Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-01
2002-01-01
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S626000
Reexamination Certificate
active
06335356
ABSTRACT:
FIELD OF THE INVENTION
The present invention features pharmaceutical formulations containing lipophilic compounds.
BACKGROUND OF THE INVENTION
Various methods are available for administering therapeutic agents into a patient. Such methods include, parenteral, oral, ocular, nasal, topical, and transmucosal administration. Variations of these different types of administrations exist. For example, parenteral administration includes intravenous, subcutaneous, intraperitoneal, intramuscular, and intramedullary injection. The chosen mode of administration should take into account the nature of the therapeutic compound and the illness being treated.
Lipophilic compounds are non-polar and have low solubility in water. Different techniques concerned with solubilizing lipophilic compounds include those described by Praveen et al., U.S. Pat. No. 5,314,685, and Fernades et al., U.S. Pat. No. 4,992,271.
SUMMARY OF THE INVENTION
The present invention features pharmaceutical formulations containing a lipophilic compound. The lipophilic compound is solubilized in solution containing alcohol (i.e. ethanol) and a surfactant. The solubilized compound can then be further dissolved in a pharmaceutically acceptable aqueous solution, such as WFI (water for injection), D5W (5% dextrose in water), and D5W 0.45% saline, to form a pharmaceutical formulation suitable for patient administration. The formulation is preferably used for parenteral administration.
Thus, a first aspect of the present invention features a formulation containing the following: (a) a solution made up of a pharmaceutically acceptable surfactant and alcohol in a ratio of 10:1 to 1:10 (v/v); and (b) preferably at least 1 mg/ml of a lipophilic compound. The compound is soluble in the formulation.
In preferred embodiments concerning the ratio, the ratio is preferably 10:1 to 1:2 (v/v), more preferably 2:1 to 1:2 (v/v).
In preferred embodiments concerning the amount of lipophilic compound, the amount is preferably 5 mg/ml, more preferably 10 mg/ml.
A “lipophilic compound” refers to a non-polar compound having a greater solubility in aqueous solution than in non-polar organic solvents such as long chain alcohols. The formulations described by the present invention facilitate solubilization of lipophilic compounds which readily dissolve in alcohol. Preferably, the lipophilic compound is insoluble in aqueous solution. More preferably, the compound has the solubility characteristics in alcohol and aqueous solution as 5-methylisoxazole-4 carboxylic acid-(4-trifluromethyl)-anilide (also known as leflunomide).
The surfactant is added to allow for dilution into a pharmaceutically acceptable solution prior to patient administration. Preferably, the surfactant is a non-ionic surfactant. Examples of pharmaceutically acceptable surfactants include POLYSORBATE 80® and other polyoxyethylene sorbitan fatty acid esters, glyceryl monooleate, polyvinyl alcohol, and sorbitan esters.
The solution containing the lipophilic compound is preferably adjusted to a pH where the lipophilic compound is stable. In a preferred embodiment, the pH is adjusted to between 2 and 7. The pH can be adjusted using pharmaceutically acceptable excipients such as ascorbic acid, citric acid, lactic acid, acetic acid, tartaric acid, sodium sulfate, hydrochloric acid, sodium hydroxide, glycerine, sodium phosphate and sodium acetate.
Because of the alcohol content, the formulation should be dissolved in a sufficient amount of a pharmaceutically acceptable aqueous solution prior to patient administration to avoid toxic effects due to the alcohol content. The added amount of a pharmaceutically acceptable aqueous solution should be sufficient to avoid hemolysis. Preferably, the alcohol:surfactant solution is diluted at least 1:5 (v/v), more preferably at least 1:10 (v/v), and most preferably 1:15 (v/v) with aqueous solution to provide a pharmaceutically acceptable formulation. Examples of suitable pharmaceutically acceptable aqueous solutions such as WFI and solutions containing isotonic saline are known in the art.
By “pharmaceutically acceptable” or “pharmaceutical”, in reference to the different formulation components, or the formulation itself, means that components or formulation do not prevent the therapeutic compound from exerting a therapeutic effect and do not cause unacceptable adverse side effects. Examples of pharmaceutically acceptable reagents are provided in
The United States Pharmacopeia The National Formulary
, United States Pharmacopeial Convention, Inc., Rockville, Md. 1990 (hereby incorporated by reference herein into the present application), Unacceptable side effects vary for different diseases. Generally, the more severe the disease the more toxic effects which will be tolerated. Unacceptable side effects for different diseases are known in the art.
A second aspect of the present invention features the use of the formulations described above to treat patients. The formulations can be used to treat different disorders preferably hyper-proliferative cell disorders. Preferably, the therapeutic agent is administered parenterally.
“Hyper-proliferative cell disorders” refer to disorders where an excess cell proliferation of one or more subset of cells in a multicellular organism occurs resulting in harm (e.g., discomfort or decreased life expectancy) to the multicellular organism. The excess cell proliferation can be determined by reference to the general population and/or by reference to a particular patient (e.g., at an earlier point in the patient's life). Hyper-proliferative cell disorders can occur in different types of animals and in humans, and produce different physical manifestations depending upon the effected cells. Hyper-proliferative cell disorders include cancers, blood vessel proliferative disorders, fibrotic disorders, and autoimmune disorders.
Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention features a formulation containing alcohol and a surfactant for solubilizing lipophilic therapeutic agents. The formulation can be used to facilitate administration of lipophilic compounds to a patient in need of such treatment.
The ability to prepare a lipophilic compound for therapeutic administration is illustrated below by reference to leflunomide. Based on the guidelines provided below and the known therapeutical utility of other lipophilic compounds, the present invention can be used to prepare formulations with these other compounds to facilitate treatment of patients, preferably human patients.
I. Lipophilic Compounds
The present invention can be used to formulate different lipophilic compounds for therapeutic administration. For example, compounds structurally related to leflunomide and N-(4-trifluoro-methylphenyl)-2-cyano-3-hydroxycrotonamide, such as those reference in Section I.B. infra., which are soluble in alcohol and have little or none aqueous solubility can be formulated for therapeutic administration using the present invention.
Additional lipophilic compounds can be identified based on their known physical characteristics and therapeutic applications. For example, compounds listed in Physician Desk Reference (Edition 48, 1994) which are indicated to be insoluble in aqueous solution or soluble in POLYSORBATE 80® are good candidate compounds. Examples of such compounds include Taxol, etoposide, BCNU, medroxyprogesterone, teniposide, and dexamethasone. Another source of candidate compounds are those compounds described by Cho Tang entitled “Compounds and Methods for Inhibiting Hyper-Proliferative Cell Growth,” U.S. application Ser. No. 08/426,789, filed Apr. 21, 1995, which is hereby incorporated by reference herein. The ability of such compounds to be dissolved in alcohol and preparation of a particular pharmaceutical formulation can be carried out using the guidelines described herein which are illustrated by the preparation of leflunomide formulations.
A. Leflunomide Formulati
Schwartz Donna Pruess
Shawver Laura Kay
Spivack Phyllis G.
Sugen Inc.
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