Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2000-10-30
2003-04-01
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S043000, C424S044000, C514S004300, C514S866000, C514S003100, C128S200140, C128S200210, C128S200230
Reexamination Certificate
active
06540982
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a medicinal aerosol formulation for treating diabetes, and more particularly, to a medicinal aerosol formulation comprising a mixture of an insulin or an insulin analog and another &bgr;-cell hypoglycemic medicament.
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 hormone replacement, pain management, immune deficiency, 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). The aerosol formulation can be presented as a liquid or a dry powder. In order to assure proper particle size in a liquid aerosol, particles can be prepared in respirable size and then incorporated into a colloidal dispersion either containing a propellant as a pressurized metered dose inhaler (PMDI) or air, such as in the case of 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 application, once prepared, an 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 the conditions related thereto.
SUMMARY OF THE INVENTION
It has surprisingly been found that a novel and stable medicinal aerosol formulation of an insulin or an insulin analog combined with a &bgr;-cell hypoglycemic medicament can be obtained without the use of a surfactant, such as sorbitan trioleate. The selected insulin or insulin analog is combined with another &bgr;-cell hypoglycemic medicament, and optionally other diabetic medicaments such as for example the &agr; cell hormone, glucagon.
DETAILED DESCRIPTION OF THE INVENTION
This application makes reference to U.S. application Ser. No. 09/209,228 filed Dec. 10, 1998, now U.S. Pat. No. 6,261,539 B1, issued Jul. 17, 2001 which is incorporated hereinto by reference in its entirety.
This invention involves a stable aerosol suspension formulation suitable for pressurized delivery which comprises (a) a particulate insulin combination, and (b) a suitable fluid carrier.
By an “insulin combination” is meant a selected insulin or insulin analog combined with at least one other &bgr;-cell hypoglycemic medicament or drug, such as an amylin.
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 ispreferably 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 in its entirety by reference, 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.
A suitable &bgr;-cell hypoglycemic medicament is one selected from an amylin. An “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 entirety.
Combined with the insulin combination, e.g. an insulin plus an amylin, is another diabetic medicament. Typically this other medicament is the a cell hormone glucagon. Other diabetic medicaments which can be employed are acetohexamide, chlorpropamide, tolazemide, tolbutamide, glipizide, glyburide, glucophage, phentolamine, etc.
For purposes of the formulations of this invention, which are intended for inhalation into the lungs, the insulin combination is preferably micronized whereby a therapeutically effective amount or fraction (e.g. ninety percent or more) of the insulin combination is particulate. Typically, the particles have a diameter of less than about 10 microns, and preferably less than about 5 microns, in order that the particles can be inhaled into the respiratory tract and/or lungs.
The particulate insulin combination is present in the inventive formulations in a therapeutically effective amount, that is, an amount such that the drug can be administered as a dispersion, an aerosol, such as topically, or via oral or nasal inhalation, and cause its desired atherapeutic effect, typically preferred with one dose, or through several doses. The particulate insulin combination is administered as an aerosol from a conventional valve, e.g., a metered dose valve, through an aerosol adapter also known as an actuator.
The term “amount” as used herein refers to quantity or to concentration as appropriate to the context. The amount of the insulin combination or formulation that constitutes a therapeutically effective amount varies according to factors such as the potency of the particular insulin or insulin analog and the particular &bgr;-cell hypoglycemic medicament or medicaments used, as well as the other diabetic medicaments, if used, the route of administration of the formulation, and the mechanical system used to administer the formulation. A therapeutically effective amount of the insulin combination can be selected by those of ordinary skill in the art with due consideration of such factors. Generally a therapeutically effective amount will be from about 0.001 parts by weight to about 5 parts by weight based on 100 parts by weight of the propellant.
Typically, the insulin combination comprises a selected insulin present in an amount of 0.0001 to about 5 parts by weight of the insulin or insulin analog to about 0.0001 to about 5 parts by weight of the selected &bgr;-cell hypoglycemic amylin or mixture thereof e.g. an amylin/insulin mixture. Typically, the mixtures of &bgr;-cell hypoglycemic medicaments in their respective ranges could be combined with a glucagon or glucagon analog or other diabetic medicament in a concentration range of about 0.001 to about 10 parts by weight based
Adjei Akwete L.
Cutie Anthony J.
Aeropharm Technology Incorporated
Frommer Lawrence & Haug
Ostrup Clinton
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