Venlafaxine formulations

Details Venlafaxine formulations Venlafaxine formulations

2002-10-25

2004-03-09

Davis, Brian (Department: 1621)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S463000, C514S653000, C564S360000

Reexamination Certificate

active

06703044

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a formulation and method for the delayed burst release of venlafaxine.
BACKGROUND OF THE INVENTION
Venlafaxine, 1-[(2-dimethylamino)-1-(4-methoxyphenyl) ethyl] cyclohexanol, is an important drug for the treatment of depression. Venlafaxine and the acid salts thereof are disclosed in U.S. Pat. No. 4,535,186, which is hereby incorporated by reference as if fully set forth herein. Venlafaxine hydrochloride is presently administered to adults in compressed tablet form in doses ranging from 75 to 350 mg/day, in divided doses two or three times a day. Currently, in therapeutic dosing with venlafaxine hydrochloride tablets, rapid dissolution results in a rapid increase in blood plasma levels of the active compound shortly after administration followed by a decrease in blood plasma levels over several hours as the active compound is eliminated or metabolized, until subtherapeutic plasma levels are approached after about twelve hours following administration, thus requiring additional dosing with the drug. With the plural daily dosing regimen, the most common side effect is nausea, experienced by about forty five percent of patients under treatment with venlafaxine hydrochloride. Vomiting also occurs in about seventeen percent of the patients.
U.S. Pat. No. 6,274,171, issued on Aug. 14, 2001, describes one attempted solution to the problem of frequent administration of venlafaxine. The disclosure teaches a formulation of spheroids, which is characterized by an outer film coating over a core which contains venlafaxine, and in which both are placed in a hard gelatine capsule. However, administration of this formulation results in blood concentration levels having a distinct peak 4-8 hours after administration.
Clearly, the ability to provide a more even plateau of blood concentration of venlafaxine, and therefore presumably to reduce the occurrence and/or severity of side effects, or even to eliminate such side effects altogether, as well as decreasing the frequency of administration of venlafaxine, would be desirable. In addition, the location of release of venlafaxine may also be problematic, as the above taught formulations clearly result in release occurring to a significant degree in the small intestine, and possibly also in the stomach. Since one of the most significant side effects of venlafaxine is nausea and/or vomiting, indicating gastric distress, clearly release of this active ingredient should not occur in the stomach and/or small intestine.
In U.S. Pat. Nos. 6,403,120 and 6,419,958 there are described and claimed methods and compositions for providing therapeutic blood plasma concentration of venlafaxine over a twenty-four hour period with diminished incidence of nausea and emesis which comprises administering orally to a patient in need thereof, an extended release formulation as defined in said patents. More specifically one finds in both of said patents a specific description and definition of the term “extended release drug formulations” wherein both of said patents provide the same following description and definition:
“Extended release drug formulations are conventionally produced as compressed tablets by hydrogel tablet technology. To produce these sustained release tablet drug dosage forms, the active ingredient is conventionally compounded with cellulose ethers such as methyl cellulose, ethyl cellulose or hydroxypropylmethylcellulose with or without other excipients and the resulting mixture is pressed into tablets. When the tablets swell upon hydration from moisture in the digestive system, thereby limiting exposure of the active ingredient to moisture. As the cellulose ethers are gradually leached away by moisture, water more deeply penetrates the gel matrix and the active ingredient slowly dissolves and diffuses through the gel, making it available for absorption by the body. An example of such a sustained release dosage form of the analgesic/anti-inflammatory drug etodolac (Lodine®) appears in U.S. Pat. No. 4,966,768. U.S. Pat. No. 4,389,393 discloses sustained release therapeutic compressed solid unit dose forms of an active ingredient plus a carrier base comprised of a high molecular weight hydroxypropylmethylcellulose, methyl cellulose, sodium carboxymethylcelluslose and or other cellulose ether.”
Following the above description in said patents there is then presented a further description which states as follows:
“Where the production of tablets is not feasible, it is conventional in the drug industry to prepare encapsulated drug formulations which provide extended or sustained release properties. In this situation, the extended release capsule dosage forms may be formulated by mixing the drug with one or more binding agents to form a uniform mixture which is then moistened with water or a solvent such as ethanol to form an extrudable plastic mass from which small diameter, typically of 1 mm, cylinders of drug/matrix are extruded, broken into appropriate lengths and transformed into spheroids using standard spheronization equipment. The spheroids, after drying, may then be film-coated to retard dissolution. The film-coated spheroids may then be placed in pharmaceutically acceptable capsules, such as starch or gelatin capsules, in the quantity needed to obtain the desired therapeutic effect. Spheroids releasing the drug at different rates may be combined in a capsule to obtain desired release rates and blood levels. U.S. Pat. No. 4,138,475 discloses a sustained release pharmaceutical composition consisting of a hard gelatin capsule filled with film-coated spheroids comprised of propanolol in admixture with microcrystalline cellulose wherein the film coating is composed of ethyl cellulose, optionally, with hydroxypropylmethylcellulose and/or a plasticizer.”
Said patents, having concluded and taught that the preferred solution for obtaining a flattened drug plasma concentration to time profile for extended release of venlafaxine is through use of such extended release drug formulations then specifically described at the top of column three of each of said patents that these formulations are achieved by providing a therapeutically effective amount of venlafaxine hydrochloride in spheroids comprised of venlafaxine, hydrochloride, microcrystalline cellulose and, optionally, hydroxypropylmethylcellulose coated with a mixture of ethyl cellulose and hydroxypropylmethylcellulose.
This is also the solution suggested and taught in U.S. Pat. No. 6,274,171 and in U.S. patent applications 2002/0025339 and U.S. 2001/0055612.
SUMMARY OF THE INVENTION
In contradistinction to the teachings of all of the above mentioned patents and applications that are based on extended release from microspheroids as a function of the structure and coating thereof, it has now been found that a different and better mechanism of long-term dispersion, e.g. for a period of at least 24 hours, of venlafaxine into the blood stream can be achieved by utilizing a formulation which provides for delayed burst release after a period of at least 3 hours after ingestion to provide for dispersion of venlafaxine into the blood stream through the colon over a period extending over at least 24 hours.
Thus, the present invention provides a method for treating a subject with venlafaxine, comprising administering to the subject a formulation having a therapeutically effective amount of venlafaxine or a pharmaceutically acceptable salt thereof, wherein said formulation provides a delayed burst release after at least three hours resulting in dispersion of the active ingredient mainly through the colon into the blood stream as a result of colon absorption over a period of at least 24 hours.
The delivery system of the present invention also advantageously uses the unique continuous absorption characterizing the colon which results in more flat, consistent concentration levels of the drug in blood. Such an absorption, of course, can significantly contribute to reduce the fluctuations in blood drug concentration thus to prevent the side effects which ma

Affiliated with

Also associated with

Rating

Venlafaxine 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 Venlafaxine formulations, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Venlafaxine formulations will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3268913