By a News Reporter-Staff News Editor at Drug Week — A patent application by the inventors Leichs, Christian (Burscheid, DE); Breitenbach, Armin (Leverkusen, DE); Lehrke, Ingo (Koln, DE); Galfetti, Paolo (IT, IT), filed on October 11, 2013, was made available online on July 3, 2014, according to news reporting originating from Washington, D.C., by NewsRx correspondents (see also Apr Applied Pharma Research Sa).
This patent application is assigned to Apr Applied Pharma Research Sa.
The following quote was obtained by the news editors from the background information supplied by the inventors: “Orally administered film strip dosage forms have been recently developed for the pharmaceutical industry, and are currently used for the sale of several popular over-the-counter drug products, including Listerine.RTM. breath strips, Triaminic.RTM. thin strips (active agent=diphenhydramine HCl), and Sudafed PE.TM. quick dissolve strips (active ingredient=phenylephrine HCl). The absolute bioavailability of diphenhydramine when ingested orally is approximately 61%, and the time to maximum serum concentration is about 3-4 hours. Phenylephrine is subject to extensive presystemic metabolism in the gut wall, such that the absolute bioavailability of phenylephrine when ingested orally is approximately 40% relative to intravenous dosing, and peak plasma concentrations are achieved in about 1-2 hours.
“In addition, several manufacturers have proposed formulations that could be used to deliver prescription drugs. The vast majority of these formulations are ‘mucoadhesive’ formulations designed for adhesion of the dosage form to mucosal tissue in the mouth, and transmission of the drug from the dosage form through the mucosal tissue into the systemic circulation. As described in U.S. Pat. No. 6,750,921 to Kim et al., film-forming agents have been used to manufacture drug delivery formulations for percutaneous or transdermal application, but these necessarily involve an adhesive composition to retain the agent in situ long enough to cause sustained release of the active ingredient. Bioerodible films are described in Tapolsky et al., U.S. Pat. No. 5,800,832. The films have an adhesive layer and a non-adhesive backing layer and are intended to adhere to the mucosal surface. Biegajski et al., U.S. Pat. No. 5,700,478, describes a water-soluble pressure-sensitive mucoadhesive suitable for use in a mucosal-lined body cavity.
“The purported advantage of these mucoadhesive films resides in their ability to bypass the gastrointestinal tract, and barriers in the gastrointestinal tract to drug absorption such as first pass metabolism and decomposition of the active ingredient in the stomach. An additional advantage for these dosage forms, when compared to tablets, capsules and other dosage forms that must be swallowed, is that some patient populations have difficulty swallowing, such as children and the elderly.
“Until now the prior art has been focused principally on improving the delivery profile of a given pharmaceutical agent with this dosage form, by increasing its rate of dissolution or absorption, or bypassing metabolic processes that reduce the bioavailability of the drug. The prior art has not appreciated that an innovator’s drug product, be it a tablet, capsule, or other oral dosage form, has already proven itself effective through rigorous clinical testing, and that the innovator’s product may already provide the optimum bioavailability of pharmaceutical agent. What is needed is a film product that mimics the pharmacokinetics of an innovator’s product, and that follows the same metabolic and bioabsorption pathways as the innovator’s product, to ensure that the dosage form achieves the proven clinical efficacy of the innovator product.”
In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventors’ summary information for this patent application: “The present invention provides film dosage forms that are formulated or administered for gastrointestinal absorption of the active pharmaceutical agent, and that are bioequivalent to and interchangeable with existing orally administered drug products. These film dosage forms are non-mucoadhesive; they quickly disintegrate in the mouth when exposed to saliva; and they are absorbed predominantly through the gastrointestinal tract. Most importantly, these dosage forms are specially formulated to meet exacting bioavailability requirements, or to be bioequivalent to existing orally administered dosage forms.
“Therefore, in a first principal embodiment, the invention provides a non-mucoadhesive orally disintegrating film, able to disintegrate upon contact with saliva in the buccal cavity within about sixty seconds, comprising a defined amount of an active pharmaceutical agent, a hydrophilic binder and a water-soluble diluent, wherein: (a) said film is formulated for delivery of said active agent through the gastrointestinal tract when applied to the tongue; (b) said film comprises from about 0.05% to about 50% (w/w) of said active pharmaceutical agent, based on the total weight of the formulation; and © said film is bioequivalent to an immediate release tablet or or orally dissolving/dispersing tablet (ODT) that comprises said active pharmaceutical agent in said defined amount.
“In one embodiment, the immediate release tablet or orally dissolving/dispersing tablet (ODT) is characterized by slow or delayed bioavailability (i.e. a ‘slowly bioavailable drug’). The inventors have developed orally disintegrating film dosage forms which, it is believed, will unexpectedly be bioequivalent to these conventional ‘slowly bioavailable drugs,’ without any substantial modification of the release characteristics from the film dosage form, as long as the film can disintegrate when placed on the tongue within about sixty seconds. Thus, for example, the immediate release dosage form can be characterized by: a T.sub.max (i.e. time to maximum plasma concentration) of greater than about 1.5 hours, 2.0 hours, 2.5 hours, 3.0 hours, 3.5 hours, 4.0 hours, 4.5 hours or even 5.0 hours; a disintegration time of greater than about 10 or 20 minutes, but less than about 90 or 60 minutes; a 90% dissolution time of greater than about 10 or 20 minutes, but less than about 90 or 60 minutes; and/or a film coating that delays the release and absorption of active ingredient from the dosage form.
“Of course, the invention could also be practiced with drugs having other pharmacokinetic profiles, and in other embodiments the T.sub.max of the drug is less than 3.0, 2.5, 2.0, 1.5 or 1.0 hours.
“In another embodiment, the film strip of the present invention, or the immediate release dosage form, can be defined by its pharmacokinetics, and in one embodiment, the film strip or immediate release dosage form has an absolute bioavailability of greater than 65%, 75%, 85% or even 95% when administered orally. In another embodiment, the film strip or immediate release dosage form has an absolute bioavailability that is greater than about 45%, 50%, or 55%, and peak plasma concentrations (C.sub.max) in less than 3.0, 2.5 or 2.0 hours. Finally, because the film dosage form is specially formulated or administered for gastrointestinal absorption, the film dosage form has a comparable absolute bioavailability or T.sub.max as an immediate release tablet or capsule or orally dissolving/dispersing tablet (ODT) that comprises the same amount of active pharmaceutical agent.
“The films themselves, and the methods of using the films, are characterized by a number of features that ensure their bioequivalence to a comparable immediate release tablet or capsule or orally dissolving/dispersing tablet (ODT), including: the films may be engineered or used so that the active pharmaceutical agent is swallowed and absorbed predominantly or entirely through the gastrointestinal tract, instead of being absorbed through the oral mucosa; if necessary, the films or active pharmaceutical agents may be formulated so that absorption of active pharmaceutical agent through the oral mucosa is retarded; the films are typically designed for rapid disintegration when taken orally, and are most often swallowed in less than thirty or sixty seconds after administration; the films are usually applied directly onto the tongue to promote mixing with the saliva and subsequent swallowing of the active ingredient, and thereby discourage mucosal absorption; and water could be additionally swallowed within about thirty or sixty seconds after administration of the film, to further promote swallowing of the active agent and gastrointestinal absorption.
“A particularly preferred drug of the present invention is a donepezil film strip, which demonstrates bioequivalence to existing immediate release tablets of donepezil hydrochloride, and which exhibits a peak plasma concentration of donepezil in from about three to about four hours. Another preferred drug is an ondansetron film strip, which is characterized by an absolute bioavailability of ondansetron of from about 45% to about 75%, and which is formulated as a base to retard absorption through the oral mucosa. Other preferred drugs are set forth in the detailed description of invention and examples which follow.
“Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
DESCRIPTION OF THE FIGURES
“FIG. 1 is a comparison of dissolution profiles over time comparing three commercially available formulations of ondansetron with two ondansetron RapidFilm formulations, as described in Table 4. The upper line at 1 minute is Zofran.RTM. 4 mg Zydis.RTM. Lingual; the second line at 1 minute is Zofran.RTM. 8 mg Zydis.RTM. Lingual; the third line is ondansetron 8 mg RapidFilm; the fourth line is ondansetron 4 mg RapidFilm; the bottom line is Zofran.RTM. 8 mg Filmtablet.
“FIG. 2 depicts mean (FIG. 2A) and log mean (FIG. 2B) drug plasma concentration profiles versus time for 8 mg ondansetron RapidFilm investigational product versus Zofran.RTM. 8 mg Lingual orally disintegrating tablets, as described in Table 6.
“FIG. 3 is a comparison of dissolution profiles over time comparing commercially available donepezil hydrochloride immediate release tablets, commercially available donepezil hydrochloride orally disintegrating tablets, and four donepezil hydrochloride RapidFilm formulations, as described in Tables 9-14. The top line at 3 minutes is RapidFilm prototype F; the second line at 3 minutes is Aricept.RTM. film tablets; the third line at 3 minutes is RapidFilm prototype E; the fourth line at 3 minutes is RapidFilm prototype A; the fifth line at 3 minutes is Aricept.RTM. ODT; the bottom line at 3 minutes is RapidFilm prototype C.
“FIG. 4 is a stacking x-ray diffraction pattern for three samples–(1) ondansetron base Form B polymorph, (2) RapidFilm comprising 4 mg of ondansetron having the formulation of Table 4 and stored at 40.degree. C., and (3) RapidFilm comprising 4 mg of ondansetron having the formulation of Table 4 (OND 013 OD), and stored at 60.degree. C. (84201506).
“FIG. 5 is a DSC heating curve for donepezil HCl Form I.
“FIG. 6 is an X-ray diffraction pattern for donepezil HCl Form I.
“FIG. 7 is an X-ray diffraction pattern for ondansetron base Form B.”
URL and more information on this patent application, see: Leichs, Christian; Breitenbach, Armin; Lehrke, Ingo; Galfetti, Paolo. Non-Mucoadhesive Film Dosage Forms. Filed October 11, 2013 and posted July 3, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=2385&p=48&f=G&l=50&d=PG01&S1=20140626.PD.&OS=PD/20140626&RS=PD/20140626
Keywords for this news article include: Pharmaceuticals, Drugs, Therapy, Mydriatics, Cardiotonic, Dosage Forms, Vasopressors, Phenylephrine, Topical Agents, Sympathomimetic, Gastroenterology, Pharmacokinetics, Nasal Decongestants, Cardiovascular Agents, Anorectal Preparations, Vasoconstrictor Agents, Ophthalmic Preparations, Adrenergic alpha-Agonist.
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