Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2000-10-30
2003-07-01
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S043000, C424S044000, C514S004300, C514S866000, C128S200140, C128S200210, C128S200230
Reexamination Certificate
active
06585957
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 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. Steroids, (&bgr;2 agonists, anti-cholinergic agents, proteins and polypeptides 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.
It is important that an aerosol formulation be stable such that the delivered dose discharged from the metered dose valve is reproducible. Rapid creaming, settling, or flocculation after agitation are common sources of dose irreproducibility in suspension formulations. This is especially true where a binary aerosol formulation containing only medicament and propellant, e.g. 1,1,1,2-tetrafluoroethane, is employed or where such formulation contains small amounts of surfactant as well. Sticking of the valve also can cause dose irreproducibility. In order to overcome these problems, MDI aerosol formulations often contain surfactants, which serve as suspending aids to stabilize the suspension for a time sufficient to allow for reproducible dosing. Certain surfactants also function as lubricants to lubricate the valve to assure smooth actuation. Myriad materials are known and disclosed for use as dispersing aids in aerosol formulations. Suitability of materials, however, is dependent on the particular drug and the propellant or class of propellant used in the formulation.
It is sometimes difficult to dissolve sufficient quantities of conventional surfactants in hydrofluorocarbon (HFC) propellants such as HFC-134a and HFC-227. Cosolvents, such as ethanol, have been used to overcome this problem, as described in U.S. Pat. No. 5,225,183. An alternative approach that avoids cosolvents involves materials that are soluble or homogeneously dispersible in hydrofluorocarbon propellants and are said to be effective surfactants or dispersing aids in an aerosol formulation. Among such materials are certain fluorinated surfactants and certain polyethyoxysurfactants.
Medicaments which are relatively small molecules are much more predictable in terms of their aerosol formulation characteristics than macromolecules. The macromolecules, such as peptides or proteins, which range in molecular size from about 1K Dalton to about 150 K Daltons in molecular size are very unpredictable and present unique problems in forming aerosol formulations thereof which are stable and provide reproducible dosage.
Most peptide and protein drugs, such as hormones, e.g. insulin, amylin, etc., enzymes, antinfectives, are quite variable in their amino acid composition and three-dimensional structure. Consequently their surface activity is highly variable, and importantly, no model is yet available that explains differences in protein surface activity based on their most basic and structural properties, such as molecular weight, adsorptivity, solubility, partition coefficient and isoelectric pH. Hemoglobin, for example, has far higher affinity for solid surfaces than does albumin, yet the molecular weights of these two proteins are very similar. Fundamentally, the diversity in surface activity of peptides and proteins originates in the linear sequence of amino acids that uniquely characterizes each type of protein. The amino acid side chains often vary dramatically in that some carry no charge at any pH, yet exhibit considerable polar character (serene, threonine). Other amino acids are ionizable and vary from fairly acidic (aspartic and glutamic acid are fully negatively charged at the physiological pH of 7.4) to basic functionalities, such as the imidazole group in histidine (which carries a partial positive charge at pH 7.4), and the still more basic amino groups in lysine and arginine that carry full positive charges at pH 7.4. Another group of amino acids, somewhat hydrocarbon-like in character, appear to demonstrate generally a much lower solubility profile in water (tryptophan, phenylalanine, isoluecine, etc.) than many of the other amino acids found in biological systems. It is noteworthy that the hydrophobicity of these water-hating amino acids varies greatly with their specific structure in the protein. For example, the single methyl group side chain in alanine contributes only 0.5 kcal/mole to the free energy of transfer from water to an organic phase, whereas the double-ringed indole group in tryptophan contributes 3.4 kcal. The variety of amino acid side chains, together with the many different types of chemical interactions that result in solution and at surfaces, should be expected to have a considerable impact on aerosol formulation stability as well as transport of these peptide and protein biotherapeutic agents across biologic membranes.
The diverse character of the amino acid side chains, together with the complexity of various combinations of amino acids present in each particular protein, means that physicochemical properties of the proteins, their intermolecular as well as intramolecular Fax reactivity, and also their ability to interact with surfaces should be highly variable. Due to their large size, and correspondingly due to the large numbers of charged amino acid side chains, proteins have many charges distributed over their exterior surface. This could lead to very large variances in aerosol formulation stability and lung uptake of these compounds. Peptide and protein drugs also generally have multiple ionization sites and therefore they often demonstrate pH-dependent solubility profiles. Importantly, the hydrophilic nature of these compounds provides excellent conditions for high aqueous solubility. Consequently, most peptide and protein drugs present extremely low lipid solubility characteristics, the latter possibly being one reason why dispersions of these drugs in hydrofluorocarbon propellants would be physically and chemically stable across a wide range of storage conditions. An aerosol medicament formulation comprising peptide and protein drugs in carrier or formulation media within which they are virtually insoluble is needed to reduce hydrolytic and chemical deactivation usually typical of aqueous solutions.
The combination of a large surface area, thin absorptive carrier, and extensive vasculature constitutes a favorable absorptive environment for proteins and peptides when delivered by the pulmonary route. Studies show that intratracheal (i.t.) administration of peptides is rapid and quantifiable; however the resultant distribution is often localized in central airways. Administration by aerosol, for example, depending on particle size distribution, may be used to give more uniform distribution with greater alveolar penetration. Drug absorption from the airways is dependent upon the sit
Adjei Akwete L.
Stefanos Simon
Sun John Z.
Zhu Yaping
Aeropharm Technology Incorporated
Frommer & Lawrence & Haug LLP
Krass Frederick
Ostrup Clinton
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