Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1999-09-07
2003-02-11
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S458000, C424S468000, C424S469000, C424S473000, C424S474000, C424S484000, C424S490000, C424S463000
Reexamination Certificate
active
06517866
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to certain salts of sertraline, and to a sustained-release dosage form of sertraline having an improved side effect profile, and to a method of treating a psychiatric or other illness comprising administering sertraline in such a sustained-release dosage form to a mammal, including a human patient, in need of such treatment
BACKGROUND OF THE INVENTION
Sertraline is a selective serotonin reuptake inhibitor (SSRI), which is useful, inter alia, as an antidepressant and anorectic agent, and in the treatment of obsessive-compulsive disorder, premenstrual dysphoric disorder, post-traumatic stress disorder, chemical dependencies, anxiety-related disorders, panic and premature ejaculation. See U.S. Pat. No. 4,536,518, Published International Application WO 92/18005, U.S. Pat. No. 5,130,338, U.S. Pat. No. 4,971,998, Published International Application WO 92/00103, U.S. Pat. No. 5,061,728, U.S. Pat. No. 4,940,731, and U.S. Pat. No. 4,962,128, each of which is incorporated herein by reference. Sertraline is also known as (1S-cis)-(
4-
(-3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine, has the empirical formula C
12
H
17
NCl
2
, and has the structural formula
Sertraline is most commonly prescribed for therapy of depressive illness, in the general dose range 50-200 mg/day. Sertraline has an elimination half-life of 23 hr, and is dosed once daily.
Patients are generally initiated on sertraline at a dose of 50 mg/day. Patients who do not respond at the 50 mg dose are given higher doses. Initiation at doses greater than 50 mg is generally avoided, when possible, because side effects such as dizziness, tremor, and sweating, and gastrointestinal upset are generally believed to be more severe at higher doses. If necessary to achieve efficacy, higher doses may be reached by slow titration up from lower doses. Improved sertraline dosage forms which exhibited a lower incidence and/or severity of side effects would be advantageous because (1) patient comfort would be improved, and (2) dosing could be initiated at doses higher than 50 mg. without the need for dose titration. Initiation at higher starting doses would, in turn, be useful by potentially effecting a shorter onset of antidepressive action. Thus, such an improved sertraline dosage form which permitted oral dosing of high doses of sertraline (e.g., 200 mg and higher) with relatively reduced side effects would permit wider therapeutic application of sertraline therapy, and would accordingly provide a significant improvement in dosing compliance and convenience. Likewise, an improved dosage form which lowered the incidence and/or severity of side-effects at lower doses would also be of significant value.
SUMMARY OF THE INVENTION
This invention provides an oral, sustained release dosage form of sertraline which decreases, relative to currently marketed instant release sertraline tablet dosage forms which deliver an equivalent bolus dose, the incidence and/or severity of gastrointestinal and/or other side effects such as dizziness, tremor and sweating. The dosage form operates by effecting the release of sertraline at a rate sufficiently slow to ameliorate side effects.
Dosage forms which release more than 70% of their contained sertraline within one hour or less are not “sustained release”, and form no part of this invention. This feature thus excludes from the invention immediate release dosage forms containing 40 mg of sertraline or less. Such dosage forms will technically release sertraline at a rate less than 40 mgA/hr, but are excluded because they do not do so in a sustained manner.
In one aspect this invention provides a sustained-release dosage form suitable for administration to a mammal, comprising sertraline, or a pharmaceutically salt thereof, and a pharmaceutically acceptable carrier,
which dosage form releases sertraline into a use environment at a rate not exceeding 0.8 mgA/hr/kg, preferably at a rate not exceeding 0.7 mgA/hr/kg,
provided said dosage form (1) releases not more than 70% of the sertraline contained therein within the first hour following entry into said use environment and (2) releases sertraline at a rate of at least 0.02 mgA/hr/kg. This aspect of the invention describes a dosage form without regard to the size of any particular mammal.
In another aspect this invention provides a sustained-release dosage form suitable for oral administration to a mammal, comprising sertraline, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
which dosage form releases sertraline into a use environment at a rate not exceeding 40 mgA/hr,
provided said dosage form (1) releases not more than 70% of the sertraline contained therein within the first hour following entry into said use environment and (2) releases sertraline at a rate of at least 1 mgA/hr. This aspect of the invention describes a dosage form suitable for administration to mammals such as average size adult humans. A dosage form according to the invention thus releases sertraline at a rate of from 1 to 40 mgA/hr. Particular release rate ranges include rates of from 2 to 40 mgA/hr, 3 to 40 mgA/hr, 1 to 30 mgA/hr, 2 to 30 mgA/hr, and 3 to 30 mgA/hr. The ranges 1 to 30 mgA/hr and 2 to 30 mgA/hr are preferred. The ranges 1 to 25 mgA/hr and 2 to 25 mgA/hr are more preferred.
Reference to a dosage form which “releases” sertraline means (1) release of sertraline to a mammal's gastrointestinal (GI) tract following ingestion or (2) release of sertraline into an in vitro test medium for analysis by an in vitro test as described below. Reference to a “use environment” can thus be either to in vivo gastrointestinal fluids or to in vitro test medium.
Rates of sertraline release lower than 25, 30 or 40 mgA/hr are also within the scope of the invention and may produce even better side effect profiles, particularly for patients under 50 kg weight for example children. Thus a sertraline release rate of 7 mgA/hr after ingestion represents a release profile within the scope of the invention and may be even more efficacious for ameliorating side effects. The rate must, of course, be high enough to provide therapeutic efficacy, that is, a therapeutically sufficient amount of sertraline should be delivered from the dosage form before the dosage form is excreted with the feces. Accordingly, dosage forms according to the invention should release sertraline at a rate of at least 1 mgA/hr.
The unit “kg” as used herein in “mgA/hr/kg” refers to kilograms of body weight for the mammal being treated.
It is noted that the mouth-to-anus transit time of a non-disintegrating (e.g., tablet or multiparticulate) dosage form is approximately 24 hours. Dosage forms of this invention release at least 6%, preferably at least 70%, of their contained sertraline within 24 hour. Absorption of sertraline from the lower gastrointestinal (GI) tract, especially from the colon, is less efficient than absorption from the upper GI tract, i.e., from the small intestine, as shown in Example 3. It is accordingly therapeutically advantageous to deliver less sertraline in the lower GI tract and more sertraline in the upper GI tract. Accordingly, controlled release sertraline dosage forms according to the invention release at least 60%, preferably at least 70%, of their contained sertraline within 24 hours, preferably within 18 hours, most preferably within 16 hours.
Although dosage forms as defined above generally release at least 70% of their contained sertraline within 24 hours, a dosage form according to the invention can release substantially all of its sertraline well before 24 hours so long as it otherwise releases sertraline at a rate not exceeding 40 mgA/hr or 0.8 mgA/hr.
The term “ingestion” as used herein is essentially synonymous with “swallowing”.
The invention is particularly useful for administering relatively large amounts of sertraline to a patient. The amount of sertraline contained within the dosage form is preferably at least 10 mgA, and can be as high as 500 mgA or more. The amount contained in the d
Am Ende Mary Tanya
Curatolo William John
Friedman Hylar Lewis
Friesen Dwayne Thomas
Herbig Scott Max
Benson Gregg C.
O'Gorman Carmella A.
Pfizer Inc.
Richardson Peter C.
Spear James M.
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