains about 20mg glatiramer acetate. The present invention also provides an oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 47 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i. poly(ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1:2:0.2 present in the film composition in an amount of about 28 percent by weight of the film composition; and ii. l-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises an adhesion powder which comprises carbopol (sodium salt) present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the patch is about 10 cm2, wherein the patch contains about 50mg glatiramer acetate.

The present invention also provides an oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 47 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i. poly (ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1:2:0.1 present in the film composition in an amount of about 28 percent by weight of the film composition; and ii . l-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film^' composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises an adhesion powder which comprises carbopol (sodium salt) present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the patch is about 10 cm2 , wherein the patch contains about 50mg glatiramer acetate.

The present invention also provides an oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 47 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i. poly (ethyl acrylate-co-methyl methacrylate) 2 : lpresent in the film composition in an amount of about 28 percent by weight of the film composition; and ii. 1-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises an adhesion powder which comprises carbopol (sodium salt) present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the patch is about 10 cm2, wherein the patch contains about 50mg glatiramer acetate.

The present invention also provides an oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 47 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i. poly(ethyl acrylate-co-methyl methacrylate) 2 : lpresent in the film composition in an amount of about 28 percent by weight of the film composition; and ii. l-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises an adhesion powder which comprises carbopol (sodium salt) present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the patch is about 10 cm2, wherein the patch contains about 50mg glatiramer acetate.

In one or more embodiments, the oral patch further comprises a support layer in contact with the liner.

In one or more embodiments the support layer is a polyethylene terephthalate (PET) support layer.

The present invention also provides a method of treating an ^• disease in a patient in need thereof comprising periodically contacting an oral patch of the present invention to the buccal tissue of the patient, so as thereby to treat the patient, wherein the disease is multiple sclerosis, relapsing remitting multiple sclerosis, clinically isolated syndrome, an autoimmune disease, an inflammatory non-autoimmune disease, an immune- mediated disease, an arthritic condition, a demyelinating disease, rheumatoid arthritis, osteoarthritis, autoimmune hemolytic anemia, autoimmune oophoritis, autoimmune thyroiditis, autoimmune uveoretinitis, Crohn's disease, chronic immune thrombbcytopenic purpura, colitis, contact sensitivity disease, diabetes mellitus, Graves disease, Guillain-Barre' s syndrome, Hashimoto's disease, idiopathic myxedema, myasthenia gravis, psoriasis, pemphigus vulgaris, systemic lupus erythematosus, host-versus-graft disease (HVGD) , graft-versus- host disease (GVHD) , and delayed-type hypersensitivity (DTH) , injury or disease of the central or peripheral nervous system, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) , diabetic neuropathy, senile dementia, ischemia, acute disseminated encephalomyelitis, transverse myelitis, demyelinating genetic diseases, spinal cord injury, virus-induced demyelination, Progressive Multifocal Leucoencephalopathy, Human Lymphotrophic T-cell Virus I (HTLVI) - associated myelopathy and nutritional metabolic disorders.

As used herein, "about" with regard to a stated number encompasses a range of +10 percent to -10 percent of the stated value. By way of example, about 100 mg therefore includes the range 90-110 mg and therefore also includes 90, 91, 92, 93, 94, 95 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109 and 110 mg. Accordingly, about 100 mg includes, in an embodiment, 100 mg.

It is understood that where a parameter range is provided, all integers within that range, tenths thereof, and hundredths thereof, are also provided by the invention. For example, "0.2- 5 mg" is a disclosure of 0.2 mg, 0.21 mg, 0.22 mg, 0.23 mg etc. up to 0.3 mg, 0.31 mg, 0.32 mg, 0.33 mg etc. up to 0.4 mg, 0.5 mg, 0.6 mg etc. up to 5.0 mg. All combinations of the various elements described herein are within the scope of the invention. This invention is illustrated in the Experimental Details section which follows. This section is set forth to aid in an understanding of the invention but is not intended to, and should not be construed to; limit in any way the invention as set forth in the claims which follow thereafter.

Examples Example 1

Oral patches are prepared with the film composition set forth in Table 1. Table 1:

Example 2

Oral patches are prepared with the film composition set forth in Table 2. Table 2: function mg/10cm² %

Glatiramer acetate 50 47.17

Eudragit RL 30% suspension film 100.00 28.30 forming

Poly (ethyl acrylate-co-methyl

agent

methacrylate-co- trimethylammonioethyl

methacrylate chloride) 1:2:0.2

PEG 1500 Softening 10 9.43 agent Sorbitol Filler and 10 9.43 humectant

Kollidon VA 64 film 2.00 1.89 Polyvinylacetate Povidone forming

mixture 80/19 agent

HEC250G Gelling 2.00 1.89

Hydroxyethyl cellulose

agent

Carbopol 980 sodium salt Adhesion 2.00 1.89 powder

TOTAL 176.00 100.00

Example 3

Oral patches are prepared with the film composition set forth in Table 3. Table 3: function mg/lOcm² %

Glatiramer acetate 50 47.17

Eudragit RS 30% suspension film 100.00 28.30 Poly(ethyl acrylate-co-methyl forming

agent

methacrylate-co- trimethylammonioethyl

methacrylate chloride) 1:2:0.1

PEG 1500 Softening 10 9.43 agent

Sorbitol Filler and 10 9.43 humectant

Kollidon VA 64 film 2.00 1.89 Polyvinylacetate Povidone forming

mixture 80/19 agent HEC250G Geling 2.00 1.89

Hydroxyethyl cellulose

agent

Carbopol 980 sodium salt Adhesion 2.00 1.89 powder

TOTAL 176.00 100.00

Example 4

Oral patches are prepared with the film composition set forth in Table 4. Table 4:

Example 5 Oral patches are prepared with the film composition set forth in Table 5.

Table 5:

Example 6

Oral patches are prepared with the film composition set forth in Table 6.

Table 6: function mg/10cm² %

Glatiramer acetate 50 47.17 Kollidon SR 30% suspension film forming 100.00 28.30 agent

Polyvinylacetate Povidone

mixture 80/19

PEG 1500 Softening 10 9.43 agent

Sorbitol Filler and 10 9.43 humectant

Kollidon VA 64 film forming 2.00 1.89 Polyvinylacetate Povidone agent

mixture 80/19

HEC250G Geling agent 2.00 1.89

Hydroxyethyl cellulose

Carbopol 980 sodium salt Adhesion 2.00 1.89 powder

TOTAL 176.00 100.00

Example 7

For a batch size of 1000cm² oral patches were prepared as follows:

GA was dissolved in lOg water

Sorbitol, PEG und Copovidone was dissolved in 5g water

Both solutions were put together and continously stirred.

Eudragit/Kollidon SR were used as 30% dispersion and added to the API solution and stirred for a minimum of 5 minutes on a magnetic stirrer.

The pre weight gelling agent Hydroxyethylcellulose was added and stirred for a minimum of 2 hours . The coating suspension was coated on a Plastoid B film at 176g/m². The Plastoid B film itself was supported by a support layer (PET) . The entire intermediate (PET support layer, insoluble liner layer and coating suspension) was dried at 60°C for 15 minutes in a cabinet dryer.

The coating knife was adjusted so that after drying the films the dry coating weight was 154g/m².

After drying and cooling for 15 minutes the film was powdered with Carbopol through a sieve with a mesh size of 500um. The PET support layer was removed before packaging.

Example 8

Oral patches are prepared according to Examples 1-7, above. A batch of patches is stored at room temperature (about 25 °C) and under refrigeration (about 4 °C) . Samples from each batch are periodically examined for stability of the glatiramer acetate. The results demonstrate that glatiramer acetate stability in the oral patches of the present invention is acceptable.

Example 9

Transport and preparation of the buccal tissue Porcine buccal tissue was obtained from a slaughterhouse. Immediately after slaughter of the pig, pieces bearing the buccal tissue were dissected from the cheek and stored in PBS pH 7.4 and cooled on ice. The buccal tissue was isolated from the inner cheek with a scalpel and used fresh. Subsequently, the suitability of the tissue biopsy was assessed. The exclusion criteria were tissue damage or scarring.

Freshly prepared buccal tissue was cut into stripes . Tissue sections with a thickness of approx. 700 - 800 um were then prepared with a dermatome. The dermatome was applied to the buccal tissue. Then the tissue was cut with 24 mm punch.

Permeation study

The cylindrical Franz cell is a diffusion chamber comprising an upper and a lower part between which the porcine buccal tissue was clamped. The two halves of the cell were held together by means of a ball and socket clamp. The lower (acceptor) chamber has a volume of approx. 12 ml, while the volume of the upper (donor) chamber is variable. The tissue specimens are punched out immediately prior to insertion in the Franz cells. The tissue is always inserted with the connective tissue (lamina propia and submucosa) facing downwards so that the mucosal epithelium layer is uppermost.

The medium temperature was adjusted to 37 °C and continuously stirred at a rate of 400 rpm. The diffusion area of the porcine buccal tissue in the Franz cell was approx. 1.77 cm².

The experiments were performed with six replicates for the glatiramer acetate oral films. The film was punched in discs (diameter 13 mm) which was fit into the donor chamber of the Franz cells and placed on the porcine buccal tissue. Before placing the film on the tissue 300 μΐ of PBS-buffer was applied to moisturize the tissue. Films were touched only with a pincer to avoid drug release prior to the permeation experiment of the film. Experiments utilizing the GA solution were performed in triplicate. For each replicate, 300 μΐ of the formulation was applied per 1.77 cm² porcine buccal tissue at the start of the experiment. For experiments with permeation enhancer 100 μΐ DMSO was applied to the buccal tissue 30 minutes before the glatiramer acetate solution was applied because glatiramer acetate is not soluble in a mixture of DMSO / PBS 50:50 v/v% . Permeation through the porcine buccal tissue into the acceptor medium was monitored over a period of 4 hours . The acceptor medium was sampled at 6 different points of time (30, 60, 90, 120, 180 and 240 min) . Determination of glatiramer acetate

Table 7 shows results for the permeation studies described above .

Table 7:

The results are shown in Figure 2 which displays the average permeation of the different formulations. Glatiramer acetate solution without pre-incubated tissue (triangular markers, solid line) , glatiramer acetate oral patch (square markers, solid line) and glatiramer acetate solution with DMSO pre-incubated tissue (square markers, dotted line) .

DISCUSSION

Cellulose derivative film forming agents are commonly used in oral patches. Applicants have discovered that film compositions containing these film forming agents break down upon the addition of glatiramer acetate and are therefore not suitable for the formulation of a film composition comprising glatiramer acetate. This problem was solved by the use of non-erodible film forming agents such as acrylic polymers. These polymers are typically used in tablet formulations. Surprisingly, applicants have discovered that, while such a film is dissolves like an immediate release formulation, in vitro tests with porcine buccal tissue showed that the oral patches deliver glatiramer acetate through the mucosa over the course of about 4 hours, as desired. In order to avoid dissolution into the saliva, which would be swallowed, the film was built as a multilayer system with an insoluble liner. The insoluble liner is on the saliva side, when the film is administrated.

In addition, applicants have discovered that it is desirable to provide a mechanism to adhere the film composition to the buccal mucosa. Applicants have solved this problem by the inclusion of an adhesion powder which is sprinkled on top of the film composition after drying.

Claims

What is claimed:

1. An oral patch comprising: a) a liner; and b) a film composition thereon, the film composition comprising: glatiramer acetate in an amount greater than 40 percent to about 80 percent by weight of the film composition; and one or more film forming agents in a total amount from about 20 percent to about 80 percent by weight of the film composition.

2. The oral patch of claim 1, wherein one of the one or more film forming agents is polyethylene glycol.

3. An oral patch comprising: a) a liner; and b) a film composition thereon, the film composition comprising: glatiramer acetate in an amount from about 10 percent to about 80 percent by weight of the film composition; and one or more film forming agents in a total amount from about 20 percent to about 80 percent by weight of the film composition, wherein the film forming agent is an acetate or acrylate polymer.

4. The oral patch of claim 3 , wherein the glatiramer acetate is present in the film composition in an amount from about 10 percent to about 20 percent by weight of the film composition; or in an amount from about 13 percent to about 14 percent by weight of the film composition.

5. The oral patch of claim 3, wherein the glatiramer acetate is present in the film composition in an amount from about 20 percent to about 80 percent by weight of the film composition.

6. The oral patch of any one of claims 1-3, wherein the glatiramer acetate is present in the film composition in an amount from about 45 percent to about 55 percent by weight of the film composition; or in an amount of about 47-48 percent by weight of the film composition.

7. The oral patch of any one of claims 1-6, wherein the film forming agents are present in the film composition in a total amount from about 25 percent to about 50 percent by weight of the film composition; in a total amount from about 25 percent to about 40 percent by weight of the film composition; in a total amount from about 25 percent to about 35 percent by weight of the film composition; or in a total amount from about 30 percent to about 31 percent by weight of the film composition.

8. The oral patch of any one of claims 1-6, wherein the film forming agents are present in the film composition in a total amount from about 60 percent to about 75 percent by weight of the film composition; or in a total amount from about 70 percent to about 71 percent by weight of the film composition.

9. The oral patch of any one of claims 1-8, wherein the film composition further comprises an adhesion powder, wherein the adhesion powder is present in the film composition in a total amount up to about 10 percent by weight of the film composition; in a total amount from about 0.5 percent to about 5 percent by weight of the film composition; or in a total amount from about 1 percent to about 2 percent by weight of the film composition.

10. The oral patch of claim 9, wherein the adhesion powder is present on the surface of the film composition which is opposite the surface of the liner and is the exposed surface of the film composition.

11. The oral patch of any one of claims 1-9, wherein the film composition further comprises one or more softening agents, wherein the softening agents are present in the film composition in an amount up to about 30 percent by weight of the film composition; in an amount from about 5 percent to about 20 percent by weight of the film; in an amount from about 5 percent to about 10 percent by weight of the film; in an amount from about 9 percent to about 10 percent by weight of the film composition; or in an amount from about 6 percent to about 7 percent by weight of the film.

12. The oral patch of any one of claims 1-11, wherein the film composition further comprises one or more fillers, wherein the fillers are present in the film composition in a total amount up to about 50 percent by weight of the film composition; or in a total amount from about 5 percent to about 45 percent by weight of the film; in a total amount from about 5 percent to about 10 percent by weight of the film.

13. The oral patch of claim 12, wherein the fillers are present in the film composition in a total amount from about 9 percent to about 10 percent by weight of the film composition.

14. The oral patch of claim 12, wherein the fillers are present in the film composition in a total amount from about 6 percent to about 7 percent by weight of the film composition.

15. The oral patch of any one of claims 1-14, wherein the film composition further comprises one or more gel forming agents, wherein the gel forming agents are present in the film composition in a total amount up to about 5 percent by weight of the film composition; in a total amount from about 0.5 percent to about 5 percent by weight of the film composition; or in a total amount from about 1 percent to about 2 percent by weight of the film composition.

16. The oral patch of any one of claims 1-15, wherein the film composition further comprises one or more permeation enhancers, wherein the permeation enhancers are present in the film composition in a total amount up to about 10 percent by weight of the film composition.

17. The oral patch of any one of claims 1-16, wherein the film composition further comprises one or more flavorant, wherein the flavorants are present in the film composition in a total amount up to about 10 percent by weight of the film composition.

18. The oral patch of any one of claims 1-17, wherein the film composition further comprises a pigment, wherein the pigment are present in the film composition in an amount up to about 5 percent by weight of the film composition.

19. The oral patch of any one of claims 1-18, wherein the one or more film forming agents are selected from the group consisting of poly(ethyl acrylate-co-methyl methacrylate) , poly (ethyl acrylate-co-methyl methacrylate) 2:1, poly (ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) , poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1, poly (ethyl acrylate-co- methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2, polyvinal acetate, a mixture of polyvinal acetate and povidone, an 80:19 mixture of polyvinal acetate and povidone and l-vinyl-2-pyrrolidone- vinyl acetate copolymer.

20. The oral patch of any one of claims 9-19, wherein the adhesion powder is selected from the group consisting of carbomer (sodium salt) , xanthan gum, gum Arabic and carbophil.

21. The oral patch of any one of claims 11-20, wherein the softening agent is selected from the group consisting of alkyl citrates such as triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl triethyl citrate, and acetyl tributyl citrate; alkyl acetates such as triethyl acetate, acetyl triethyl acetate, tributyl acetate, acetyl triethyl acetate, and acetyl tributyl acetate; sucrose fatty acid esters; glycerin mono-, di- and tri-fatty acid esters such as triacetin, glycerin mono-fatty acid esters, glycerin monostearate and acetylated monoglyceride; polyglycerin fatty acid esters; polyethylene glycols such as PEG400, PEG600, PEG1500, PEG4000, PEG6000 dibutyl sebacate; tributyl sebacate; vinyl pyrrolidone; propylene glycol; castor oil; glycerin; phytosterol; alkyl phthalates such as diethyl phthalate, dibutyl phthalate and dioctyl phthalate; adipate polyesters; medium chain triglyceride; butyl phthalyl butyl glycolate; polyoxyethylene polyoxypropylene glycol; and combinations thereof.

22. The oral patch of any one of claims 12-21, wherein the one or more fillers are selected from the group consisting of sorbitol, mannitol and glycerol.

23. The oral patch of any one of claims 15-22, wherein the one or more gel forming agents are selected from the group consisting of hydroxyethyl cellulose, carbomer, hydroxypropyl cellulose and hydroxypropyl methylcellulose.

24. The oral patch of any one of claims 1-23, wherein the one or more film forming agents comprises poly (ethyl acrylate- co-methyl methacrylate) 2:1, wherein the poly (ethyl acrylate-co-methyl methacrylate) 2:1 is present in the film composition in an amount from about from about 60 percent to about 80 percent by weight of the film composition; or in an amount from about from about 69 percent to about 70 percent by weight of the film composition.

25. The oral patch of any one of claims 1-23, wherein the one or more film forming agents comprises poly (ethyl acrylate- co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2, wherein the poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 is present in the film composition in an amount from about from about 25 percent to about 50 percent by weight of the film composition; or in an amount from about from about 28 percent to about 29 percent by weight of the film composition.

26. The oral patch of any one of claims 1-23, wherein the one or more film forming agents comprises poly (ethyl acrylate- co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1, wherein the poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1 is present in the film composition in an amount from about from about 25 percent to about 50 percent by weight of the film composition; or in an amount from about from about 28 percent to about 29 percent by weight of the film composition.

27. The oral patch of any one of claims 1-23, wherein the one or more film forming agents comprises poly (ethyl acrylate- co-methyl methacrylate) 2:1, wherein the poly (ethyl acrylate-co-methyl methacrylate) 2:1 is present in the film composition in an amount from about from about 25 percent to about 50 percent by weight of the film composition; in an amount from about from about 28 percent to about 29 percent by weight of the film composition.

28. The oral patch of any one of claims 1-23, wherein the one or more film forming agents comprises poly (ethyl acrylate- co-methyl methacrylate) 2:1, wherein the poly(ethyl acrylate-co-methyl methacrylate) 2:1 is present in the film composition in an amount from about from about 25 percent to about 50 percent by weight of the film composition; or in an amount from about from about 28 percent to about 29 percent by weight of the film composition.

29. The oral patch of any one of claims 1-28, wherein the one or more film forming agents comprises l-vinyl-2- pyrrolidone-vinyl acetate copolymer, wherein the 1-vinyl- 2-pyrrolidone-vinyl acetate copolymer is present in the film composition in an amount from about from about 0.1 percent to about 45 percent by weight of the film composition; or in an amount from about from about 1 percent to about 2 percent by weight of the film composition.

30. The oral patch of any one of claims 9-29, wherein the adhesion powder comprises carbomer (sodium salt) , wherein the carbomer (sodium salt) is present in the film composition in an amount from about from about 1 percent to about 10 percent by weight of the film composition; or in an amount from about from about 1 percent to about 2 percent by weight of the film composition.

31. The oral patch of any one of claims 11-30, wherein the one or more softening agents comprises polyethylene glycol, wherein the polyethylene glycol is present in the film composition in an amount from about from about 5 percent to about 20 percent by weight of the film composition; in an amount of about 9 percent by weight of the film composition; or in an amount of about 7 percent by weight of the film composition.

32. The oral patch of any one of claims 12-31, wherein the one or more fillers comprises sorbitol, wherein the sorbitol is present in the film composition in an amount from about from about 5 percent to about 20 percent by weight of the film composition; in an amount of about 9 percent by weight of the film composition; or in an amount of about 7 percent by weight of the film composition.

33. The oral patch of any one of claims 15-32, wherein the one or more gel forming agents comprises hydroxyethyl cellulose, wherein the hydroxyethyl cellulose is present in the film composition in an amount from about from about 0.5 percent to about 5 percent by weight of the film composition; or in an amount from about from about 1 percent to about 2 percent by weight of the film composition.

34. The oral patch of any one of claims 1-33, wherein the patch is about 5 to about 15 cm²; or is about 10 cm².

35. The oral patch of any one of claims 1-34, wherein the patch contains about lOmg to about lOOmg glatiramer acetate; about 20mg glatiramer acetate; or about 50mg glatiramer acetate .

36. The oral patch of any one of claims 1-35, wherein the liner is a butyl methacrylate, methyl methacrylate copolymer liner .

37. An oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 14 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i. poly (ethyl acrylate-co-methyl methacrylate)

2 : lpresent in the film composition in an amount of about 70 percent by weight of the film composition; and ii. l-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.4 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 7 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 7 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.4 percent by weight of the film composition, wherein the patch is about 10 cm², wherein the patch contains about 20mg glatiramer acetate. An oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 47 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i . poly (ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1:2:0.2 present in the film composition in an amount of about 28 percent by weight of the film composition; and ii . l-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises an adhesion powder which comprises carbopol (sodium salt) present in the film composition in an amount of about 1.9 percent by- weight of the film composition, wherein the patch is about 10 cm², wherein the patch contains about 50mg glatiramer acetate. An oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 47 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i. poly(ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1:2:0.1 present in the film composition in an amount of about 28 percent by weight of the film composition; and ii. l-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises an adhesion powder which comprises carbopol (sodium salt) present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the patch is about 10 cm², wherein the patch contains about 50mg glatiramer acetate.

An oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 47 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise: i. poly (ethyl acrylate-co-methyl methacrylate)

2 : lpresent in the film composition in an amount of about 28 percent by weight of the film composition; and ii. 1-vinyl-2-pyrrolidone- inyl acetate copolymer present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises an adhesion powder which comprises carbopol (sodium salt) present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the patch is about 10 cm², wherein the patch contains about 50mg glatiramer acetate. An oral patch comprising: a) a butyl methacrylate, methyl methacrylate copolymer liner; and b) a film composition thereon, the film composition comprising glatiramer acetate in an amount of about 47 percent by weight of the film composition and film forming agents, wherein the film forming agents comprise : i. poly (ethyl acrylate-co-methyl methacrylate)

2 : lpresent in the film composition in an amount of about 28 percent by weight of the film composition; and ii. l-vinyl-2-pyrrolidone-vinyl acetate copolymer present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises a softening agent which comprises polyethylene glycol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a filler / humectant which comprises sorbitol present in the film composition in an amount of about 9 percent by weight of the film composition, wherein the film composition further comprises a gelling agent which comprises hydroxyethyl cellulose present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the film composition further comprises an adhesion powder which comprises carbopol (sodium salt) present in the film composition in an amount of about 1.9 percent by weight of the film composition, wherein the patch is about 10 cm², wherein the patch contains about 50mg glatiramer acetate.

42. The oral patch of any one of claims 1-41, further comprising a support layer in contact with the liner.

43. The oral patch of claim 42, wherein the support layer is a polyethylene terephthalate (PET) support layer. A method of treating an disease in a patient in need thereof comprising periodically contacting an oral patch of any one of claims 1-43 to the buccal tissue of the patient, so as thereby to treat the patient, wherein the disease is multiple sclerosis, relapsing remitting multiple sclerosis, clinically isolated syndrome, an autoimmune disease, an inflammatory non-autoimmune disease, an immune- mediated disease, an arthritic condition, a demyelinating disease, rheumatoid arthritis, osteoarthritis, autoimmune hemolytic anemia, autoimmune oophoritis, autoimmune thyroiditis, autoimmune uveoretinitis , Crohn's disease, chronic immune thrombbcytopenic purpura, colitis, contact sensitivity disease, diabetes mellitus, Graves disease, Guillain-Barre ' s syndrome, Hashimoto's disease, idiopathic myxedema, myasthenia gravis, psoriasis, pemphigus vulgaris, systemic lupus erythematosus, host-versus-graft disease (HVGD) , graft-versus-host disease (GVHD) , and delayed-type hypersensitivity (DTH) , injury or disease of the central or peripheral nervous system, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) , diabetic neuropathy, senile dementia, ischemia, acute disseminated encephalomyelitis, transverse myelitis, demyelinating genetic diseases, spinal cord injury, virus-induced demyelination, Progressive Multifocal Leucoencephalopathy, Human Lymphotrophic T-cell Virus I (HTLVI) -associated myelopathy and nutritional metabolic disorders.