(I2) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`CORRECTED VERSION
`
`(I9) World Intellectual Property Organization
`International Bureau
`
`IlllillllllllllllllllflllllllIlllIllllllllllllllllllllllllllll
`
`
`
`(10) International Pu blieation Number
`(43) International Publication Date
`17 August 2000 (17.08.2000)
`PCT
`WO 00/47203 A1
`
`(51)
`
`International Patent Classification’:
`31144.9/S0. A6|L 9/04. 9/I4
`
`A6lI( 3]/28.
`
`(21) International Application Number:
`
`PCT/11800103555
`
`ml
`
`International Filing Date: 11 February zooon 1.01.2000)
`
`(8l) Designated States (nationai): AE. AL. AM. AT. AU. AZ.
`BA. BB, BG. BR. BY. CA. CH. CN. CR. CU. CZ. DE. DK.
`DM. EE. ES. FI, GB, GD, GE. GH. GM. HR. HU. ID, IL,
`IN. IS. JP, KE. KG. KP. KR. KZ. LC. LK. LR. LS. LT. LU.
`LV. MA. MD. MG. MK. MN. MW. MX. NO. NZ. PL. PT.
`RO, RU, SD, SE. SG, SI, SK. SL,'I‘J, 'I‘M.TR.TT.TZ,UA.
`UG. UZ. VN. YU. ZA. zw.
`
`(151 ""‘""8 L*'“%"='%°=
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/] 19.923
`
`I2 February l999(l2.0’2.l999)
`
`US
`
`(34) Designated States (regional): ARIPO patent (GH. GM.
`KE. LS. MW. SD. SL. SZ. TZ. UG. ZW). Eurasian patent
`(AM. AZ, BY, KG, KZ, MD, RU.'I‘J. TM). European patent
`(AT. BE. CH. CY. DE. DK. ES. Fl. FR. GB. GR. IE. IT. LU.
`MC. NL. PI‘. SE), OAPI patent (BF, BJ. CF, CG, CI, CM,
`GA, GN, GW. ML. MR. NE. SN. TD. TG).
`
`(7I) Applicant: MQS. INC. [US/US]; Suite I02. 241 Forsgatc
`Drive. Jamesburg. NJ 08831 (US).
`
`Published :
`with international search report
`
`(7l) Applicants and
`(72) Inventors: MCCOY. Randall [US/US]: I0 High Court.
`Littles Falls. NJ 07424 (US). WILLIAMS, Robert, 0., III
`[US/US]; 4514 W. Rapid Springs Cove. Austin, TX 78746
`(US). LIBBEY. Miles. A.. III [US/US]: 2 Blue Spruce
`Drive. Pennington. NJ 08534 (US).
`
`(48) Date of publication of this corrected version:
`7 September 200i
`
`(15) Information about Correction:
`see PCT‘ Gazette No. 36/200] of 7 September 200i. Sec-
`tion II
`
`(74) Agent: WINSLOW, Anastasia, P.; Mathews. Collins.
`Shepherd & Gould. P.A.. Suite 306. 100 Thanct Circle.
`Princeton. NJ 08540 (US).
`
`For rwo—IeIler codes and other abbreviatiom. refer to the "Guid-
`ance Notes on Codes and Abbreviations" appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`||||||||l||||1||l|l|||||||I||llllllllllllllllllllllll||||Il||l||||||||II|
`
`47203A1 (57) Abstract: A stable formulation is disclosed that enables the effective intra-oral delivery to a patient of a pharmaceutical agenn
`
`The formulation comprises the pharmaceutical agent mixed with an orally-acceptable oral-absorption enhancer in an orally-acccph
`able carrier-solvent. wherein the oral-absorption enhancer is adapted to modify the surface membrane such that absorption through
`the surface membrane is initiated or increased. The oral-absorption enhancer may comprise hydroxypropyl-beta-cyclodcxtrin and
`surfactants including benzalkonium chloride. bcnzuthonium chloride. polysorbate 80. sodium Iauryl sulfate. Brij surfactants. Tween
`and Pluronic surfactants. Also disclosed is a system for delivering the formulation including a rnecltnnism for dispensing predeter-
`mined doses of the inventive fonnulation intra~orally as with an aerosol or spray pump or propellant device.
`
`K 0
`
`00
`B
`
`(54) Title: FORMULATION AND SYSTEM FOR INTRA-ORAL DELIVERY OF PHARMACEUTICAL AGENTS
`
`Page 1 of 30
`
`Insys Exhibit 2019
`CFAD v. Insys
`IPR2015—01 799
`
`

`
`WO 00/47203
`
`
`
`
`PCT/US00/03555
`
`
`
`
`FORMULATION AND SYSTEM FOR INTRA-ORAL DELIVERY OF
`
`
`
`
`
`
`
`PHARMACEUTICAL AGENTS
`
`
`
`
`
`RELATED APPLICATIONS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`This application is related to, and claims the benefit of priority under, U.S.
`
`
`
`
`
`
`
`
`
`
`provisional patent application Serial No. 60/119,923, filed February 12, ‘I999.
`
`
`
`FIELD OF THE INVENTION
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`This invention relates to a formulation effective for the intra-oral delivery of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutical agents and to a system comprising the formulation in a metered-
`
`
`
`
`
`
`
`
`
`dose applicator device for dispensing the pharmaceutical agents intra—ora|ly.
`
`
`
`BACKGROUND OF THE INVENTION
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The poor aqueous solubility and the hydrophobic nature of many therapeutic
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`agents prevent them from being suitable for conventional oral delivery, due to their
`
`
`
`
`
`
`
`
`poor absorption and bioavailability.
`
`
`
`
`
`
`
`
`
`
`
`
`In other cases, the current means of delivery are
`
`
`
`
`
`
`
`
`
`
`
`
`
`primarily limited to parental means, often compromising the desired level of patient
`
`
`
`
`
`
`
`
`
`
`
`compliance. Many small and large molecule proteins and peptides are effective
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`therapeutically, yet are not ordinarily easily absorbed through, or are otherwise not
`
`
`
`
`
`
`effective when administered through,
`
`
`
`
`the GI
`
`
`
`tract,
`
`
`
`
`
`including insulin, calcitonin,
`
`
`
`
`
`
`
`
`
`human growth factors, and others.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Difficulties inhere in administering certain pharmaceutical agents orally (such as
`
`
`
`
`
`
`
`
`
`
`
`
`proteins), as saliva and/or gastrointestinal compounds tend to degrade or digest the
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutical agents, rendering them ineffective. For example, patients suffering
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`from diabetes are required to administer insulin to themselves by injection on a
`
`
`
`Page 2 of 30
`
`

`
`
`WO 00/47203
`
`
`
`2
`
`
`
`PCT/US00/03555
`
`
`
`
`regular basis.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Injection delivery of insulin and other drugs is inconvenient and can
`
`be painful, discomforting, and embarrassing.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`lnjectionable drug delivery also may be used to achieve a quick and efficient
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`administration. Chronic pain management is an area where speedy drug delivery is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`desired. For example, there is a significant increase in the prevalence and number
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of cancer deaths worldwide. Pain occurs in more than 80% of cancer patients before
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`death. Because of its high frequency, combined with the lack of availability of
`
`
`
`
`
`
`
`
`
`
`
`opioids in many countries and the under—treatment of pain,
`
`
`
`
`
`the World Health
`
`
`
`
`
`
`
`
`
`
`
`Organization declared pain a world medical emergency in 1986.
`
`
`
`
`Since then,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`emphasis has been on the appropriate treatment of cancer pain. As a result, the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`use of opioid analgesics has increased worldwide. Fentanyl is an opioid analgesic
`
`
`
`
`
`
`
`
`commonly used in chronic pain management.
`
`
`
`Currently,
`
`
`
`
`
`research is being
`
`
`
`
`
`conducted which searches
`
`
`
`
`
`
`
`
`
`for alternative means of quickly and effectively
`
`
`
`
`
`administering this drug.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Efforts to achieve quicker and more convenient methods of drug delivery have
`
`
`
`
`
`
`
`
`
`
`
`
`involved the development of nasal and pulmonary delivery mechanisms. These
`
`
`
`
`
`
`
`
`
`
`
`
`
`delivery mechanisms have been available for a select number of pharmaceutical
`
`
`
`agents.
`
`
`
`
`
`
`
`
`
`
`For example, aerosol delivery systems with various inha|ation—actuated
`
`
`
`
`
`
`
`
`
`
`
`
`aerosol-dispensing devices have been employed for treatment of asthma, and
`
`
`
`
`
`
`
`
`
`
`
`
`
`recently they have been investigating for delivery of insulin.
`
`
`
`
`
`Such devices are
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`breath-activated and designed for delivery to the pulmonary system. See, e.g., U.S.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Pat. No. 5,544,646 to Lloyd et aI., “Systems for the Intrapulmonary Delivery of
`
`
`
`
`
`
`
`
`
`
`
`
`
`Aerosolized Aqueous Formulations"; US. Pat. No. 5,320,094 to Laube, “Method of
`
`
`
`Page 3 of 30
`
`

`
`
`wo on/47203
`
`
`
`3
`
`
`
`PCT/US00/03555
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Administering Insulin”; and U.S. Pat. No. 4,648,393 to Landis et a/., “Breath
`
`
`
`
`
`
`
`
`
`Activated Medication Spray’, all of which are incorporated herein.
`
`
`
`
`
`
`
`
`
`
`
`
`
`There remains a need for improved formulations and methods for delivering
`
`
`
`
`
`
`pharmaceutical agents to patients,
`
`
`
`
`
`
`
`
`
`
`
`
`
`In particular, there is a need for a quick and easy
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`method of administration that may be used effectively for a wide range of
`
`
`
`pharmaceutical
`
`
`
`agents
`
`
`
`
`and that
`
`
`
`avoids
`
`
`
`
`long—term toxicological
`
`
`
`effects
`
`
`
`
`as
`
`
`
`
`experienced with lung delivery.
`
`
`
`SUMMARY OF THE INVENTION
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The invention comprises a formulation effective for the delivery of pharmaceutical
`
`
`
`
`
`
`
`
`
`agents through the mucosa of
`
`
`
`
`
`
`
`the intra-oral cavity comprising at
`
`
`
`
`least one
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutical agent, one or more oral-absorption enhancers, and optionally, one
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`or more solvent carriers, propellants (e.g., where a propellant device is used for
`
`
`
`
`
`
`
`
`
`
`
`delivery), stabilizers, anti—microbia| agents, and auxiliary components. The invention
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`further relates to a system for delivering the formulation including a mechanism for
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`dispensing predetermined doses of the inventive formulation intra—orally as with an
`
`
`
`
`
`
`
`aerosol or spray pump or propellant device.
`
`
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`For a better understanding of the invention, exemplary embodiments are
`
`
`
`
`
`
`
`
`
`
`
`
`described below, considered together with the accompanying figures, in which:
`
`
`
`
`
`
`FIG. 1
`
`
`
`
`
`
`
`
`
`
`
`
`
`is a graph showing the effect of inventive formulations containing insulin
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`administered to rats intra—orally wherein plot A reflects application of the invention
`
`
`
`and plots B,C, and D reflect controls; and
`
`
`
`
`
`
`
`
`
`
`Page 4 of 30
`
`

`
`“/0 00/47203
`
`
`
`
`4
`
`
`
`PCT/US00/03555
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`FIG. 2 is a graph showing the effects of inventive formulations containing highly
`
`
`
`
`
`
`
`
`
`
`
`
`
`purified porcine insulin administered intra—orally to two human subjects; and
`
`
`
`
`
`
`
`
`
`
`FIGS. 3 and 4 are graphs showing the effects of
`
`
`
`
`inventive formulations
`
`
`
`
`
`containing human recombinant
`
`
`
`
`
`
`
`
`insulin administered intra—oraI|y to two human
`
`
`
`
`
`subjects.
`
`
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`
`
`
`
`
`
`
`
`
`
`
`
`Applicants have discovered a formulation that enables
`
`
`
`
`
`the delivery of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutical agents through the mucosa of the intra-oral cavity. This target site
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`provides a large surface area and cell membranes with high permeability and
`
`
`
`
`
`
`
`
`
`
`
`
`
`significant vascularization for rapid and efficient drug absorption. The formulation of
`
`
`
`
`
`
`this invention comprises at
`
`
`
`
`
`
`
`
`
`
`least one pharmaceutical agent, one or more oral-
`
`
`
`
`
`
`
`
`
`
`
`
`absorption enhancers, and optionally, one or more solvent carriers, propellants (e.g.,
`
`
`
`
`
`
`
`
`
`
`
`
`where a propellant device is used for delivery), stabilizers, anti-microbial agents, and
`
`
`
`
`auxiliary components
`
`
`
`
`
`such as
`
`
`flavor enhancers
`
`
`
`
`
`
`typically included in orally-
`
`
`
`
`
`
`
`
`
`
`
`administered formulations. The invention further relates to a system for delivering
`
`
`
`
`
`
`
`
`
`
`
`
`the formulation. The system comprises a mechanism for dispensing predetermined
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`doses of the inventive formulation intra—oraIly as with a pump or propellant device,
`
`
`
`which are described further below. The mechanism is referred to as a metered-dose
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`applicator (MDA""), wherein MDATM is a trademark of MOS, lnc., the assignee of the
`
`
`
`
`
`
`
`
`present application (located in Jamesburg, NJ).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The invention provides an efficient and convenient drug delivery method for
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`many pharmaceutical agents that results in rapid onset of therapeutic action. avoids
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the hepatic first pass effect, and reduces the amount of drug needed for an effective
`
`
`
`Page 5 of 30
`
`

`
`WO 00/47203
`
`
`
`
`
`
`PCT/US00/03555
`
`
`
`doses,
`
`
`
`thus reducing the cost. With this invention, a noninvasive alternative is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`provided to pulmonary, nasal, or gastrointestinal delivery of pharmaceutical agents,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and absorption is increased and accelerated. The pharmaceutical agent can be
`
`
`
`
`
`
`
`
`
`
`
`
`directly targeted to the intra—oral delivery site of absorption through the inventive
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`delivery system which combines appropriate droplet size, strength of dose, and
`
`
`
`
`
`
`
`
`
`
`absorption enhancers formulated to provide optimum bioavailability and onset of
`
`
`
`action.
`
`
`
`
`
`
`
`
`
`
`
`
`Additionally, the invention is advantageous for therapeutic reasons. The method
`
`
`
`
`
`
`
`
`of delivery described herein is easier,
`
`
`
`
`
`
`less inconvenient, and/or less—embarrassing
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`than other methods of administration, thus increasing patient compliance. A further
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`benefit of oral versus inhalation administration is that oral spray delivery does not
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`have the same long-term toxicological effects as when inhaling the compounds. The
`
`
`
`
`
`
`
`
`
`
`
`
`
`invention also is advantageous in delivering pharmaceutical agents to animals which
`
`
`
`often are resistant to traditional means of drug delivery. The inventive formulations
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`may be incorporated into morsels including meats or flavor-enhancers to make them
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`more appealing to animals (cats and dogs) to enable their oral delivery.
`
`
`
`
`
`
`
`
`
`
`
`
`
`The formulation of this invention comprises at least one pharmaceutical agent.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Suitable pharmaceutical agents for use in the invention include large and small
`
`
`
`
`
`
`
`
`
`
`
`molecular weight compounds, peptides, polypeptides, and proteins. Examples of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`such compounds include proteins and peptides up to 50,000 Datoms, glucocorticoid
`
`
`
`
`
`
`
`
`
`
`steroids, testosterone, dexamethasone, prednisolone, and salts thereof, prednisone,
`
`
`
`
`stanozolol, barbituates,
`
`
`
`seconal
`
`
`
`
`and salts
`
`
`
`
`thereof, benzodizepines
`
`
`
`
`such as
`
`
`
`
`
`flurazepam and
`
`salts
`
`
`
`
`thereof, miscellaneous
`
`
`
`sedative
`
`
`
`hypnotics
`
`
`
`
`
`such as
`
`
`
`
`
`
`
`
`
`
`ethchlorvynol and salts. Suitable peptides include hormones such as calcitonin,
`
`
`
`Page 6 of 30
`
`

`
`WO 00/47203
`
`
`
`
`
`
`PCT/US00/(13555
`
`
`
`
`
`
`
`
`
`
`
`
`
`leuprolide, human growth hormone (HGH), glycogen—like protein (GLP), and salts
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`thereof, and insulin. Various types of insulin may be used, such as bovine, porcine
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`or human—recombinant insulin. Nitroglycerine also may be used, e.g., as a blood
`
`
`
`
`pressure medication
`
`
`
`
`to
`
`counter
`
`
`
`
`heart-attacks. Typically,
`
`
`
`nitro-glycerine
`
`
`
`is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`administered in tablet form for delivery under the patients tongue, but with the
`
`
`
`
`
`
`
`
`
`
`instant method of delivery, entry of the agent
`
`
`
`
`
`
`
`
`into the patient’s bloodstream is
`
`accelerated.
`
`
`
`
`
`
`
`
`
`
`
`
`
`The formulation may comprise one or more analgesics as the pharmaceutical
`
`
`
`
`
`
`
`
`
`
`
`
`
`agent. For example, non-narcotic analgesics such as ketorolac and salts thereof,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and oxandrolone may be used, or narcotic analgesics, such as morphine, fentanyl
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and salts thereof, sedative hypnotic agents, and codeine fentanyl citrate. Such
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`analgesic formulations can be used to control pain in cancer patients undergoing
`
`
`
`
`
`
`
`
`
`
`
`chemotherapy who experience debilitating breakthrough pain. Nicotine and related
`
`
`
`
`
`
`
`
`
`
`
`
`stimulants may also be administered in accordance with the invention.
`
`
`
`
`
`
`
`
`
`
`
`
`While concentrations will vary with the particular pharmaceutical agents and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`formulations used, typically the pharmaceutical agent will be present in the amount
`
`
`
`
`
`
`
`
`
`of about 0.01 to 25% by weight.
`
`
`
`
`
`
`
`
`For example, embodiments of the formulation
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`comprising use of insulin and fentanyl citrate may comprise use of 0.5 % w/w of the
`
`
`
`
`pharmaceutical agent.
`
`
`
`
`
`
`
`
`
`
`
`
`The inventive formulation further comprises one or more oral absorption
`
`
`
`enhancers.
`
`
`
`
`
`
`
`
`
`
`
`
`The term “oral absorption enhancer" is used herein to refer
`
`
`
`to
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`compounds that disrupt or modify the absorptive surface of the targeted site (such
`
`
`
`
`as wetting)
`
`
`
`
`
`
`
`
`
`
`
`
`to improve absorption across the membrane, either alone or as
`
`
`
`administered with a metered dose applicator. The term “intra—oral cavity" refers to all
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 7 of 30
`
`

`
`W0 00/47203
`
`
`
`7
`
`
`
`PCT/US00/03555
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`areas within the mouth, including the cheeks, gums, lips, tongue, thorax. back of the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`throat, and beneath the tongue. Typically, the droplet will be sized within the range
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of about 1 to 200 microns, more preferably within the range of 10-100 microns. The
`
`
`
`
`
`
`
`
`
`
`
`
`droplets may be presented to the mucosa within a liquid,
`
`
`
`
`
`solid, or gaseous
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`suspension, including an aerosol system which refers to a gaseous suspension of
`
`
`
`
`
`
`
`
`
`particles dispensed within the form of a mist.
`
`
`
`
`
`
`
`
`
`
`
`The oral-absorption enhancer may comprise one or more orally-acceptable
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`surfactants or other compounds. The important consideration is that the absorption ‘
`
`
`
`
`
`
`
`
`
`
`
`
`enhancer be effective for preparing the mucosa to absorb the pharmaceutical agent.
`
`
`
`
`
`Exemplary,
`
`
`
`suitable
`
`
`
`oral
`
`
`
`absorption
`
`
`
`enhancers
`
`
`
`include
`
`
`
`hydroxypropyl-beta-
`
`
`
`
`
`
`
`
`
`
`cyclodextrin and surfactants such as benzalkonium chloride, benzethonium chloride,
`
`
`
`
`
`
`
`
`
`
`polysorbate 80, sodium lauryl sulfate, Brij surfactants, Tween surfactants, and
`
`
`
`
`Pluronic surfactants.
`
`
`
`
`
`
`
`Surfactants of the Brij
`
`
`
`
`family may comprise polyoxy(n)-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`oleoether, wherein n is from 1 to 100. Notably, one or more of these and/or other
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`surfactants may be included for other purposes such as increasing the miscibility of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the formulation ingredients or reducing the size of the pharmaceutical agents to
`
`droplet size.
`
`
`
`
`In such case, the surfactant is referred to herein as a “formulation
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`surfactant.” As used herein, the term “droplet" refers to a single unit of atomized
`
`
`
`
`
`
`
`
`
`
`
`spray having a sufficiently small size that it
`
`
`
`
`
`
`
`is capable of being absorbed by a
`
`
`
`
`
`
`
`
`
`
`mucosa of the intra—ora| cavity.
`
`
`
`
`
`
`
`
`
`
`
`While the concentration of oral-absorption enhancers will vary with the particular
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutical agents and/or method of delivery, typically these components will be
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`present in the amount of up to 50% by weight, more preferably in the range of 0.1%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to 20% by weight, and even more preferably at about 110.5% by weight.
`
`
`
`For
`
`
`
`Page 8 of 30
`
`

`
`
`WO 00/47203
`
`
`
`8
`
`
`
`
`PCT/US00/03555
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`example, exemplary embodiments of the formulation comprise use of sodium lauryl
`
`
`
`
`
`
`
`sulfate at .9 to 1.2% by weight.
`
`
`
`
`
`
`
`
`
`
`
`
`Typically, the formulation will comprise an orally—acceptable carrier solvent.
`
`
`
`
`
`
`
`
`
`
`
`
`The carrier solvent may include water but preferably is non—aqueous. The carrier
`
`
`
`
`
`
`
`
`
`
`
`
`
`solvent preferably comprises ethanol, glycerol, glycol, propylene glycol, polyethylene
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`glycol, sorbitoi, vitamin E and derivatives of vitamin E, polyvinylpyrrolidone, water,
`
`
`
`
`
`
`
`
`
`
`
`
`and other orally-acceptable solvents known in the field. Typically, the carrier solvent
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`will be present in an amount of from 0.5 to 50% by weight, more preferably at about
`
`
`
`20% by weight.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`One embodiment of the invention comprises a system for formulating and
`
`delivering desired pharmaceutical agents intra-orally comprising use of a propellant-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`based assembly, and for such cases,
`
`
`
`
`
`
`
`the formulation will comprise use of a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`propellant. Typically, the propellant will be present in an amount of from 20 to 95%
`
`
`
`
`
`
`
`
`
`
`
`
`
`by weight, more preferably at about 50-80% by weight. Various propellants are
`
`
`
`
`
`
`
`
`
`
`
`
`known in the field and discussed in the literature. However, exemplary propellants
`
`
`
`
`
`
`
`
`
`
`
`
`
`comprise carbon dioxide, and hydrofluoroalkane (HFA), which is available from
`
`
`
`
`
`
`
`
`
`
`DuPont Corporation, under the tradename HFA 134ATM. Also, HFA compounds
`
`
`
`referred to in
`
`
`
`
`the trade as DYMELTM 152A, HFA 152*“, and HFA 227"“
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`advantageously may be used.
`
`
`
`
`
`
`
`
`
`
`Such products are known and available in the
`
`
`
`
`
`
`
`
`
`
`
`aerosol industry as earth friendly (green) propellants. Ozone—depleting propellants,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`such as freone 12, freone 13, butane, and propane, also may be used but are less
`
`
`
`preferred.
`
`
`
`
`
`
`
`
`
`
`
`
`Also optionally included within the compositions are stabilizers and anti-microbial
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`agents. Stability of the pharmaceutical agent over an extended storage period may
`
`
`
`Page 9 of 30
`
`

`
`
`WO 00/47203
`
`
`
`9
`
`
`
`
`PCT/US00/03555
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`be aided by stabilizers, such as 1% sodium dodecyl sulfate solution or benzalkonium
`
`
`
`
`
`
`
`
`
`
`
`chloride. Most proteins degrade in the presence of heat,
`
`
`
`
`For example,
`
`
`
`insulin
`
`
`
`
`
`
`
`
`
`
`
`
`
`usually must be kept refrigerated to be protected from decomposition. Additionally,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the presence of water contributes to the decomposition of pharmaceutical agents by
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`providing a polar vehicle in which the agents can react. Decomposition of the
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutical agents resulting from interaction with water and heat during storage
`
`
`
`may be reduced by use of stabilizers such as lactic acid, citric acid, and preservative
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`systems including benzoic acid, benzyl alcohol,
`
`
`
`
`
`thimerosal, phenylethyl alcohol.
`
`
`
`
`
`
`
`
`
`
`
`
`benzethonium chloride, methyl paraben, ethyl paraben, butyl paraben or propyl
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`paraben. When included, stabilizers may comprise up to about 5 weight °/o of the
`
`
`
`formulation.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`in some forms, such as aqueous~based formulations, anti—microbial agents may
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`be included, as microbial growth may affect the chemical stability of the ingredients,
`
`
`
`
`
`
`
`
`
`
`
`safety and acceptability of the product, and the physical
`
`
`
`
`
`
`integrity of the system.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Lactic acid and citric acid are also exemplary, effective anti-microbial agents. The
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`amount of such agents desirably included will depend upon the particular formulation
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and can be determined by one skilled in the field with use of micro—organism growth
`
`
`
`tests .
`
`
`
`Optionally,
`
`
`
`the
`
`
`
`formulation
`
`
`
`
`also may
`
`
`
`comprise
`
`
`
`viscosity/mucoadhesive
`
`
`
`
`
`
`
`
`
`
`
`
`
`enhancing agents such as cellulose ether polymers and chitosan; flavoring agents;
`
`
`
`
`
`
`
`
`
`
`and/or preservative systems including benzoic acid, benzyl alcohol,
`
`
`
`thimerosal,
`
`
`
`
`
`
`
`
`
`
`
`phenylethyl alcohol, benzethonium chloride, methyl paraben, ethyl paraben, butyl
`
`
`
`
`
`
`paraben or propyl paraben.
`
`
`
`Page 10 of 30
`
`

`
`
`W0 00/47203
`
`
`
`10
`
`
`
`PCT/US00/03555
`
`
`
`
`
`
`
`
`
`
`
`
`
`It may include anti—oxidants, kelating agents, preservatives, agents to adjust
`
`
`
`osmolarity, agents to adjust pH, and non cross—linked polymers.
`
`
`
`
`
`
`
`
`
`
`
`It will be appreciated that the invention can be used to treat a large variety of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`diseases,
`
`
`
`
`
`including male hypogonadism,
`
`
`
`
`
`
`impotence, pain management, diabetes,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and osteoporosis, as well as diseases and disorders requiring the administration of
`
`
`
`small and large molecule proteins and peptides.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The invention further comprises a system for formulating and delivering desired
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutical agents intra—orally comprising use of a mechanism for delivering
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`predetermined doses of the inventive formulation intra-orally, as with a pump or
`
`
`
`
`
`
`
`
`
`
`
`
`
`propellant device. Any type of delivery mechanism for administering the formulation
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`intra—oraIly in metered doses may be used. For example, the formulation can be
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`prepared in a tube (as is used for containing toothpaste) having a nozzle thereon for
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`delivering predetermined units of formulation. Metal, glass, plastic, or other types of
`
`
`
`containers can be used.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The delivery system or metered dose applicator (MDATM) can be pressurized
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(pMDA“") or unpressurized (MDATM). Aerosol-type actuators can by used, applying
`
`
`
`
`
`
`
`
`
`
`
`
`
`inhalation and pump technology. These actuators may have dual chamber systems
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`that allow for reactive components to be separated until the time of delivery, as is
`
`
`
`
`
`
`
`
`
`
`important for some active pharmaceutical products. The applicators may have
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`specialized combination valves to deliver the product adequately and effectively.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Thus, the inhalation technology and mechanical configurations for inhalers can be
`
`
`
`
`
`
`
`
`
`
`
`
`
`used with the formulations described above to deliver pharmaceutical agents intra-
`
`
`
`
`
`orally, not to the lung.
`
`
`
`
`For example,
`
`
`
`
`
`
`
`the delivery mechanism may comprise
`
`
`
`
`
`
`
`
`
`
`
`
`inhalation actuators and nasal actuators sold under the tradenames VALOISW,
`
`
`
`Page 11 of 30
`
`

`
`
`WO 00/47203
`
`
`
`1 1
`
`
`
`PCT/US00/03555
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`BESPAKT“, and PFlFFER7”. A representative actuator is described in U.S. Pat. No.
`
`
`
`5,284,133 to Bums et a/., “/nhalation Device with a Dose-Tinter, An Actuator
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Mechanism. and Patient Compliance Monitoring Means,” which is
`
`incorporated
`
`
`
`herein.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`With the pump applicators, the mechanism will include a container or chamber
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`coupled to a pump and actuator. The volume of the chamber will determine the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`dose that is administered with each depression of the pump. The pump applies
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pressure to the formulation disposed within the chamber and causes the formulation
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to move through the actuator. The actuator is adapted to reduce the formulation into
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`droplets capable of forming an aerosol spray for oral administration. The surfactant
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`or other oral absorption enhancer is effective in reducing surface tension in providing
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a formulation capable of being reduced to droplet size by the actuator, forming an
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`aerosol spray. The effectiveness of the delivery system is enhanced as the size of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`droplets is decreased to the point of where the particle has a minimum aerodynamic
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`particle size distribution for effective transport. Typically, this is about 10 microns. A
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`decreased droplet size translates to a higher surface area to be absorbed by the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`mucosa of the intra-oral cavity. With the propellant device, a chamber, valve, and
`
`
`
`
`actuator are also used.
`
`
`
`
`
`
`
`
`
`The formulation is pressured within the chamber.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Depression of the valve causes pressure to be released so that the formulation
`
`
`
`
`
`
`
`
`moves through the actuator.
`
`
`
`
`Again,
`
`
`the actuator
`
`
`
`
`
`
`
`is adapted to reduce the
`
`
`
`formulation into droplets for oral administration.
`
`
`
`
`
`
`
`
`The surfactant or other oral
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`absorption enhancer is effective in providing a formulation capable of being reduced
`
`
`
`
`
`
`
`
`to droplet size by the actuator.
`
`
`
`Page 12 of 30
`
`

`
`WO 00/47203
`
`
`
`
`12
`
`
`
`PCT/US00/03555
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The following examples will serve to further typify the nature of the invention but
`
`
`
`should not be construed as a limitation on the scope thereof, which is defined by the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`appended claims.
`
`
`
`ingredients
`
`
`
`Example 1
`
`
`
`
`°/o W/W
`
`
`
`0.5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Pharmaceutical Agent
`lnsulin
`
`
`
`
`
`
`Oral absorption enhancer
`Surfactant
`
`
`
`
`Carrier-solvent
`
`
`Tris-base
`Ethanol
`
`
`
`
`
`Balance propellant
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The ingredients are thoroughly mixed to form a solution. The solution is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`placed within a container of a propellant dispenser and administered orally to
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`provide insulin to a patient in need thereof. The 0.5% insulin solution is effective in
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`administering 17 units (“International Units” or “U.l.'s") to a patient per dose when a
`
`
`
`
`
`
`
`150 microliter p-MDATM is used.
`
`
`
`Example 2
`
`
`g
`
`Ingredients
`
`
`Pharmaceutical Agent
`
`
`Fentanyl Citrate
`
`
`
`
`
`Oral absorption enhancer
`Surfactant
`
`
`
`
`% w/w
`
`
`
`0.5
`
`
`
`1.2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 13 of 30
`
`

`
`WO 00/47203
`
`
`
`
`
`
`PCT/USOD/03555
`
`
`
`
`20
`
`
`
`21.7
`
`78.3
`
`
`
`Carrier-solvent
`
`Ethanol
`
`
`
`Balance propellant
`
`
`
`100
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The ingredients are thoroughly mixed to form a solution. The solution is
`
`
`
`
`
`
`
`
`
`
`
`
`
`placed within a container of a propellant dispenser and administered orally to
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`provide pain relief to a patient in need thereof. The formulation is effective in
`
`
`
`
`
`
`
`
`
`
`treating patients suffering from pain associated with cancer and chemotherapy.
`
`
`
`Example 3
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A bioavailability study was performed in a rat model, and the results are shown
`
`
`
`
`
`
`
`
`
`
`in FIG. 1. Plot A of FIG.
`
`
`
`
`
`
`
`
`1 reflects a formulation containing 30 units (international
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`units or “l.U.’s") of Bovine insulin. To achieve a dose of 30 units, the formulation
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`may be prepared essentially as described above in Example 1, but using about 1%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of the insulin. As can be seen, the formulation produced a 45% decrease in blood
`
`
`
`
`
`
`
`
`
`
`
`
`glucose over 90 minutes post administration of the insulin formulation.
`
`
`
`The
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`decrease in blood glucose following administration was linear up to 90 minutes post
`
`
`
`
`
`
`
`
`
`
`
`
`
`dosing. Control formulations were administered and no decrease in blood glucose
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`was observed. Plot B, for example, reflects a control comprising no active ingredient
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(no insulin) and no formulation according to the invention. Plot C reflects a control
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`comprising the inventive formulation but without the active ingredient. Plot D reflects
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a control comprising the active ingredient but without the inventive formulation. This
`
`
`
`
`
`
`
`
`
`
`
`
`
`bioavailability study demonstrated that the method of preparation and composition of
`
`
`
`Page 14 of 30
`
`

`
`W0 00/4 7203
`
`
`
`
`1 4
`
`
`
`PCT/US00/03555
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the formulation was effective in delivering the insulin to the patient and enabling a
`
`
`
`
`
`
`
`
`
`
`
`
`significant reduction in blood glucose level with an intra-oral delivery.
`
`
`
`
`Examgle 4
`
`
`
`
`