Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1999-09-16
2001-09-25
Bawa, Raj (Department: 1619)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C424S450000, C424S184100, C424S130100, C424S198100, C514S002600
Reexamination Certificate
active
06294153
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an improved delivery system for the administration of large-molecule pharmaceuticals, e.g. peptidic drugs, vaccines and hormones. In particular it relates to pharmaceuticals which may be administered by means of an aerosol into the mouth, for buccal or pulmonary application.
BACKGROUND TO THE INVENTION
For many years, attempts have been made to provide drug delivery technologies which are patient-friendly, non-invasive, and economically viable alternatives to injecting large macromolecule proteins. Some of the earliest efforts involved transdermal delivery via electroporations but this has mostly been abandoned because of technical difficulties in providing systems to carry large molecules through the skin. Oral delivery, which would clearly be the preferable dosage form, has had some success. However, a major obstacle is the degradation and denaturization of proteins in the gastrointestinal tract. The likelihood of the right amount of drug actually getting into the bloodstream reproducibly seems difficult even with the most advanced carrier technology. The lung appears advantageous because of the enormous surface area of the alveoli, and the fact that the lung can absorb both small and large molecules while simultaneously filtering out microparticle carriers and other unwanted toxins in the air. Large proteins, including antibodies, are readily absorbed through the alveoli either directly into the circulatory system or, more frequently, via the lymphatic system, which subsequently releases the drug into the bloodstream. Proteins in excess of 50 kilodaltons in molecular weight, which include the overwhelming majority of all biotech products on the market and in development, have been successfully delivered via the lung. No other non-invasive drug delivery system seems to have the potential to deliver large molecules as efficiently and quickly as pulmonary delivery through the lung.
Conventional metered dose inhalers, primarily used for asthma, deliver drugs into the upper branches of the lung. The ability to deliver drugs via small molecules through the deep lung and into the alveoli was one of the most significant technical breakthroughs in drug delivery. Conventional metered-dose inhalers (MDIs) deliver between 0-80% of the drug depending on the formulation and the propellant drug ratio.
In the current U.S. market for many drugs, improvements in drug delivery technology could have a significant impact. Rapid onset of action via non-injectable methods is an enormous opportunity. Pain management situations, e.g. breakthrough pain, post-surgical, migraine, and trauma/emergency room, represent a huge opportunity. New products are needed to address these drug delivery needs, while simultaneously providing patients with a convenient user friendly mechanism and physicians with a tool to improve overall diseases by improving therapy, compliance, and to prevent or reduce expensive hospital stays.
The terms “comprising” and “comprises” when used in this specification are taken to specify the presence of the stated features, integers, steps or components but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.
SUMMARY OF THE INVENTION
It has now been found that improvements in penetration and absorption of certain micellar formulations can be achieved by mixing the mixed micellar formulation with propellants such as tetrafluoroethane, heptafluoroethane, dimethylfluoropropane, tetrafluoropropane, butane, isobutane, dimethyl ether and other non-CFC and CFC propellants, especially when delivered (e.g. applied to the buccal mucosa) through aerosol devices, e.g. metered dose inhalers (MDIs). Metered dose inhalers are a proven technology and a popular drug delivery form for many kinds of drug. The use of the present novel formulations and excipients can improve the quality (in terms of absorption), stability and performance of MDI formulations. The formulation ingredients are selected specifically to give enhancement in the penetration through the pores and facilitate the absorption of the drugs to reach therapeutic levels in the plasma. With the proper formulation changes and changes in administration technique, the formulation can be delivered to the deep lungs, through the nasal cavity and the buccal cavity.
Pressurized inhalers also offer a wide dosing range, consistent dosing efficiency. In this local delivery greater than 95% of the dose is reached to the target area. The smaller particle size (4-15 microns) of pressurized inhalers also enhances dosing due to broader coverage within the lung cavity. In this situation, increased coverage can help more absorption of drug like insulin. Furthermore, because these devices are self-contained, the potential for contamination is avoided.
Accordingly the present invention provides an aerosol pharmaceutical formulation comprising i) a proteinic pharmaceutical agent, ii) water, iii) a phenol selected from the group consisting of phenol and methyl phenol in a concentration of from 1 to 10 wt./wt. % of the total formulation, and v) a propellant selected from the group consisting of C1-C2 dialkyl ether, butanes, fluorocarbon propellant, hydrogen-containing fluorocarbon propellant, chlorofluorocarbon propellant, hydrogen-containing chlorofluorocarbon propellant, and mixtures thereof, and optionally iv) at least one excipient selected from the group consisting of salts, antioxidants, coloring agents, flavouring agents, protease inhibitors, stabilizers, glycerin, polyglycerin, lysine, polylysine and mixtures thereof.
In one embodiment, the proteinic pharmaceutical agent is in micellar form.
In another embodiment, the ratio of proteinic pharmaceutical agent, e.g. insulin, to propellant is from 5:95 to 25:75.
In a further embodiment, the methyl phenol is m-cresol.
In yet a further embodiment, the propellant is selected from the group consisting of tetrafluoroethane, tetrafluoropropane, dimethylfluoropropane, heptafluoropropane, dimethyl ether, n-butane and isobutane.
In yet another embodiment, the aerosol pharmaceutical formulation is contained in an aerosol dispenser.
The present invention also provides a metered dose aerosol dispenser with the aerosol pharmaceutical composition of the present invention therein.
The present invention also provides a method for administering an aerosol pharmaceutical compositions of the present invention, by spraying a predetermined amount of the composition into the mouth with a metered dose spray device.
The present invention also provides a method for administration of a proteinic pharmaceutical agent in a buccal cavity of a human being by spraying into the cavity, without inhalation, from a metered dose spray dispenser, a predetermined amount of an aerosol pharmaceutical formulation comprising i) a proteinic pharmaceutical agent, ii) water, iii) a phenol selected from the group consisting of phenol and methyl phenol in a concentration of from 1 to 10 wt./wt. % of the total formulation, and v) a propellant selected from the group consisting of C1-C2 dialkyl ether, butanes, fluorocarbon propellant, hydrogen-containing fluorocarbon propellant, chlorofluorocarbon propellant, hydrogen-containing chlorofluorocarbon propellant, and mixtures thereof, and optionally iv) at least one excipient selected from the group consisting of salts, antioxidants, coloring agents, flavouring agents, protease inhibitors, stabilizers, glycerin, polyglycerin, lysine, polylysine and mixtures thereof.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention provides an improved method for delivery of macromolecular (high molecular weight) pharmaceutical agents, particularly through the membranes in the mouth or lungs. The pharmaceutical agents cover a wide spectrum of agents, including proteins, peptides, hormones, vaccines and drugs. The molecular weights of the macromolecular pharmaceutical agents are preferably above 1000, especially between 1000 and 2 000 000.
For example, preferred pharmaceutical agents incl
Anderson Debra Z.
Bawa Raj
Eckert Seamens Cherin & Mellott, LLC
Generex Pharmaceuticals Inc.
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