Patent US8895066
Medslesti.com

Medslesti.comUltracet composition

Patent US8895066


5.21.2018 | Isabella Little

7A-7C are graphs illustrating the in vivo mean plasma concentrations (+SD) of tramadol ( FIG. 7C ) following a single, two-tablet dose of Composition 2 (each tablet containing 75 mg tramadol and 650 mg of acetaminophen) under fasting conditions;. 7B ), and acetaminophen (APAP) ( FIG. 7A ), O-desmethyltramadol (M1)( FIG. FIGS.

Furthermore, when administered as a single bolus to a mammal, for example, a human, the bilayer composition can achieve (i) a therapeutically effective plasma concentration of acetaminophen starting within about half an hour after initial administration and (ii) combined therapeutically effective plasma concentrations of tramadol and acetaminophen for at least about twelve hours after initial administration.

Ultracet composition
Patent US8895066

TABLE 1 Time Acetaminophen Tramadol (hours) % release (by weight) % release (by weight) 1 30-60 ≦35 4 60-90 45-65 8 80-90 ≦90 12 ≧90 ≧90.

8A-8C are graphs illustrating the in vivo mean plasma concentrations (+SD) of tramadol ( FIG. 8C ) following either (i) a single, two-tablet dose of Composition 2 (each tablet containing 75 mg tramadol and 650 mg of acetaminophen) under fasting conditions (●) or (ii) a two, two-tablet doses of Ultracet tablets (each tablet containing 37.5 mg tramadol HCl and 325 mg acetaminophen) each dose 6 hours apart (▴), under fasting conditions;. FIGS. 8A ), O-desmethyltramadol (M1)( FIG. 8B ), and acetaminophen (APAP) ( FIG.

In particular, the formulation is designed to provide a therapeutically effective plasma concentration of acetaminophen starting about half an hour to about one hour after administration, after which the simultaneous release of both tramadol and the residual acetaminophen provide plasma concentrations of each active agent sufficient to achieve analgesic synergy and, therefore, continued effective analgesia over at least twelve hours. The invention is based, in part, upon the discovery that it is possible to produce a formulation that permits the independent release of tramadol and acetaminophen from a single dosage form over a twelve hour period of time so as to produce analgesia over the entire twelve hour period. Thus, after an initial rapid release of acetaminophen sufficient to bring about the onset of analgesia, the compositions release acetaminophen and tramadol together but at different rates such that they are both capable of achieving intestinal absorption rates and subsequent plasma levels appropriate for synergy in vivo and thereby provide analgesia over a twelve hour period of time. As far as the inventors are aware, it has not been possible to produce until now a formulation in which a single dosage form containing acetaminophen and tramadol achieves the appropriate release and uptake kinetics so as to facilitate rapid but yet sustained analgesia for twelve hours as the dosage form traverses a subject's stomach, upper gastrointestinal tract and lower gastrointestinal tract.

The bilayer composition comprises a first layer defining a rapid release portion of the composition that comprises acetaminophen. The bilayer composition, when administered to a mammal (for example, a human), releases the acetaminophen and the tramadol so that the ratio by weight of acetaminophen:tramadol in the plasma of the mammal is at least 6:1 for at least 12 hours following initial administration to the mammal. The bilayer composition comprises a second layer defining a sustained release portion of the composition that comprises acetaminophen, tramadol, and cross-linked high amylose starch. In another aspect, the invention provides a bilayer composition for the delivery of tramadol and acetaminophen.

It is contemplated that the compositions release the acetaminophen and tramadol so that both active ingredients are capable of acting synergistically with one another in vivo to provide pain relief over a twelve hour period of time. Administration of such a composition provides a rapid onset of analgesia, for example, in about half an hour to about one hour after administration, and a duration of analgesia lasting at least about twelve hours after administration. The invention provides a bilayer composition for the delivery of tramadol and acetaminophen over at least twelve hours following administration.

1 provides a schematic illustration of an exemplary formulation of the invention. Rapid release 20 comprises acetaminophen 40. 1, bilayer composition 10 comprises a rapid release layer 20 and a sustained release layer 30. In particular, as shown in FIG. It is understood, however, that for certain formulations, rapid release layer 20 may also include a certain amount of tramadol 50. FIG. Sustained release layer 30 comprises both acetaminophen 40 and tramadol 50 in a controlled release excipient, for example, cross-linked high amylose starch.

The similarity factor should be between about 50 and about 100 for bioequivalence, e.g., between the subunit forms and intact dosage forms. The fit factor f 1 represents relative error between two curves, or in other words, the mean relative difference on all measured points. The fit factor f 2 is a logarithmic transformation of the mean of squares differences between two curves. The mean relative difference for each sample point should be between about 0 to about 15% for bioequivalence. In vitro dissolution profiles of intact and separated bilayer compositions as described herein may be compared using fit factors or other mathematical comparisons. In some embodiments, compositions and/or formulations can have similarity factors between an intact dosage form and the subunits derived from the intact dosage form of at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, and at least 85. Fit factor f 1 is sometimes referred to as the difference factor. In some embodiments, compositions and/or formulations may have difference factors between an intact dosage form and subunits of the intact dosage form of less than about 15%, less than about 10%, or less than about 7%. Fit factor f 2 is sometimes referred to as the similarity factor. Such fit factors are known to those skilled in the art and are used to predict bioequivalency of different dosage forms.

7,374,781 and U.S. In general, because Acetaminophen is a low potency drug requiring large doses to be administered for effective and prolonged analgesia and because the distal regions of the gastrointestinal tract such as the colon have a small surface area for absorption as compared to the proximal small bowel, it is believed that it is difficult to administer acetaminophen in a single dosage to achieve sufficiently high plasma concentrations to achieve sustained analgesia for more than eight hours. Patent Publication No. No sustained release formulations containing both tramadol and acetaminophen, however, have been approved to date in the U.S. No. A number of sustained release formulations for the delivery of a combination of acetaminophen and tramadol have been described, for example, in U.S. or Europe. Pat. US2003/0092724 A1.

6B ), and acetaminophen (APAP) ( FIG. 6A ), O-desmethyltramadol (M1)( FIG. FIGS. 6C ) following either (i) a single, two-tablet dose of Composition 1 (each tablet containing 75 mg tramadol and 650 mg of acetaminophen) under fasting conditions (●) or (ii) a two, two-tablet doses of Ultracet tablets (each tablet containing 37.5 mg tramadol HCl and 325 mg acetaminophen) each dose 6 hours apart (▴), under fasting conditions;. 6A-6C are graphs illustrating the in vivo mean plasma concentrations (±SD) of tramadol ( FIG.

Nevertheless, there is a desire to produce sustained release formulations containing both tramadol and acetaminophen to facilitate better pain management and patient convenience and quality of life. Furthermore, it is believed that sustained release products will improve quality of life since they generally reduce fluctuations in plasma concentrations, potentially providing more consistent analgesia. This feature has the added benefit of avoiding break-through pain which may occur if a repeat dose of an immediate release product is omitted or mis-timed. It is contemplated that sustained release products will provide improved patient convenience as they would not require remembering to take, and then taking, as many doses over a twelve hour period.

The bilayer compositions of the invention, when administered to a mammal, for example, a human, as a single bolus dose can produce analgesia within about one half hour to about one hour after ingestion that lasts for at least twelve hours after ingestion. Accordingly, the compositions of the invention can be used to provide both rapid and sustained analgesic relief to a patient in need thereof.

The invention is illustrated but is not limited by the annexed drawings, in which.

apparatus Type III;. 2 is a graph illustrating the in vitro dissolution profile of an exemplary intact bilayer composition (Composition 1 of Example 1) showing the release of acetaminophen (●) or tramadol (Δ) over a 12 hour period using a U.S.P. FIG.

5B ), and acetaminophen (APAP) ( FIG. 5A-5C are graphs illustrating the in vivo mean plasma concentrations (+SD) of tramadol ( FIG. 5C ) following a single, two-tablet dose of Composition 1 (each tablet containing 75 mg tramadol and 650 mg of acetaminophen) under fasting conditions;. FIGS. 5A ), O-desmethyltramadol (M1)( FIG.

It is understood that the release kinetics can be measured on an intact bilayer tablet, for example, by deconvoluting the release profiles discussed, for example, in Example 1 or by measuring the release of labelled (for example, radiolabelled or fluorescently labelled) acetaminophen. Type III apparatus under the conditions noted above. The bilayer compositions of the invention contain a first layer defining a rapid release portion (for example, via an immediate release matrix) in which at least 50% (optionally at least 60% or 70%) by weight of the acetaminophen in the rapid release portion is released within 30 minutes when measured in a U.S.P. For example, the release kinetics can be measured from a composition that contains the same formulation as the rapid release portion and then in a separate experiment from a composition that contains the same formulation as the sustained release portion. Alternatively, the release kinetics of each layer can be measured separay. Furthermore, the bilayer compositions contain a second layer defining a sustained release portion (for example, via a controlled release matrix) in which no more than 50% (optionally no more than 40% or 30%) by weight of the acetaminophen in the sustained release portion is released within 30 minutes when measured in a U.S.P. Type III apparatus under the conditions noted above.

For example, certain compositions of the present invention may be administered in sufficient amounts to achieve sufficient plasma concentrations to produce reasonable benefit/risk ratios applicable to such treatment. The phrase “therapeutically effective amount” means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. The therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term “therapeutic effect” is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance.

In one aspect, the invention provides a bilayer composition for the release of acetaminophen and tramadol. The bilayer composition also comprises a second layer adjacent the first layer defining a sustained release portion that comprises acetaminophen and tramadol as active ingredients, and cross-linked high amylose starch as a controlled release excipient. Type III Apparatus at 20 dips per minute at 37° C. in a solution of 250 mL of potassium phosphate monobasic pH 6.8 for one hour, after which the solution is removed and replaced with a fresh 250 mL of potassium phosphate monobasic pH 6.8 for eleven hours, the acetaminophen and tramadol are released with kinetics set forth in TABLE 1. The compositions have in vitro release kinetics such that, when tested in a U.S.P. The bilayer composition comprises a first layer defining a rapid-release portion that comprises acetaminophen.

FIGS. 10B ) from Composition 2 of Example 1 using a Type III apparatus where the release kinetics of the active ingredient from the intact tablets are denoted by -*- and the release kinetics of active ingredient from half tablets created by breaking intact tablets in half are denoted by -▴. 10A-10B are graphs illustrating the release of acetaminophen ( FIG. 10A ) or tramadol ( FIG.

It is understood that in certain embodiments, the weight ratio of acetaminophen to tramadol in plasma ranges from about 200:1 within about 30 minutes to 1 hour after administration and then declines to about 6:1 to 10:1 over 12 hours. is at least 8:1, is at least 9:1, or is at least 10:1. It is understood that in certain embodiments, the weight ratio of acetaminophen to tramadol released ranges from about 25:1 when measured within about 30 minutes to 1 hour, and then falls gradually to about 8:1 over 12 hours when measured in vitro in a U.S.P. The bilayer compositions of the invention release acetaminophen and tramadol so that over a twelve hour period of time, the weight ratios of acetaminophen to tramadol released is at least 6:1, is at least 7:1. Type III apparatus. As a result, it is contemplated that the amount of acetaminophen released from the bilayer composition is sufficient for the acetaminophen and tramadol to act synergistically with one another over a prolonged period of time so that the bilayer composition can provide rapid pain relief that is believed to be sustainable over 12 hours.

For example, smaller doses may be useful for patients lighter in weight and/or for pediatric use. The ability to alter dosage on a patient by patient basis with one dosage form may also be convenient for, e.g., a physician or a pharmacist. For example, a patient may be able to divide a dosage into easier-to-swallow components while still maintaining the release properties of the dosage form. Alternatively, one dosage may be provided, but in a smaller form that may be more acceptable to a patient. Specific sustained dosages can be tailored using the dosage forms by breaking the dosage forms disclosed herein into substantially similar but smaller doses having substantially similar release profiles.

As a result, there is still a need for compositions that permit the delivery of acetaminophen and tramadol over prolonged periods of time, for example, at least about twelve hours, to facilitate pain management over that period of time.

4 is a graph showing the ratio of acetaminophen to tramadol released from Composition 1 of Example 1 (-Δ-) or Composition 2 of Example 2 (-●-) as a function of time in a U.S.P. The dashed line illustrates the ratio of acetaminophen to tramadol (about 5.7:1 based on preclinical studies), above which, the effects of the active ingredients are believed to be synergistic and, below which, the effects of the active ingredients are believed to be additive. Type III apparatus. FIG.

No. Ultracet has been used successfully in acute pain management for many years. Acetaminophen and tramadol are commonly used analgesics, and have been used alone or in combination for a number of years. Pat. RE39,221. No. Immediate release compositions have been available commercially under the tradename Ultracet, which usually are administered in adults every four to six hours. Pat. 5,336,691, which reissued as U.S. An immediate release tablet composition comprising tramadol and acetaminophen, and its use, has been described, for example, in U.S.

FIG. 1 is a schematic representation of an exemplary bilayer composition of the invention;.

In one embodiment, the first layer comprises from about 70% to about 90% w/w of acetaminophen, whereas the second layer comprises, from about 40% to about 60% w/w of acetaminophen and from about 5% to about 15% w/w of tramadol.

The invention relates generally to tramadol and acetaminophen containing compositions, and more particularly to a bilayer composition for the controlled release tramadol and acetaminophen.

3 is a graph illustrating the in vitro dissolution profile of an exemplary intact bilayer composition (Composition 2 of Example 1) showing the release of acetaminophen (●) or tramadol (Δ) over a 12 hour period using a U.S.P. FIG. apparatus Type III;.

No. 60/980,203, filed Oct. 16, 2007, the entire disclosure of which is incorporated by reference herein. Patent Application Ser. This application claims the benefit of and priority to U.S.

Dosage forms may also be divided into unequal sections, e.g., one-third/two-thirds. Dosage forms may be bisected, e.g., divided into two substantially equal pieces, or may be divided into other fractional sections, e.g., thirds or fourths. As shown in Example 5, the bilayer compositions of the invention can be broken or otherwise divided into subunits, wherein each subunit has substantially the same release properties as the intact or unbroken solid dosage form from which it was derived.

In one aspect, the bilayer composition comprises a first layer defining a rapid release portion that comprises acetaminophen. Type III Apparatus at 20 dips per minute at 37° C. in a solution of 250 mL of potassium phosphate monobasic pH 6.8 for one hour, after which the initial solution of potassium phosphate is removed and replaced with a fresh 250 mL solution of potassium phosphate monobasic pH 6.8 for another eleven hours, the acetaminophen and tramadol are released with the kinetics set forth in TABLE 1. The compositions have in vitro release kinetics such that, when tested in a U.S.P. The bilayer composition also comprises a second layer adjacent the first layer defining a sustained release portion that comprises acetaminophen and tramadol as active ingredients, and cross-linked high amylose starch as a controlled release excipient.

The bilayer composition, when administered to a mammal (for example, a human), releases the acetaminophen and the tramadol so that the ratio by weight of acetaminophen:tramadol in the plasma of the mammal is greater than 5.7:1, preferably at least 6:1 for at least 12 hours following initial administration to the mammal. In another aspect, the invention provides a bilayer composition for the delivery of tramadol and acetaminophen. The bilayer composition comprises a second layer defining a sustained release portion of the composition that comprises acetaminophen, tramadol, and cross-linked high amylose starch. The bilayer composition comprises a first layer defining a rapid release portion of the composition that comprises acetaminophen.

9 is a graph illustrating the ratio by weight of acetaminophen:tramadol in the plasma following administration of Composition 1 (-♦-) or Composition 2 (-▪-) as a function of time following administration; and. FIG.

9, the plasma concentrations of acetaminophen and tramadol are such that the weight ratio of acetaminophen:tramadol is greater than about 6:1 for at least 12 hours. For example, the compositions of the invention release acetaminophen and tramadol so that the ratio of release is in the range of about 25:1 to about 8:1. Furthermore, as discussed in Example 4 and as shown in FIG. The compositions of the invention, as discussed in Example 2 and as illustrated in FIG. It is understood that under certain conditions, the analgesic properties of acetaminophen and tramadol can be additive (for example, where the weight ratio of acetaminophen to tramadol is less than 5.7:1) whereas under certain circumstances the analgesic properties of acetaminophen and tramadol can be synergistic (for example, based on preclinical data, where the weight ratio of acetaminophen to tramadol is greater than 5.7:1). 4, release acetaminophen and tramadol over 12 hours so that they are capable of interacting synergistically with one another to provide analgesia over the twelve hour period.

Ultracet composition