WO2014014645A1 - Systèmes et procédés pour l'administration par voie orale d'une thérapie - Google Patents

Systèmes et procédés pour l'administration par voie orale d'une thérapie Download PDF

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Publication number
WO2014014645A1
WO2014014645A1 PCT/US2013/048907 US2013048907W WO2014014645A1 WO 2014014645 A1 WO2014014645 A1 WO 2014014645A1 US 2013048907 W US2013048907 W US 2013048907W WO 2014014645 A1 WO2014014645 A1 WO 2014014645A1
Authority
WO
WIPO (PCT)
Prior art keywords
recited
medicinal
appliance
active ingredient
mouth
Prior art date
Application number
PCT/US2013/048907
Other languages
English (en)
Inventor
Philip S. Green
Original Assignee
Miranda Technologies, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Miranda Technologies, Inc. filed Critical Miranda Technologies, Inc.
Publication of WO2014014645A1 publication Critical patent/WO2014014645A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • Heartburn or gastroesophageal reflux disease (GERD)
  • GFD gastroesophageal reflux disease
  • GERD symptoms In addition to frequent heartburn, GERD symptoms often include sour or bitter taste resulting from stomach fluid entering the mouth, a burning sensation on the tongue, hoarseness, repeatedly feeling a need to clear the throat, difficulty swallowing food or liquid, and wheezing or coughing.
  • GERD can result in much more serious conditions, such as severe esophageal inflammation, stricture, bleeding, erosion of tooth enamel, gingivitis, and potentially, esophageal carcinoma.
  • reflux symptoms occur only at night. Nocturnal aspiration of stomach acid in the mouth can cause recurrent chronic cough, chemical pneumonias, and bronchospasm.
  • antacids are used to relieve symptoms of GERD.
  • Many antacid compounds and combinations are available commercially, including sodium bicarbonate, calcium carbonate, and various compounds of magnesium, aluminum, potassium and bismuth. Though in moderate doses they are safe for long-term use, all common antacids have potentially significant side effects when taken in large doses over an extended period,
  • H2 -receptor blockers e.g., ranitidine ⁇ Zantac
  • cimetidine ⁇ Tagamet e.g., cimetidine
  • PPIs proton pump inhibitors
  • Nissen fundoplication involves wrapping the fundus of the stomach around the base of the esophagus and securing it with sutures, thereby cause a tightening of the GE sphincter.
  • Fundoplication can be performed as an open or laparoscopic procedure.
  • a recently introduced alternative employs a clip applier delivered through a gastric endoscope, to restrict the GE sphincter.
  • Methods for orally administering a treatment are disclosed herein.
  • the methods can include placing a medicinal element comprising an active ingredient in a mouth between a cheek and an upper gum, dissolving a portion of the active ingredient in saliva, and flowing the portion of the active ingredient dissolved in saliva into an esophagus.
  • the active ingredient includes an antacid.
  • the active ingredient includes a salivant.
  • the active ingredients include a salivant and an antacid.
  • the methods are used to treat gastro-esophageal reflux disease (GERD).
  • gastro-esophageal reflux disease includes acid reflux from the stomach to the esophagus and an antacid is used to neutralize the acid reflux in the esophagus.
  • the medicinal element can be in the form of a tablet. In some embodiments the medicinal element is in the form of granules in a permeable enclosure. The medicinal elements can be configured to fit between the upper gum and the cheek.
  • dissolving and flowing can include an active period of release that exceeds two hours. Dissolving and flowing can be at least partially performed while a user is sleeping.
  • placing the medicinal element includes placing the medicinal element adjacent to an outflow duct of a parotid saliva gland in the mouth.
  • Placing the medicinal element can include placing one medicinal element on a left side of the mouth and placing a second medicinal element on a right side of the mouth.
  • placing the medicinal element includes inserting an appliance with a first end comprising the medicinal element and a second end comprising the medicinal element.
  • the methods include integrating the medicinal element into an appliance prior to placing the medicinal element in the mouth.
  • the appliance can include a first permeable container adjacent to the first end and a second permeable container adjacent to the second end.
  • the methods can include placing the medicinal element in the first permeable container and the second permeable container prior to placing the medicinal element in the mouth.
  • the active release period of the medicinal element can be extended.
  • the medicinal element can include low-solubility components to extend the release time of the active ingredient.
  • the medicinal element can include a coating with low-solubility to extend the release time of the active ingredient.
  • the active ingredients can be imbedded in a low-solubility matrix to extend a release time of the active ingredient.
  • the granules can be at least partially coated with a low-solubility material to extend the release time of the active ingredient.
  • the appliances can include an elongated member having a first end and a second end with one or more medicinal elements comprising one or more active ingredients, the medicinal element coupled at or proximal to one or both of the first end and second end, the appliance configured to place and maintain the medicinal elements between a cheek and an upper gum when the appliance is inserted in a patient's mouth.
  • the appliance includes first and second medicinal elements. The first medicinal element can be coupled proximal to the first end and the second medicinal element can be coupled proximal to the second end.
  • the appliance includes an antacid.
  • the appliance includes a salivant.
  • the appliance includes an antacid and salivant.
  • the medicinal element is provided with the appliance as a tablet or capsule.
  • the medicinal elements can be configured to fit between an upper gum and a cheek.
  • the appliance is disposable.
  • the appliance includes a first permeable enclosure adjacent to the first end and a second permeable enclosure adjacent to the second end with the medicinal element provided in granules within the first and second permeable enclosures.
  • the granules are at least partially coated with a low-solubility material to extend a release time of the active ingredient.
  • the medicinal element includes low-solubility components to extend a release time of the active ingredient.
  • the medicinal element includes a coating with low-solubility to extend a release time of the active ingredient.
  • the active ingredients are imbedded in a low-solubility matrix to extend a release time of the active ingredient.
  • methods for the oral administration of a medicinal substance include providing the medicinal substance in a tablet; integrating the tablet with an oral insertion device; and inserting the oral insertion device and tablet into a mouth, the tablet being positioned between a cheek and an upper gum in the mouth.
  • the medicinal substance can be provided as a slow-release tablet.
  • the medicinal substance can include an antacid.
  • the medicinal substance can include a salivant.
  • Fig. 1 is a quasi-cross-sectional illustration of a recumbent person undergoing therapy according to the present invention.
  • Fig. 2 is an illustration of one possible configuration of a tablet suitable for incorporating the medically active and inactive ingredients of the present invention.
  • Fig. 3 indicates a preferred location of the tablet, as seen through the open mouth, into which the tablet is inserted.
  • Fig. 4 is a side-view cutaway illustration of the face, wherein the several salivary glands are depicted, as is a preferred position of the tablet of the present invention with respect to the terminus of the parotid duct and of the molars of the upper jaw.
  • Fig 5 is a cross-sectional schematic illustration of the tablet entrained between the cheek and the gum of the upper jaw, above a molar.
  • FIG. 6 schematically illustrates another embodiment of the present invention in which the active elements are combined with a connecting element for positioning the elements in the mouth and preventing aspiration.
  • the present disclosure is directed to inhibiting the passage of gastric acid through the EG-junction into the esophagus. Another objective is to neutralize any acid that does enter the esophagus and mouth. Most GERD sufferers have their worst symptoms while sleeping; many experience reflux only while sleeping. Thus, one objective is to enable substantially continuous anti-GERD activity over a prolonged period of time; thereby making it applicable for use during sleep.
  • prior-art antacid therapies are directed to neutralizing or adsorbing acid in the stomach
  • the present disclosure is directed to eliminating the much smaller quantity of acid that actually passes through the EG-junction and enters the esophagus.
  • relatively small doses of antacid agents are administered.
  • a salivant is administered to stimulate saliva production - saliva flow itself has significant acid-cleansing activity in the esophagus.
  • both antacid and salivant therapies are combined.
  • the active ingredients are combined with other elements, such as slow-release agents as well as, flavoring, coating and coloring agents.
  • the ingredients are combined into tablets suitable for retaining in the mouth for an extended period of time.
  • a particular factor of this embodiment is the location of the tablets within the mouth wherein they will be especially effective and secure against aspiration.
  • another embodiment is the shape of the tablets, which are configured for comfort and locational stability.
  • a retaining appliance is incorporated to position and hold the tablets in the mouth and to further ensure that they will not be aspirated.
  • the retaining appliance may be a separate component into which the tablets or their granular equivalent are inserted, or it may be integrated with the tablets as a single disposable unit.
  • one or more soluble or partially soluble active elements with acid clearing properties are positioned in the oral cavity so as to facilitate the generation of a flow of saliva 2 of increased pH down the esophagus 3.
  • stomach acid 4 that has leaked through the GE junction 5 and entered the esophagus will be neutralized and/or washed back into the stomach.
  • the tablet 1 may be shaped in such a way as to facilitate easy insertion into the mouth, stable positioning in the preferred location, between the cheek and upper gum, especially for extended-term use during sleep.
  • Fig. 3 illustrates the direction of insertion 7, 8 into the desired position.
  • salivants i.e., salivation-stimulating agents— are incorporated into the active elements to enhance their effectiveness.
  • FIG. 5 The cross-sectional illustration of Fig. 5 reveals another favorable aspect of the position of the active element, as previously described - an active element, shown here as a tablet, occupies a secure position between the cheek 13 and the gum 14 of the upper jaw, adjacent to the second or third molar 15. Note that the gum typically flares toward the cheek owing to the presence of the tooth. This creates a pocket that encompasses the active element, preventing its escape and possible aspiration. This aspect can be important, because the treatments disclosed herein are intended to be suitable for extended use during sleep. Moreover, it is well known that a tablet positioned otherwise within the mouth will be readily dissolved and swallowed in minutes, defeating the objective of extended-time activity.
  • FIG. 6 Another embodiment is illustrated in Fig. 6. Although prolonged testing suggests that tablets positioned as described above will remain stationary during extended sleep, other means may be desirable to further secure them.
  • the active elements 1A and IB may be integrated with an appliance 16 that is designed to correctly position and secure them, preventing their aspiration.
  • the appliance can also be designed to fit the user comfortable and stably.
  • the design of mouth-fitting appliances suitable for night-time use has been well demonstrated; for example, appliances for aligning the jaws and for prevention of snoring. Many materials and design principles are available to achieve the intended function of the appliance.
  • the appliance employed may be of various designs. For example, rather than bonding the appliance to the active elements, it may incorporate, at each end, containers with perforated or porous walls.
  • the active elements could, for example, be in granular form inside each container. Saliva seeping into the containers through the permeable walls would slowly dissolve or otherwise break down the granules and wash the active ingredients into the mouth.
  • Patent 5,047,248 describes formulations comprising "a retarding base or matrix consisting of a polysaccharide of natural origin, alone or mixed with one or more natural or synthetic polymers which may be used to modify the release pattern so as to obtain a therapeutically effective formulation.”
  • the porosity may be adjusted to achieve the desired dose rate.
  • coatings may be applied to the granules to retard their dissolution. It is anticipated that the effectiveness may be enhanced by the addition of agents to promote salivation.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Zoology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des systèmes et des procédés pour l'administration par voie orale d'une thérapie. La thérapie permet de traiter, par exemple, des symptômes du reflux gastro-oesophagien pathologique (GERD) par l'administration d'un agent médicinal dans la bouche et l'oesophage afin de contrer le reflux acide. Dans un mode de réalisation, l'agent comprend un antiacide. Dans un autre mode de réalisation, l'agent comprend un agent salivant. L'antiacide et l'agent salivant peuvent en outre être employés ensemble. Les agents actifs peuvent de plus être combinés avec d'autres ingrédients, y compris des matières qui favorisent la libération prolongée des principes actifs, ainsi que des enrobages et des arômes. Les agents actifs peuvent être fournis sous la forme d'un comprimé ou en tant que granules. Les agents actifs peuvent être positionnés dans la zone buccale, c.-à-d. entre la gencive supérieure et la joue, et en particulier à proximité étroite de la sortie du conduit salivaire parotidien. L'invention concerne aussi un appareil qui positionne les agents actifs dans la bouche.
PCT/US2013/048907 2012-07-17 2013-07-01 Systèmes et procédés pour l'administration par voie orale d'une thérapie WO2014014645A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261741297P 2012-07-17 2012-07-17
US61/741,297 2012-07-17

Publications (1)

Publication Number Publication Date
WO2014014645A1 true WO2014014645A1 (fr) 2014-01-23

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4163777A (en) * 1977-04-29 1979-08-07 Lewis/Howe Company Controlled antacid delivery form and method of treatment therewith
US5047248A (en) * 1986-03-07 1991-09-10 Eurand Italia S.P.A. Formulation for preparing sustained release drugs for oral administration
US5194003A (en) * 1988-06-13 1993-03-16 Transpharm Group, Inc. Removable device for delivering beneficial agents orally
US6180682B1 (en) * 1999-01-26 2001-01-30 Virgil A. Place Buccal drug delivery system for use in male contraception
US20060165759A1 (en) * 2005-01-27 2006-07-27 Warner-Lambert Company Llc Antacid lozenge containing micronized particles

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4163777A (en) * 1977-04-29 1979-08-07 Lewis/Howe Company Controlled antacid delivery form and method of treatment therewith
US5047248A (en) * 1986-03-07 1991-09-10 Eurand Italia S.P.A. Formulation for preparing sustained release drugs for oral administration
US5194003A (en) * 1988-06-13 1993-03-16 Transpharm Group, Inc. Removable device for delivering beneficial agents orally
US6180682B1 (en) * 1999-01-26 2001-01-30 Virgil A. Place Buccal drug delivery system for use in male contraception
US20060165759A1 (en) * 2005-01-27 2006-07-27 Warner-Lambert Company Llc Antacid lozenge containing micronized particles

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