(12) United States Patent
`McCoy et al.
`
`US006495120B2
`US 6,495,120 B2
`Dec. 17, 2002
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`(54) FORMULATION AND SYSTEM FOR INTRA-
`ORAL DELIVERY OF PHARMACEUTICAL
`AGENTS
`(76) Inventors; Randal] McCoy, 10 High CL, Little
`Falls, NJ (US) 08551; Robert O.
`Williams, III, 4514 Rapid Springs
`Cove, Austin, TX (US) 78746; Miles A,
`Libbey, HI, 2 Blue Spruce DR,
`Pennington, NJ (US) 08534
`
`OTHER PUBLICATIONS
`
`Aungst et al, Comparison of the effects of various transmu
`cosal absorption promoterson buccal insulin delivery, Inter
`national Journal of Pharmaceutics, 1989, pp. 227—235.*
`
`Senel et al, Drug permeation enhancement via buccal route:
`possibilities and limitations, Journal of Controlled Release
`2001 pp 133_144 *
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`_
`_
`* Clted by examlner
`
`(21) Appl. No.: 09/944,492
`(22) Filed
`Au 3 0 2001
`'
`g‘
`’
`Prior Publication Data
`
`(65)
`
`US 2002/0055496 A1 May 9, 2002
`
`Related US. Application Data
`
`_
`_
`_
`_
`(63) Continuation of application No. 09/502,871, ?led on Feb.
`11’ 2009
`(60) ligg‘gsional application NO- 60/119,923, ?led On Feb- 12,
`'
`7
`(51) Int. Cl. .......................... .. A61K 9/12; A61K 9/10;
`A61K 38/10- A61K 38/28
`424/45_ 424M} 514/2
`’
`514/3’. 514/4;
`
`(52) U S C]
`i
`l
`l """"""""""""""" "
`
`(58) Field of Search ....................... .. 424/45, 43; 514/2,
`514/3, 4
`
`(56)
`
`References Cited
`
`U_S_ PATENT DOCUMENTS
`
`5,011,678 A * 4/1991 Wang et al. ................ .. 424/45
`
`5,047,230 A * 9/1991 Nagy et al. . . . . . . .
`. . . .. 424/45
`5,288,498 A * 2/1994 Stanley et al. ............ .. 424/440
`
`Primary Examiner—Jose‘ G. Bees
`Assistant Examiner—M. Haghighatian
`(74) Attorney, Agent,
`or Firm—MatheWs, Collins,
`Shepherd & McKay, PA.
`
`(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
`absorption enhancer is adapted to modify the surface mem
`brane Suchthat absor tionthrou h the Surface membrane is
`p
`g
`initiated or increased. The oral-absorption enhancer may
`comprise hydroXypropyl-beta-cyclodeXtrin and surfactants
`
`including benzalkonium Ch1°ride> benzethonium Ch1°ride>
`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.
`
`27 Claims, 4 Drawing Sheets
`
`
`
`
`
`TIME POSI ACTUAIIU N (MINI
`
`

`
`U.S. Patent
`
`Dec. 17, 2002
`
`Sheet 1 0f 4
`
`US 6,495,120 B2
`
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`FIG. 1.
`
`Page 2
`
`

`
`U.S. Patent
`
`Dec. 17, 2002
`
`Sheet 2 of 4
`
`US 6,495,120 B2
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`Page 3
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`

`
`U.S. Patent
`
`Dec. 17, 2002
`
`Sheet 3 0f 4
`
`US 6,495,120 B2
`
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`TIME POST ACTUATION (MINUTES)
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`
`Page 4
`
`

`
`U.S.
`Patent
`
`Dec. 17, 2002
`
`Sheet 4 0f 4
`
`US 6,495,120 B2
`
`-| O O
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`TIME POST ACTUATION (MINUTES)
`
`FIG. 4.
`
`Page 5
`
`

`
`US 6,495,120 B2
`
`1
`FORMULATION AND SYSTEM FOR INTRA
`ORAL DELIVERY OF PHARMACEUTICAL
`AGENTS
`
`RELATED APPLICATIONS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This is a continuation of the prior application Ser. No.
`09/502,871, ?led Feb. 11, 2000.
`This application is related to, and claims the bene?t of
`priority under, US. provisional patent application Ser. No.
`60/119,923, ?led Feb. 12, 1999.
`
`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-orally.
`
`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.
`Dif?culties inhere in administering certain pharmaceuti
`cal agents orally (such as proteins), as saliva and/or gas
`trointestinal compounds tend to degrade or digest the phar
`maceutical agents, rendering them ineffective. For eXample,
`patients suffering from diabetes are required to administer
`insulin to themselves by injection on a regular basis. Injec
`tion delivery of insulin and other drugs is inconvenient and
`can be painful, discomforting, and embarrassing.
`Injectionable drug delivery also may be used to achieve a
`quick and ef?cient administration. Chronic pain manage
`ment is an area Where speedy drug delivery is desired. For
`eXample, there is a signi?cant 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 in declared pain a World medical emer
`gency 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 manage
`ment. Currently, research is being conducted Which searches
`for alternative means of quickly and effectively administer
`ing 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 mecha
`nisms have been available for a select number of pharma
`ceutical agents. For example, aerosol delivery systems 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 pul
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`2
`monary system. See, e.g., US. Pat. No. 5,544,646 to Lloyd
`et al., “Systems for the Intrapulmonary Delivery of Aero
`soliZed Aqueous Formulations”; US. Pat. No. 5,320,094 to
`Laube, “Method of Administering Insulin”; and US. Pat.
`No. 4,648,393 to Landis et al., “Breath Activated Medica
`tion 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 toXico
`logical 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-microbial agents, and auXiliary components. The inven
`tion 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 ?gures, in Which:
`FIG. 1 is a graph shoWing the effect of inventive formu
`lations containing insulin administered to rats intra-orally
`Wherein plot Are?ects application of the invention and plots
`B,C, and D re?ect controls; and
`FIG. 2 is a graph shoWing the effects of inventive formu
`lations containing highly puri?ed porcine insulin adminis
`tered intra-orally to tWo human subjects; and
`FIGS. 3 and 4 are graphs shoWing the effects of inventive
`formulations containing human recombinant insulin admin
`istered intra-orally 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 signi?cant
`vasculariZation for rapid and ef?cient drug absorption. The
`formulation of this invention comprises at least one phar
`maceutical 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 ?avor 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-orally as With a pump or pro
`pellant device, Which are described further beloW. The
`mechanism is referred to as a metered-dose applicator
`(MDATM), Wherein MDATM is a trademark of MOS, Inc., 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
`
`Page 6
`
`

`
`US 6,495,120 B2
`
`3
`in rapid onset of therapeutic action, avoids the hepatic ?rst
`pass effect, and reduces the amount of drug needed for an
`effective 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 bio
`availability and onset of action.
`Additionally, the invention is advantageous for therapeu
`tic 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 bene?t 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 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 ?avor-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, ben
`ZodiZepines such as ?uraZepam and salts thereof, miscella
`neous sedative hypnotics such as ethchlorvynol and salts.
`Suitable peptides include hormones such as calcitonin,
`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 patient’s 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 anal
`gesics 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 chemo
`therapy 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 phar
`maceutical agents and formulations used, typically the phar
`maceutical agent Will be present in the amount of about 0.01
`to 25% by Weight. For example, embodiments of the for
`mulation 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
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`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. 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 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 suf?ciently
`small siZe that it is capable of being absorbed by a mucosa
`of the intra-oral 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 example,
`exemplary embodiments of the formulation comprise use of
`sodium lauryl sulfate at 0.9 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 phrase “substan
`tially nonaqueous” means that in the nonaqueous solvents
`used, all reasonable care is used to avoid exposure to
`atmospheric moisture and remove Water present as hydra
`tion; hoWever, the presence of small amounts of Water in the
`?nished formulation Which have no impact on the properties
`of the formulation can not be precluded. 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 ?eld. 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 ?eld and discussed in the literature. HoWever, exemplary
`propellants comprise carbon dioxide, and hydro?uoroalkane
`(HFA), Which is available from DuPont Corporation, under
`the tradename HFA 134ATM. Also, HFA compounds referred
`to in the trade as DYMELTM 152A, HFA 152TM, and HFA
`227TM 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.
`
`Page 7
`
`

`
`US 6,495,120 B2
`
`5
`Also optionally included Within the compositions are
`stabilizers and anti-microbial agents. Stability of the phar
`maceutical 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.
`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 % 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 formu
`lation and can be determined by one skilled in the ?eld With
`use of micro-organism groWth tests.
`Optionally, the formulation also may comprise viscosity/
`mucoadhesive enhancing agents such as cellulose ether
`polymers and chitosan; ?avoring agents; and/or preservative
`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,
`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 predeter
`mined 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
`toothpaste) having a noZZle thereon for delivering predeter
`mined 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 (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 special
`iZed combination valves to deliver the product adequately
`and effectively. Thus, the inhalation technology and
`mechanical con?gurations 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
`
`6
`actuators sold under the tradenames VALOISTM,
`BESPAKTM, and PFIFFERTM. A representative actuator is
`described in US. 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.
`
`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 provid
`ing 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. Adecreased 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.
`
`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 de?ned by the
`appended claims.
`
`EXAMPLE 1
`
`Ingredients
`
`Pharmaceutical Agent
`Insulin
`Oral absorption enhancer
`Surfactant
`Carrier-solvent
`
`Tris-base
`Ethanol
`
`Balance propellant
`
`% W/W
`
`0.5
`
`1.2
`
`0.48
`20
`
`22.18
`77.82
`
`100
`
`15
`
`25
`
`35
`
`45
`
`55
`
`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.
`
`65
`
`Page 8
`
`

`
`US 6,495,120 B2
`
`7
`EXAMPLE 2
`
`Ingredients
`
`Pharmaceutical Agent
`Fentanyl Citrate
`Oral absorption enhancer
`Surfactant
`Carrier-solvent
`Ethanol
`
`Balance propellant
`
`% w/w
`
`0.5
`
`1.2
`
`2O
`
`21.7
`78.3
`
`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
`
`Abioavailability study was performed in a rat model, and
`the results are shown in FIG. 1. Plot A of FIG. 1 re?ects 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 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, re?ects a
`control comprising no active ingredient (no insulin) and no
`formulation according to the invention. Plot C re?ects a
`control comprising the inventive formulation but without the
`active ingredient. Plot D re?ects a control comprising the
`active ingredient but without the inventive formulation. This
`bioavailability study demonstrated that the method of prepa
`ration and composition of the formulation was effective in
`delivering the insulin to the patient and enabling a signi?
`cant reduction in blood glucose level with an intra-oral
`delivery.
`
`EXAMPLE 4
`
`Insulin formulation and adapted for use in a pMDA, using
`0.5% highly-puri?ed 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 hydro?uoroalkane (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 ?nished pMDA units were stored at room
`temperature, 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.
`
`8
`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 com
`pared with the baseline.
`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 desa
`mido insulin peak was detected for either the initial DDV
`sample or the 1,2,3 or 4 month stability DDV sample,
`indicating that no signi?cant 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
`
`A formulation was prepared essentially as in 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 following
`a 12-hour fast and the actuation of the pMDa. The percent
`change in blood glucose level from the baseline was estab
`lished as a function of time to demonstrate the hypoglycemic
`effect.
`Signi?cant 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 (?ve 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 ?rst 20
`minutes after dosing, and the maximum hypoglycemic effect
`was observed between 100 and 150 minutes post dosing.
`As can be seen, a stable propellant-driven pMDa formu
`lation 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
`
`Two formulations containing fentanyl citrate were
`prepared, wherein one formulation (identi?ed as 12A) was
`prepared in accordance with Example 2, above, and the
`second formulation (12B) was prepared as per Example 2,
`with the exception that in 12B, water used as the solvent
`carrier in place of ethanol. The formulations were adminis
`tered at pre-determined doses to six different rats and
`righting re?ex was monitored at six different time intervals.
`Two rats under the same formulation lost their righting
`
`10
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`Page 9
`
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`
`US 6,495,120 B2
`
`re?ex, both at similar actuation intervals and after consecu
`tive doses, and both regained righting re?exes Within thirty
`four minutes. One of these rats had been administered its
`dose by means of spray actuation and one by pipette. The
`second formulation containing the aqueous base (12B) did
`not appear to have a signi?cant effect on either of the tWo
`rats administered (spray only) With it, as the righting re?ex
`Was regained in a short amount of time.
`The procedure applied in this experiment Was as folloWs:
`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 re?ex or other signs of
`somnolence at 5, 10, 15, 30, 60, 120 minutes. The time Was
`marked When the righting re?ex Was gone. If righting re?ex
`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 re?ex returned
`Was marked.
`The data and results are reported beloW in Tables I, II, and
`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
`
`10
`
`15
`
`20
`
`25
`
`30
`
`TABLE II
`
`Formulation 12A
`
`Rat #
`
`5 min. 10 min.
`
`15 min.
`
`30 min. 60 min.
`
`120 min.
`
`35
`
`634
`635
`
`Intact
`Intact
`
`Intact
`Intact
`
`Intact
`Gone
`
`Intact
`Gone
`
`intact
`Intact
`
`intact
`intact
`
`TABLE III
`
`Formulation 2A/50 15g dose administered by pipette
`
`Rat #
`
`5 min. 10 min.
`
`15 min.
`
`30 min. 60 min.
`
`120 min.
`
`636
`637
`
`Intact
`Intact
`
`Intact
`Inta