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 The leading web portal for pharmacy resources, news, education and careers March 20, 2019
Pharmacy Choice - Pharmaceutical News - Patent Issued for Nicotine Salt With Meta-Salicylic Acid And Applications Therein (USPTO 10,166,224) - March 20, 2019

Pharmacy News Article

 1/10/19 - Patent Issued for Nicotine Salt With Meta-Salicylic Acid And Applications Therein (USPTO 10,166,224)

By a News Reporter-Staff News Editor at Pharma Business Week From Alexandria, Virginia, NewsRx journalists report that a patent by the inventors Myers, Daniel J. (Mountain View, CA); Cassella, James (Essex, CT), filed on August 7, 2017, was published online on January 14, 2019 (see also Alexza Pharmaceuticals Inc.).

The patent's assignee for patent number 10,166,224 is Alexza Pharmaceuticals Inc. (Mountain View, California, United States).

News editors obtained the following quote from the background information supplied by the inventors: "Cigarette smoking provides an initial sharp rise in nicotine blood level as nicotine is absorbed through the lungs of a smoker. In general, a blood level peak produced by cigarettes of between 30-40 ng/mL is attained within 10 minutes of smoking. (Hukkanen et al., Am Soc. Pharm Exp Therapy 2013) The rapid rise in nicotine blood level is postulated to be responsible for the postsynaptic effects at nicotinic cholinergic receptors in the central nervous system and at autonomic ganglia which induces the symptoms experienced by cigarette smokers, and may also be responsible for the craving symptoms associated with cessation of smoking.

"While many nicotine replacement therapies have been developed, none of the therapies appear to reproduce the pharmacokinetic profile of the systemic nicotine blood concentration provided by cigarettes. As a consequence, conventional nicotine replacement therapies have not proven to be particularly effective in enabling persons to quit smoking. For example, many commercially available products for nicotine replacement in smoking cessation therapy are intended to provide a stable baseline concentration of nicotine in the blood. Nicotine chewing gum and transdermal nicotine patches are two examples of smoking cessation products which, while providing blood concentrations of nicotine similar to that provided by cigarettes at times greater than about 30 minutes, do not reproduce the sharp initial rise in blood nicotine concentrations obtained by smoking cigarettes. Nicotine gum is an ion-exchange resin that releases nicotine slowly when a patient chews, and the nicotine present in the mouth is delivered to the systemic circulation by buccal absorption. Nicotine patches provide a consistent, steady release rate, which leads to low, stable blood levels of nicotine. Thus, both nicotine gum and transdermal nicotine do not reproduce the pharmacokinetic profile of nicotine blood levels obtained through cigarette smoking, and thus do not satisfy the craving symptoms experienced by many smokers when attempting to quit smoking.

"Inhalation products which generate nicotine vapor are also ineffective as inhaled vapors are predominately absorbed through the tongue, mouth and throat, and are not deposited into the lungs. Smokeless nicotine products such as chewing tobacco, oral snuff or tobacco sachets deliver nicotine to the buccal mucosa where, as with nicotine gum, the released nicotine is absorbed only slowly and inefficiently. Nicotine blood levels from these products require approximately 30 minutes of use to attain a maximum nicotine blood concentration of approximately 12 ng/mL, which is less than half the peak value obtained from smoking one cigarette. Low nicotine blood levels obtained using a buccal absorption route may be due to first pass liver metabolism. Orally administered formulations and lozenges are also relatively ineffective.

"Rapid vaporization of thin films of drugs at temperatures up to 600.degree. C. in less than 500 msec in an air flow can produce drug aerosols having high yield and high purity with minimal degradation of the drug. Condensation drug aerosols can be used for effective pulmonary delivery of drugs using inhalation medical devices. Devices and methods in which thin films of drugs deposited on metal substrates are vaporized by electrically resistive heating have been demonstrated. Chemically-based heat packages which can include a fuel capable of undergoing an exothermic metal oxidation-reduction reaction within an enclosure can also be used to produce a rapid thermal impulse capable of vaporizing thin films to produce high purity aerosols, as disclosed, for example in U.S. application Ser. No. 10/850,895 entitled 'Self-Contained heating Unit and Drug-Supply Unit Employing Same' filed May 20, 2004, and U.S. application Ser. No. 10/851,883, entitled 'Percussively Ignited or Electrically Ignited Self-Contained Heating Unit and Drug Supply Unit Employing Same,' filed May 20, 2004, the entirety of both of which are herein incorporated by reference. These devices and methods are appropriate for use with compounds that can be deposited as physically and chemically stable solids. Unless vaporized shortly after being deposited on the metal surface, liquids can evaporate or migrate from the surface. Therefore, while such devices can be used to vaporize liquids, the use of liquid drugs can impose certain undesirable complexity. Nicotine is a liquid at room temperature with a relatively high vapor pressure. Therefore, known devices and methods are not particularly suited for producing nicotine aerosols using the liquid drug.

"It is postulated that treatment of nicotine craving and smoking cessation can be addressed by treatment regimens and/or therapies that reproduce the rapid onset of high nicotine blood concentrations achieved during cigarette smoking. A cigarette smoker typically inhales about 10 times over a period of about 5 minutes. Therefore, a nicotine delivery device capable of simulating the use profile of cigarette smoking can include from 5 to 20 doses of up to about 200 .mu.g each of nicotine, which could then be intermittently released upon request by the user.

"Thus, there remains a need for a nicotine replacement therapy that provides a pharmacokinetic profile similar to that obtained by cigarette smoking, and thereby directly addresses the craving symptoms associated with the cessation of smoking."

As a supplement to the background information on this patent, NewsRx correspondents also obtained the inventors' summary information for this patent: "Accordingly, one aspect of the present disclosure teaches nicotine meta-salicylate. One aspect of the present disclosure provides a compound comprising a volatile nicotine meta-salicylate compound, wherein the compound is selectively vaporizable when heated.

"One aspect of the present disclosure provides a nicotine delivery device comprising an electric multidose platform (EMD) as shown in FIG. 13.

"One aspect of the present disclosure provides a nicotine delivery device comprising a housing defining an airway, wherein the airway comprises at least one air inlet and a mouthpiece having at least one air outlet, at least one heat package disposed within the airway, at least nicotine meta-salicylate disposed on the at least one heat package, and a mechanism configured to actuate the at least one heat package.

"One aspect of the present disclosure provides a nicotine delivery device comprising a housing defining an airway, wherein the airway comprises at least one air inlet and a mouthpiece having at least one air outlet, at least one percussively activated heat package disposed within the airway, at least nicotine meta-salicylate disposed on the at least one percussively activated heat package, and a mechanism configured to impact the at least one percussively activated heat package. For purpose of clarity, 'percussively activated heat package' herein means a heat package that has been configured so that it can be fired or activated by percussion. An 'unactivated heat package' or 'non-activated heat package' refers herein to a percussively activated heat package in a device, but one that is not yet positioned in the device so that it can be directly impacted and fired, although the heat package itself is configured to be activated by percussion when so positioned.

"One aspect of the present disclosure provides a method of producing an aerosol of nicotine by selectively vaporizing the compound from a thin film comprising nicotine meta-salicylate.

"One aspect of the present disclosure provides a method of delivering nicotine to a person comprising providing a nicotine delivery device comprising, a housing defining an airway, wherein the airway comprises at least one air inlet and a mouthpiece having at least one air outlet, at least two or more heat packages disposed within the airway, at least nicotine meta-salicylate disposed on the heat packages, and a mechanism configured to activate heat packages, inhaling through the mouthpiece, and activating the heat package, wherein the activated heat package vaporizes the at least nicotine meta-salicylate to form an aerosol comprising the nicotine in the airway which is inhaled by the person.

"One aspect of the present disclosure provides a method for treating nicotine craving and smoking cessation using a nicotine aerosol.

"One aspect of the present disclosure provides for tapering of the nicotine dose through behavior modification therapy, utilizing electronic dose controlling and/or tapering through dose reduction.

"It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of certain embodiments, as claimed.

"The present invention relates to methods of manufacture and compositions which facilitate the inhalation delivery of nicotine to a patient for use as either a smoking substitute, an aid to smoking cessation, or, as will be discussed later, in the treatment of illnesses. One embodiment of the present disclosure is capable of delivering nicotine into a patient's blood in a manner which results in attainment of blood nicotine concentrations similar to the blood nicotine concentrations attained through smoking cigarettes to thereby address the physical cravings for nicotine which a smoker develops. In addition, the nicotine-containing dosage form disclosed provides a patient the opportunity, if desired, for physical manipulation and oral stimulation associated with repeated insertion and removal of the dosage form into and out of the patient's mouth to thereby address some of the psychological cravings which a smoker develops.

"It is one object of the present disclosure to provide a nicotine-containing dosage form which can be utilized as part of a long-term smoking cessation program. Another object is to provide a nicotine-containing dosage form which is suitable for use as a smoking substitute whenever smoking is not allowed or desired. A further object of the disclosure is to provide a nicotine aerosol highly free of the toxins present in cigarettes. A further object of the disclosure is to provide a nicotine-containing dosage form which can maintain nicotine plasma concentrations within a range which alleviates smoking withdrawal symptoms. Another object of the present disclosure is to provide a nicotine-containing dosage form which can provide nicotine plasma concentrations similar to those achieved by smoking a cigarette, including a similar pharmacological profile of nicotine delivery. Additionally, the disclosure teaches a nicotine-containing dosage form which addresses some of the psychological needs of an individual who desires to quit smoking. The disclosure also teaches a nicotine-containing dosage form which is easy to use in order to promote patient compliance. The disclosure further teaches the cessation/diminution of the craving for a cigarette by allowing the patient to self-titrate the amount of nicotine to overcome the person's individual craving.

"The disclosure teaches a new nicotine salt, nicotine m-salicylate (nicotine meta-salicylate). It is noted that m-salicylic acid is also referred to as 3-hydroxybenzoic acid. In one aspect, the disclosure teaches a novel composition for delivery of nicotine comprising a condensation aerosol formed by volatilizing a heat stable nicotine meta-salicylate composition under conditions effective to produce a heated vapor of said nicotine meta-salicylate composition and condensing the heated vapor of the drug composition to form condensation aerosol particles, wherein said condensation aerosol particles are characterized by less than 10% nicotine degradation products, wherein the aerosol MMAD is less than 3 microns and wherein said heat stable nicotine meta-salicylate composition comprises nicotine meta-salicylate.

"In some variations, the aerosol comprises at least 50% by weight of nicotine condensation particles. In other variations the aerosol comprises at least 90% or 95% by weight of the nicotine condensation particles. Similarly, in some variations, the aerosol is substantially free of thermal degradation products, and in some variations, the condensation aerosol has a MMAD in the range of 0.1-3 .mu.m. In certain embodiments, the particles have an MMAD of less than 5 microns, preferably less than 3 microns. Preferably, the particles have a mass median aerodynamic diameter of from 0.2 to 5 microns, or most preferably from 0.2 to 3 microns. Typically, the aerosol comprises a therapeutically effective amount of nicotine and in some variations may comprise pharmaceutically acceptable excipients. In some variations, the carrier gas is air. In some variations, other gases or a combination of various gases may be used. In some variations, the percent of nicotine free base is at least 10%. In some variations, the percent of nicotine free base in the aerosol is at least 20%. In some variations, the percent of nicotine free base in the aerosol is at least 30%. In some variations, the percent of nicotine free base in the aerosol is at least 40%. In some variations, the percent of nicotine free base in the aerosol is at least 50%. In some variations, the percent of nicotine free base in the aerosol is between 1% and 10%. In some variations, the percent of nicotine free base in the aerosol is between 10% and 20%. In some variations, the percent of nicotine free base in the aerosol is between 20% and 30%. In some variations, the percent of nicotine free base in the aerosol is between 30% and 40%. In some variations, the percent of nicotine free base in the aerosol is between 40% and 50%.

"In another aspect of the invention, the invention provides compositions for inhalation delivery, comprising an aerosol of vaporized nicotine condensed into particles, characterized by less than 5% drug degradation products, and wherein said aerosol has a mass median aerodynamic diameter between 0.1-3 microns.

"In some variations of the aerosol compositions, the carrier gas is a non-propellant, non-organic solvent carrier gas. In some variations of the aerosol compositions, the carrier gas is air. In some variations, the aerosol is substantially free of organic solvents and propellants.

"In other embodiments, aerosols of nicotine are provided that contain less than 5% nicotine degradation products, and a mixture of a carrier gas and condensation particles, formed by condensation of a vapor of nicotine in said carrier gas; wherein the MMAD of the aerosol increases over time, within the size range of 0.1 to 3 microns as said vapor cools by contact with the carrier gas.

"In some variations, the aerosol comprises at least 50% by weight of nicotine condensation particles. In other variations the aerosol comprises at least 90% or 95% by weight of the nicotine condensation particles. In some variations, the MMAD of the aerosol is less than 2 microns and increases over time. In some variations, the carrier gas is air. In some variations, other gases or a combination of various gases may be used.

"The condensation aerosols of the various embodiments are typically formed by preparing a film containing a nicotine meta-salicylate composition of a desired thickness on a heat-conductive and impermeable substrate and heating said substrate to vaporize said film, and cooling said vapor thereby producing aerosol particles containing said composition. Rapid heating in combination with the gas flow helps reduce the amount of decomposition. Thus, a heat source is used that typically heats the substrate to a temperature of greater than 200.degree. C., preferably at least 250.degree. C., more preferably at least 300.degree. C. or 350.degree. C. and produces substantially complete volatilization of the nicotine meta-salicylate composition from the substrate within a period of 2 seconds, preferably, within 1 second, and more preferably, within 0.5 seconds.

"Typically, the gas flow rate over the vaporizing compound is between about 1 and 10 L/minute. Further, the gas flow rate over the vaporizing compound can be between about 2 and 8 L/minute.

"The film thickness is such that an aerosol formed by vaporizing the nicotine meta-salicylate by heating the substrate and condensing the vaporized compound contains 10% by weight or less nicotine-degradation product. The use of thin films allows a more rapid rate of vaporization and hence, generally, less thermal nicotine degradation. Typically, the film has a thickness between 0.05 and 30 microns. In some variations, the film has a thickness between 0.5 and 25 microns. In some variations the film has a thickness of about 21 microns. The selected area of the substrate surface expanse is such as to yield an effective dose of the nicotine aerosol.

"In a related aspect, the disclosure teaches kits for delivering a nicotine condensation aerosol that typically comprises a composition devoid of solvents and excipients and comprising a heat stable nicotine meta-salicylate, and a device for forming and delivering via inhalation a condensation aerosol. The device for forming a drug aerosol typically comprises an element configured to heat the composition to form a vapor, an element allowing the vapor to condense to form a condensation aerosol, and an element permitting a user to inhale the condensation aerosol. Typically, the element configured to heat the composition comprises a heat-conductive substrate and formed on the substrate is typically a nicotine meta-salicylate composition film containing an effective dose of nicotine when the nicotine is administered in an aerosol form. A heat source in the device is operable to supply heat to the substrate to produce a substrate temperature, typically that is greater than 300.degree. C., to substantially volatilize the nicotine meta-salicylate composition film from the substrate in a period of 2 seconds or less, more preferably, in a period of 500 milliseconds or less. The device may further comprise features such as breath-actuation, lockout elements, dose counting/logging or tapering methods.

"In yet another aspect, the disclosure teaches kits for delivering nicotine aerosol comprising a thin film of a nicotine meta-salicylate composition and a device for dispensing said film as a condensation aerosol. Typically, the film thickness is between 0.5 and 30 microns. The film can comprise pharmaceutically acceptable excipients and is typically heated at a rate so as to substantially volatilize the film in 500 milliseconds or less.

"To achieve the foregoing objects, and in accordance with the invention as embodied and broadly described herein, a nicotine-containing dosage form is provided. The dosage form is configured having a nicotine-containing composition wherein the nicotine composition comprises nicotine meta-salicylate.

"These and other objects and features of the invention will be more fully appreciated when the following detailed description of the invention is read in conjunction with the accompanying drawings."

The claims supplied by the inventors are:

"What is claimed is:

"1. A drug supply article comprising: a heat-conductive substrate having an impermeable surface; a nicotine composition comprising nicotine meta-salicylate coated on at least a portion of the surface in the form of a film having a thickness; and a heat source operable to supply heat to the substrate at a rate that achieves a temperature sufficient to vaporize all or a portion of the coated nicotine composition within a period of 2 seconds; wherein the vaporized nicotine composition comprises an effective amount of the nicotine; wherein the film has a thickness between 0.05 and 30 microns.

"2. The drug supply article of claim 1, wherein the nicotine composition comprises a pharmaceutically acceptable excipient.

"3. The drug supply article of claim 1, wherein the film thickness is between 0.1 and 30 microns."

For additional information on this patent, see: Myers, Daniel J.; Cassella, James. Nicotine Salt With Meta-Salicylic Acid And Applications Therein. U.S. Patent Number 10,166,224, filed August 7, 2017, and published online on January 14, 2019. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=10,166,224.PN.&OS=PN/10,166,224RS=PN/10,166,224

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