(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`
`
`(43) International Publication Date
`20 January 2005 (20.01.2005)
`
`(10) International Publication Number
`
`PCT
`
`WO 2005/004989 A2
`
`(51) International Patent Classification7:
`
`A61P
`
`(21) International Application Number:
`PCT/US2004/021038
`
`(22) International Filing Date:
`
`30 June 2004 (30.06.2004)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/484,009
`60/497,426
`
`1 July 2003 (01.07.2003)
`21 August 2003 (21.08.2003)
`
`US
`US
`
`(71) Applicant and
`(72) Inventor: MAIBACH, TODD [US/US]; 1050 Lassen
`Drive, Menlo Park, CA 94024 (US).
`
`(74) Agents: SUNG, Lawrence et al.; Prestom Gates Ellis &
`Rouvelas Meeds LLP, 1735 New York Avenue NW, Suite
`500, Washington, DC 20006 (US).
`
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GII, GM, IIR, IIU, ID, IL, IN, IS, JP, KE.
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI,
`SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`without international search report and to be republished
`upon receipt of that report
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`
`For tworletter codes and other abbreviations, refer to the ”Guide
`ance Notes on Codes and Abbreviations ” appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: FILM COMPRISING THERAPEUTIC AGENTS
`
`
`
`005/004989A2|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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`N (57) Abstract: The present invention is related to the composition and methods of manufacture of orally—dissolvable, edible films as
`a vehicle for the noninvasive administration of nitroglycerin, as well as other therapeutic agents either with or without nitroglycerin,
`through the mucosa] tissues of the oral cavity. The films include a water soluble film—forming polymer such as pullulan. Methods
`for producing the films are also disclosed.
`
`

`

`WO 2005/004989
`
`PCT/U82004/021038
`
`FILM COMPRISING THERAPEUTIC AGENTS
`
`CROSS REFERENCE TO RELATED APPLICATION
`
`The present application claims the benefit, under 35 U.S.C. § 119, of US.
`
`Provisional Patent Application Serial Number 60/484,009, filed 1 July 2003, and,U».S.
`
`Provisional Patent Application Serial Number 60/497,426, filed 21 August 2003,
`
`the
`
`contents of which are incorporated herein by reference.
`
`FIELD OF THE INVENTION
`
`This invention relates to the administration of therapeutic agents including
`
`nitroglycerin, via consumable, edible films.
`
`BACKGROUND OF THE INVENTION
`
`Nitroglycerin is a powerful vasodilator used to prevent chest pain (angina
`
`pectoris) by relaxing the smooth muscle of blood vessels in the heart, increasing blood
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`flow and oxygen to the heart muscle, and reducing the pumping force the heart must
`
`exert to circulate blood through the body. This reduction in the heart’s workload relieves
`
`the pain of angina pectoris. Nitroglycerin also finds additional utility in controlling
`
`blood pressure in perioperative hypertension, or hypertension resulting from intratracheal
`
`intubation, anesthesia, skin incision, sternotomy, cardiac bypass, and postsurgical
`
`recovery, in addition to producing controlled hypotension during surgery.
`
`Existing methods of administration of nitroglycerin include a nitroglycerin pump-
`
`spray, nitroglycerin sublingual
`
`tablet,
`
`nitroglycerin sustained released tablets,
`
`nitroglycerin transdermal patches, nitroglycerin 2% ointment, and an intravenous
`
`nitroglycerin drip. However, each of these methods have inherent drawbacks.
`
`Oral administration is probably the most prevalent method of administering
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`nitroglycerin because of its convenience.
`
`It is generally non-threatening, painless, and
`
`simple to accomplish for most patients. Nevertheless,
`
`the oral administration of
`
`nitroglycerin suffers from several disadvantages. Specific problems associated with the
`
`oral administration of compressed sustained-release nitroglycerin tablets
`
`include
`
`friability, content uniformity, such as weight and dosage variations, migration of
`
`nitroglycerin to other tablets, the storage container and container components and the
`
`resulting potency loss.
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`A further problem with oral administration in pill form is that the rate of
`
`absorption of the drug into the bloodstream after swallowing varies from patientrto
`
`patient. The absorption of the drug is dependent upon the movement of the drug from
`
`the stomach to the small and large intestines and the effects of secretions from these
`
`organs and on the resulting pH within the stomach and intestines. Anxiety and stress can ..
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`dramatically reduce these movements and secretions, prevent or reduce the final effects ,
`
`of the drug, and delay onset of the drug’s effects. Most significant is the fact that there is
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`normally a substantial delay between the time of oral administration and the time thatfthe .
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`-~
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`-
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`therapeutic effect of the drug begins.
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`An additional disadvantage of oral pill form administration is that many drugs
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`almost immediately experience metabolism or inactivation. The veins from the stomach
`
`and the small and large intestines pass directly through the liver. Thus, drugs entering
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`the bloodstream must first pass through the liver before distribution into the general
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`blood circulation. More than sixty percent of most drugs (and essentially one hundred *
`
`percent of certain drugs) are removed from the patient’s bloodstream during this “first
`
`' pass” through the liver. The result is that oral pill form administration is impractical for
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`many drugs, particularly cardiovascular-acting drugs that are used for rapid onset in
`
`critical care situations.
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`In order to avoid some of the disadvantages of oral administration, injection is
`
`frequently used.
`
`Injecting nitroglycerin intravenously results in rapid entry of the drug
`
`into the patient’s bloodstream.
`
`In addition, this type of delivery avoids the removal of
`
`large quantities of the drug by the patient’s liver. As a result, less total drug is usually
`
`needed compared to orally distributed to various portions of the patient’s body before
`
`exposure to the liver. However, most patients, particularly children and geriatric adults,
`
`have an aversion to injections.
`
`In some patients, this aversion may be so pronounced as
`
`to make the use of injections a serious. concern. Since intense psychological stress can
`
`exacerbate a patient’s debilitated condition, it sometimes becomes undesirable touse
`
`injections where the patient is seriously ill or suffers from a debilitating condition
`
`or injury.
`
`Another method of administration of therapeutic agents, such as nitroglycerin,
`
`includes the transdermal patch.
`
`In this method of administration, a dose of nitroglycerin
`
`is administered by absorption through the dermal layers into the blood stream. However,
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`WO 2005/004989
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`PCT/U82004/021038
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`a serious disadvantage of the transderrnal patch method of nitroglycerin administration is.
`
`the development of a drug tolerance within a twenty-four (24) hour period when patches
`
`are worn continuously, subsequently reducing the effectiveness of the medication.
`
`Revised labeling approved by FDA recommended a dosing schedule alternatinga daily’
`
`patch-on period of 12 to 14 hours a day with a patch-off period of 10 to 12 hours, making
`
`this time consuming and easily forgotten. Moreover, the patch cannot be used on parts
`
`of the body with hair, cuts, abrasions, calluses or scars, and may lead to skin irritation,
`
`where the patch is applied.
`
`Some investigators have suggested that
`
`it may be possible to administer
`
`medication through the buccal mucosa of the cheek pouch or by sublingual
`
`administration.
`
`See, US. Patent No. 4,671,953,
`
`the entire content of which is
`
`incorporated by reference herein. Such administration through the mucosal tissues of the
`
`mouth, pharynx, and esophagus of therapeutic drugs possesses a distinct usefulness.
`
`Administration of drugs by4 this route does not expose the drug to the gastric and
`
`intestinal digestive juices. In addition, the drugs largely bypass the liver on the first pass
`
`through the body,
`
`thereby avoiding additional metabolism and/or
`
`inactivation of
`
`the drug.
`
`Generally the drugs which are administered by any of the methods described.
`
`above have an unpleasant taste. As a result, in order to allow for buccal or sublingual
`
`administration through the oral mucosal tissues, it is also necessary to incorporate the
`
`drug into some type of pleasant tasting mass, such as a “candy” matrix.
`
`For effective application of the drug, a candy product may contain the drug
`
`uniformly distributed throughout
`
`in order to ensure uniform levels of medication.
`
`Alternatively, for some applications, varying concentrations within known and controlled
`
`ranges may be desired to vary the rate of drug administration. Difficulties are
`
`encountered in attempting to blend solid drugs in a uniform or otherwise carefully
`
`controlled manner. Many drugs are insoluble, or only partially soluble, in one or more of
`
`the ingredients of the hard candy base. Thus, the resultant product is often found to be
`
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`20
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`lacking in uniform or controlled distribution of the drug. Moreover, sublingual tablets
`
`30
`
`also experience issues related to inter-tablet migration of nitroglycerin, similar to the
`
`sustained—release tablet methodology, which can produce a high degree of weight and
`
`dose variation between tablets.
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`WO 2005/004989
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`PCT/U82004/021038
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`Furthermore, many presently available medicated candy lozenges tend to crumble
`
`when placed in the mouth. As a result, uniform release of the drug into the mucosal
`
`tissues does not take place. Rather, the crumbled lozenge is mostly chewed, and
`
`swallowed, and the drug enters the bloodstream through the stomach and intestines as
`
`described above. Thus, it will be appreciated that candy lozenges have very definite
`
`limitations for use in the administration of a drug through the oral mucosal tissues. As a
`
`result, lozenges have not been used to administer potent, fast-acting drugs, such as drugs
`
`that affect
`
`the central nervous
`
`system,
`
`the cardiovascular system, or
`
`the renal
`
`vascular system.
`
`While the administration of certain'drugs through the oral mucosal tissues has .
`
`shown promise, development of a fully acceptable method for producing a medication in
`
`a desirable form and administering the medication has been elusive.
`
`It would be an important advancement in the art of orally administering potent,
`
`fast-acting drugs, if suitable methods and compositions provided a precise dosage to a
`
`‘ precise effect in every patient.
`
`It Would be a'further advancement in the art to provide
`
`methods and compositions for uniformly incorporating drugs (including insoluble drugs)
`
`into a soluble matrix without heating the mixture to the point that degradation occurs.
`
`A need,
`
`therefore, exists for an improved vehicle for the administration of
`
`therapeutic agents, such as nitroglycerin, beyond existing preparations.
`
`SUMMARY OF THE INVENTION
`
`The invention provides a physiologically acceptable edible or consumable film,
`
`which is particularly well adapted to rapidly dissolve in the mouth of a patient.
`
`In an
`
`embodiment of the present invention, the film comprises nitroglycerin.
`
`In another
`
`embodiment,
`
`the
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`film comprises
`
`nitroglycerin
`
`and
`
`at
`
`least
`
`one
`
`additional
`
`phannaceutically active agent.
`
`In another embodiment of the present invention, the edible or consumable film
`
`comprises a therapeutic agent or combination of two or more therapeutic agents, wherein
`
`the therapeutic agents include, but are not limited to agents useful as anti-microbial
`
`agents, non-steroidal anti-inflammatory drugs, anti-inflammatory drugs, anti-tussives,
`
`decongestants, anti-histamines, expectorants, anti-diarrheals, Hz-antagonists, proton ,
`
`pump inhibitors, general nonselective CNS depressants, general nonselective CNS
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`PCT/U82004/021038
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`stimulants, drugs that selectively modify CNS fiinction, anti-parkinsonism drugs,
`
`narcotic—analgesics,
`
`analgesic—antipyretics,
`
`psychophannacological
`
`drugs,
`
`anti—
`
`hypertension and cardiovascular treatment agents, dermatological agents, glucocorticoid's
`
`and steroids, antimalarial and anti-parasitic agents, anti-fungal agents, anti-periodontitis
`
`agents, emetic agents,
`
`treatments for gout,
`
`treatments for glaucoma,
`
`treatments for
`
`attention-deficit hyperactivity disorder, pre-treatment and treatment for exposure to
`
`chemical weapons, treatments for acute radiation exposure, narcotic analgesic agents,
`
`hemostatic agents, treatments for Sjorgren’s Syndrome and smoking cessation agents. .
`
`The invention is also directed to a method for producing a supple, non-self-
`
`,
`
`adhering film especially suitable for oral delivery of nitroglycerin.
`
`The method
`
`comprises mixing at least one film forming agent with an aqueous solution .to provide a
`
`hydrated polymer gel; casting the hydrated polymer gel on a substrate; and allowing the
`
`cast gel to solidify to provide a film. In another embodiment, the nitroglycerin or other
`
`therapeutic agent or agents are added to one or more of the components of the mixture
`
`prior to forming the hydrated polymer gel.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`It
`
`is understood that the present
`
`invention is not
`
`limited to the particular
`
`methodology, protocols, reagents, etc. described herein, as these may vary.
`
`It is also to
`
`be understood that the terminology used herein is used for the purpose of describing
`
`particular embodiments only, and is not
`
`intended to limit the scope of the present
`
`invention.
`
`It must be noted that as used herein and in the appended embodiments, the
`
`singular forms “a,” “an,” and “the” include plural reference unless the context clearly
`
`dictates otherwise.
`
`Unless defined otherwise, all technical and scientific terms used herein have the
`
`same meanings as commonly understood by one of ordinary skill in the art to which this
`
`invention belongs. Preferred methods, system components, and materials are described,
`
`although any methods and materials similar or equivalent to those described herein can
`
`be used in the practice or testing of the present invention. All references cited herein are
`
`incorporated by reference herein in their entirety.
`
`All publications and patents mentioned herein are incorporated herein by
`
`reference for the purpose of describing and disclosing,
`
`for example,
`
`the system
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`components and methods that are described in the publications, which might be used in
`
`connection with the presently described invention. The publications discussed herein are
`
`provided solely for their disclosure prior to the filing date of the present application.
`
`Nothing herein is to be construed as an admission that the inventors are not entitled to
`
`antedate such disclosure by virtue of prior invention or for any other reason.
`
`The present invention relates to the composition and methods of manufacture of
`
`orally—dissolvable, edible or consumable films as a vehicle for the non-invasive
`
`administration of nitroglycerin through the mucosal tissues of the oral cavity including,
`
`but not limited to, the mouth, pharynx, and esophagus. The present invention also relates
`
`to the composition and methods of manufacture of orally-dissolvable, edible or
`
`consumable films as a vehicle for the non-invasive administration of a variety of
`
`therapeutic agents, which may or may not also include nitroglycerin in the film, through
`
`the mucosal tissues of the oral cavity including, but not limited to, the mouth, pharynx,
`
`and esophagus.
`
`One embodiment ofthe present invention is a physiologically acceptable film that
`
`is particularly well adapted to dissolve in a mouth of a patient to deliver a nitroglycerin
`
`agent that can be used as an effective tool in the treatment or prevention of diseases or
`
`conditions including, but not
`
`limited to, angina pectoris, ventricular arrhythmia,
`
`supraventricular arrhythmia, and other cardio—vascular conditions and diseases, or any
`
`other disease or condition that may be treated with nitroglycerin. This film may
`
`comprise any edible or consumable polymer or film forming agent and nitroglycerin.
`
`In another embodiment of the present invention, the edible or consumable film
`
`comprises a therapeutic agent or combination of two or more therapeutic agents, wherein
`
`the therapeutic agents include, but are not limited to, agents useful as anti-microbial
`
`agents, non-steroidal anti-inflammatory drugs, anti-inflammatory drugs, anti-tussives,
`
`decongestants, anti-histamines, expectorants, anti-diarrheals, Hz—antagonists, proton
`
`pump inhibitors, general nonselective CNS depressants, general nonselective CNS
`
`stimulants, drugs that selectively modify CNS function, anti-parkinsonism drugs,
`
`narcotic-analgesics,
`
`analgesic-antipyretics,
`
`psychopharrnacological
`
`drugs,
`
`anti-
`
`hypertension and cardiovascular treatment agents, dermatological agents, glucocorticoids
`
`and steroids, antimalarial and anti-parasitic agents, anti-fungal agents, anti-periodontitis
`
`agents, emetic agents,
`
`treatments for gout,
`
`treatments for glaucoma,
`
`treatments for
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`PCT/US2004/021038
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`attention-deficit hyperactivity disorder, pre-treatment and treatment for exposure to
`
`chemical weapons, treatments for acute radiation exposure, narcotic analgesic agents,
`
`hemostatic agents, treatments for Sjorgren’s Syndrome and smoking cessation agents.
`
`These films may or may not also comprise nitroglycerin.
`
`US. Patent No. 5,518,902 to Ozaki et a1. (Hayashibara), the entire contents of
`which are incorporated by reference herein, discloses high pullulan content products,
`
`such as edible films, dentifrices and pharmaceuticals (column 3,
`
`lines 44-56 and
`
`Example B-8). The products can include a variety of ingredients in addition to pullulan,
`such as other polysaccharides, polyhydric alcohols, antiseptics and flavor-imparting
`
`agents (column 4, line 58 to column 5, line 11).
`
`US. Patent No. 5,411,945 to Ozaki et a1. (Hayashibara), the entire contents of
`
`which are incorporated by reference herein, discloses a pullulan binder and products
`
`produced therewith, including edible films (Example B—2). The products can include a
`
`variety of ingredients in addition to pullulan, such as other polysaccharides, antibacterial
`
`agents, flavor-imparting agents and pharmaceutically active substances (column 4, lines
`
`5-15).
`
`US. Patent No. 4,851,394 to Kubodera,
`
`the entire contents of which are
`
`incorporated by reference herein, discloses glucomannan/polyhydric alcohol edible films,
`
`which can comprise pullulan (column 3, line 59 to column 4, line 21). The films are
`
`contrasted with existing pullulan—based films, which are said to lack resistance to water
`
`(column 1, lines 40—44).
`
`US. Patent No. 3,784,390 Hijiya et al.,
`
`the entire contents of which are
`
`incorporated by reference herein, discloses pullulan films and their use in coating and
`
`packing materials for foods, pharmaceuticals and other oxygen sensitive materials. All
`
`of the examples in this patent teach mixing pullulan in hot water.
`
`US. Patent No. 4,623,394 Nakamura et al., the entire contents of which are
`
`incorporated by reference herein, discloses a gradually disintegrable molded article that
`
`can be a film made with pullulan. The articles contain a particular heteromannan, which
`
`can be locust bean gum.
`
`US. Patent No. 4,562,020 Hijiya et al.,
`
`the entire contents of which are
`
`incorporated by reference herein, discloses a process for producing a self—supporting film
`
`of a glucan, which can be pullulan.
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`US. Patent No. 5,569,482 to Naga et al.,
`
`the entire contents of which are
`
`incorporated by reference herein, discloses a method for the manufacture of an edible
`
`proteinaceous film from various sources of soybean protein.
`
`US. Pat No. 5,288,497 to Stanley et al.,
`
`the entire contents of which are
`
`incorporated by reference herein, discloses methods of manufacture for the production ‘
`
`and administration of lipophilic and nonlipophilic drugs capable of absorption through
`
`the mucosal tissues of the mouth, pharynx, and esophagus.
`
`US. Patent No. 6,020,002 to Fuisz Technologies, Ltd., the entire contents of
`
`which are incorporated by reference herein, discloses a shearform matrix based
`
`composition which may be formed into tablets (column 4 though column 7, line 47).
`
`The matrix is formed using a flash-shear process disclosed therein. No mention is made
`
`of producing a film using the disclosed matrix, and the matrix disclosed requires heating.
`
`,
`
`_
`
`US. Patent No. 6,337,082 to Fuisz et al.,
`
`the entire contents of which are
`
`incorporated by reference herein, discloses . matrices which can be used to deliver
`
`therapeutic agents, and to make foodritems.
`
`W0 03/01 125 9, the entire contents of which are incorporated by reference herein,
`
`discloses maltodextrin edible films for release into the oral cavity.
`
`W0 03/04365 9, the entire contents of which are incorporated by reference herein,
`
`discloses an edible film comprised of a hydrocolloid film-forming agent that rapidly
`
`disintegrates when placed in the mouth to release an active agent.
`
`WO 02/43657, the entire contents of which are incorporated by reference herein,
`
`discloses pullulan-free edible film compositions and methods for making same.
`
`WO 02/02645, the entire contents of which are incorporated by reference herein,
`
`discloses a process for using cold-water soluble B-glucan to create a gel for use in
`
`numerous applications, including the formation of an edible film.
`
`W0 99/17753, the entire contents of which are incorporated by reference herein,
`
`discloses rapidly dissolving films for delivery of drugs to be adsorbed in the digestive .
`tract.
`
`WO 98/26780, the entire contents of which are incorporated by reference herein,
`
`discloses a flat, foil, paper or wafer type presentation for the application and release of
`
`active substances in the buccal cavity. The specific active ingredient disclosed in WO
`
`98/26780 is buprenorphine.
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`WO 98/20862, the entire contents of which are incorporated by reference herein,
`
`discloses a film for use in the oral cavity that can contain a cosmetic or pharmaceutical
`
`active substance.
`
`US. Application Serial No. 2003/0107149, the entire contents of which are
`
`incorporated by reference herein, discloses a method for making films to be used for oral
`
`drug delivery. No mention is made of delivering nitroglycerin.
`
`WO 98/26763, the entire contents of which are incorporated by reference herein,
`
`discloses a flat, foil, paper or wafer like presentation for release of active substances into
`
`the buccal cavity. The particular active substance disclosed is apomorphine.
`
`US. Patent Appl. Serial No. 2003/00080008, the entire contents of which are
`
`incorporated by reference herein, discloses a consumable film with high concentrations
`
`of anti-microbial agents and essential oils.
`
`US. Patent Appl. Serial No. 2003/0035841, the entire of contents of which are
`
`incorporate by reference herein, discloses an edible film for use in the oral cavity, with at
`
`least three types film forming agents other than pullulan,
`
`including maltodextrins,
`
`hydrocolloids and fillers.
`
`»
`
`Despite the existence of rapidly dissolving orally consumable films in the prior
`
`art, there remains'room for improvement in such films, and in processes for making
`
`them, in particular, such films for the delivery of nitroglycerin.
`
`Nitroglycerin, as referred to herein, is also known as 1,2,3-Propanetriol trinitrate,
`
`glyceryl trinitrate, glycerol nitric acid triester, nitroglycerol, trinitroglycerol, glonoine,
`
`trinitrin, blasting gelatin, blasting oil, and S.N.G., and is known by numerous
`
`commercial brand names, including, but not limited to, Adesitrin, Angibid, Angiolingual,
`
`Anginine, Angorin, Aquo-Trinitrosan, Cardamist, Coro-Nitro, Corditrine, Deponit,
`
`Diafusor, Gilucor “nitro”, GTN, Klavikordal, Lenitral, Lentonitrina, Millithrol, Minitran,
`
`Myoglycerin, Niong, Nitradisc, Nitran, Nitriderm, Nitro-Bid, Nitrobon, Nitrocap,
`
`Nitrocap TD, Nitrocine, Nitrocontin, Nitroderm TTS, Nitrodisc, Nitro-Dur, Nitrofortin,
`
`Nitro-Gesanit, Nitroglin, Nitroglyn, Nitroguard, Nitro], Nitrolan, Nitrolande, Nitrolar,
`
`Nitro-lent, Nitrolin, Nitrolingual, Nitro Mack, Nitromel, Nitromin, Nitron, Nitronal,
`
`Nitronet, Nitrong, Nitro-Pflaster-ratiopharm, NitroPRN, Nitroquick, Nitrorectal,
`
`Nitroretard, Nitrosigma, Nitrospan, Nitrostat, Nitrotab, Nitro—Time, Nitrozell retard,
`
`Notrong, Nysconitrine, organic nitrate, organic nitrite, Percutol, Perlinganit, Perglottal,
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`Reminitrol, Suscard, Sustac, Sustonit, Transderm-Nitro, Transiderm—Nitro, Tridil,
`
`Trinalgon, Trinitrosan and Vasoglyn.
`
`Nitroglycerin is commercially available from a wide variety of sources
`
`-‘
`
`specifically for pharmaceutical use, including, but not limited to, 3M Pharmaceuticals,
`
`Abbott Labs, Aventis Pharmaceuticals, Baxter Healthcare, Cellegy Pharmaceuticals, Inc.,
`
`DuPont-Merck Pharmaceutical Co., F. Hofflnan La-Roche, Ltd., Forest Laboratories,
`
`Inc., GlaxoSmithKline, Hoechst Marion Roussel, Kenwood Laboratories, Key
`
`Pharmaceuticals, Medley Pharmaceuticals, Merck & Co, Inc., Novartis Pharma AG,
`
`Parke-Davis, Pfizer, G. Pohl-Boskamp GmbH & Co., Rhone-Poulene Rorer
`
`10
`
`Pharmaceutical, Inc., Schwartz Pharma AG, Solvay Pharma, Vortech Pharmaceuticals,
`
`and Warner Lambert Company.
`
`Pure nitroglycerin is a violent explosive which must be handled with great care.
`
`,
`
`The stable form of nitroglycerin crystals melts in the temperate region of 55.4°F (13°C)
`
`and is extremely unstable as it thaws; liquid nitroglycerin will detonate if subjected to
`
`intense heat or percussion. Therefore, nitroglycerin is most useful when its explosive ~
`
`properties are controlled, ofien by dispersing the compound in an inert substance.
`
`Commercially available nitroglycerin may be diluted to a concentration of about 90% by
`
`weight, about 80% by weight, about 70% by weight, about 60% by weight, about 50%
`
`by weight, about 40% by weight, about 30% by weight, about 20% by weight, about
`
`10% by weight, about 9% by weight, about 8% by weight, about 7% by weight, about
`
`.
`
`6% by weight, about 5% by weight, about 4% by weight, about 3% by weight, about 2%
`
`by weight, about 1% by weight, or less than about 1% by weight, prior to manufacturing
`
`into an edible film of the present invention. In one embodiment, nitroglycerin may be .
`
`diluted to a concentration below 2% by weight prior to use in the methods of the present
`
`invention for making edible films. Additionally, in the present invention, it is
`
`recommended that certain protective apparel such as gowns, respirators, gloves and
`
`goggles, should be worn when working with nitroglycerin to avoid its toxic effects. The ,
`
`skin and mucus membranes readily absorb nitroglycerin and direct skin contact must
`
`therefore be avoided. Rapid absorption through the skin makes nitroglycerin a useful
`
`drug for the treatment of angina pectoris, but may be harmful to the healthy individual
`
`‘
`
`experiencing no oxygen deficiency in the myocardium.
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`WO 2005/004989
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`PCT/U82004/021038
`
`Nitroglycerin may be prepared in aqueous form and is described in US. Patent
`
`No. 4,879,308, the entire disclosure of which is incorporated by reference herein, and
`
`may also be prepared in non-polar liquid form as described in US. Patent No. 5,869,082,
`
`the entire disclosure of which is incorporated by reference herein.
`
`Composition of Films
`
`An embodiment of the invention is a fast dissolving film that comprises a
`
`physiologically acceptable amount of nitroglycerin. The expression “physiologically
`
`acceptable” amounts of nitroglycerin, as used herein,
`
`is intended to encompass'an'
`
`amount or dose, which upon administration to a patient,
`
`is adequately tolerated and
`
`effective
`
`for
`
`treatment without causing undue negative
`
`side
`
`effects, and are
`
`physiologically acceptable and compatible with oral films. The amount of nitroglycerin
`
`that can be used in the rapidly dissolving films, according to the present invention, is
`
`dependent upon the dose needed to provide an effective amount of nitroglycerin. As
`
`described herein for nitroglycerin, physiologically acceptable amounts of any. other'
`
`to be formulated in the films of the present
`therapeutic agent
`determined in a similar manner.
`
`invention may be
`
`The dosage needed to provide an effective amount of nitroglycerin or any other
`
`therapeutic agent may be readily determined by one of ordinary skill in the art using well
`
`known techniques, and is typically an amount that will cause an amelioration of
`
`symptoms or disease. Specific doses may be adjusted depending on conditions of the
`
`disease, the age, body weight, general health, sex, diet of the subject, dose intervals,
`
`excretion rate and combinations with other drugs. As used herein, a therapeutically
`effective amount of nitroglycerin is an amount in the range of about 0.001 mg to about
`1000 mg, or in the range of about 0.01 mg to about 100 mg, or in the range of about 0.05
`
`mg to about 50 mg, or in the range of about 0.1 mg to about 40 mg.
`
`Preparation of Films
`
`The nitroglycerin comprising film of the present invention, or the films of the
`
`present invention comprising any other therapeutic agent, in one embodimentcomprises
`
`at least one film-forming agent and may further comprise water, additional film—forming
`
`agents, triglycerides, preservatives, polyethylene oxide compounds, propylene glycol,
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`WO 2005/004989
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`PCT/U82004/021038
`
`potentiating agents, saliva stimulating agents, plasticizing agents, cooling agents,
`
`surfactants, nitroglycerin stabilizing agents, film stabilizing agents, emulsifying agents,
`
`thickening agents, binding agents, buffers,
`
`releasing agents, permeation enhancers,
`
`sweeteners, additional natural and artificial flavoring agents, coloring agents, coating
`
`agents, additional pharrnaceutically active agents, antibacterial agents, antiviral agents,
`
`other therapeutic agents, and the like.
`
`The film-forming agent used in the films according to the present invention can
`be any suitable film-forming agent including, but not limited to, pullulan, hydrocolloids,
`
`B-glucan, maltodextrin,
`
`celluloses,
`
`including
`
`hydroxypropylmethyl
`
`cellulose,
`
`hydroxyethyl
`
`cellulose,
`
`hydroxypropyl
`
`cellulose,
`
`carboxymethyl
`
`cellulose,
`
`methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, polyvinyl pyrrolidone,
`
`polyvinyl alcohol, sodium alginate, polyethylene glycol, ethyl cellulose, hydroxypropyl
`
`ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate,
`
`natural gums, such as locust bean gum, carrageenan gum, xanthan gum, tragacanth gum,
`
`, guar gum, acacia gum, arabic gum, karaya, ghatti, tamarind gum, polyacrylic acid,
`
`methylmethacrylate copolymer, carboxyvinyl polymer, amylose, high amylose starch,
`
`hydroxypropylated high amylose starch, dextrin, pectin, chitin, chitosan, levan, elsinan,
`
`collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein, and
`
`mixtures thereof.
`
`The film-forming agent used in the films may also include
`
`biodegradable polymers, copolymers, block polymers,
`
`including, but not
`
`limited to,
`
`poly(glycolic acid)
`
`(PGA), poly(lactic acid)
`
`(PLA), polydioxanoes, polyoxalates,
`
`poly(.alpha.-esters), polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters),
`
`polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates, polyamides,
`
`poly(alkyl cyanoacrylates), stereopolymers of L— and D-lactic acid, copolymers of bis(p-
`
`carboxyphenoxy) propane acid and sebacic acid, sebacic acid copolymers, copolymers of
`
`caprolactone, poly(lactic
`
`acid)/poly(glycolic
`
`acid)/polyethy