Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-10-31
2003-12-30
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S499000, C424S501000, C424S422000, C424S424000, C424S425000, C424S426000, C514S003100
Reexamination Certificate
active
06669959
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to modulated release aerosol particles, and more particularly, to medicinal aerosol particles comprising polymeric vesicles which entrap a selected medicament and provide slow release thereof.
2. Description of the Related Art
Many drugs currently administered by inhalation come primarily as liquid or solid aerosol particles of respirable size. For biotherapeutic drugs, this may present a problem, as many of these medicaments are unstable in aqueous environments for extended periods of time and are rapidly denatured if micronized by high shear grinding or other comminution methods when presented as dry powders. Additionally, a number of these medicaments do not survive long enough in the lung as they are extracted quickly from the lung environment after they are administered as inhalation aerosols. Significant drug loss could also occur by deactivation either as a result of reactivity of the medicament with device and container surfaces, or during aerosolization, particularly in high shear, energy intensive, nebulized systems [Mumenthaler, M., et al.,
Pharm. Res
., 11: 12-20 (1994)].
To overcome these instability problems, many drug and excipient systems containing biodegradable carriers, such as poly(lactide-co-glycolides,have been developed for biotherapeutic proteins and peptides [Liu, R., et al.,
Biotechnol. Bioeng
., 37:177-184 (1991)]. These medicaments, presumably, are adequately protected in their carrier systems, and thus do not undergo as much denaturation as realized in aqueous media.
Most therapeutic peptides and proteins are poorly absorbed through biologic membranes even upon formulation with penetration enhancers, possibly due to a combination of several factors, including large molecular size (i.e., ≧1000 daltons), ionization, high surface charge, enzymatic and chemical instability, and low permeability of absorption barriers in the body of a patient, e.g. human being or other animal. In numerous therapies, drug dosimetry is increased by orders of magnitude to achieve minimum systemic concentrations required for efficacy. In other cases the drug product is formulated with exotic absorption promoters in order to improve permeability across the absorption barrier. But such formulations usually present serious toxicological liabilities. The clinical and pharmaceutical chemistry sciences, in an attempt to accomplish the highest level of therapeutic benefit for these compounds, have resorted to chemical modifications as a principal mode for improving biological activity of these drugs in the body of the patient. The mode of drug administration to the body has also gradually expanded from oral and parenteral to transdermal, rectal and the pulmonary routes of administration, i.e., nose and lung. Success and achievement with these drug delivery approaches are mixed largely due to lack of acceptance of the newer, complex molecules that must be used for treating difficult diseases of the body, e.g., infections, malignancies, cardiovascular, endocrine, neurologic diseases, and a variety of immunologically compromised diseases, like AIDS.
Accordingly, what is desired and needed is a fluid propelled formulation system comprising an active pharmaceutical ingredient (“API”) that is stable and protected by a rate-limiting carrier, easily manufactured, and therapeutically effective when administered as fluid dispersed particles to the lung of a patient, e.g. a human being or another animal.
SUMMARY OF THE INVENTION
This invention relates to modulated release aerosol particles, and more particularly, to medicinal, respirable aerosol particles comprising polymeric vesicles which are associated with, e.g. form a part of a construct with or entrap therewithin a selected medicament and provide slow release thereof.
DETAILED DESCRIPTION OF THE INVENTION
This application makes reference to U.S. applications Ser. No. 09/158,369 filed on Dec. 10, 1998, and 60/177,983 filed on Jan. 25, 2000, which are incorporated hereinto by reference in their entirety.
This invention involves stable, modulated release, respirable, aerosolizable particles suitable for delivery of medicaments to the lung, which comprise (1) a medicament or drug, (2) a polymeric construct into which the drug is associated, i.e. is encapsulated therewithin or being part of the construct, (3) a suitable fluid or propellant, and (4) a suitable stabilizer. The polymeric construct, comprising a block copolymer, modulates release of the encapsulated drug to the body of a patient, e.g. a human being or another animal, when the formulation is administered to the patient's respiratory tract.
A suitable macromolecular medicament or drug is one which is suitable for administration by inhalation, the inhalation being used for oral and nasal inhalation therapy. A stable, colloidal dispersion of a 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 an inactive formulation component, which triggers loss of adhesive bond strength between the medicament particles, may optionally be employed. An electret or sterially stabilized aerocolloid particles of the selected medicaments is thus formed. An electret is the electrostatic equivalent of a permanent magnet 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 particles formulated for use in 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 selected medicament or drug particles reach the alveolar or other absorption sites in the airways of a patient, e.g. human, other animal, being treated. Once at the absorption site, the drug particles 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.
As used herein the following terms are defined as follows.
The term “biodegradable” means that the block copolymer can chemically break down or degrade within the body to form nontoxic components. The rate of degradation can be the same or different from the rate of drug release.
The term “rate of release” from the biodegradable medicament carrier is defined as the amount of medicament released per unit time either to the lung environment or from the lung environment to the systemic circulation of the body of the patient treated.
The term “poly(lactide-co-glycolide)” shall mean a copolymer derived from the condensation copolymerization of lactic acid and glycolic acid, or, by the ring opening polymerization of .alpha.-hydroxy acid precursors, such as lactide or glycolide.
The terms “lactide” and “lactate” and “glycolide” and “glycolate” are used interchangeably.
The terms “peptide”, “polypeptide”, “oligopeptide” and “protein” shall be used interchangeably when referring to peptide or protein drugs and shall not be limited as to any particular molecular weight, peptide sequence or length, field of bioactivity or therapeutic use unless specifically stated.
A suitable medicament to which the subject invention is directed includes a peptide, polypeptide, or protein biotherapeutic medicament 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; such as insulins and insulin analogs; amylin; glucagon; surfactants; immunomodulating peptides such as cytokines, chemokines, lymphokines; interleukins, such as taxol, interleukin-1, interleukin-2, an
Adjei Akwete L.
Cutie Anthony J.
Sun John Z.
Zhu Yaping
Aeropharm Technology Incorporated
Di Nola-Baron Liliana
Frommer & Lawrence & Haug LLP
Spear James M.
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