Exhibit 1005
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1005
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01799
`
`

`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2002/0055496 A1
`(43) Pub. Date:
`May 9, 2002
`McCoy et al.
`
`US 20020055496A1
`
`(54) FORMULATION AND SYSTEM FOR
`INTRA-ORAL DELIVERY OF
`PHARMACEUTICAL AGENTS
`
`(76)
`
`Inventors: Randall McCoy, Little Falls, NJ (US);
`Robert O. Williams, Austin, TX (US);
`Miles A. Libbey III, Pennington, NJ
`(US)
`
`Correspondence Address:
`MATHEWS, COLLINS, SHEPHERD &
`GOULD, P.A.
`100 THANET CIRCLE, SUITE 306
`PRINCETON, NJ 08540-3674 (US)
`
`(21) Appl. No.:
`
`09/944,492
`
`(22)
`
`Filed:
`
`Aug. 30, 2001
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 09/502,871, filed on
`Feb. 11, 2000. Non-provisional of provisional appli-
`cation No. 60/119,923, filed on Feb. 12, 1999.
`
`Publication Classification
`
`Int. Cl.7 ................................................... ..A61K 31/56
`(51)
`(52) U.S.Cl.
`............................................................ ..514/179
`
`(57)
`
`ABSTRACT
`
`A stable formulation is disclosed that enables the effective
`
`intra-oral delivery to a patient of a pharmaceutical agent.
`The formulation comprises the pharmaceutical agent mixed
`with an orally-acceptable oral-absorption enhancer in an
`orally-acceptable carrier-solvent, wherein the oral-absorp-
`tion enhancer is adapted to modify the surface membrane
`such that absorption through the surface membrane is initi-
`ated or increased. The oral-absorption enhancer may com-
`prise
`hydroxypropyl-beta-cyclodextrin
`and
`surfactants
`including benzalkonium chloride, benzethonium chloride,
`polysorbate 80, sodium lauryl sulfate, Brij surfactants,
`Tween and Pluronic surfactants. Also disclosed is 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.
`
`

`
`Patent Application Publication May 9, 2002 Sheet 1 of 4
`
`US 2002/0055496 A1
`
`Figure1
`
`
`AC-MPFH
`
`% n
`g
`
`-0» AB-Empie
`vs?-~ A93-W}???
`
`_ ’
`A‘
`
`_
`
`.
`
`‘
`
`.1
`'
`
`..
`
`‘£643
`
`$40
`
`,’t* s °
`
`I
`
`~
`
`l
`
`
`
`‘I
`
`
`
`It
`R‘
`E
`i
`‘é
`“W \
`£1
`333
`
`._’
`
`'5.
`E
`In
`
`g:
`
`-
`
`-
`
`

`
`Patent Application Publication May 9, 2002 Sheet 2 of 4
`
`US 2002/0055496 A1
`
`4xww
`
`$3§¥$§%tagfiwwm
`
`N?W?mafiaW3
`
`3%.
`
`am?
`
`03
`
`3
`
`S
`
`.3
`
`mm
`
`W“-*3 gam; aaczmgg
`
`
`

`
`Patent Application Publication May 9, 2002 Sheet 3 of 4
`
`US 2002/0055496 A1
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`120
`
`140
`
`160
`
`180
`
`200
`
`220
`
`240
`
`260
`
`280
`
`300
`
`Time Post Actuation (minutes)
`
`am 3
`
`

`
`Patent Application Publication May 9, 2002 Sheet 4 of 4
`
`US 2002/0055496 A1
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`120
`
`140
`
`160
`
`180
`
`200
`
`220
`
`240
`
`260
`
`280
`
`300
`
`Time Post Actuation (minutes)
`
`ifiiér ‘I’:
`
`

`
`US 2002/0055496 A1
`
`May 9, 2002
`
`FORMULATION AND SYSTEM FOR INTRA-ORAL
`DELIVERY OF PHARMACEUTICAL AGENTS
`
`RELATED APPLICATIONS
`
`[0001] This application is related to, and claims the benefit
`of priority under, U.S. provisional patent application Ser.
`No. 60/119,923, filed Feb. 12, 1999.
`
`FIELD OF THE INVENTION
`
`[0002] 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 appli-
`cator device for dispensing the pharmaceutical agents intra-
`orally.
`
`BACKGROUND OF THE INVENTION
`
`[0003] 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, calci-
`tonin, human growth factors, and others.
`
`[0004] Difficulties inhere in administering certain pharma-
`ceutical 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 regular
`basis. Injection delivery of insulin and other drugs is incon-
`venient and can be painful, discomforting, and embarrass-
`mg.
`
`Injectionable drug delivery also may be used to
`[0005]
`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 ion
`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 com-
`monly used in chronic pain management. Currently, research
`is being conducted which searches for alternative means of
`quickly and effectively administering this drug.
`
`[0006] 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 sys-
`tems with various inhalation-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 al., “Systems for the Intrapulmonary Delivery of
`Aerosolized Aqueous Formulations”; U.S. Pat. No. 5,320,
`094 to Laube, “Method of Administering Insulin”; and U.S.
`Pat. No. 4,648,393 to Landis et al., “Breath Activated
`Medication Spray”, all of which are incorporated herein.
`
`[0007] 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
`
`[0008] 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 enhanc-
`ers, and optionally, one or more solvent carriers, propellants
`(e.g., where a propellant device is used for delivery), stabi-
`lizers, anti-microbial agents, and auxiliary components. The
`invention further relates to a system for delivering the
`formulation including a mechanism for dispensing prede-
`termined doses of the inventive formulation intra-orally as
`with an aerosol or spray pump or propellant device.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`[0009] For a better understanding of the invention, exem-
`plary embodiments are described below, considered together
`with the accompanying figures, in which:
`
`[0010] 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
`
`[0011] FIG. 2 is a graph showing the effects of inventive
`formulations containing highly purified porcine insulin
`administered intra-orally to two human subjects; and
`
`[0012] FIGS. 3 and 4 are graphs showing the effects of
`inventive formulations containing human recombinant insu-
`lin administered intra-orally to two human subjects.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0013] 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 permeabil-
`ity and significant vascularization for rapid and efficient
`drug absorption. The formulation of this invention com-
`prises 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 predeter-
`mined doses of the inventive formulation intra-orally as with
`a pump or propellant device, which are described further
`below. The mechanism is referred to as a metered-dose
`
`

`
`US 2002/0055496 A1
`
`May 9, 2002
`
`0.01 to 25% by weight. For example,
`
`
`
`[0019] 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 areas within the mouth,
`including the cheeks, gums, lips, tongue, thorax, back of the
`
`throat, and beneath the tongue.
`
`[0020] 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 pharma-
`ceutical agent. Exemplary, suitable oral absorption enhanc-
`ers 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-oral cavity.
`
`[0021] While the concentration of oral-absorption enhanc-
`ers 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 example,
`exemplary embodiments of the formulation comprise use of
`sodium lauryl sulfate at 0.9 to 1.2% by weight.
`
`[0022] 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, sorbitol, vitamin E and deriva-
`tives 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.
`
`[0023] One embodiment of the invention comprises a
`system for formulating and delivering desired pharmaceu-
`tical 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, exem-
`
`applicator (MDATM), wherein MDATM is a trademark of
`MQS, Inc., the assignee of the present application (located
`in Jamesburg, N.J
`
`[0014] The invention provides an efficient and convenient
`drug delivery method for many pharmaceutical agents that
`results in
`
`The
`
`
`
`
`pharmaceutical agent can be directly targeted to the intra-
`oral delivery site of absorption through the inventive deliv-
`ery system which combines appropriate droplet
`size,
`strength of dose, and absorption enhancers formulated to
`provide optimum bioavailability and onset of action.
`
`the invention is advantageous for
`[0015] Additionally,
`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.
`
`
`
`The invention also is advantageous in deliver-
`
`ing pharmaceutical agents to animals which often are resis-
`tant 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.
`
`[0016] 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, ben-
`zodizepines such as flurazepam and salts thereof, miscella-
`neous sedative hypnotics such as ethchlorvynol and salts.
`Suitable peptides include hormones such as calcitonin, leu-
`prolide, human growth hormone (HGH), glycogen-like pro-
`tein (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 patient’s tongue, but with the instant
`method of delivery, entry of the agent into the patient’s
`bloodstream is accelerated.
`
`[0017] The formulation may comprise one or more anal-
`gesics as the pharmaceutical agent. For example, non-
`narcotic analgesics such as ketorolac and salts thereof, and
`oxandrolone ma be used, or narcotic analgesics, such as
`morphine, i and salts thereof, sedative hypnotic
`agents, and codeine fentanyl citrate. Such analgesic formu-
`lations 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.
`
`[0018] While concentrations will vary with the particular
`pharmaceutical agents and formulations used, typically the
`pharmaceutical agent will be present in the amount of about
`
`

`
`US 2002/0055496 A1
`
`May 9, 2002
`
`[0030] The delivery system or metered dose applicator
`(MDATM) can be pressurized (pMDATM) 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 VALOISTM,
`BESPAKTM, and PFIFFERTM. A representative actuator is
`described in U.S. Pat. No. 5,284,133 to Burns et al., “Inha-
`lation Device with a Dose-Timer, An Actuator Mechanism,
`and Patient Compliance Monitoring Means,” which is incor-
`porated herein.
`
`the mechanism will
`[0031] With the pump applicators,
`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 provid-
`ing a formulation capable of being reduced to droplet size by
`the actuator, forming an aerosol spray.
`
`
`
`
`
`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 formula-
`tion 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.
`
`[0032] 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.
`
`EXAMPLE 1
`
`Ingredients
`
`Pharmaceutical Agent
`Insulin
`Oral absorption enhancer
`Surfactant
`Carrier-solvent
`
`Tris-base
`Ethanol
`
`% w/w
`
`0.5
`
`1.2
`
`0.48
`20
`
`22.18
`
`plary propellants comprise carbon dioxide, and hydrofluo-
`roalkane (HFA), which is available from DuPont Corpora-
`tion, under
`the
`tradename HFA 134ATM. Also, HFA
`compounds referred to in the trade as DYMELTM 152A,
`HFA 152”, and HFA 227TM advantageously may be used.
`Such products are known and available in the aerosol
`industry as earth friendly (green) propellants. Ozone-deplet-
`ing propellants, such as freone 12, freone 13, butane, and
`propane, also may be used but are less preferred.
`[0024] Also optionally included within the compositions
`are stabilizers and anti-microbial agents. Stability of the
`pharmaceutical agent over an extended storage period may
`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. Addi-
`tionally, the presence of water contributes to the decompo-
`sition of pharmaceutical agents by providing a polar vehicle
`in which the agents can react. Decomposition of the phar-
`maceutical 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, phenyl-
`ethyl alcohol, benzethonium chloride, methyl paraben, ethyl
`paraben, butyl paraben or propyl paraben. When included,
`stabilizers may comprise up to about 5 weight % of the
`formulation.
`
`In some forms, such as aqueous-based formula-
`[0025]
`tions, 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 par-
`ticular formulation and can be determined by one skilled in
`the field with use of micro-organism growth tests.
`[0026] Optionally,
`the formulation also may comprise
`viscosity/mucoadhesive enhancing agents such as cellulose
`ether polymers and chitosan; flavoring agents; and/or pre-
`servative systems including benzoic acid, benzyl alcohol,
`thimerosal, phenylethyl alcohol, benzethonium chloride,
`methyl paraben, ethyl paraben, butyl paraben or propyl
`paraben.
`It may include anti-oxidants, kelating agents, pre-
`[0027]
`servatives, agents to adjust osmolarity, agents to adjust pH,
`and non cross-linked polymers.
`[0028]
`It will be appreciated that the invention can be used
`to treat a large variety of diseases, including male hypogo-
`nadism,
`impotence, pain management, diabetes,
`and
`osteoporosis, as well as diseases and disorders requiring the
`administration of small and large molecule proteins and
`peptides.
`[0029] The invention further comprises a system for for-
`mulating and delivering desired pharmaceutical agents intra-
`orally comprising use of a mechanism for delivering prede-
`termined doses of the inventive formulation intra-orally, as
`with a pump or propellant device. Any type of delivery
`mechanism for administering the formulation intra-orally in
`metered doses may be used. For example, the formulation
`can be prepared in a tube (as is used for containing tooth-
`paste) having a nozzle thereon for delivering predetermined
`units of formulation. Metal, glass, plastic, or other types of
`containers can be used.
`
`

`
`US 2002/0055496 A1
`
`May 9, 2002
`
`EXAMPLE 1 -continued
`
`Ingredients
`
`Balance propellant
`
`% w/w
`
`77.82
`100
`
`[0033] 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.I.’s”) to a patient per dose when a 150 microliter
`p-MDATM is used.
`
`EXAMPLE 2
`
`Ingredients
`
`Pharmaceutical Agent
`
`Oral absorption enhancer
`Surfactant
`Carrier—solVent
`—
`
`Balance propellant
`
`% w/w
`
`.
`
`1.2
`
`_
`
`21.7
`78.3
`100
`
`[0034] 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
`
`[0035] 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 “I.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 administra-
`tion of the insulin formulation. The decrease in blood
`
`glucose following administration was linear up to 90 min-
`utes 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 formula-
`tion but without the active ingredient. Plot D reflects a
`control comprising the active ingredient but without the
`inventive formulation. This bioavailability study demon-
`strated that the method of preparation and composition of
`the formulation was eifective in delivering the insulin to the
`patient and enabling a significant reduction in blood glucose
`level with an intra-oral delivery.
`EXAMPLE 4
`
`Insulin formulation and adapted for use in a
`[0036]
`pMDA, using 0.5% highly-purified porcine insulin. The
`
`lyophilized human insulin was dispersed along with tris-
`base (introducing initially at about 0.48) and Brij 98 (0.9%)
`(as a dispersing aid) and absorption enhancers (sodium
`lauryl sulfate at 1.2%) and surfactants in hydrofluoroalkane
`(HFA 134a) propellant in the presence of ethanol (20%).
`Here, the Brij surfactant comprises a formulation surfactant
`for increasing the formulation miscibility. The dose delivery
`through-the-valve (DDV) (e.g., of the pMDA) was analyzed
`by HPLC for insulin potency assay and degradation prod-
`ucts. The finished pMDA units were stored at room tem-
`perature, and the DDV was determined at initial, 1, 2, 3, 4
`and 14 months in order to follow the dosing consistency and
`chemical stability of insulin throughout the storage period.
`The formulation was administered to the intra-oral cavity of
`two humans. Two actuations were delivered into the intra-
`
`oral cavity of the two humans for each dose. Aliquots of
`blood were collected periodically in the next two hours
`following dosing. Hypoglycemic effect was measured as the
`percent change in blood glucose concentration compared
`with the baseline.
`
`[0037] Stability tests revealed that the prepared insulin
`pMDA units delivered 32 to 38 IU per actuation, and DDV
`remained consistent after four months storage. In addition,
`no desamido insulin peak was detected for either the initial
`DDV sample or the 1,2,3 or 4 month stability DDV sample,
`indicating that no significant insulin degradation occurred in
`the product during the pMDa preparation process or the
`four-month stability storage period. The human study
`showed that the blood glucose level in humans started to
`decrease 20 minutes after administration of two actuations
`
`from the pMDA into the intra-oral cavity of humans, and a
`30% decrease in the blood glucose level was observed
`between 40 and 100 minutes after dosing. The blood glucose
`level returned to baseline in 2 hours following the initial
`dosing. The results are plotted in FIG. 2.
`EXAMPLE 5
`
`in
`[0038] A formulation was prepared essentially as
`Example 4, except a human recombinant insulin at about 1%
`was used and the concentration of HFA decreased to make
`
`up the difference. The formulation was administered to two
`healthy male human volunteers (RM and ML). A baseline
`blood glucose level was established for each volunteer prior
`to the experiment. After fasting overnight, each volunteer
`was administered insulin pMDA into the intra-oral cavity.
`The glucodynamic effects were monitored for 5 hours fol-
`lowing a 12-hour fast and the actuation of the pMDa. The
`percent change in blood glucose level from the baseline was
`established as a function of time to demonstrate the hypogly-
`cemic effect.
`
`[0039] Significant hypoglycemic effects were observed in
`this human study. FIGS. 3 and 4 are graphs plotting the
`glucose levels in the human subjects as a function of time,
`wherein each graph relates to a different subject. FIG. 3
`pertains to subject “RM” after a single actuation of the
`pMDA. As can be seen, the glucose levels decrease along a
`basically linear plot for up to 300 minutes (five hours) after
`the single actuation. FIG. 4 pertains to subject “ML”, also
`after a single actuation. Although the glucose levels are more
`Varied, overall a generally downward trend is reported. In
`each case, the blood glucose level decreased sharply in the
`first 20 minutes after dosing, and the maximum hypoglyce-
`mic effect was observed between 100 and 150 minutes post
`dosing.
`
`

`
`US 2002/0055496 A1
`
`May 9, 2002
`
`[0040] As can be seen, a stable propellant-driven pMDa
`formulation was developed for intra-oral delivery of insulin.
`Intra-oral delivery of insulin employing a pMDA formula-
`tion for treating diabetes has been established as feasible in
`this study. The administration was user friendly (no bad taste
`or chilled throat). In addition, administration of the formu-
`lation resulted in lowering glucose levels substantially
`below baseline levels.
`
`EXAMPLE 6
`
`[0041]
`
`
`
`The formulations were adminis-
`
`tered at pre-determined doses to six different rats and
`righting reflex was monitored at six different time intervals.
`Two rats under the same formulation lost
`their righting
`reflex, both at similar actuation intervals and after consecu-
`tive doses, and both regained righting reflexes within thirty-
`four minutes.
`
`
`
`procedure applied in this experiment was as fol-
`[0042]
`lows: The rates were selected and weighed. One formulation
`was administered to each rat at a predetermined dose, the
`time was noted, and a time clock was begun. Each rat was
`monitored for loss of righting reflex or other signs of
`somnolence at 5, 10, 15, 30, 60, 120 minutes. The time was
`marked when the righting reflex was gone. If righting reflex
`was not gone in 30 minutes, the rat was re-dosed with 2
`actuations and monitored as in time intervals as noted
`
`immediately above. The time when righting reflex returned
`was marked.
`
`[0043]
`and II:
`
`data and results are reported below in Tables I, II,
`
`TABLE I
`
`Formulation 12B
`
`Rat #
`
`5 min.
`
`10 min.
`
`15 min.
`
`30 min.
`
`60 min.
`
`120 min.
`
`632
`633
`
`Intact
`Intact
`
`intact
`intact
`
`Intact
`Intact
`
`Intact
`Intact
`
`Intact
`Intact
`
`intact
`intact
`
`[0044]
`
`TABLE II
`
`Formulation 12A
`
`Rat #
`
`5 min.
`
`10 min.
`
`15 min.
`
`30 min.
`
`60 min.
`
`120 min.
`
`634
`635
`
`Intact
`Intact
`
`Intact
`Intact
`
`Intact
`Gone
`
`Intact
`Gone
`
`intact
`Intact
`
`intact
`intact
`
`[0045]
`
`TABLE III
`
`Formulation 2A/50 gg dose administered by pipette
`5 min.
`10 min.
`15 min.
`30 min.
`60 min.
`
`Intact
`Intact
`
`Intact
`Intact
`
`Gone
`Intact
`
`Gone
`Sleepy
`
`sleepy
`sleepy
`
`120 min.
`
`sleepy
`sleepy
`
`Rat #
`
`636
`637
`
`[0046] As can be seen, all rats maintained righting reflex
`for intervals up to 30 min. with one actuation and, therefore,
`the above data reflects intervals with two actuations admin-
`
`istered. Rats 636 and 637 received 90 microliters (one
`actuation) and 180 microliters (two actuations) of formula-
`tion 12A fentanyl citrate by pipette. The remaining subjects
`received the fentanyl citrate by spray actuations. The two
`rats (635 and 636) that lost righting reflex remained sleepy
`and weak after righting reflex again became intact at 60 and
`120-minute intervals. Both of these rats were given formu-
`lation 12A, however, Rat 635 received the formulation by
`spray and Rat 636 received the formulation by pipette. The
`formulation was proven effective as well as both methods of
`administration. Rat 637 also began showing signs of som-
`nolence at 15, 30, and 60-minute intervals although righting
`reflex remained intact. There were no signs of somnolence
`in either of the two rats that received the 12B formulation.
`
`[0047] Thus, formulation 12A effected three of the four
`rats at high levels of fentanyl citrate in relation to this study.
`Because both rats received fentanyl by different means, the
`two forms of administration (spray and pipette) proved to be
`equally effective. After 30 minutes administering one actua-
`tion at the specified intervals and more than 15 minutes
`administering two actuations of the fentanyl citrate formu-
`lation, a response was manifested in the animals receiving
`formulation 12A. Formulation 12B did not effect either of
`the two rats that received it, and thus, an alcoholic-based
`system was preferred over an aqueous-based system in this
`instance.
`
`We claim:
`
`1. A predominantly nonaqueous formulation for intra-oral
`delivery of at least one pharmaceutical agent to a patient
`comprising a dispersion of an effective amount of the
`pharmaceutical agent and an orally-acceptable oral-absorp-
`tion enhancer operable to modify the absorptive surface of
`the targeted intra-oral membrane and enhance bioavailabil-
`ity of the pharmaceutical agent across the membrane, in an
`orally-acceptable nonaqueous carrier-solvent containing a
`quantity of a formulation surfactant at least suflicient to
`increase the miscibility of the pharmaceutical agent in the
`nonaqueous carrier-solvent.
`2. The formulation according to claim 1 in which the
`pharmaceutical agent is a glucocorticoid steroid, testoster-
`one, dexamethasone, prednisolone, prednisone, stanozolol,
`barbituates, seconal, benzodizepines, a sedative-hypnotic,
`nitroglycerine, an analgesic or a peptide or protein having a
`molecular weight up to about 50,000 Daltons, or an orally
`administerable non-toxic salt of said pharmaceutical agent.
`24. The formulation according to claim 2 in which the
`peptide or protein is calcitonin,
`insulin, GLP, HGH, or
`leuprolide.
`
`

`
`US 2002/0055496 A1
`
`May 9, 2002
`
`25. The formulation according to claim 2 in which the
`analgesic is ketorolac, oxandrolone, morphine, fentanyl,
`codeine, or a salt thereof.
`3. The formulation according to claim 2 in which the
`pharmaceutical agent is present in an amount of about 0.01
`to 25% by weight of the composition.
`4. The formulation according to claim 1 in which the
`oral-absorption enhancer is selected from the group consist-
`ing of hydroxypropyl-beta-cyclodextrin, benzalkonium
`chloride, benzethonium chloride, polysorbate 80, sodium
`lauryl sulfate, polyoxyethylene ethers of aliphatic alcohols,
`polyoxyethylene derivatives of fatty acid partial esters of
`s