Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-10-28
2001-03-06
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S422000, C514S282000, C514S289000, C514S938000, C514S964000
Reexamination Certificate
active
06197344
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The field of this invention is long-term pain management. More particularly, the present invention relates to controlled release formulations of the opioid analgesic, butorphanol, and the use of such formulations for pain management over periods of time ranging from 12 to 24 hours.
BACKGROUND OF THE INVENTION
Butorphanol is a synthetic opioid agonist-antagonist that is highly effective for the treatment of both chronic and acute pain. Parenterally administered butorphanol is more potent than morphine and most other morphine analogs. Butorphanol is metabolized in the liver and excreted by the kidney. The elimination of butorphanol and its metabolites is rapid and the duration of analgesia is usually in the range of three to four hours, with maximal analgesia obtained one-half to one hour following parenteral administration. Butorphanol can be used to treat acute surgical pain, severe post-operative pain and chronic pain. The drug has been shown to be an effective pain management therapy in treating pain associated with numerous types of surgery, burns and kidney stones.
Parenteral formulations of butorphanol and the use of parenteral butorphanol for the relief of acute and chronic pain are known in the art (See, e.g., U.S. Pat. No. 3,819,635). A parenteral formulation of butorphanol is commercially available under the name STADOL® from Bristol-Meyers Laboratories, Inc. 2-4 mg of that formulation are typically injected intramuscularly for the treatment of post-operative pain. Typically, dosing interval ranges from about three to about four hours are needed to sustain analgesia.
A sustained release formulation of butorphanol encapsulated in phospholipid vesicles or Liposome is disclosed in European Patent Application 0300806A1. In accordance with that disclosure, butorphanol tartrate in phosphate buffered saline is encapsulated with lipid films of distearoylphosphatidylcholine and cholesterol. Effective levels of analgesia ranging from 12 to about 24 hours can be achieved by administering such Liposome encapsulated butorphanol.
South African Patent Application 91/4549 discloses sustained release pharmaceutical formulations and the use of those formulations in delivering therapeutic agents over periods of time of from about 12 to about 24 hours. Formulations disclosed in that South African patent application are microspheres of between 5 to 300 micrometers that contain at least one pharmaceutically active substance contained in a spherical structure formed by at least one pharmacologically inactive carrier substance. The carrier substance is naturally present in the organism to be treated and is stable in the solid state up to a temperature of at least 60° C. Exemplary such carrier substances are coprosterol, glycocholic acid, cholesterol and cholesterol esters. Pharmaceutically active substances that can be administered using such micro spheres are tranquilizers, anti-emetics, vasodialators, antihistiminics, steroids and analgesics.
Existing sustained release formulations are costly and require multi-step manufacturing procedures. There continues to be a need in the art for simple, inexpensive formulations of butorphanol that provide a controlled, sustained release of the drug over long periods of time.
BRIEF SUMMARY OF THE INVENTION
In one aspect, the present invention provides a pharmaceutical composition for the controlled release of butorphanol. The composition contains an effective therapeutic amount of butorphanol free base suspended in an aqueous buffer having a pH less than about 7.0. In a preferred embodiment, the pH is from about 6.2 to about 6.5 and, more preferably from about 6.2 to about 6.3. The composition is preferably in the form of microparticles having an average diameter of from about 5 to about 25 microns. Preferably, the sizes of the microparticles are from about 5 to about 15 microns.
The aqueous composition can contain a wide range of effective butorphanol concentrations. A particularly suitable concentration range is from about 4 to about 10 mg/ml and, preferably from about 5 to about 7.5 mg/ml.
An aqueous composition of this invention can further include an effective amount of a non-ionic solubilizing agent. Exemplary and preferred such solubilizing agents are polyoxyethylene sorbitan fatty acid esters such as polysorbate 80. The composition can still further include an effective amount of a preservative. A preferred preservative is an alkylparaben such as methylparaben or propylparaben.
In another aspect, the present invention provides a pharmaceutical composition for the controlled release of butorphanol, which composition includes an effective therapeutic amount of a butorphanol salt suspended in oil. A preferred butorphanol salt for use in such a composition is butorphanol tartrate.
In a preferred embodiment, butorphanol is present in such a composition in a concentration range of from about 5 to about 30 mg/ml and, more preferably from about 10 to about 20 mg/ml. Any GRAS oil known in the pharmaceutical art can be used in the composition. Exemplary and preferred such oils are cottonseed oil, corn oil, peanut oil, sesame oil and soybean oil. Soybean oil is most preferred.
The oil-based composition can further include an effective amount of a suspending agent or emulsifier. A preferred suspending agent is a sorbitan fatty acid ester such as a sorbitan mono-, di- or tri-laurate, a sorbitan mono-, di- or tri-oleate, a sorbitan mono-, di- or tri-palmitate, or a sorbitan mono-, di- or tri-stearate. An especially preferred sorbitan fatty acid ester is span 85.
Either the aqueous- or oil-based composition can be used to provide effective long-term pain management in patients. The injection of an effective therapeutic amount of either composition provides effective pain management over a period of time of about 12 to about 24 hours and preferably over a time period of 18 to 24 hours. Effective long-term pain management is accomplished by injecting an amount of either composition sufficient to maintain plasma butorphanol concentration at a level of between about 20 and 100 ng/ml.
DETAILED DESCRIPTION OF THE INVENTION
I. The Invention
Pharmaceutical compositions for the controlled, sustained release of an opioid analgesic are provided. The composition can be formulated either as an aqueous- or an oil based formulation. Injection of a composition of this invention has use in providing long-term pain management in patients in need of such therapy.
II. Aqueous Formulation
In one embodiment, a composition of this invention is an aqueous suspension of butorphanol. Butorphanol is an art recognized pain relieving agent that belongs to the class of analgesics known as synthetic opioid agonists-antagonists. Butorphanol can exist either as a free base or as a salt. For use in an aqueous formulation of the present invention, the free base form is used. As is known in the art, the free base can be made by titrating a butorphanol salt (e.g., butorphanol tartrate) with an alkali metal salt such as NaOH.
The composition contains an effective therapeutic amount of butorphanol free base suspended in a buffered aqueous medium. The pK
a
of butorphanol is 8.6. The solubility of butorphanol is inversely proportional to pH over the pH range of 6.0 to 8.5. By way of example, at a pH of about 6.25, about 60% of butorphanol is in solution whereas at a pH of about 7.0, only about 5% of the drug is in solution. As shown hereinafter in the Examples, however, formulations at either pH release virtually 100% of the drug over 48 hours. The initial rate of release of the drug is somewhat higher at low pH's. A preferred pH for an aqueous composition of the present invention is between about 6.0 and 7.5. More preferably, the pH is from about 6.25 to about 7.0. pH of the composition is maintained at the desired level through the use of pharmaceutically acceptable buffers such as sodium citrate or sodium phosphate.
The aqueous composition can be made to contain a wide range of effective butorphanol concentrations. The only limit on butorphanol levels is th
Chang Hung-Chih
Li Lukchiu
Tian Youqin
Abbott Laboratories
Channavajjala Lakshmi
Page Thurman K.
Steele Gregory W.
LandOfFree
Butorphanol sustained release formulations does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Butorphanol sustained release formulations, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Butorphanol sustained release formulations will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2512772