Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2002-04-08
2003-05-20
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S469000, C424S468000, C424S471000, C424S472000, C424S488000, C424S489000, C424S490000
Reexamination Certificate
active
06565883
ABSTRACT:
This invention relates to a controlled release oral pharmaceutical composition and more particularly to a unit dosage that upon administration releases an active agent in a time-controlled fashion.
Controlled release formulations may be formulated with following aspects in mind:
a) the time until the release of active agent (lag time or delay time)
b) the rate of release of active agent (fast or slow)
c) the duration of release of active agent (long or short)
Such aspects may be observed in standard in vitro dissolution tests, e.g., in water or if desired in body fluids, e.g., artificial gastric juices.
Little has been published on reliable time-controlled release formulations allowing a release at a pre-determined time of a single or repeated doses of active agents. There exists a need for such formulations which are commercially acceptable.
After extensive testing, we have now found that it is possible to produce a pharmaceutical composition capable of releasing at a specific time, i.e., with a time delay or lag time, a pharmaceutical active agent or active agent mixture, e.g., substantially independently of the concentration and type of ions present in the gastrointestinal environment, e.g., hydrogen ions and hydroxyl ions, i.e., independently of pH, phosphate ions, and also independently of enzymes, present into the surrounding body fluid.
The present invention provides in one aspect a pharmaceutical composition comprising a first component comprising a first active agent dose wherein on contact with water (or body fluid) 70 to 95% of said dose is released in water within 3 to 4 hours, and a second component comprising a second active agent dose, a water soluble osmosis inducing agent and a water swellable excipient, said second component having a water (or body fluid) permeable coating which, in use upon penetration by water, ruptures after a certain delay time, e.g., due to the swelling of the swellable excipient, and releases (at a predetermined time) the active agent (hereafter referred to additionally as pharmaceutical compositions of the present invention).
The present invention also provides a pharmaceutical composition comprising
a first component comprising an active agent wherein 70 to 95% of said active agent in first component is released in water within 3 to 4 hours, and
a second component comprising the active agent, a water soluble osmosis inducing agent and a swellable excipient in water, said second component having a coating which, upon penetration by the aqueous fluids, breaks after a certain period due to the swelling of the swellable excipient, and releases the active agent at a pre-determined time.
By “within 3 to 4” hours is meant that at the end of a period of 3 to 4 hours the specified dose of active agent, e.g., >80% or >85%, has been released.
The active agent may be a single active agent or may be a mixture. The active agent may be the same in the first and second doses or different in each dose. Preferably the active agent is the same.
In one embodiment, the coating for the second component is a film, e.g., semi-permeable membrane. The swellable excipient swells in presence of water or body fluid which penetrates through the coating and creates mechanical pressure within the second component thereby causing the coating to rupture or break and the system to open, e.g., like a lid of a box. Also, the swellable excipient may act as an osmotic agent drawing the water into the second component. The thickness of the coating is one of the parameters that controls the time delay, with more coating resulting in a longer time delay.
It will be appreciated that the term “rupture” preferably refers to breaching but it may also refer to any film system which rapidly (e.g. over 30 minutes or less) dissolves or disappears or changes its properties to permit egress of the active agent.
In another aspect there is provided a controlled release formulation, e.g., the second component, for releasing an active agent dose after a lag time wherein the active agent is released 6 to 12 hours, e.g., 8 hours, after ingestion.
The second component may be coated with two films. A first film is directly in contact with the second component and is preferably a semi-permeable membrane. The second film may be a semi-permeable (e.g., allowing the passage of e.g. water or active agent in one direction) or permeable. The films used in this embodiment may be, e.g., 2 to 5 times, thinner than the one used in a one-film embodiment. Such a composition may provide if desired longer delay times for the second component with a good release of the second dose of active agent. It further provides certain advantages as, e.g., reducing the amount of coating used.
By “first component” is meant a component capable of releasing immediately or in a controlled manner, e.g., sustained release, a first therapeutically effective dose of active agent when said first component is put in contact with water or body fluids.
By “second component” is meant a component capable of releasing immediately or in a controlled manner, e.g., sustained release, a second therapeutically effective dose of active agent when said second component is contacted to water or body fluids.
By “semi-permeable membrane” is meant a membrane suitable for the passage of the water (or body fluid) into an active agent containing core which is coated with said membrane and hinders egress of a dissolved active agent out of the core.
By “film”, “film-coating” or “membrane” is meant, unless stated otherwise, a coating which is applied onto a core component, e.g., the first or second component.
By “delay time or lag time” is meant the duration of time between administration of the composition and the release of an effective dose of active agent from the first or second component.
A person skilled in art will appreciate that various plasma profiles may be obtained by varying, e.g.:
the composition of the first and/or second components, e.g., the nature and amount of excipients and/or active agent(s)
the delay time
the type of semi-permeable and/or non semi permeable membrane
the speed and nature of the active agent release onset (e.g. fast, slow, exponential, logarithmic, linear), which may depend on the rate of rupture of the membrane.
The composition according to the invention may be used for administrating a wide variety of active agents.
The composition according to the invention is suitable for example for water-soluble and also water-insoluble, solid, pharmaceutical active ingredients, which may be inorganic or in particular organic active substances, and are to be used in accordance with their indication as analgesics, antipyretics, antirheumatics, sedatives, hypnotic agents, anti-epileptics, depressants and stimulants, anaesthetics, neuroleptic analgesics, antihistamines, antihypertensive agents, anticoagulants, antithrombotic agents, psychopharmacological agents, psycholeptics, chemotherapeutic agents, e.g. antibiotics, sulphonamides, antituberculosis agents (tuberculostatic agents) or also chemotherapeutic agents against tropical infections, diuretics, spasmolytics, cardiovascular agents, e.g. sympathomimetics, antihypertensive agents, cardiac stimulants, e.g. cardiac glycosides and digitaloids, parenteral sugar therapeutics, analeptics acting on the central nervous system, geriatric agents, tonolytics (of striated muscles), anti-Parkinson agents, cytostatic agents, immunosuppressants, tonics and vitamins, according to B. Helwig (Moderne Arzneimittel), 1980.
As antibiotics, penicillin, tetracycline, chlorotetracycline, bacitracin, nystatin, streptomycin, neomycin, polymicin, gramicidin, oxytetracyclin, chloramphenicol, erythromycin, rifampicin, cefazolin, cefoxitin, cefsulodin, cefotiam and mefoxin may be used, and as chemo-therapeutic agents sulfamethazine, sulfamerazine, sulfamethizole and sulfisoxazole may be used, as solid active ingredients for the presentation according to the invention. In addition, e.g. as sedatives and hypnotic agents chloral hydrate, pentabarbital, phenobarnital, secobarbital, codeine and carbr
Kalb Oskar
Khanna Satish Chandra
Ogorka Jörg
Shah Rajen
Borovian Joseph J.
Novartis AG
Page Thurman K.
Tran S.
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