Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0043—Nose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
  • A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases or cochleates; Sponge phases
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • 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
  • A61K9/0046—Ear

Definitions

• Otitis media is a pathological condition common to mammalian species and most common to children During episodes of otitis media fluid accumulates in the middle ear or as it is also known, the tympanic cavity
• Acute otitis media is a condition in which fluid accumulation in the middle ear is accompanied by signs or symptoms of ear infection (including both viral and bacterial etiologies) Such pathology may exhibit a bulging eardrum accompanied by pain or, in some instances, perforation of the tympanic membrane Such perforations may also be accompanied by drainage of purulent material
• otitis media with effusion is typified by fluid accumulation within the tympanic cavity without signs of infection
• Both acute otitis media and otitis media with effusion may cause substantial pain as pressure increases, positively or negatively, within the confines of the tympanic chamber
• Antibiotics, steroids and antibiotics in combination with steroids have been utilized to treat otitis media
• Antihistamine/decongestants have also been utilized in the treatment of otitis media with effusion
• the anatomical features of the middle ear define what can be described as a sealed chamber On its lateral border the middle ear is effectively isolated from
• the central lumen of the eustachian tube does provide a pathway to the tympanic cavity, it is, as described below, ordinarily closed and resistant to fluid passage due to its inherent anatomical configuration During episodes of otitis media, the relatively high surface tensions present at the air/liquid interface located upon the epithelial lining of the tube lumen further increase the opening pressure required to open this channel
• therapeuticaUy active agents effective in the treatment of otitis media
• no method or composition has yet been disclosed capable of overcoming the surface tension within the tube lumen so as to facilitate opening of the tube and transport of such drugs throughout the lumen and on to the tissues of the middle ear
• What is needed is a composition and method of applying same, especially formulated and adapted to decrease the surface tension of the auditory tube so as to decrease the opening pressure thereof thereby providing a patent conduit for therapeutic agents, effective
• DPPC has been administered to infants with respiratory distress syndrome as a therapeutic measure
• DPPC has been administered by means of an aqueous aerosol generator (utilized with an incubator in which the infant resided during treatment)
• Endotracheal administration has also been utilized
• DPPC therapy has been typified as utilizing natural surfactants (harvested from porcine or bovine lungs), or artificial, commercially synthesized compounds
• U S Patent No 5,306,483 discloses a process to prepare lipid crystalline figures in fluorocarbon propeUants for the delivery of therapeuticaUy active substances which form amorphous fluids on delivery at the air/liquid interface of the lung and which can be utilized as an effective drug delivery system More specifically, said patent discloses a process comprising (a) preparing a mixture of one or more lipids of the group of
• Otitis media can, due to fluid accumulation, cause significant pressure, both positive and negative, in the afore-mentioned confines of the middle ear Pressure differentials between the middle ear and the surrounding atmosphere, whether due to the addition of such fluids, or due to the relative decrease or increases of ambient atmospheric pressure, can cause great pain and discomfort
• Pressure differentials between the middle ear and the surrounding atmosphere whether due to the addition of such fluids, or due to the relative decrease or increases of ambient atmospheric pressure, can cause great pain and discomfort
• Such pressure conditions subject the tympanic membrane, and the associated pain receptors, to bulging and stretching
• the accumulation of fluids, and the resulting static tension applied to the tympanic membrane can greatly reduce hearing.
• the eustachian tube is specifically adapted to provide communication between the middle ear (a sealed chamber), and ambient atmospheric pressure, by providing a pathway between the tympanic cavity and the nasopharynx.
• the auditory tube serves as a pressure equalization means for the middle ear.
• the eustachian tube, and the pathway it provides between the middle ear and the nasopharynx are ordinarily closed.
• the lumen of the tube is ordinarily open only during the act of swallowing and other movements that cause contraction of the attached musculature.
• the eustachian tube is, on the average, 3.5 cm in length.
• the posterior one third of the tube is comprised of a bony wall with the anterior two thirds of the tubular structure being cartilaginous in composition.
• the auditory tube provides, by means of a central lumen, a fluid passage way between the nasopharynx and middle ear.
• the somewhat flattened medial and lateral walls of the tube are ordinarily in direct contact occluding and effectively limiting passage of liquids and gasses therethrough and allowing optimal sound conduction function of the middle ear which requires a sealed chamber.
• the tensor veli palatini muscle which inserts into the lateral surface of the cartilaginous portion of the tube, contracts and pulls the wall of the tube laterally opening the central lumen thereby providing the communicating pathway needed for fluid flow between the middle ear and the nasopharynx.
• the action of the muscle upon the tube is needed to overcome the surface tension attracting the flattened medial and lateral walls of the central lumen together as well as the elastic recoil of the tube cartilage which also tends to close the lumen.
• the surface tension is due to the sero-mucous secretions found on the epithelial lining of the lumen.
• the sero-mucous secretions of the auditory tube do not interfere with the normal opening and related pressure equalization functions of the auditory tube.
• middle ear, tube and upper respiratory infections and/or inflammatory conditions can greatly effect the nature and increase the amount of the secretions found upon the lumen surface.
• pathologic conditions greatly increase the surface tension of the lumen walls by increasing the relative amount of mucoid secretions, effectively interfering with, or completely preventing the opening of the tube.
• the tissues of the eustachian tube may become inflamed and engorged with fluids and cause further increases in opening pressures.
• Rapid changes in ambient pressure may also inhibit or completely prevent normal equalization functions of the auditory tube. If ambient pressure changes too quickly, the pressure gradient between the atmosphere and tympanic cavity may be too great to allow lumen opening. For example, the pressure within the tympanic cavity of a diver who, for example, ascends from a relatively deep dive without effectively and continuously equilibrating his or her middle ear through action of the eustachian tube (by swallowing, wiggling the jaw or utilizing other means to contract the attached musculature) can experience terrific pain know as a "squeeze" which may be very difficult to overcome.
• a diver may simply descend back a few feet to a depth where the pressure gradient is non-existent or minimal, and thereby lower the opening pressure of the auditory tube allowing it to open and equalize the tympanic cavity
• a passenger on a plane is in no position to change altitudes to obtain a "second chance" to equilibrate If such a passenger is unable to frequently and effectively equilibrate the middle ear during altitude changes due to, for example increased secretions within the tube resulting from a cold, he or she is forced to bear significant pain
• surfactant compositions both natural and artificial, have been heretofore known, formulated and utilized to decrease surface tension within the lung
• no such compositions, or methods for administering said compositions have been heretofore suggested, taught or disclosed in regards to decreasing the surface tension within the lumen of the eustachian tube
• no method has heretofore been known which provides an effective decrease in opening resistance of the eustachian tube while simultaneously enhancing the pressure equilibration functions thereof
• a method of increasing and enhancing mammalian eustachian tube lumen patency and pressure equalization performance is disclosed
• a mixture of one or more lipids and one or more spreading agents selected from the group consisting of cholesteryl esters, phospholipids, carbohydrates, and proteins, all in powder form, and one or more fluorocarbon propeUants is prepared
• the lipids and the spreading agents are advantageously selected to be insoluble in the propeUants
• the lipids utilized in practicing the method of the present invention are present in an amount of about 80 to 99 5 percent by weight and the spreading agents are present in an amount of about 0 5 to about 20 percent by weight, both based upon the total weight of the mixture
• Combination of the one or more lipids one or more spreading agents and one or more fluorocarbon propeUants results in the formation of lipid crystals and described in more detail, below
• a metered dose of the mixture of lipid crystals is then administered, via an external nasal orific
• the lipid crystals deposited upon the lumen surfaces and air/liquid interface thereupon is comprised of one or more lipids which are advantageously selected to demonstrate powerful surfactant activity
• the spreading agent combined therewith provides complete and uniform distribution of the surfactant over and upon the lumen air/liquid surface resulting in substantial decreases in lumen opening pressure
• the decrease in lumen opening pressure results in greater patency of the eustachian tube and thereby providing a resultant increase in fluid conduction/equalizing function of this anatomical structure
• the aerosolized lipid crystals through the nasal orifice also results in deposition of said crystals upon the mucosal surfaces of the sinus passages and sinus airways
• the mucosal surfaces of these airways and sinuses also demonstrates an air/liquid interface formed by the secretion of muco and muco-serous secretions thereupon
• said crystals form a uniform and amorphous spread film and effectively reduce the surface tension thereupon Therefore, the present invention also contemplates a method for reducing the surface tension of the air/liquid surfaces resident upon mammalian sinus and sinus air way mucosal surfaces
• a method of administering therapeuticaUy active agents, effective in the treatment of otitis media directly to mammalian eustachian tube and middle ear target tissues is disclosed
• a mixture of one or more lipids, one or more spreading agents, one or more therapeuticaUy active agent(s), effective in the treatment of otitis media, and one or more fluorocarbon propeUants is prepared
• the one or more lipids and spreading agents are advantageously selected from the group consisting of cholesteryl esters phospholipids, carbohydrates, and proteins, all being in powder form
• the one or more lipids, spreading agents and therapeuticaUy active agent(s), effective in the treatment of otitis media are also advantageously selected to be insoluble in the propeUants
• the lipids are present in an amount of about 80 to 99 5 percent by weight and the spreading agents are present in an amount of about 0 5 to about
• the lipid crystals deposited upon the lumen surfaces and air/liquid interface thereof is comprised of one or more lipids which are advantageously selected to demonstrate powerful surfactant activity and to serve as a carrier for selected therapeutic agent(s).
• the spreading agent deposited therewith provides complete and uniform distribution of the surfactant and therapeutic agent(s) throughout the lumen air/liquid surface resulting in substantial decreases in lumen opening pressure.
• the decrease in lumen opening pressure provides greater patency of the eustachian tube and thus a resultant increase in fluid conduction/equalizing function of this anatomical structure is provided while simultaneously providing direct application of therapeuticaUy active agent to target tissues of the auditory tube and middle ear.
• the present invention also contemplates a method for reducing the surface tension of the air/liquid surfaces resident upon mammalian sinus and sinus air way mucosal surfaces while simultaneously delivering therapeuticaUy agents thereto.
• the lipids utilized in practicing the method of the present invention may be advantageously selected to be ⁇ hospholipids, neutral lipids or mixtures thereof.
• the phospholipids utilized may be ⁇ urther advantageously selected to be any phosphohpid of the class known as phosphatidlycholine including any fully saturated diacyl phosphatidlycholine including 1 ,2 dipalmitoyl phosphatidylcholine (DPPC); a diacylphosphatidylglycerol; a diacylphosphatidylethanolamine; a diacyiphosphatidylserine; a diacylphosphatidylinositol; sphingomyelin.
• DPPC dipalmitoyl phosphatidylcholine
• Cardiohpin lysophospholipid; a plasmalogen; a diether phosphonolipid; or a dialklyphospholipid.
• the cholesteryl esters utilized in practicing the method of the present invention may be advantageously selected to be cholesteryl palmitate, cholesteryl oleate or cholesteryl stearate.
• Carbohydrates utilized in the present invention may be advantageously selected to be glucose, fructose, galactose, pneumogalactan, or dextrose. Proteins especially suited and advantageously selected for use in the present invention include albumin, pulmonary surfactant specific proteins A or B or C or D, their synthetic analogs, and mixtures thereof.
• the fluorocarbon propeUants may be advantageously selected to be chlorofluorocarbon propeUants, hydrofluorocarbons or mixtures thereof
• the present invention contemplates carbon dioxide as a suitable propellant
• the mixture is advantageously prepared to yield crystalline demonstrate a particle size equal to or less than 16 microns in diameter The diminutive nature of the crystalline particles is, as discussed in detail below, highly advantageous in enabling dispersion and application of the aerosolized mixture
• the phrase 'therapeuticaUy active agent includes any substance which is capable of altering a biologic, physiologic and/or immunologic function, in nature or degree and includes those substances generally referred to pharmacologic agents and drugs
• fluorocarbons includes the class of both chlorofluorocarbons and hydrofluorocarbons
• lipids includes the class of phospholipids including, but not limited to PC, PG, PE, PI and Cardiohpin
• shpreading agent(s) refer to and includes PG, PE, PS, PI, Sph , Card , lysophosphohpids, plasmalogens, dialkylphosphohpids, and all others in the class phosphohpid as well as cholesteryl esters (like CP), proteins and carbohydrates
• spreading agent(s) refers to compounds, as listed above, which assist the one or more lipid such as, for example, DPPC, in rapidly adsorbing and forming an amorphous spread film on air/hquid interfaces such as that found upon the epithelial lined lumen of the auditory tube
• the compounds referred to as spreading agent(s)" are responsible for achieving and maintaining biophysical properties including, but not limited to, reduction of intermolecular attractive forces, surface tension, and the resultant attractive forces generated thereby, that tend to cause opposed surfaces, such as the lateral and medial epithelial lined lumen walls of the auditory tube, to adhere to each other
• the major lipid component utilized in practicing a preferred embodiment of the present invention is advantageously selected to be phosphohpid 1 ,2 dipalmitoyl, phosphatidlycholine (DPPC)
• DPPC dipalmitoyl, phosphatidlycholine
• DPPC is the most surface active of the phospholipids or any of the subclass of fully saturated acyl chain phospholipids That is to say that DPPC, in combination with any spreading agent(s) disclosed herein, has a maximum effect in reducing surface tension at an air/liquid interface.
• DPPC and PG diacylphosphatidylglycerol
• R and R' diacylphosphatidylglycerol
• DPPC and PG can be synthesized. However, since DPPC and PG are the main phosphohpid constituents of cells, they are also readily extractable from such cells by non-polar solvents, i.e., chloroform, ether, acetone.
• DPPC's structural formula is: O
• R R' Phospholipids such as DPPC and CP may be obtained commercially, in a highly purified form from Fluka Chemical Co. of Ronkonkoma, N.Y.; Sigma Chemical CO. of St. Louis Mo.; and Avanti Polar Lipids of Birmingham, Ala. and Primedica of Cambridge, Mass.
• DPPC and PG are preferred component(s) advantageously utilized in the present inventions methods for administering therapeuticaUy active agents to the middle ear and auditory tube.
• these lipids increase the pressure equalizing performance of the auditory tube by direct result of their surfactant qualities.
• DPPC may be selected to be present in the composition over a fairly wide range. Percentages of DPPC may be s as low as 70% and as high as 99.5% of the lipids by weight with little change in the m-vitro properties, and the effectiveness of the present method However, 99 5% DPPC by weight is selected for the preferred embodiment
• the increased ease and ability is the result of the decrease in opening pressure of the lumen of the mammalian eustachian tube provided by the present invention
• cholesteryl palm ⁇ tate( CP) Another lipid that can be utilized in practicing the methods of the present invention is cholesteryl palm ⁇ tate( CP), which also serves as a spreading agent
• This cholesteryl ester is a neutral lipid which belongs to a class of organic compounds that are also cell constituents and are extractable by non-polar solvents such as chloroform, methanol, ether, etc
• the structural formula of CP is
• CP may be obtained commercially in a highly purified form from Fluka Chemical Co and Sigma Chemical Co
• the CP component constitutes a minor portion of the composition, since it is selected to be present in an amount ranging from 0 5% to 10% by weight
• the preferred ratio of DPPC to CP is 99 5 DPPC to 0 5 CP by weight
• the percentages may be altered within that range without undue interference in desired properties needed for drug delivery and surfactant activity
• therapeuticicaUy active agent and "therapeuticaUy active agent effective in the treatment of otitis media” refers to those drugs effective in treatment of otitis media including, but not limited to anti-inflammatory agents including, for example, betamethasone, including for example betamethasone dipropionate and betamethasone valerate as well as all other effective formulations, de-congestive agents such as phenylephnne, including, for example, phenylephnne HCL and phenylephn
• lipid component(s) and spreading agent component(s) disclosed herein may be referred to, collectively, as the ' carrier" when said combination is mixed with a therapeuticaUy active agent so as to act as a carrier therefore
• carrier the mixture of one or more lipids and one or more spreading agents, be comprised of a mixture of DPPC and CP in a 200 1 ratio (by weight)
• DPPC/CP a ratio range of from 5 1 to 300 1
• the therapeutic agent is selected to be betamethasone
• the weight ratio of betamethasone to carrier is advantageously selected to be 1 microgram betamethasone to 5 milligrams carrier
• the therapeuticaUy active agent is selected to be phenylephnne it is preferred to select the weight ratio of phenylephnne to carrier to be 160 m ⁇ crograms/995 milligrams.
• a weight ratio range of from 50 to 5000 micrograms (phenylephnne) 995 to 900 milligrams carrier, respectively forms an effective mixture and functional mixture
• the term "effective and functional mixture” as utilized throughout this application and in the claims refers to the effectiveness of the mixture of lipid crystals in combination with said therapeuticaUy active agent resulting from the combinations disclosed herein in (a) reaching the target tissue of the eustachian tube and middle ear, (b) reducing the surface tension thereupon, and (c) delivering a uniform dose of therapeutic agent directly to and spreading uniformly upon said tissues so as to effectively bring symptomatic relief and/or resolution of the afore-mentioned pathological conditions including otitis media
• the ratio of erythromycin to carrier is advantageously selected to be 200 mg antibiotic to 800 mg carrier (DPPC/CP) by weight
• DPPC/CP antibiotic to 800 mg carrier
• a weight range of from 50 to 200 mg erythromycin from 950 to 800 mg carrier, respectively has been found to be fully effective in practicing the present method
• the fluorocarbon propeUants utilized in practicing the method of the present invention namely trichlorodifluoromethane, dichlorodifluoromethane, and tetrafluoromethane or mixtures thereof, which are commercially available from Union Carbide Corp , Danbury, Conn and Armstrong Laboratories, West Roxbury Mass are advantageously selected for formation of the lipid crystalline figures of the present invention
• the fluorocarbon propeUants are present over a range of 2 to 30 times the amount, by weight, of lipid, but components of lipid and fluorocarbon propeUants both are needed in order to obtain the required lipid
• DPPC is advantageously selected as the major lipid component since the amphotenc nature of this phosphohpid allows the molecule to act as a carrier for any drug or therapeutic agent
• the presence of a charge on other lipid components would alter and further improve the carrying capacity of the lipid crystals for a particular therapeutic agent
• the method of the present invention also contemplates selecting zythromax and Augmentin (amoxicillin + clavuhnic acid) as antibiotic therapeutic agents
• zythromax and Augmentin amoxicillin + clavuhnic acid
• the aerosolized drug delivery system of the present invention was prepared from chromatographically pure (greater than 99%) DPPC and CP Both materials were purchased from suppliers on the commercial market where they are available from several chemical supply houses Specifically, the DPPC and CP were purchased from Sigma Chem , St Louis, Mo All purchased materials were checked for purity by standard chromatographic analysis The betamethasone utilized in this example was also purchased from Sigma Chemical The DPPC and CP were then mixed in the dry powder form in a weight ratio of 200 1 (DPPC CP) To 5 milligrams of the resultant carrier, 1 microgram of betamethasone was added in order to yield a weight ratio of 5000 1 (carrier betamethasone) Then 5 grams of this mixture was suspended in 55 grams of the first propellant, t ⁇ chloromonofluoromethane (P11 ) and subdivided into 30 ml Wheaton plastic-coated glass bottles with a 20 mm neck finish Valois metered dose valves were then crimped onto each bottle through which 40 g
• the aerosolized drug delivery system of the present invention was prepared from chromatographically pure (greater than 99%) DPPC and CP Both materials were purchased from suppliers on the commercial market where they are available from several chemical supply houses Specifically the DPPC and CP were purchased from Sigma Chem , St Louis Mo The phenylephnne utilized in this example can also be purchased from Sigma Chem , St Louis, Mo All purchased materials were checked for purity by standard chromatographic analysis The DPPC and CP were then mixed in the dry powder form in a weight ratio of 200 1 (DPPC CP) Thereafter, to 995 milligrams of the resultant carrier, 160 micrograms of phenylephnne was added so as to yield an approximate 6200 1 weight ratio of carrier to phenylephnne Then 5 grams of the resultant mixture (DPPC/CP/phenylephnne) was suspended in 55 grams of the first propellant t ⁇ chloromonofluoromethane (P11) and subdivided into 30
• the aerosolized drug delivery system of the present invention was prepared from chromatographically pure (greater than 99%) DPPC and CP Both materials were purchased from suppliers on the commercial market where they are available from several chemical supply houses Specifically, the DPPC and CP were purchased from Sigma Chem , St Louis, Mo The erythromycin utilized in this example can also be purchased from Sigma Chem , St Louis, Mo All purchased materials were checked for purity by standard chromatographic analysis The DPPC and CP were then mixed in the dry powder form in a weight ratio of 200 1 (DPPC CP) Thereafter, to 800 milligrams of the resultant carrier, 200 milligrams of erythromycin was added so as to yield an approximate 4 1 weight ratio of carrier to erythromycin Then 5 grams of the resultant mixture (DPPC/CP/erythromycin) was suspended in 55 grams of the first propellant, t ⁇ chloromonofluoromethane (P1 1 ) and subdivided into 30 ml Wheaton plastic-coated glass bottles with a 20
• the aerosolized drug delivery system of the present invention was prepared from chromatographically pure (greater than 99%) DPPC, PG and CP All of these materials were purchased from suppliers on the commercial market where they are available from several chemical supply houses Specifically, the DPPC, CP and PG were purchased from Sigma Chem , St Louis, Mo The erythromycin utilized in this example can also be purchased from Sigma Chem All purchased materials were checked for purity by standard chromatographic analysis The DPPC, PG and CP were then mixed in the dry powder form in a weight ratio of 7 1 0.35 (DPPC PG CP) Thereafter, to 800 milligrams of the resultant carrier, 200 milligrams of erythromycin was added so as to yield an approximate 4 1 weight ratio of carrier to erythromycin Then 5 grams of this mixture was suspended in 55 grams of the first propellant, trichioromonofluoromethane (P11) and subdivided into 30 ml.
• P11 trichioromonofluoromethane
• Valois metering valves were crimped onto each bottle through which 40 gms of the second propellant, dichlorodifluoromethane (P12), was passed. The filled bottles were then gently shaken to disperse the solids that are insoluble in the propeUants. The bottles were thereafter immersed in a water bath to test for leaks and then fitted with a nasal administration adapter. The suspension was homogenous. After standing at room temperature for about three days, a pellicle forms on top of the propeUants but was easily resuspended by gentle shaking. The size of the metering valve can be varied to deliver from 1 mg up to 5.4 mg of the DPPC:PG:CP: erythromycin aerosolized mixture.
• DPPC and CP were mixed in a weight ratio of 200:1 (DPPC:CP) . Then 5 grams of this mixture was suspended in 55 grams of the first propellant, trichioromonofluoromethane (P11) and subdivided into 30 ml. Wheaton plastic- coated glass bottles with a 20 mm neck finish. Valois metering valves were crimped onto each bottle through which 40 gms of the second propellant, dichlorodifluoromethane (P12), was passed. The filled bottles were then gently shaken to disperse the solids that are insoluble in the propeUants. The bottles were thereafter immersed in a water bath to test for leaks and then fitted with a nasal inhalation adapter. The suspension was homogenous.
• a pellicle forms on top of the propeUants but was easily re-suspended by gentle shaking.
• the size of the metering valve can be varied to deliver from 1 mg up to 5.4 mg of the DPPC:CP aerosolized mixture.
• Example "V" preparation of an aerosolized mixture of lipid crystals for use in practicing the method of the present invention is disclosed that is advantageously formulated for enhancing pressure equalization performance of mammalian eustachian tubes without the use of a therapeuticaUy active agent
• the aerosolized mixture, propelled by the above-described propeUants is deposited about the anterior terminus of the eustachian tube at its communication with the nasopharynx
• the crystalline lipid figures come in contact with auditory tube and form an amorphous spread film layer upon the air/hquid interface of the epithelial lined lumen which, in turn, uniformly spreads the lipid mixture throughout the lumen of the tube and into the middle ear
• surface tension of an air/ quid interface located upon the eustachian tube's epithelial lined lumen is reduced to provide said increased performance
• composition and method of the present invention effectively increased eustachian tube patency by means of an exogenous nasally administered surfactant
• Otitis media with effusion was developed in 75 gerbils by intra tympanic injection of 100-ug/mL solution of lipopolysacchande derived from Klebsiella pneumoniae
• the animals were grouped and the following drugs were sprayed intra nasally, prepared in an aerosolized metered dose inhaler (MDI) viz 1) Placebo (normal saline), 2) Surfactant alone (DPPC CP (200 1), 3) Surfactant with betamethasone (5 mg carrier to 10 micrograms betamethasone dipropnonate) 4) Surfactant with phenylephnne (995 mg carrier to 160 micrograms phenylephnne HCI) In-vivo Typanometry and Micro-otoscopy was done on the 3 rd , 5 tn , 7 th , 9 th , 10 th ,
• Particle size of the nebulized crystals produced and utilized in practicing the present invention is, as discussed below, critical to effective administration
• the size (diameter) of the lipid crystals were therefore determined utilizing in a cascade impactor Flow through the impactor was adjusted to be substantially identical to the flow from a nebulizer utilized in practicing the disclosed method All of the lipid crystals were found to have a diameter equal to or less than 16 microns The diameter of about 95 percent of the particles were found to be equal to or less than 4 microns in diameter Of the particles found to be 4 microns or less half were in fact, 1 micron in diameter
• the mean diameter demonstrated by the lipid crystals utilized in the method of the present invention was 1 75+/- 25 microns
• Micronization may be advantageously utilized in order to insure reduced particle size Therefore, the methods of the present invention also contemplate the use of a micronization mill such as, for example, the DYNO mill type KDL manufactured by Glen Mills Inc , of New Jersey in the preparation of the aerosolized mixture
• a micronization mill such as, for example, the DYNO mill type KDL manufactured by Glen Mills Inc , of New Jersey
• approximately 83 grams of CP and 13 33 g of DPPC powder were weighed and transferred to a bead mill within the milling chamber of a DYNO mill (having about 480 cc of glass beads) The chamber was then sealed
• the mixture of one or more lipids, one or more spreading and one or more fluorocarbon propeUants disclosed in the present invention is especially formulated and combined to form a unique crystalline structure with physical dimensions highly advantageous to all embodiments
• the crystalline structure results in, as discussed above, a mean particle size of 1 75 microns
• the minute physical dimensions of the individual nebulized particles enables the propellant utilized in practicing the present invention to easily and effectively transfer the disclosed mixture to and throughout the desired target tissue
• a larger physical configurations such as, for example, a hposome, would not enable such diminutive particle size within and effective physical transport by the propellant
• the aerosolized mixture of the present invention is crystalline
• the crystalline nature of the mixture imparts increased efficiency of particle dispersion within the aerosol mist applied by means of a metered-dose nebulizer
• the fluorocarbon medium either chlorofluorocarbon or hydrofluorocarbon vaporizes rapidly and the DPPC/CP, DPPC/CP drug DPPC/PG drug or DPPC/PG/CP drug dispersion deposits on an aqueous surface at 37°C , initially in the crystalline form, and then, instantaneously, spreads over the surface as an amorphous surface film
• the drug likewise is spread, uniformly, upon the aqueous surface
• the surfactant/spreading agent functions and characteristics of the method and composition of the present invention were tested as follows Aerosolized crystalline figures of the present invention were impacted upon a liquid surface (normal saline solution, NSS) at 37' C , 100% humidity in a surface balance resulted in a rapid spreading of a principally amorphous film that covered the entire surface (18 1 cm 2 ) Surface tension of the film was measured during expansion and compression at 37° C , 100% humidity Film expansion to 110 4 cm 2 produced a surface tension of 72 dynes/cm and compression to 18 1 cm 2 lowered surface tension to less than 1 dyne/cm

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• 1999
  • 1999-11-28 US US09/450,884 patent/US6156294A/en not_active Expired - Lifetime
• 2000
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  • 2000-08-16 US US09/639,682 patent/US6616913B1/en not_active Expired - Lifetime
  • 2000-08-28 JP JP2001539421A patent/JP2003514842A/ja active Pending
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