Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Solid synthetic organic polymer
Reexamination Certificate
2002-04-23
2004-10-19
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Solid synthetic organic polymer
C424S464000, C424S468000, C424S472000, C424S474000
Reexamination Certificate
active
06806294
ABSTRACT:
The invention is relative to a pharmaceutical preparation, especially for oral administration, with at least one active substance and with formulation components influencing the release of active substance, which preparation comprises at least one opiod analgesic as active substance that is formulated proportionally on the one hand for rapid release and on the other hand for delayed release. The invention is especially relative to pharmaceutical preparations containing tramadol or a pharmaceutically compatible salt of tramadol, especially tramadol hydrochloride, as active substance.
So-called “multiphase” pharmaceutical preparations in which the active-substance content is formulated on the one hand for a rapid release and on the other hand for a delayed (retarded) release have long been known. Such preparations have also already been frequently described for analgesics.
EP-A 0,243,366 teaches a sustained-[controlled-]release formulation for tramadol that is suitable for a uniform and long-lasting release of the active substance over twenty-four hours or longer.
EP-A 1 0,642,788 teaches pharmaceutical preparations in tablet form containing a tramadol salt as active substance that is present in a matrix for the delayed release of active substance. Cellulose ether[s] and/or cellulose ester[s] are an essential component of this matrix and exhibit a viscosity between 300 and 150,000 mPas in a 2% by wt. aqueous solution at 20° C. It is pointed out in the specification that the tablet core, that contains the matrix containing the active substance, can be encased with additional active substance that is not delayed and is therefore rapidly released. Multi-layer tablets and laminated tablets are cited as examples.
Multiphase tramadol preparations art commercially available. The product “Tramadolor ID 100” of Hexal AG, that contains tramadol on the one hand in sustained-release formulation and on the other hand in a rapid-release formulation is an example thereof. However, the in vitro release data as well as the blood plasma level development in time correspond to a relatively slow initial flooding, so that the start of the desired analgesic action after administration of the preparation does not always take place as rapidly as would be desired.
EP-A2 0,864,325 recently disclosed another two-phase preparation containing an opiod analgesic, e.g., tramadol hydrochloride, in sustained-release and rapid release formulation. According to this publication the in vitro release rate (determined according to the paddle test described in Ph. Eur.) is extremely high; at least 50% by wt. of the active substance is released from the preparation within one hour in vitro. The examples of EP-A2 0,864,325 even correspond in part to much greater release rates: After two hours approximately 70% by wt. and after four hours approximately 90% by wt. of the active substance has been released and after six hours the release of active substance is practically concluded.
This corresponds to an extremely rapid buildup of a high plasma level of the active substance and to a correspondingly very rapidly beginning analgesic action.
However, it is indicated on the other hand in EP-A2 0,864,325 that after a one-time application under fasting conditions blood plasma levels of 90 to 200 ng/ml and in the preferred range blood plasma levels of far above 100 ng/ml were still found after five hours.
The active-substance dosage applied in a one-time manner to which this blood plasma level development corresponds is not indicated in the application. However, it can be deduced from a consideration of the magnitude [size], that such high plasma level values after five hours are only possible, in view of the extremely rapid total release of the active substance from the preparation, if the dosing of the active substance in the unit [standard] dosage is very high. The data in EP-A2 0,864,325 probably corresponds to a unit dose of 200 mg active substance. Since a twice daily application is provided, the maximum daily dose of 400 mg given in the tramadol monograph of the Federal Health Office dated 1994 is not exceeded (but is reached) at such a high amount of active substance in the unit dose; however, this also means that the patient is exposed for hours to a very high concentration of active substance in the time between the first attainment of the analgetically active concentration on the one hand and the dropping of the plasma level below the analgetically active concentration on the other hand, which very high concentration of active substance is far above that necessary for analgetic action.
On the other hand, it also follows from the data of this application that the action in the sense of a freedom from pain in the patient can not last twelve hours. The very rapid total release of the active substance also corresponds to a correspondingly short half-life W
50
. Thus, in the case of a twice-daily administration the patient is supplied with too much active substance for hours and subsequently with too little active substance for several hours.
In view of this state of the art, a significant problem of the invention is to create a pharmaceutical preparation of the initially cited type that combines the most rapid possible start of the analgetic action with the longest possible duration of action while avoiding high plasma concentrations of the active substance in the interim.
The invention has the further significant problem of creating such a preparation of the initially cited type that makes possible a uniform and sufficiently analgetic action over the entire 24-hour period at a dosage of twice to three times daily.
Further problems and advantages of the invention result from the following description.
Preparations preferred in accordance with the invention comprise as active substance at least an opiod analgesic, preferably bupivacaine, buprenorphine, clofenadol, codeine, dextromoramide, diamorphine, dihydrocodeine, dihydromorphine, ethylmorphine, fentanyl, hydrocodone, hydromorphone, levomethadone, meperidine, methadone, morphine, nalbuphine, nefopam, normethadone, oxycodone, oxymorphone, pentazocine, pethidine, phenpyramide, piritramide, propoxyphene, tebacone, tilidine, tramadol and/or their physiologically compatible salts as well as derivatives of the previously cited active substances.
The invention basically solves the problem, according to the features of the independent claims, with the formulation of the pharmaceutical preparation in such a manner that the opioid analgesic contained in the preparation, in particular a tramadol salt such as tramadol hydrochloride, is in part formulated for a rapid release and in part for a delayed release in such a manner that the in vitro release rate from the preparation according to the paddle test in accordance with Ph. Eur. shows a mean value [an average value] of more than 40% by wt. already after one hour but on the other hand 80% by wt. active substance had not yet been achieved after four hours under the same test conditions.
In a preferred embodiment of the invention more than 70% by wt. of the active substance has already been released after four hours in vitro. After seven to ten hours, and especially preferably after approximately eight hours approximately 90% by wt. of the active substance has been released in vitro. However, it is preferable if a complete release has not yet been achieved after fourteen hours, in particular not yet after sixteen hours.
In comparison to EP-A2 0,864,325, the initial course of the release up to approximately one hour is similar. The release after one hour attains 40% by wt. in every instance but must not attain the 50% by wt. prescribed in the state of the art. However, it is possible and is also preferred if the release in vitro has a mean value of approximately 50% by weight or even more according to the mentioned paddle test.
This can be achieved by appropriately adjusting the release rate. To this end, especially the type and amount of the disintegrant worked into the r
Brogmann Bianca
Hahn Udo
Spitzley Christof
Wimmer Walter
Davidson Davidson & Kappel LLC
Euro-Celtique S.A.
Fubara Blessing
Page Thurman K.
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