WO2009015456A1 - Formulation pharmaceutique sous forme micellaire mélangée et distributeur pour administration orale d'agents en pulvérisation - Google Patents

Formulation pharmaceutique sous forme micellaire mélangée et distributeur pour administration orale d'agents en pulvérisation Download PDF

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Publication number
WO2009015456A1
WO2009015456A1 PCT/CA2007/001345 CA2007001345W WO2009015456A1 WO 2009015456 A1 WO2009015456 A1 WO 2009015456A1 CA 2007001345 W CA2007001345 W CA 2007001345W WO 2009015456 A1 WO2009015456 A1 WO 2009015456A1
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WIPO (PCT)
Prior art keywords
pharmaceutical formulation
insulin
actuator
pharmaceutical
formulation
Prior art date
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PCT/CA2007/001345
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English (en)
Inventor
Anna E. Gluskin
Muhammad Waseem Tahir Qazi
Original Assignee
Generex Pharmaceuticals Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Generex Pharmaceuticals Inc. filed Critical Generex Pharmaceuticals Inc.
Priority to PCT/CA2007/001345 priority Critical patent/WO2009015456A1/fr
Publication of WO2009015456A1 publication Critical patent/WO2009015456A1/fr
Priority to TNP2009000504A priority patent/TN2009000504A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/06—Head
    • A61M2210/0625—Mouth
    • A61M2210/065—Throat; Pharynx

Definitions

  • the present invention relates to pharmaceutical formulations effective to deliver a pharmaceutical agent across oral membranes (e.g. buccal and pharyngeal mucosae) as well as to methods of administering, and metered dose dispensers containing, the pharmaceutical formulations.
  • oral membranes e.g. buccal and pharyngeal mucosae
  • Proteinic drug molecules are extremely large molecules with molecular weights exceeding 5500 daltons. In addition to being large, these molecules typically have very poor lipid solubility, and are not easily absorbed through oral or pulmonary mucosae. Substances that facilitate the absorption or transport of large molecules (which are defined herein to mean molecules >1000 daltons) across biological membranes are referred to in the art as “enhancers” or “absorption aids.” These compounds generally include chelators, bile salts, fatty acids, synthetic hydrophilic and hydrophobic compounds, and biodegradable polymeric compounds. Many enhancers lack a satisfactory safety profile respecting irritation, lowering of the barrier function, and impairment of the mucociliary clearance protective mechanism.
  • Metered dose dispensers are presently used to administer many different medications to the mouth and lungs, for example, asthma medication and nitroglycerin for treatment of heart disease.
  • a typical metered dose dispenser includes a container for containing a solution or suspension of medication, a metering valve, and an actuator.
  • the container will contain the medication to be dispensed, possibly a solvent for the medication, and a propellant.
  • the propellant is a substance having a low boiling point and high vapor pressure, so that as liquid is dispensed from the container the propellant evaporates, maintaining a constant pressure within the container.
  • Actuation of the metering valve causes the metering chamber within the valve to close with respect to the container, and open with respect to the mouthpiece. Propellants within the metering chamber will evaporate due to the sudden decrease in pressure when the valve is actuated, propelling the medication into the patient's mouth.
  • Currently available metered dose dispensers are not suitable for dispensing large molecule drugs for absorption through the oral mucosae (e.g. buccal mucosa).
  • the dispensed medication tends to be either inhaled or swallowed and ingested by a patient.
  • a suitable dispenser must dispense appropriately sized particles at an appropriate velocity to penetrate the epithelium lining the oral mucosae to gain access to rich vascularization of the lamina limba tissue underneath the lining, and must dispense a suitable volume to ensure that the portion actually reaching the oral mucosae represents the desired dose.
  • the dispenser must not clog, which could prevent administering a dose when one is needed during an emergency.
  • the dispenser must contain an insulin formulation adapted for oral cavity delivery.
  • Present metered dose dispensers typically dispense too little volume to ensure reliable oral cavity delivery of a desired dose, and produce a fine aerosol mist of particles less than 5 microns in size, increasing the likelihood of inhalation of the medication into the lungs. The particles are not directed towards any specific portion of the mouth, but are placed generally inside the mouth where they may be inhaled or absorbed. Therefore, if the medication dispensed is insulin, use of a presently available metered dose dispenser would result in possible side effects associated with lung delivery. Therefore, a metered dose dispenser dispensing a sufficiently high quantity of medication, at a sufficiently high pressure, to ensure that a sufficient quantity will be propelled into the oral cavity for proper absorption of the desired dose, is necessary.
  • the present invention is intended to address at least one of the above needs by providing a pharmaceutical formulation for absorption through oral mucosae comprising an effective amount of (a) a large molecule pharmaceutical agent in mixed micellar form, (b) trihydroxyoxocholanyl glycine or salt thereof, (c) glycerin, and (d) a suitable solvent.
  • trihydroxyoxocholanyl glycine, a salt thereof, and glycerin are micelle-forming compounds.
  • the salt of trihydroxyoxocholanyl glycine is sodium glycocholate.
  • the pharmaceutical formulation may further comprise at least one additional micelle- forming compound selected from the group comprising alkali metal alkyl sulfates, block copolymers of polyoxyethylene and polyoxypropylene, monooleates, polyoxyethylene ethers, polyglycerin, lecithin, hyaluronic acid, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linoleic acid, linolenic acid, monoolein, monolaurates, borage oil, evening primrose oil, menthol, lysine, polylysine, triolein, polidocanol alkyl ethers, chenodeoxycholate, deoxycholate, alkali metal salicylates (e
  • the at least one additional micelle-forming compound is selected from the group comprising alkali metal alkyl sulfates, block copolymers of polyoxyethylene and polyoxypropylene, monooleates, polyoxyethylene ethers, lecithin, oleic acid, polyglycerin, chenodeoxycholate, deoxycholate, lactic acid and pharmaceutically acceptable salts and analogues thereof.
  • the micelle-forming compounds comprise (i) at least one of an alkali metal alkyl sulfate and a polyoxyethylene sorbitan monooleate, and (ii) a block copolymer of polyoxyethylene and polyoxypropylene.
  • the monooleates are preferably polyoxyethylene sorbitan monooleates and, more preferably, an (x)-sorbitan mono-9-octadecenoate poly(oxy-l,2-ethanediyl) monooleate (e.g. a surfactant also known as polysorbate 80, sold in association with the trademark, TWEEN 80).
  • an (x)-sorbitan mono-9-octadecenoate poly(oxy-l,2-ethanediyl) monooleate e.g. a surfactant also known as polysorbate 80, sold in association with the trademark, TWEEN 80.
  • the micelle-forming compounds including trihydroxyoxocholanyl glycine, a salt thereof, and glycerin, when present, are each present in a concentration of from about 0.001 to 20 wt./wt.%, from about 0.001 to 10 wt./wt.%, from about 0.001 to 5 wt./wt.%, from about 0.001 to 2 wt./wt.%, from about 0.001 to 1 wt./wt.%, or from about 0.001 to 0.15 wt./wt.%.
  • the pharmaceutical formulation may further comprise an effective amount of at least one stabilizer and/or preservative (e.g. phenolic compound, sodium benzoate).
  • Each of these ingredients when present, may be present in a concentration of from about 0.01 to 10 wt./wt.%, or from about 0.1 to 7 wt./wt.%, or from about 0.1 to 5 wt./wt.%, or from about .1 to 3 wt./wt.%.
  • one or more inorganic salts and isotonic agents may also be added to provide necessary or desired properties. The selection of these ingredients and concentrations thereof in the formulation will depend on the pharmaceutical agent employed and is within the expertise of the person of ordinary skill in the art.
  • the pharmaceutical agent is present in mixed micellar form in the formulation.
  • the formulation is dispensed as particles having a size that is equal to or greater than 7, 8, 9, 10, or 11 microns ( ⁇ m).
  • particles Preferably, particles have a size that is equal to or less than 50, 40, 30, 15, or 11 microns. Particles of this size have been found to lead to reduced deposition of the pharmaceutical agent in the lungs and effective absorption by the oral membranes. Thus, absorption of the pharmaceutical agent occurs mostly through the oral (e.g. buccal and pharyngeal) mucosae.
  • a metered dose dispenser dimensioned and configured to administer the present pharmaceutical formulation to the oral cavity (including buccal cavity) of a patient's mouth.
  • a metered dose dispenser is particularly useful for administering insulin.
  • a metered dose dispenser comprising a formulation according to the present invention is also provided.
  • the invention provides a metered dose dispenser comprising a container housing a pharmaceutical formulation according to the invention.
  • the container may further house a propellant, and the dispenser may further comprise:
  • a metering valve coupled to the container for dispensing a selected quantity of the pharmaceutical formulation, the metering valve having a metering chamber with a volume of from 500 to 700 ⁇ L,
  • an actuator coupled to the metering valve, the actuator having an actuator sump with a volume less than 77 mm 3 and a discharge orifice in fluid communication with the actuator sump, the discharge orifice having a diameter of about 1.2 to 1.3 mm,
  • the metering valve is biased towards a closed position in which the metering chamber is in fluid communication with the container to receive a selected quantity of pharmaceutical formulation from the container in the metering chamber, and the metering valve is movable to an open position wherein the metering chamber is in fluid communication with the actuator sump and discharge orifice, by movement of the actuator, to dispense the selected quantity of pharmaceutical formulation.
  • the metering valve may comprise a valve stem having two inlets and an outlet downstream of the inlet, the valve stem being movable by the actuator between said closed position wherein the inlets and outlet are in fluid communication with the actuator sump and not with the metering chamber, and said open position wherein the inlets are in fluid communication with the metering chamber and the outlet is in fluid communication with the actuator sump, whereby pharmaceutical formulation from the metering chamber can flow through the inlets and into the actuator sump via the outlet.
  • the invention provides a method of administering the present pharmaceutical formulation comprising spraying the pharmaceutical formulation into the oral cavity of a patient using the metered dose dispenser.
  • the method may further comprise spraying the pharmaceutical formulation into the oral cavity of a patient at intervals throughout the day to maintain blood glucose levels within normal limits.
  • This method is performed in addition to administering insulin or an insulin analogue as part of a baseline therapy.
  • the formulation is administered immediately before and after each meal (e.g. breakfast, lunch, and dinner) and snack.
  • the amount of insulin administered immediately before and after each meal may be greater than 14, 20, 26, 30 or 40 units and less than 110 or 85 units.
  • the formulation may also be administered between meals to achieve fine adjustment of glycemic levels.
  • the amount of insulin administered between meals may be greater than 14, 20 or 30 units and less than 80 or 60 units.
  • the amount of insulin administered per dose and specific schedules will depend on patient requirements as can be determined through blood glucose monitoring.
  • the present invention satisfies the need for an easy and convenient means for controlling post-prandial glucose levels (i.e. blood glucose levels at about one to two hours after eating).
  • Formulations according to the present invention administered pre- and post- prandially give rise to pharmacokinetic profiles which show a normalization of post- prandial glucose levels.
  • controlling post-prandial glucose levels is expected to give rise to additional health benefits.
  • Figure l is a front isometric view of a metered dose which can be used to deliver formulations according to the present invention.
  • Figure 2 is a side view of an aerosol container and metering valve assembly for the metered dose dispenser.
  • Figure 3 is a cross-sectional side view of an actuator, aerosol container and metering valve for the metered dose dispenser, showing the metering valve at rest (closed position).
  • Figure 4 is a side cross-sectional view of an actuator, container and metering valve for the metered dose dispenser, showing the metering valve in an open position.
  • Figure 5 is a graph in which average blood glucose levels are plotted as a function of time to show the pharmacokinetic/pharmacodynamic (PK/PD) profiles of formulations according to the present invention when given in single versus divided dose around meals and to compare the bioavailability of such formulations with injected insulin.
  • Figure 6 is a graph in which average mean blood glucose concentrations are plotted as a function of time to compare the bioavailability of a formulation according to another embodiment of the invention with injected insulin.
  • PK/PD pharmacokinetic/pharmacodynamic
  • Figure 7 is a graph in which average blood glucose levels are plotted as a function of time to show the show the pharmacokinetic/pharmacodynamic (PK/PD) profiles of a formulation according to a further embodiment of the present invention when given in single versus divided dose around meals and to compare the bioavailability of such formulation with injected insulin.
  • PK/PD pharmacokinetic/pharmacodynamic
  • the term “comprising” when used herein means “including without limitation.” Thus, an element comprising a number of integers may also comprise additional integers not specifically recited.
  • the term “consisting essentially of,” when used herein, means including the recited integers and such additional integers as would not materially affect the basic and novel properties of the invention.
  • the basic and novel properties of the invention are the absorption characteristics of the present pharmaceutical agents through oral mucosae (e.g. buccal, pharyngeal, lingual, sublingual, and palate mucosae) into a patient's bloodstream.
  • the present pharmaceutical formulations comprise an "effective amount" of the pharmaceutical agent.
  • the term "effective amount” refers to that amount of the pharmaceutical agent needed to bring about the desired result, such as obtaining the intended treatment or prevention of a disorder, or regulating a physiological condition in a patient. Such an amount will therefore be understood as having a therapeutic and/or prophylactic effect in a patient.
  • the term "patient” refers to members of the animal kingdom, including but not limited to humans. It will be appreciated that the effective amount will vary depending on the particular pharmaceutical agent used, the nature and severity of the disorder being treated, and the patient being treated. The determination of what constitutes an effective amount is within the skill of one practising in the art based upon the general guidelines provided herein. For absorption through oral membranes, it is often desirable to increase, such as by doubling or tripling, the dosage of pharmaceutical agent which is normally required through injection or administration through the gastrointestinal tract. In formulations containing insulin as the pharmaceutical agent, the amount of insulin administered per dose can be increased as much as 10-fold as the bioavailability of sprayed insulin is much lower.
  • the present formulations will contain pharmaceutical agents in a concentration of from about 0.001 to 20 wt./wt. %, about 0.1 to 15 wt./wt. %, about 0.1 to 10 wt./wt. %, about 0.1 to 5 wt./wt. %, or about 0.1 to 1 wt./wt. %.
  • pharmaceutical agent covers a wide spectrum of agents, and can include agents used for both human and veterinary applications including but not limited to treatment and study.
  • the term broadly includes proteins, peptides, hormones, vaccines and other drugs.
  • macromolecular or “large molecule” refers to pharmaceutical agents having a molecular weight greater than about 1000 daltons; preferably the macromolecular pharmaceutical agents of the present invention have a molecular weight between about 2000 and 2,000,000 daltons, although even larger molecules are also contemplated.
  • dalton means 1/12 the mass of the nucleus of carbon- 12 (i.e. equivalent to 1.657 x 10 "24 grams, also known as an "atomic mass unit").
  • Preferred pharmaceutical agents include large molecule drugs of varying sizes, including insulin, heparin, low molecular weight heparin (molecular weight less than about 5000 daltons), hirulog, hirugen, hirudin, interferons, cytokines, mono and polyclonal antibodies, immunoglobins, chemotherapeutic agents, vaccines, glycoproteins, bacterial toxoids, hormones, calcitonins, glucagon like peptides (GLP-I), large molecular antibiotics (i.e., greater than about 1000 daltons), protein based thrombolytic compounds, platelet inhibitors, DNA, RNA, gene therapeutics, antisense oligonucleotides, opioids, narcotics, hypnotics, steroids and pain killers.
  • large molecule drugs of varying sizes, including insulin, heparin, low molecular weight heparin (molecular weight less than about 5000 daltons), hirulog, hirugen,
  • Hormones which may be included in the present formulations include but are not limited to thyroids, androgens, estrogens, prostaglandins, somatotropins, gonadotropins, erythropoetin, interferons, steroids and cytokines.
  • Cytokines are small proteins with the properties of locally acting hormones and include, but are not limited to, various forms of interleukin (IL) and growth factors including various forms of transforming growth factor (TGP), fibroblast growth factor (FGF) and insulin-like growth factor (IGF).
  • IL interleukin
  • TGP transforming growth factor
  • FGF fibroblast growth factor
  • IGF insulin-like growth factor
  • Vaccines which may be used in the formulations according to the present invention include bacterial and viral vaccines such as vaccines for hepatitis, influenza, tuberculosis, canary pox, chicken pox, measles, mumps, rubella, pneumonia, BCG, HIV and AIDS.
  • Bacterial toxoids include but are not limited to diphtheria, tetanus, Pseudomonas sp. and Mycobacterium tuberculosis.
  • Examples of drugs, more specifically cardiovascular or thrombolytic agents include heparin, hirugen, hirulos and hirudin.
  • Pharmaceutical agents included in the present invention further include monoclonal antibodies, polyclonal antibodies and immunoglobins. These lists are not intended to be exhaustive.
  • a pharmaceutical agent that can be used in the present invention is insulin, a very large molecule.
  • Insulin used herein encompasses naturally extracted human insulin, insulin extracted from bovine, porcine or other mammalian sources, recombinantly produced human, bovine, porcine or other mammalian insulin, insulin analogues, insulin derivatives, and mixtures of any of these insulin products.
  • the term further encompasses the insulin polypeptide in either its substantially purified form, or in its commercially available form in which additional excipients are added.
  • Various forms of insulin are widely commercially available.
  • insulin analogue encompasses any of the insulins defined above wherein one or more of the amino acids within the polypeptide chain has been replaced with an alternative amino acid, wherein one or more of the amino acids have been deleted, or wherein one or more amino acids is added.
  • derivatives of insulin refers to insulin or analogues thereof wherein at least one organic substituent is bound to one or more of the amino acids in the insulin chain.
  • a micelle is a colloidal aggregate of amphipathic molecules in which the polar hydrophilic portions of the molecule extend outwardly while the non-polar hydrophobic portions extend inwardly, or vice versa depending on the hydrophilic-lipophilic balance of the micelle forming compounds and type of solvent and pharmaceutical agent used.
  • various combinations of micelle-forming compounds are utilized in order to achieve the present formulation. It is believed that the presence of the micelles significantly aids in the absorption of the pharmaceutical agent both because of their enhanced absorption ability, and also because of their size.
  • the term "mixed micelles” refers to either (a) at least two different types of micelles each of which has been formed using one or more micelle-forming compounds; or (b) one type of micelle formed with at least two micelle-forming compounds.
  • the present formulation may comprise a mix of at least two different types of micelles: micelles formed between the pharmaceutical agent and sodium glycocholate and micelles formed between the pharmaceutical agent and glycerin. However, it may also comprise micelles wherein each micelle is formed from these two or more micelle- forming compounds.
  • the mixed micelles of the present invention tend to be smaller than the pores of the membranes in the oral cavity.
  • the extremely small size of the present mixed micelles helps the encapsulated pharmaceutical agent penetrate efficiently through the oral mucosae.
  • the present formulations offer increased bioavailability of active drug when compared with pharmaceutical preparations known in the art.
  • the shape of the micelle can vary and be, for example, prolate, oblate or spherical; spherical micelles are most typical.
  • the formulation may further comprise at least one additional micelle-forming compound selected from the group comprising alkali metal alkyl sulfates, block copolymers of polyoxyethylene and polyoxypropylene, monooleates, polyoxyethylene ethers, polyglycerin, lecithin, hyaluronic acid, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linoleic acid, linolenic acid, monoolein, monolaurates, borage oil, evening primrose oil, menthol, lysine, polylysine, triolein, polidocanol alkyl ethers, chenodeoxycholate, deoxycholate, alkali metal salicylates (e.g. sodium salicylate), pharmaceutically acceptable edetates (e.g. disodium edetate), and pharmaceutically acceptable salts and analogues thereof.
  • alkali metal salicylates e.g. sodium salicylate
  • any alkali metal alkyl sulfate can be used in the present formulations, provided compatibility problems do not arise.
  • the alkyl is a C8 to C22 alkyl, more preferably lauryl (C 12). Any alkali metal can be utilized, with sodium being preferred.
  • the lecithin can be saturated or unsaturated, and is preferably selected from the group consisting of phosphatidylcholine, phosphatidylserine, sphingomyelin, phosphatidylethanolamine, cephalin, and lysolecithin.
  • Preferred salts of hyaluronic acid are alkali metal hyaluronates, especially sodium hyaluronate, alkaline earth hyaluronates, and aluminum hyaluronate.
  • a concentration of between about 0.001 and 5 wt./wt. % is preferred, more preferably less than about 3.5 wt./wt. %.
  • use of three or more micelle-forming compounds is preferred as it achieves a cumulative effect in which the amount of pharmaceutical agent that can be delivered is greatly increased as compared to when only one or two micelle-forming compounds are used.
  • Use of three or more micelle-forming compounds also enhances the stability of the pharmaceutical agent formulations.
  • Suitable micelle-forming compound combinations include the following: i) a block copolymer of poly oxy ethylene and poly oxypropylene, glycerin, sodium glycocholate, and sodium lauryl sulfate; ii) a polyoxyethylene ether, glycerin, sodium glycocholate, and sodium lauryl sulfate; iii) glycerin, sodium glycocholate and polyoxyethylene sorbitan monooleate; iv) glycerin, sodium glycocholate, sodium lauryl sulfate and oleic acid; v) chenodeoxycholate, sodium glycocholate, sodium lauryl sulfate, and glycerin; vi) deoxycholate, sodium glycocholate, sodium lauryl sulfate, and glycerin; vii) glycerin, sodium glycocholate, sodium lauryl sulfate, deoxycholate, and lactic acid; viii) gly
  • micelle-forming compounds are generally described as fatty acids, bile acids, or salts thereof.
  • the micelle-forming compounds to use may vary depending on the pharmaceutical agent used and can be readily determined by one skilled in the art.
  • bile salts are suitable for use with hydrophilic drugs and fatty acid salts are suitable for use with lipophilic drugs. Because the present invention uses relatively low concentrations of bile salts, problems of toxicity associated with the use of these salts is minimized, if not avoided.
  • suitable solvent is used herein to refer to any solvent in which the components of the present invention can be solubilized, in which compatibility problems do not arise, and which can be administered to a patient.
  • suitable aqueous or nonaqueous solvent can be used such as water and alcohol solutions (e.g. ethanol). Alcohol should be used at concentrations that will avoid precipitation of the components of the present formulations. Enough of the solvent should be added so that the total of all of the components in the formulation is 100 wt./wt. %, i.e., solvent to q.s.
  • Embodiments of pharmaceutical formulations containing insulin employ aqueous solvents.
  • the pH of the solution is typically in the range of 5 to 8, 6 to 8, or 7 to 8.
  • Hydrochloric acid or sodium hydroxide can be utilized to adjust the pH of the formulation as needed.
  • the present formulations optionally contain a stabilizer and/or a preservative (e.g. sodium benzoate and phenolic compounds). Phenolic compounds are particularly suited for this purpose as they not only stabilize the formulation, but they also protect against bacterial growth. It is also believed that phenolic compounds aid in absorption of the pharmaceutical agent.
  • a phenolic compound will be understood as referring to a compound having one or more hydroxy groups attached directly to a benzene ring.
  • Preferred phenolic compounds according to the present invention include phenol, o- cresol, m-cresol, and p-cresol, with phenol and m-cresol being most preferred.
  • the formulations of the present invention can further comprise one or more of the following optional ingredients: inorganic salts and isotonic agents.
  • inorganic salts and isotonic agents The amount of any of these optional ingredients to use in the present formulations can be determined by one skilled in the art.
  • inorganic salts may be added that open channels in the GI tract thereby providing additional stimulation to release insulin in vivo.
  • inorganic salts are sodium, potassium, calcium and zinc salts, especially sodium chloride, potassium chloride, calcium chloride, zinc chloride and sodium bicarbonate.
  • the inorganic salts are typically in a concentration of from about 0.001 to about 10 wt./wt.%.
  • An isotonic agent such as glycerin or dibasic sodium phosphate may also be added after formation of the mixed micellar formulation.
  • the isotonic agent serves to keep the micelles in solution.
  • glycerin When used as a micelle-forming compound, it also functions as an isotonic agent.
  • dibasic sodium phosphate When dibasic sodium phosphate is used it will also serve to inhibit bacterial growth.
  • flavoring agents are menthol, sorbitol and fruit flavours.
  • menthol When menthol is used as one of the micelle-forming compounds, it will also impart flavour to the composition.
  • the formulations of the present invention may be stored at room temperature or at cold temperature (i.e. from about 2 to 8 0 C). Storage of proteinic drugs is preferable at a cold temperature to prevent degradation of the drugs and to extend their shelf life.
  • the present invention therefore, provides a novel and inventive pharmaceutical formulation in which a pharmaceutical agent is encapsulated in mixed micelles formed by a combination of micelle-forming compounds.
  • the formulation can be delivered through oral membranes, e.g. pharyngeal, sublingual and buccal mucosae.
  • the pharyngeal mucosae is the lining of the posterior of the oral cavity, i.e. the upper the part of the throat that is located below the soft palate and above the larynx
  • the sublingual mucosa includes the membrane of the ventral surface of the tongue and the floor of the mouth
  • the buccal mucosa is the lining of the cheeks.
  • the pharyngeal, sublingual and buccal mucosae are highly vascularized and permeable, allowing for the rapid absorption and acceptable bioavailability of many drugs. In comparison to the GI tract and other organs, the oral environment has lower enzymatic activity and a neutral pH that allows for a longer effective life of the drug in vivo.
  • the pharyngeal, sublingual, lingual, palate and buccal mucosae are collectively referred to herein as the "oral mucosae".
  • Absorption of the pharmaceutical agent through oral mucosae offers a number of advantages, including the avoidance of the first pass effect of hepatic metabolism and degradation of the drug within the hostile GI environment, easy or convenient access to membrane sites, and a pain free form of administration (as compared to administration by subcutaneous injection).
  • the present formulations are delivered using a metered dose dispenser according to the present invention that is charged with a propellant.
  • a metered dose dispenser provides improvements in penetration and absorption of the present mixed micellar formulations.
  • the propellant may be selected from the group comprising Ci to C 2 dialkyl ether, butanes, fluorocarbon propellant, hydrogen-containing fluorocarbon propellant, chlorofluorocarbon propellant, hydrogen-containing chlorofluorocarbon propellant, other non-CFC and CFC propellants, and mixtures thereof.
  • suitable propellants include tetrafluoroethane (e.g.
  • HFA 134a which is 1,1,1,2 tetrafluoroethane), heptafluoroethane, dimethylfluoropropane, tetrafluoropropane, butane, isobutane, dimethyl ether and diethyl ether.
  • the propellant is a liquid under pressure and causes the pharmaceutical formulation to be propelled from the metered dose dispenser in a fine spray.
  • the dispenser has a metered dose valve of which the associated metering chamber is of a size that is large enough to deliver a sufficient quantity of drug to achieve the desired dose.
  • the metering chamber may have a volume that is equal to or greater than about 10, 50, 250, 540 or 570 ⁇ l but equal to or less than about 800 or 630 ⁇ l.
  • the volume of the metering chamber is preferably from about 500 to 700 ⁇ l, or from about 540 to 660 ⁇ l.
  • the amount of propellant to be added to the metered dose dispenser will depend on a number of factors including the size of the pressurized container and the amount of pharmaceutical formulation contained therein.
  • the amount of the propellant is selected to provide administration of a suitable amount of the pharmaceutical agent per actuation, while avoiding undesirable events such as foaming.
  • the amount of pharmaceutical formulation is from 50, 67, 71, 77, or 83 parts per 1000 parts of the total composition in the container (i.e. pharmaceutical formulation plus propellant).
  • the amount of pharmaceutical formulation is less than or equal to 91 parts per 1000 parts of the total composition in the container.
  • the amount of pharmaceutical agent emitted per actuation of the dispenser or dispenser will vary according to a number of factors including the concentration of pharmaceutical agent in the formulation, and the size of the metering chamber of the metering valve of the dispenser.
  • the present formulations may be prepared by mixing the pharmaceutical agent with the micelle-forming compounds and optional stabilizers and other additives in a suitable solvent.
  • the compounds may be added in one step or sequentially. When added sequentially, they can be added in any order provided solubility issues do not arise.
  • Mixed micelles will form with substantially any kind of mixing of the ingredients but vigorous mixing is preferred. Vigorous mixing may be accomplished by using highspeed stirrers, such as magnetic stirrers, propeller stirrers, or sonicators.
  • a pharmaceutical formulation containing insulin, Solution III is prepared by making two solutions, Solutions I and II, and then mixing them together and with a solvent in accordance with the following protocol. Preparation of Solution I
  • Solution I a bulk insulin solution containing 200 units of insulin, is prepared as follows. Absolute amounts of each ingredient in Solutions I, II and III can be calculated based on the final batch size of Solution III. Note that the amount of units of insulin per mg of commercial insulin varies with the commercial insulin product generally between about 25.3 and 28.3 units per mg of insulin. Knowledge of the number of units per mg is readily determinable from product specifications.
  • Solution II is an aqueous solution of micelle-forming compounds to be added to Solution I.
  • Step - 1 Add 50 ⁇ 5 w/w % water for injection into appropriate sized beaker equipped with a magnetic stir bar i
  • Step - 2 Slowly add 0.25 w/w % glycerin to the beaker and while continuously stirring gently
  • Solution III is a pharmaceutical formulation according to one embodiment of the invention. It is prepared as follows.
  • the invention also provides a metered dose dispenser containing a formulation (e.g. Solution III) according to the invention.
  • a formulation e.g. Solution III
  • the invention employs the metered dose dispenser shown in Figures 1 to 4.
  • the metered dose dispenser 10 includes an actuator assembly 12 comprising an aerosol container 14 and a metering valve 16.
  • the container 14 has a 28 ml capacity but the capacity may range from 5 to 35 ml.
  • the container 14 is made of stainless steel but it can also be made of any pre-treated metal (e.g. aluminum), glass, plastic (e.g. Polyester or acetal resins), or combinations thereof.
  • 2 ml of Solution III is put into the aerosol container 14 according to a known method.
  • the container 14 is then charged with about 27.06 grams of HFA-134a propellant also in a known manner.
  • the aerosol container 14 is best illustrated in Figures 3-4.
  • the aerosol container 14 is preferably cylindrical having an open end 18.
  • the metering valve 16 includes a 3 -slot housing 20 with a valve stem 22 slidably contained therein.
  • the metering valve 16 also includes a ferrule 24, dimensioned and configured to fit around the outside of an open end 18 of the aerosol container 14, being crimped around the end 18 to secure the metering valve to the container.
  • a preferred material for the ferrule is aluminum and the thickness of the ferrule may vary.
  • a sealing gasket 26 provides a seal between the container's open end 18 and the ferrule 24.
  • a preferred material for the sealing gasket is Nitrile (Buna) rubber.
  • a metering chamber 28 within the 3-slot housing 20 is defined between the first stem gasket 30 and the second stem gasket 32.
  • a preferred material for the first and second stem gaskets is Nitrile (Buna) rubber.
  • the stem includes an upper stem and a lower stem, with the lower stem having a U-shaped retention channel 34 having ends 36 and 38, and the upper stem having a channel 40 having inlet ends 42a and 42b and an outlet end 44.
  • the lower stem allows the passage of the fluid under the differential pressure from the aerosol container to valve metering chamber after actuation, but prevents the return (due to gravity) of the fluid to the aerosol container by the capillary action of the retention channel 34.
  • the upper and lower stems are made in one unitary piece. However, it will be appreciated that they may be made as separate components that cooperate with each other in the structure.
  • the 3-slot housing and stem may be made of Polyester or acetal resins, pre-treated metal (e.g. stainless steel or aluminum), or combinations thereof.
  • the upper and lower stems are made of stainless steel; however, it will be appreciated that they can be made, at least in part, of Polyester or acetal resins, though it is preferred that the portion of the upper stem that includes the inlet ends 42a and 42b be made of metal (e.g. stainless steel) as this has been found to reduce the likelihood of clogging of the inlet ends 42a and 42b by the formulation during administration.
  • the stem 22 moves between the rest (closed) position and an open position to place the metering valve in either a closed or open position, respectively.
  • the inlet end 36 of the retention channel 34 is above the first stem gasket 30, so that the contents of the aerosol container 14 may enter the retention channel 34.
  • the outlet end 38 of the retention channel 34 is below the first stem gasket 30 and within the metering chamber 28. Both the inlet ends 42a and 42b and the outlet end 44 of the channel 40 are outside the metering chamber 28, thereby preventing passage of fluid from the metering chamber 28 to the channel 40.
  • both the inlet end 36 and outlet end 38 of the retention channel 34 are above the first stem gasket 30 of the metering chamber 28, thereby preventing any fluid flow from the aerosol container 14 to the metering chamber 28.
  • the inlet ends 42a and 42b of the channel 40 are above the second stem gasket 32 and inside the metering chamber 28, thereby permitting passage of fluid from the metering chamber 28 through the passage 40.
  • Having two inlet ends 42a and 42b allows for more rapid flow of the medication out of the metering chamber 28 during actuation.
  • the diameter of each of the inlet ends 42a and 42b is selected to prevent clogging of medication therein during actuation.
  • the stem 22 is biased by the spring 46 into the rest (closed) position of Figure 3.
  • the metering chamber 28 within the metering valve 16 holds a total volume of approximately 600 ⁇ L.
  • Embodiments of the metering chamber 28 for use with the formulation containing insulin or other large molecules may hold between 500 - 700 ⁇ L, i.e. be approximately 3 to 4 times larger than the largest metering chambers currently used in metered dose dispensers for the delivery of pharmaceutical aerosols.
  • the large dose is necessary because large molecules like insulin are poorly absorbed through the epithelial membrane, easily destroyed by enzymes found in saliva, and are relatively insoluble. Therefore, more medication needs to be delivered to the oral cavity to compensate for these losses.
  • the actuator assembly 12 is best illustrated in Figures 1, 3, and 4.
  • the actuator assembly 12 includes a mouthpiece 50 and a stem block 48 defining or having an internal passageway extending between an inlet 53 and an outlet 55.
  • the portion of the internal passageway adjacent to the inlet 53 is dimensioned and configured to receive the lower end 56 of the valve stem 22, and the portion of the internal passageway adjacent to the outlet 55 defines a spray orifice 58.
  • the spray orifice 58 of the actuator sump 52 is dimensioned and configured to direct medication towards the oral cavity (including buccal cavity and back of the throat).
  • the spray orifice 58 may have a round configuration, or may have an oval, rectangular, or similar elongated configuration, thereby directing medication to either side of the mouth, increasing the likelihood of medication hitting the oral mucosae.
  • the spray orifice 58 has a diameter of approximately 1.25 mm. However, in other embodiments, the diameter may range from 1.2 to 1.3 mm, or from 1.23 to 1.27 mm.
  • the portion of the internal passageway in the stem block 48 between the lower end 56 of the valve stem 22 and the outlet 55 is herein referred to as an actuator sump 52.
  • the actuator sump 52 includes an inlet end 54 for receiving the flow of medicament from the valve stem 22.
  • the volume of the actuator sump 52 is no greater than 77 mm 3 . In other embodiments, the volume can be less than 45, 42, or 37 mm 3 . These sump volumes will be sufficient to generate a high-pressure stream of fluid upon actuation of the metered dose dispenser.
  • the actuator assembly 12 may also include a cap 60 fitting over the actuator assembly 12 and aerosol container 14.
  • the cap 60 is preferably slidably and removably secured to the actuator assembly 12.
  • One method of slidably and removably securing the cap 60 to the actuator assembly 12 is by friction, thereby permitting removal or reattachment of the cap 60 and actuator assembly 12 by merely pulling upward on the cap 60.
  • the actuator assembly 12 may also include a dust cover 68, dimensioned and configured to cover the mouthpiece 50. Use of the metered dose dispenser 10 begins with the valve 16 in its rest position.
  • the formulation within the aerosol container 14 is free to move through openings within the metering valve's 3 -slot housing 20 (not shown, but well known in the art), through the U-shaped retention channel 34, and into the metering chamber 28.
  • the propellant specifically selected for its high vapor pressure, evaporates to the maximum extent permitted by the volume of the aerosol container 14.
  • the formulation within the aerosol container 14 is thereby forced through the retention channel 34 until the metering chamber 28 is full.
  • the elongated and curved shape of the retention channel 34 keeps the medication in the metering channel 28 from traveling back into the aerosol container 14.
  • the location of the channel 40 below the second stem gasket 32 prevents medication from exiting the metering chamber 28 prematurely.
  • the lower end 56 of the stem 22 is first inserted into the inlet end 54 of the actuator sump 52, located in the stem block 48 of the actuator.
  • the cap 60 may be placed on top of the actuator assembly 12, thereby completely concealing the aerosol container 14.
  • the dust cover 68 is removed from the mouthpiece 50.
  • the mouthpiece 50 is inserted into the patient's mouth and the aerosol container 14 is depressed towards the actuator assembly 12. This action causes the metering valve 16 to move from its rest position of Figure 3 to its open position of Figure 4.
  • the outlet opening 38 of the retention channel 34 is moved above the first stem gasket 30, thereby preventing the formulation from moving from the aerosol container 14 to the metering chamber 28.
  • the inlet ends 42a and 42b of the channel 40 is brought above the second stem gasket 32, thereby providing a path from the metering chamber 28, through the channel 40 and actuator sump 52, spray orifice 58, through the mouthpiece 50, and into the patient's mouth. Opening the metering valve 16 also decreases the pressure within the metering chamber 28, causing the propellant in the metering chamber 28 to evaporate, thereby pushing the medication out through the channel 40 into the actuator sump 52, where it undergoes further evaporation as it attempts to fill the chamber and displace the air, and finally through spray orifice 58 and out the mouthpiece 50.
  • the droplets dispensed are greater than 6 and may be greater than 8 micron in size, thereby reducing the chances of inhalation into the lungs. In this embodiment about 7 to 13 units of insulin (average 10 units) are emitted per actuation. This is equivalent to about 0.27 mg to about 0.50 mg of insulin dispensed per actuation.
  • Releasing downward pressure on the aerosol container 14 causes the metering valve 16 to return to its rest position under pressure from the spring 46, thereby permitting a new dosage of medication to enter the metering chamber through the retention channel 34, under pressure from the evaporated propellant within the aerosol container 14.
  • the cap 60 When desired, the cap 60 may be removed, thereby permitting the aerosol container 14 to be removed from the actuator assembly 12.
  • the actuator assembly 12 may thereby be easily cleaned.
  • the propellant which is under pressure, is in liquid form in the container and forms a single phase with Solution III.
  • the aqueous phase may separate from the propellant phase. In such case, it is recommended that the patient shake the dispenser prior to dispensing a portion of the contents.
  • the present invention also provides a method for administering the pharmaceutical formulation of the present invention, by spraying the formulation into the mouth with a metered dose dispenser according to the present invention.
  • Crossover Treatment phase In this phase, the same 19 patients were exposed to each of the following four treatment regimens on different days:
  • Each treatment regimen was administered over a 24 hour period.
  • the single dose regimen involved administering 16 puffs of Solution V over an 8 minute period, with one puff administered every 30 seconds. The first puff was timed such that the last puff was received 30 seconds before the test meal.
  • Solution IV was administered 4 minutes prior to the meal for the first Vi dose (1 puff every 30 seconds, for a total of 8 puffs, with a 30 second interval between the last puff and the test meal).
  • the patient was given two sips of water and received the second Vi dose (8 puffs every 30 seconds) starting at about 2 minutes after completion of the meal.
  • Solution V was administered 4 minutes prior to the meal for the first Vi dose (1 puff every 30 seconds, for a total of 8 puffs, with a 30 second interval between the last puff and the test meal).
  • the patient was given two sips of water and received the second Vi dose (1 puff every 30 seconds, for a total of 8 puffs) starting at about 5 minutes after completion of the meal.
  • Each puff of Solution IV contained, on average, about 50 units of insulin.
  • Each puff of Solution V contained, on average, about 25 units of insulin.
  • HumulinTM brand insulin were injected 15 minutes prior to meals to the same group of 19 patients on a different day.
  • the average blood glucose levels for each group were plotted in a graph shown in Figure 5.
  • the blue line represents Solution IV given as a split dose
  • the green line represents the Solution V given as a split dose
  • the orange line represents Solution IV given as a single dose
  • the black line represents Humulin brand insulin given by injection.
  • Solutions IV and V are effective at controlling blood glucose levels with the split dose of Solution IV achieving slightly better results than the single dose of Solution IV.
  • Example II
  • the study compared the effect on blood glucose levels of Solution III administered to the buccal cavity using the above described metered dose dispenser, with the effect on blood glucose levels of injected insulin.
  • Fructosamine a parameter of protein glycation, was determined as part of a panel of safety monitoring.
  • each patient received his or her regular dose of HumulinTM brand insulin (recombinantly produced human insulin sold by Eli Lilly and Company) by injection 30 minutes before each of three meals: breakfast, lunch and dinner.
  • the amount of insulin injected varied with the patient based on 0.1 units of insulin per kilogram body weight.
  • Patients were also allowed mid-morning and mid-afternoon snacks and had the option of administering up to 4 units at snack-time.
  • Patients opting to administer treatment at snack- time recorded the snack- time dose on individual diary cards.
  • each patient received from five to eight puffs of Solution III, based on their recommended dose (as determined through prior experiments) before and after each meal (breakfast, lunch and dinner).
  • Solution III was administered to the buccal cavity using the above described metered dose dispenser. An additional single dose following each meal of up to 4 puffs was allowed for immediate administration if measured glucose value exceeded 100 mg/dL at 30 to 60 minutes after the end of the meal. Thus, the total maximum dose of Solution III relating to each meal was 20 puffs (or up to 60 puffs daily).
  • the patients were allowed mid-morning and mid- afternoon snacks. Patients were allowed to administer up to 5 puffs at snack-time as a divided dose (e.g. 2 puffs before and 2 or 3 puffs after the snack).
  • Each puff of Solution III contained, on average, about 10 units of insulin.
  • blood samples were drawn beginning 30 minutes before breakfast and ending 4 hours after breakfast.
  • a standardized meal (Ensure Plus: 4.8 kCal/kg ideal body weight) was served for breakfast at 8:00 AM (0 minutes).
  • Blood samples were drawn at - 30 minutes, immediately prior to (0 minutes) and 5, 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 minutes after breakfast.
  • Peripheral glucose concentrations were determined in duplicate by the Roche Accu-Check system. Duplicate measurements of glycosylated hemoglobin (HbA l c- n) and fructosamine were also obtained using Roche commercial assays.
  • the average mean blood glucose concentrations resulting from this study were plotted on a graph shown in Figure 6.
  • the black line shows the mean blood glucose concentrations for the 10 patients as a function of time, averaged over the first three days during which insulin was administered by injection.
  • the red line shows the mean blood glucose concentrations for the 10 patients as a function of time, averaged over days 4 to 12 during which Solution III was administered using the above described metered dose dispenser.
  • Figure 6 shows that HumulinTM brand injected insulin and Solution III induced similar glucodynamic responses.
  • Solution III provided an appropriate glycemic control as assessed by individual daily-glycemic curves and, especially, normal preprandial glycemia. Measurements of protein glycation displayed a tendency towards lower values after the 12-day study period. This suggests that Solution III is safe for long term use.
  • Example HI The average mean blood glucose concentrations resulting from this study were plotted on a graph shown in Figure 6.
  • the black line shows the mean blood glucose concentrations for the 10 patients as a function
  • Example I A study similar to that described in Example I was done to determine the difference in the pharmacokinetic/pharmacodynamic (PK/PD) profiles of Solution XIV (listed in Table VI above) when given in single versus divided dose around meals. The study was also done to compare the bioavailability and glucodynamic profile of Solution XIV with injected insulin, HumulinTM brand insulin (recombinantly produced human insulin sold by EH Lilly and Company). In this study, the same protocol and 19 patients described in Example I above was employed.
  • PK/PD pharmacokinetic/pharmacodynamic

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Abstract

L'invention porte sur une formulation pharmaceutique administrée sous forme de pulvérisation par distributeur de dosettes dans la cavité buccale pour absorption par la muqueuse orale. Les dosettes renferment une quantité efficace de (a) un agent pharmaceutique sous forme micellaire mélangée; (b) un composé de formation de micelles qui est un alkylsulfate de métal alcalin ou un polyoxyéthylène de monooléate de sorbitane; (c) un copolymère à blocs de polyoxyéthylène et de polyoxypropylène; (d) au moins un composé de formation de micelles supplémentaire; et (e) un solvant approprié. L'invention porte également sur un distributeur de la présente formulation et sur un procédé d'administration de la formulation à laquelle est ajoutée de l'insuline en tant qu'agent pharmaceutique, le procédé consistant à diviser une dosette pour administration avant et après chaque repas.
PCT/CA2007/001345 2007-07-30 2007-07-30 Formulation pharmaceutique sous forme micellaire mélangée et distributeur pour administration orale d'agents en pulvérisation WO2009015456A1 (fr)

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PCT/CA2007/001345 WO2009015456A1 (fr) 2007-07-30 2007-07-30 Formulation pharmaceutique sous forme micellaire mélangée et distributeur pour administration orale d'agents en pulvérisation
TNP2009000504A TN2009000504A1 (en) 2007-07-30 2009-11-30 Pharmaceutical formulation in mixed micellar form and dispenser for oral delivery of agents as a spray

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9260503B2 (en) 2011-06-15 2016-02-16 Novo Nordisk A/S Multi-substituted insulins
US10040839B2 (en) 2014-02-28 2018-08-07 Novo Nordisk A/S Insulin derivatives and the medical uses hereof
US10588914B2 (en) 2009-08-31 2020-03-17 Encore Dermatology, Inc. Topical formulations comprising a steroid
WO2020095175A1 (fr) * 2018-11-07 2020-05-14 3M Innovative Properties Company Boîtier d'actionneur pour dispositif inhalateur
US11166912B2 (en) 2016-03-03 2021-11-09 Ctt Pharma Inc. Orally administrable composition
US11179465B2 (en) 2014-03-11 2021-11-23 Primus Pharmaceuticals, Inc. Topical compositions comprising a corticosteroid
US11298336B2 (en) 2019-05-30 2022-04-12 Soluble Technologies, Inc. Water soluble formulation
US20230107497A1 (en) * 2020-02-07 2023-04-06 Aptar France Sas Metering valve having an improved metering chamber
US11786475B2 (en) 2020-07-22 2023-10-17 Soluble Technologies Inc. Film-based dosage form

Citations (1)

* Cited by examiner, † Cited by third party
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WO2007062494A1 (fr) * 2005-11-30 2007-06-07 Generex Pharmaceuticals Inc. Formulation pharmaceutique absorbee par voie orale et procede d'administration

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2007062494A1 (fr) * 2005-11-30 2007-06-07 Generex Pharmaceuticals Inc. Formulation pharmaceutique absorbee par voie orale et procede d'administration

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10588914B2 (en) 2009-08-31 2020-03-17 Encore Dermatology, Inc. Topical formulations comprising a steroid
US10905697B2 (en) 2009-08-31 2021-02-02 Encore Dermatology, Inc. Topical formulations comprising a steroid
US9260503B2 (en) 2011-06-15 2016-02-16 Novo Nordisk A/S Multi-substituted insulins
US10040839B2 (en) 2014-02-28 2018-08-07 Novo Nordisk A/S Insulin derivatives and the medical uses hereof
US11179465B2 (en) 2014-03-11 2021-11-23 Primus Pharmaceuticals, Inc. Topical compositions comprising a corticosteroid
US11166912B2 (en) 2016-03-03 2021-11-09 Ctt Pharma Inc. Orally administrable composition
WO2020095175A1 (fr) * 2018-11-07 2020-05-14 3M Innovative Properties Company Boîtier d'actionneur pour dispositif inhalateur
US11298336B2 (en) 2019-05-30 2022-04-12 Soluble Technologies, Inc. Water soluble formulation
US20230107497A1 (en) * 2020-02-07 2023-04-06 Aptar France Sas Metering valve having an improved metering chamber
US11878855B2 (en) * 2020-02-07 2024-01-23 Aptar France Sas Metering valve having an improved metering chamber
US11786475B2 (en) 2020-07-22 2023-10-17 Soluble Technologies Inc. Film-based dosage form

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