Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2000-11-20
2003-08-26
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C128S200140, C514S002600, C514S340000, C514S341000
Reexamination Certificate
active
06610272
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a medicinal aerosol formulation, and more particularly, to a medicinal aerosol formulation comprising pioglitazone hydrochloride and a protective colloid stabilizer.
2. Description of the Related Art
Delivery of drugs to the lung by way of inhalation is an important means of treating a variety of conditions, including such common local conditions as cystic fibrosis, pneumonia, bronchial asthma and chronic obstructive pulmonary disease and some systemic conditions including pain management, immune deficiency, hormonal therapy, erythropoiesis, diabetes, etc. Anti-diabetic drugs, e.g. an insulin are among the drugs that are administered to the lung for such purposes. Such drugs are commonly administered to the lung in the form of an aerosol of particles of respirable size (less than about 10 &mgr;m in diameter). In order to assure proper particle size in the aerosol, particles can be prepared in respirable size and then incorporated into a colloidal dispersion containing either a propellant, as a pressurized metered dose inhaler (MDI), or air such as is the case with a dry powder inhaler (DPI). Alternatively, formulations can be prepared in solution or emulsion form in order to avoid the concern for proper particle size in the formulation. Solution formulations must nevertheless be dispensed in a manner that produces particles or droplets of respirable size.
For MDI preparations, once prepared, the aerosol formulation is filled into an aerosol canister equipped with a metered dose valve. In the hands of the patient the formulation is dispensed via an actuator adapted to direct the dose from the valve to the patient.
What is needed and desired is a stable aerosol formulation for the treatment of diabetes and conditions related thereto comprising pioglitazone or a salt thereof, e.g. pioglitazone maleate.
SUMMARY OF THE INVENTION
It has surprisingly been found that novel and stable medicinal aerosol formulations of pioglitazone or a salt thereof, e.g. pioglitazone maleate, can be obtained without the use of either cosolvents, such as ethanol, or surfactants, such as sorbitan trioleate which are typically added to a binary aerosol formulation. Such stable medicinal aerosol formulations are obtained by the use of a protective colloid stabilizer.
DETAILED DESCRIPTION OF THE INVENTION
This application makes reference to U.S. application Ser. No. 09/158,369 filed Sep. 22, 1998, which is incorporated hereinto by reference in its entirety.
This invention involves a stable suspension aerosol formulation suitable for pressurized delivery which comprises (1) pioglitazone, e.g. maleate, (2) a suitable propellant, and (3) a suitable stabilizer.
Pioglitazone or any of its derivatives, such as the maleate, is a suitable medicament or drug which is suitable for administration by inhalation, the inhalation being used for oral and nasal inhalation therapy. A stable, colloidal dispersion of the medicament in a fluid, e.g. air, hydrocarbon gases, chlorofluorocarbon (CFC) propellants or non-CFC propellants, such as tetrafluoroethane (HFA-134a) and heptafluoropropane (HFA-227), is described.
A stabilizer of a polyionic species, such as an amino acid and a small molecule peptide, as inactive formulation components which trigger loss of adhesive bond strength between the medicament particles is employed. An electret or sterially stabilized aerocolloid particles of the selected medicament is thus formed. Electrets are the electrostatic equivalent of permanent magnets but can be susceptible to breakdown in the presence of moisture, such as that present in air or at ambient humidity conditions of the respiratory tract. Accordingly the present invention applies to dry powder aerosols, portable nebulizer systems, as well pressurized metered dose inhaler formulations.
The resultant aerocolloid is chemically and physically stable and can remain in suspension until the particles of pioglitazone, e.g. maleate, reach the alveolar or other absorption sites in the airways of a patient, e.g. human, animal, being treated. Once at the absorption site, the particles of, for example, pioglitazone hydrochloride should be efficiently trapped at the deposition site as a result of moisture in the ambient, dissolve rapidly in the epithelial lining fluids, and be absorbed quickly across the biomembranes of the patient, thereby limiting possible deactivation by metabolizing enzymes in the airways.
Pioglitazone and its derivatives, e.g. maleate, to which the subject invention is directed is one that forms a stable dispersion suitable for delivery to a patient, e.g., human or animal. Pioglitazone alone can be delivered to the patient or it can be combined with another suitable anti-diabetic agent selected from an acetohexamide, chlorpropamide, tolazemide, tolbutamide, glipizide, glyburide, glucophage, phentolamine, etc., and a mixture of any two or three of the foregoing medicaments or other medicaments. Typically, additional medicaments combined with pioglitazone hydrochloride includes a peptide, polypeptide, or protein biotherapeutic ranging from 0.5 K Dalton to 150 K Dalton in molecular size. In particular, the peptide, polypeptide, or protein biotherapeutic medicament includes diabetic aids; insulins and insulin analogs; amylin; glucagon; surfactants; immunomodulating peptides such as cytokines, chemokines, lymphokines interleukins such as taxol, interleukin-1, interleukin-2, and interferons; antibiotics and other antiinfectives; hormones and growth factors; enzymes; vaccines; immunoglobulins; vasoactive peptides; antisense agents; genes, oligonucleotides, and nucleotide analogs.
The term diabetic aid includes natural, synthetic, semi-synthetic and recombinant medicaments such as activin, glucagon, insulin. somatostatin, proinsulin, amylin, and the like.
The term “insulin” shall be interpreted to encompass natural extracted human insulin, recombinantly produced human insulin, insulin extracted from bovine and/or porcine sources, recombinantly produced porcine and bovine insulin and mixtures of any of these insulin products. The term is intended to encompass the polypeptide normally used in the treatment of diabetics in a substantially purified form but encompasses the use of the term in its commercially available pharmaceutical form, which includes additional excipients. The insulin is preferably recombinantly produced and may be dehydrated (completely dried) or in solution.
The terms “insulin analog,” “monomeric insulin” and the like are used interchangeably herein and are intended to encompass any form of “insulin” as defined above wherein one or more of the amino acids within the polypeptide chain has been replaced with an alternative amino acid and/or wherein one or more of the amino acids has been deleted or wherein one or more additional amino acids has been added to the polypeptide chain or amino acid sequences which act as insulin in decreasing blood glucose levels. In general, the “insulin analogs” of the present invention include “insulin lispro analogs,” as disclosed in U.S. Pat. No. 5,547,929, incorporated hereinto by reference in its entirety, insulin analogs including LysPro insulin and humalog insulin, and other “super insulin analogs”, wherein the ability of the insulin analog to affect serum glucose levels is substantially enhanced as compared with conventional insulin as well as hepatoselective insulin analogs which are more active in the liver than in adipose tissue. Preferred analogs are monomeric insulin analogs, which are insulin-like compounds used for the same general purpose as insulin, such as insulin lispro i.e., compounds which are administered to reduce blood glucose levels.
The term “amylin” includes natural human amylin, bovine, porcine, rat, rabbit amylin, as well as synthetic, semi-synthetic or recombinant amylin or amylin analogs including pramlintide and other amylin agonists as disclosed in U.S. Pat. No. 5,686,411, and U.S. Pat. No. 5,854,215, both of which are incorporated hereinto by reference in their entiret
Adjei Akwete L.
Cutie Anthony J.
Sexton Frederick A.
Aeropharm Technology Incorporated
Frommer & Lawrence & Haug LLP
Haghighatian M.
Hartley Michael G.
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