HK1163525A - Extended release oral acetaminophen/tramadol dosage form - Google Patents

Description

Acetaminophen/tramadol oral extended release dosage form

Technical Field

The present invention relates to delayed drug release. In particular, the present invention relates to extended release dosage forms of acetaminophen and tramadol combinations.

Background

Chronic pain (such as low back pain and osteoarthritis breakthrough pain) is a major health problem that causes severe pain to patients, significant loss of economic productivity, and greatly increases direct and indirect costs throughout society. It is estimated that approximately 60% to 80% of adults in the united states sometimes suffer chronic low back pain during their lifetime. Currently, chronic pain is receiving increasing attention as the population ages in many countries. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of chronic pain, but have limited efficacy. In addition, NSAIDs are often associated with significant health risks, including gastrointestinal damage, ulceration, bleeding, and even death. Therefore, there is a need to improve the medical effects of these chronic pains.

Tramadol (2- (dimethylaminomethyl) -1- (3-methoxyphenyl) -cyclohex-1-ol, C₁₆H₂₅NO₂) Is a centrally acting analgesic, while the NSAID is a peripherally acting analgesic. The mode of action of tramadol is not fully understood, but a dual mechanism is proposed based on in vivo results: the parent molecule and its metabolites bind to mu-type opioid receptors and have weak inhibitory effects on norepinephrine and serotonin reuptake. Acetaminophen (N- (4-hydroxyphenyl) acetamide, C₈H₉NO₂) (or "APAP"), such as the well-known TYLENOL brand, has been the first analgesic for many years to treat chronic pain. Although the mechanism of action of APAP is not yet understood, it appears to be centrally mediated, involving selective inhibition of prostaglandin synthesis in the central nervous system, inhibition of N-methyl-D-aspartate or substance P mediated nitric oxide synthesis, and inhibition of prostaglandin E2 release in the spinal cord.

Tramadol and APAP have been administered in combination. Us patent RE39221 describes that the combination employs less of both tramadol material and APAP than either of tramadol material and APAP alone necessary to achieve the same analgesic effect. The patented oral immediate release dosage form of tramadol/APAP (37.5/325mg) combination (ULTRACET) was developed by Ortho-McNeil Pharmaceutical and has been approved by the FDA for acute pain treatment in 2001. The product does not exhibit the side effects associated with the use of NSAIDs, such as gastrointestinal ulcers or bleeding. In addition, clinical trials have demonstrated a synergistic potentiation of this combination which provides a longer duration of action than APAP and a faster onset of action than tramadol. ULTRACET must be administered every 4 to 6 hours.

Acetaminophen (or APAP herein) (molecular weight 151.163g/mol) and tramadol (which may be referred to herein as TRD) (molecular weight 263.375g/mol) are weak bases with pKa values of 9.38 and 9.41, respectively. APAP has a water solubility of about 14mg/ml, while tramadol hydrochloride is optionally soluble in water. After oral administration, APAP and tramadol hydrochloride are rapidly absorbed and significant first-pass metabolism of both drugs occurs. Although the absorption of APAP after administration of a pharmaceutical dosage form is mainly in the small intestine, it also appears to have good colonic absorption. Delayed release (ER) oral dosage form of APAP (TYLENOL)ER, manufactured by McNeil Consumer Healthcare) was marketed in 1995. The bilayer matrix tablet consisted of 325mg of APAP in the immediate release layer and an additional 325mg of APAP in the delayed release layer. The delayed release of APAP is achieved by controlling the diffusion of the drug in the hydrophilic polymer backbone.

Existing extended release dosage forms for tramadol, tramadol hydrochloride, ULTRAMCONTRAMD of ER and tramadol hydrochlorideThe bioavailability of OAD means that it has acceptable absorption in the lower gastrointestinal tract. Both products are effective in controlling pain over 24 hours in a convenient form for once a day administration. ULTRAMER products having a polymeric structure formed by semi-permeable polymerizationA core coated with a mixture of a substance and a water-soluble penetration enhancer. The graduated release of tramadol hydrochloride from the tablets is achieved by controlling the coating film. CONTRAMIDOAD is a press coated matrix tablet. The core matrix is a cross-linked high amylose starch which provides sustained release, while the compression coating imparts a relatively fast release profile.

However, the development of APAP/tramadol hydrochloride multi-combination extended release dosage forms has presented technical challenges, either with TYLENOLHydrophilic polymer backbone approach for ER, either ULTRAMER and CONTRAMIDTablet coating methods for OAD. For highly water-soluble drugs like tramadol hydrochloride, undesirable drug breakage due to rapid diffusion of the dissolved drug through the hydrophilic gel network is often observed with hydrophilic matrix systems. In addition, the great difference in water solubility of the two drugs makes it impractical to provide a delayed release with a coating to achieve simultaneous release of both APAP and tramadol hydrochloride. Attempts have been made to provide extended release of APAP and tramadol, such as WO2004026308 and U.S. patent publication US 20040131671. However, good synergistic release is difficult to achieve. What is needed is an extended release dosage form of both tramadol and APAP that achieves a simultaneous (or synergistic) release of both drugs over a longer period of time, wherein the cumulative release weight percentages of the two drugs do not differ significantly. All references, patents, and patent publications cited herein are hereby incorporated by reference in their entirety.

Disclosure of Invention

The present invention provides methods and dosage forms that provide for extended administration of APAP and tramadol. In the dosage form of the present invention, the drug/polymer ionic interaction between tramadol and the anionic polymer causes slow release of tramadol, resulting in a synergistic release of APAP and tramadol.

In one aspect, the present invention provides a pharmaceutical composition comprising APAP and a complex tramadol material that exhibits synergistic sustained release upon oral dissolution in a patient, resulting in synergistic tramadol and APAP cumulative release over time. The composition may be a tablet or a part of a tablet that slowly disintegrates while in the gastrointestinal tract and releases tramadol and APAP in a synergistic release pattern. Preferably, the composition comprises a complex tramadol material, and the complexing is preferably accomplished using carrageenan. Tramadol is preferably a tramadol salt, more preferably a hydrochloric acid (HCl) salt thereof.

In another aspect, the composition comprising the complex tramadol material and APAP is such that the period of sustained release is from 4 hours to 12 hours, especially from more than 6 hours to 12 hours, over the entire period of sustained administration, whereby the dosage form is designed for both tramadol and APAP. It is noted that when a drug is approved by a regulatory agency (e.g., the USFDA) for treatment of a patient, the dosage form is approved for periodic administration at periodic intervals. Thus, dosage form patent applications and approvals should dictate the dosage period for which the dosage form is designed.

In one aspect, the present invention provides a method of preparing a dosage form of a pharmaceutical composition, wherein the method comprises the steps of forming a tramadol material complex and forming a compressed form (compacted form) comprising the tramadol material complex and APAP. The compressed tablet form exhibits a synergistic sustained release when orally administered to a patient, resulting in a synergistic tramadol and APAP cumulative release over time. The composition may be a tablet or a portion of a tablet, such as a layer, that provides sustained, synergistic Extended Release (ER) of tramadol and APAP. In one aspect, the dosage form may be a bilayer tablet, wherein two layers are affixed together in a stacked manner: one is an Extended Release (ER) layer containing a complex of APAP and tramadol and the other is a quick release (IR) layer containing APAP and uncomplexed tramadol. In another aspect, the dosage form may contain an ER material comprising a complex of APAP and tramadol surrounded on four sides by an IR layer comprising APAP and non-complex tramadol or sandwiched between two IR layers.

In one aspect, the invention provides the use of a composite tramadol material for the preparation of a medicament for the treatment of pain, and a method of treating pain with the medicament. The medicament comprises a complex tramadol material and APAP, which upon oral dissolution by a patient exhibits a synergistic sustained release of tramadol and APAP, resulting in a synergistic cumulative release of tramadol and APAP over time.

We have found that certain anionic polymers, particularly carrageenan, can reduce drug solubility and diffusivity or solubility, resulting in sustained release of tramadol. Thus, the combination of APAP and the tramadol complex with carrageenan resulted in sustained release of tramadol that closely matched the APAP release profile in terms of cumulative percent release of drug. The synergistic administration of both drugs over an extended period of time has significant advantages over previously available dosage forms which often require frequent dosing and cause large fluctuations in blood levels of APAP and tramadol. The release of a drug in an extended release formulation depends on the controlled release of two different drugs, one of which is usually released more rapidly than the other if not controlled. It is surprising that a drug that releases rapidly may be delayed in its release to match the release of a drug that releases relatively slowly. It is therefore surprising that the use of selected anionic complexing polymers (especially carrageenan) enables us to achieve a very matched delayed release of APAP and tramadol. We have found that the complex can modify the release kinetics, changing it from Fickian diffusion (n is about 0.45 in Korsmeyer's equation) to closer to zero order release (n is close to 1 in Korsmeyer's equation), while also reducing the release rate. Thus, complexing tramadol with carrageenan (especially lambda carrageenan) will reduce the release rate gap between tramadol and APAP, thereby synchronizing their release rates. The formulation may preferably contain two other excipients, PEO and HPMC K4M, which together with the complexing agent carrageenan act as a sustained release agent. Without PEO, the composite mixture is more difficult to tablet due to lamination and/or capping, and it is difficult to achieve the proper hardness when compressed into tablets. In addition, even though the drug is synchronized with the carrageenan complexing effect, the PEO-free compressed ER tablets show less zero order kinetics in dissolution than the PEO-containing compressed ER tablets. Thus, PEO helps to obtain near zero order release kinetics for APAP and tramadol, and also helps to obtain better compressibility and manufacturability. HPMC K4M was also found to help increase the compressibility of the tablet and improve the sustained release of both APAP and tramadol.

Drawings

Figure 1A shows a partial cross-sectional view of an APAP and tramadol bi-layer tablet dosage form according to the invention.

Figure 1B shows a cross-sectional view of another embodiment of an APAP and tramadol tablet dosage form according to the invention in which the ER layer is surrounded by an IR layer.

Figure 1C shows a cross-sectional view of another embodiment of an APAP and tramadol tablet dosage form according to the invention in which an ER layer is sandwiched between layers of IR material.

Figure 2 shows the release profile of the APAP/tramadol combination in a matrix in which tramadol is complexed and non-complexed.

Fig. 3, 4 and 5 show the release profiles of formulations C, D and E, respectively, with different amounts of hydroxypropylmethylcellulose K4M (HPMC K4M).

FIG. 6 shows T of APAP₈₀And tramadol duration ratio to show the effect of HPMC.

Figures 7a and 7b show the release profiles of tramadol and APAP in compositions F and G, respectively, showing the effect of complexes with and without tramadol and carrageenan.

FIG. 8 is a graph of the release profile of APAP from 4 formulations (F-No.2 to F-No.5) with fillers such as lactose, AEROSIL and polyethylene oxide.

FIG. 9 is a graph of the release profile of tramadol hydrochloride from the 4 formulations of FIG. 8 (F-Nos. 2 through 5) having fillers such as lactose, AEROSIL, and polyethylene oxide.

FIG. 10 is a graph of APAP release profiles from the 4 formulations of FIG. 8 (F-No.2 through F-No.5) with fillers such as lactose, AEROSIL and polyethylene oxide, and assumed to be a bilayer dosage form of IR and ER.

FIG. 11 is a graph of the release profile of tramadol hydrochloride from the 4 formulations of FIG. 8 (F-Nos. 2 to 5) having fillers such as lactose, AEROSIL and polyethylene oxide, and assuming a bilayer dosage form of IR and ER.

FIG. 12 is a graph showing the release profile of APAP and tramadol hydrochloride from formulation F-No. 6.

FIG. 13 is a graph of the release profile of APAP and tramadol hydrochloride from formulation F-No.6, and is assumed to be a bi-layer dosage form of IR and ER.

FIG. 14 is a graph of the release profile of APAP from formulation F-No.7 and formulation F-No. 8.

FIG. 15 is a graph of the release profile of tramadol hydrochloride from formulation F-No.7 and formulation F-No. 8.

FIG. 16 is a graph of APAP release from formulations F-No.7 and F-No.8, and assumes a bi-layer dosage form of IR and ER.

FIG. 17 is a graph of the release profile of tramadol hydrochloride from formulation F-No.7 and formulation F-No.8, and is assumed to be a bilayer dosage form of IR and ER.

FIG. 18 is a graph of the release profiles of APAP from formulation F-No.7, formulation F-No.9, and formulation F-No. 10.

FIG. 19 is a graph of the release profiles of tramadol hydrochloride from formulation F-No.7, formulation F-No.9, and formulation F-No. 10.

FIG. 20 is a graph of the release profiles of APAP from formulation F-No.7, formulation F-No.9, and formulation F-No.10, and assumes a bilayer dosage form of IR and ER.

FIG. 21 is a graph of the release profiles of tramadol hydrochloride from formulation F-No.7, formulation F-No.9 and formulation F-No.10, and assumes a bilayer dosage form of IR and ER.

FIG. 22 is a graph of the release profiles of APAP from formulation F-No.10, formulation F-No.11, and formulation F-No. 12.

FIG. 23 is a graph of the release profiles of tramadol hydrochloride from formulation F-No.10, formulation F-No.11, and formulation F-No. 12.

FIG. 24 is a graph of the release profiles of APAP from formulation F-No.10, formulation F-No.11, and formulation F-No.12, and assumes a bilayer dosage form of IR and ER.

FIG. 25 is a graph of the release profiles of tramadol hydrochloride from formulation F-No.10, formulation F-No.11, and formulation F-No.12, and assumes a bilayer dosage form of IR and ER.

FIG. 26 is a graph of the release of APAP from formulation F-No.10 in buffer and distilled water at various pH's.

FIG. 27 is a graph of the release profile of tramadol hydrochloride from formulation F-No.10 in buffer and distilled water at different pH.

FIG. 28 is a graph of APAP release from formulation F-No.10 in buffer and distilled water at various pH's and is assumed to be a bilayer dosage form of IR and ER.

FIG. 29 is a graph of the release profile of tramadol hydrochloride from formulation F-No.10 in buffer and distilled water at various pH's and assuming a bi-layer dosage form of IR and ER.

FIG. 30 is a graph of the release profile of APAP from formulation F-No.7 when dissolved with agitation at different speeds (rpm).

FIG. 31 is a graph of the release profile of tramadol hydrochloride from formulation F-No.7 when dissolved with agitation at different speeds (rpm).

FIG. 32 is a graph of the release of APAP from formulation F-No.7 when dissolved with agitation at different speeds (rpm) and assuming a bi-layer dosage form of IR and ER.

FIG. 33 is a graph of the release profile of tramadol hydrochloride from formulation F-No.7 when dissolved with agitation at different speeds (rpm) and assuming a bi-layer dosage form of IR and ER.

FIG. 34 shows the dissolution profiles of (a) APAP and (b) tramadol hydrochloride in F-No.13 in buffer at pH 1.2 for the first 2 hours and pH 6.8 for hours 2 to 12, and stirred at 50 rpm.

FIG. 35 shows a flow chart of a manufacturing process for making an embodiment of the bilayer tablet of F-No. 13.

Figure 36 shows a partial graphical representation of mean plasma concentration-time curves for tramadol following multiple oral administrations of ULTRACET tablets and ER tablets of the invention.

Figure 37 shows a partial graphical representation of the mean plasma APAP concentration-time curve after multiple oral administrations of ULTRACET tablets and ER tablets of the invention.

Detailed Description

The invention relates to a dosage form which can realize the synergistic delivery of APAP and tramadol by oral administration to a patient. More particularly, the present invention relates to dosage forms that achieve synergistic delivery of APAP and tramadol by administration to a patient via the gastrointestinal tract over an extended period of administration, wherein the dosage form disintegrates during administration and the drug is gradually released over a longer period of time.

In describing the present invention, the following terms will be employed and are intended to be defined in the following specification. As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

As used herein, unless the context dictates otherwise, the term "tramadol" may refer to tramadol bases, tramadol salts, or tramadol derivatives that have the cationic character of being complexed with carrageenan through ionic interactions. The amounts of tramadol referred to herein refer to tramadol hydrochloride equivalents.

"bioactive agent" is to be understood in its broadest sense as any material intended to produce some biological, beneficial, therapeutic or other desired effect, such as penetration enhancement, pain relief and contraception. As used herein, the term "drug" refers to any material that is intended to produce some biological, beneficial, therapeutic, or other desired effect.

Fig. 1A is a schematic cross-sectional artistic reproduction of a bilayer tablet (i.e., a tablet having two layers). In a bilayer tablet, the two layers may be in direct intimate contact, such as with one layer on top of the other. In an embodiment, tablet 20 includes an Extended Release (ER) layer 24 (containing tramadol complex particles 28) joined to an Immediate Release (IR) layer 22 next to it. The dosage form has only two layers containing the Active Pharmaceutical Ingredients (API) (APAP and tramadol). In another embodiment, the structure shown in FIG. 1A may be a portion of the entire cross-section of the form shown in FIG. 1B. The form may be in the form of a conventional pill, an elongated tablet, a sphere, a cucumber, etc., and the word "tablet" is referred to herein as a "tablet" for convenience, unless the word "tablet" is otherwise specified to have a special meaning. In the form shown in fig. 1B, tablet 30 includes an Extended Release (ER) layer 24 (containing tramadol complex particles 28) surrounded by an Immediate Release (IR) layer 22. Thus, the ER material may be a core (preferably in the form of a layer or tablet) surrounded by an IR layer. Alternatively, the tablet may have an ER layer sandwiched between two IR layers, such as tablet 40 shown in FIG. 1C. Any form of tablet additionally includes an outer coating (or coating, but not shown in fig. 1A-1C). The outer coating may surround the IR layer 22 and any ER material not surrounded by the IR layer.

In one aspect, the dosage form of the present invention comprises a solid tableted form that slowly releases APAP and tramadol in a delayed release manner over a period of time. For example, the solid compressed tablet dosage form may be a bilayer tablet having one layer or a core surrounded by a fast-release (or immediate release) outer layer. Typically, the solid tableted form includes a composite tramadol material that slowly releases the active portion of tramadol into the gastrointestinal tract and is absorbed. Complexes of Carrageenan with alkaline Drugs were formed in Aguzzi et al, "influx of Complex solubility on Formulations based on Lambda Carrageenan and Basic Drugs", AAPS PharmSciTech 2002; 3(3) Article 27(Aguzzi et al, journal of the society of pharmaceutical science and technology of the American society of pharmaceutical scientists, 2002, 3 rd No. 27 Article "Effect of Complex solubility on formulations based on lambda carrageenan and basic drugs".

The composite tramadol material includes a tramadol material that may be tramadol base or a salt or ester thereof. The tramadol material is any one of (1R, 2R or 1S, 2S) - (dimethylaminomethyl) -1- (3-methoxyphenyl) -cyclohexanol (tramadol), an N-oxide derivative thereof ("tramadol N-oxide"), and an O-demethyl derivative thereof ("O-demethyltramadol"), or a mixture thereof. It also includes individual stereoisomers, mixtures of stereoisomers, including racemic mixtures, pharmaceutically acceptable salts of amines (such as hydrochloride, citrate, acetate), solvates and polymorphs of tramadol material. Tramadol is commercially available from Grunenthal. Methods of preparing tramadol are known in the art, as described in U.S. Pat. No.3,652,589 and RE39221, both incorporated herein by reference. O-desmethyltramadol is prepared by treating tramadol as the free base under O-desmethyl reaction conditions, such as by reacting it with a strong base (such as NaOH or KOH), thiophenol, and diethylene glycol (DEG) under heating to reflux conditions. See Wildes et al, j. org. chem., 36, 721(1971) (Wildes et al, journal of organic chemistry, 1971, volume 36, page 721). Tramadol hydrochloride is preferred as the tramadol material for complexing with anionic polymers. It is envisaged that the use of tramadol base or a different salt associated with tramadol (such as a different halide salt of tramadol etc.) will not have a significant effect on the complex formation of tramadol with carrageenan and thus will not result in a significant difference in the release rate of the resulting ER tablet. Thus, one skilled in the art can adjust the formulation without undue experimentation in light of the description herein.

The composite polymer is water-soluble, gel-forming and anionic; they contain side chain groups such as sulfate, carboxylate, phosphate or other negatively charged groups to interact with the cationic drug. Preferably, the complexed polymer is a polysaccharide-based material containing pendant anionic groups (in other words, an anionic polysaccharide, especially a sulfated polysaccharide). Particularly preferred is carrageenan. Carrageenans are sulfated polysaccharides extracted from seaweed. In general, carrageenan types include k, iota and lambda, all of which can form gels with water at room temperature. Different types of carrageenan can form gels of different softness or toughness. The complexation of lambda carrageenan with a basic drug has been described in Aguzzi et al (AAPS PharmSciTech 2002; 3(3) Article 27) (Aguzzi et al, J. am. pharmaceutical science and technology, 2002, Vol. 3, No.3, paper 27), which is incorporated herein by reference.

The composite polymer is biocompatible and nontoxic. Their molecular weight is sufficiently high that gels can be prepared with the active agent. While not wishing to be bound by a particular theory, it is believed that the cationic drug interacts with the anionic side chain groups of the anionic polymer and causes electrostatic interactions between the polymer strands, resulting in the polymer strands being arranged in a manner that slows the permeation of tramadol into polar solvents such as water. Typically, lambda carrageenan has a molecular weight between 100,000 daltons and 500,000 daltons. Lambda carrageenan is commercially available in two categories, based on viscosity. A VISCARIN is obtained from FMCGP 109 (Low viscosity at 37 ℃ for 20 s)^-1Has a viscosity of about 760 centipoise measured at a shear rate of (a), and another is a VISCARINGP209 (high density at 37 ℃ for 20 s)^-1A viscosity of about 1600 centipoise measured at a shear rate of (d).In this study, it has been found that VISCRINThe GP 109 is more effective. Preferred grades of carrageenan are low molecular weight lambda carrageenan. Other carrageenans, such as k-carrageenan, may also be used. Lambda carrageenan is characterized by the highest number of sulfate groups compared to similar kappa and iota carrageenans. Lambda carrageenan has been shown to interact strongly with very soluble drugs and has been shown to interact well with tramadol. The table below shows the effectiveness of carrageenan as a complexing agent for tramadol in delaying the release of tramadol.

Table 1: complexing with lambda carrageenan to reduce the release duration difference (T) ₈₀ Ratio)

As shown in Table 1 above, the T of lambda carrageenan₈₀The ratio is the minimum (1.4). T is₈₀Meaning the time when the cumulative dissolution of APAP (similarly tramadol if the drug is tramadol) reaches 80%. T is₈₀Ratio means T of APAP₈₀T of tramadol₈₀. T in lambda carrageenan formulations₈₀A minimum ratio (1.4) means that the difference in dissolution time between the two Active Pharmaceutical Ingredients (APIs) (i.e. drugs) in the formulation is most effectively shortened. For comparison, T₈₀The ratio was 2.0 for the k-carrageenan containing formulation, 2.2 for the Ethylcellulose (EC) containing formulation and 2.4 for the non-complex formulation. Therefore, ethylcellulose can also act as a release retardant, but it is not as effective as carrageenan. The diffusion index n of lambda carrageenan (as described below) also shows a characteristic closer to zero order.

Other anionic materials that may be used to complex with tramadol include alginic acid, carboxymethyl cellulose, and the like. However, such other anionic materials have a weaker complexing force than carrageenan. Other sulfated or sulfonated polysaccharides or polymers, including dextran sulfate or strong cation exchange resins (AMBERLITE IRP69), may be anionic materials for complexing with tramadol.

The weight ratio of tramadol material to anionic polymeric material (such as carrageenan) in forming the tramadol complex is generally in the range of about 1: 0.1 to about 1: 100, preferably in the range of about 1: 0.5 to about 1: 10.

In compressed solid dosage forms, the APAP and tramadol materials are typically present in the following weight ratios: the weight ratio of APAP to tramadol material is from about 20: 1 to 1: 1, preferably from about 5: 1 to 10: 1, even more preferably from about 6: 1 to 9: 1. Additionally, in the Immediate Release (IR) layer, the APAP and tramadol materials are typically present in the following weight ratios: the weight ratio of APAP to tramadol material is from about 20: 1 to 1: 1, preferably from about 5: 1 to 18: 1, more preferably from about 10: 1 to 16: 1. We have found that when the ratio of APAP to tramadol is within the above range, a synergistic delivery of the two drugs at very close wt% cumulative release rates in a single tablet can be obtained, resulting in a cumulative release of significantly more than 30 wt% from sustained over the first hour of administration to prolonged delivery over about 12 hours.

The IR layer useful for attachment to the ER material may comprise APAP, tramadol and excipients such as disintegrants, binders and fillers. Materials such as magnesium stearate, powdered cellulose, corn starch, gelatinized starch, sodium starch, and the like may be used. Readily soluble binders (such as gelatinized starches, polyvinylpyrrolidones, gums, and the like) help to temporarily hold the various ingredients together until the formulation enters an aqueous environment. Such a binder will dissolve rapidly and hold the IR layers apart, thereby releasing the drug. Disintegrants (such as sodium starch glycolate, powdered cellulose, fibrous cellulose and powdered silicon dioxide) help the layers to space quickly and make the binder dissolve more uniformly. Lubricants such as magnesium stearate, sodium stearyl fumarate may also be used.

With consideration of the ER layer and without consideration of its immediate IR layer, it is possible to achieve a release such that when the cumulative release of tramadol is 40 wt%, the cumulative release of APAP is less than 25 wt%, unlike the cumulative release of tramadol. It is also possible to achieve a release such that in the sustained release process, starting from a cumulative release of tramadol of 40 wt%, the cumulative release wt% of APAP is never greater than 20 wt%, different from the cumulative release wt% of tramadol. It is also possible to achieve such a release that when the cumulative release (in wt.%) of tramadol is 40 wt.%, the cumulative release (in wt.%) of APAP is never greater than 10 wt.%, unlike the cumulative release (in wt.%) of tramadol. It is also possible to achieve a sustained release during the sustained release process that the wt% cumulative release of APAP after the first hour of sustained release for at least 12 hours is never greater than 10 wt% other than the wt% cumulative release of tramadol. The cumulative release of the sustained release can be determined according to the usp apparatus ii (usp ii) slurry method under the following conditions: in vitro experiments, 37 ℃, 50rpm/900ml, dissolved in buffer solution at pH 6.8 (standard USP simulated intestinal fluid, but no enzyme).

A part of a tablet according to the invention, such as one of the bilayer tablet layers, is preferably prepared by tabletting particles, wherein the particles or granules comprise the active pharmaceutical ingredient and other excipients, if present. The delayed release layer material is first compressed into a dense unit, then coated with an immediate release layer, etc., such as shown in fig. 1A. The average particle size of these particles is preferably about 30 μ to 3000 μ, more preferably about 100 μ to 1000 μ, and most preferably about 150 μ to 400 μ. The term "particle size" generally refers to the larger size of a particle when the particle is not spherical.

Preferably, the tramadol complex has a particle size of about 30 to 3000 μ, more preferably about 100 to 900 μ, and most preferably about 150 to 300 μ.

The extended release layer or core may comprise various water insoluble materials as excipients. Examples of such water insoluble materials include polymers which may be hydrophobic polymers. Examples of useful water-insoluble materials include, but are not limited to, one or more of ethyl cellulose, butyl cellulose, cellulose acetate, cellulose propionate, and the like.

The ER layer or core may be prepared by combining the active pharmaceutical ingredient and at least one agent capable of limiting the release of the active ingredient, and other ingredients. For example, the ER layer or core may comprise a variety of excipients including diluents, glidants, binders, granulating solvents, granulating agents, anti-aggregating agents, buffers, lubricants. For example, the optional diluent may include one or more of sugars (such as sucrose, lactose, mannitol, glucose, starch, microcrystalline cellulose, sorbitol, maltodextrin), calcium and sodium salts (such as calcium phosphate, calcium sulfate, sodium sulfate or similar anhydrous sulfates, calcium lactate), other lactose materials (such as anhydrous lactose and lactose monohydrate). One preferred diluent is lactose.

A binder may be used to bind materials together, such as the materials in the ER material. Suitable binders may include one or more of the following exemplary materials: polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, sucrose, sorbitol, hydroxyethylcellulose, Hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, polyethylene glycol, gum arabic, gelatin, agar, polyethylene oxide (PEO), and the like. HPMC is preferred for use in formulations as it tends to help prolong the release time. HPMC E5 has a molecular weight much lower than HPMCK4M and acts as a binder. The viscosity of the 2% solution used for HPMC E5 was about 5 centipoise, while the viscosity of the 2% solution used for HPMC K4M was about 4000 centipoise. Due to the difference in viscosity, HPMC E5 is preferred as a binder for Immediate Release (IR) granulation, while HPMC K4M is preferred for extended release formulations. Another preferred material is polyethylene oxide. During drug release of the formulation, first, water penetrates into the polymer; relaxation of the polymer chains then occurs in response to water penetration. Thus, when the material swells, the drug molecules diffuse through the polymer. Binders like HPMC and PEO also have the property of forming a gel that prevents liquid penetration of the drug, such that release of the drug from the formulation is retarded. HPMC and PEO are useful in extended release formulations due to their high molecular weight and viscosity.

Lubricants and anti-aggregants include, but are not limited to, one or more of talc, magnesium stearate, calcium stearate, colloidal silicon dioxide, stearic acid, waxes, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and DL-leucine. Useful lubricants are silica materials, such as AEROSIL, which is a commercially available colloidal silica, i.e., a sub-microstructured fumed silica having a particle size of about 15 nm.

Optionally, one or more outer coatings may be applied to the tablet to protect it during packaging, handling and aid in swallowing. Such outer coatings preferably break rapidly to enable the immediate release layer to rapidly release the active ingredient therein. The coating may comprise one or more tablet coating materials. Suitable coating materials include gelatin, sugars (e.g. monosaccharides, disaccharides, polysaccharides (such as starch), cellulose derivatives). Other useful coating materials include polyols such as xylitol, mannitol, sorbitol, polyalkylene glycols, and the like. Such coating materials and methods of use thereof are known to those skilled in the art. Examples of useful coating materials are SURELEAE and OPADRY (both available from Colorcon (West Point, Pa., USA)). Apparatus and methods for tablet coating are well known in the art of tablet preparation. Waxy materials such as carnauba wax may also optionally be used as a surface polish to provide a more shiny surface.

The process for preparing the tablets of the present invention employs conventional techniques in forming the tablets. In one aspect, the extended release layer is formed of an extended release material and then covered with an immediate release layer, and optionally covered with one or more outer coatings. The ER material may also be the core of the tablet. ER materials can be formed by pressing the component particles together into a compact form. Preferably, the hardness of the compact form embodiment of the present invention is about 4KP/cm²To 20KP/cm². In addition, canThe granulated or granulated form of the ingredient is formed by granulation with one or more suitable techniques, which may include granulation in the following different kinds of granulators: low shear granulators, fluid bed granulators, high shear granulators, and the like.

The tablets of the invention may be prepared by any means known in the art. Conventional methods for tablet production include direct compression ("dry blending"), compression after dry granulation, and drying and compression after wet granulation.

Preferably, the tablet or layer of the tablet is formed by a direct compression method involving direct compression of a blend of the active ingredients. For example, the powder blend is filled into the die cavity of a tablet press (such as a rotary tablet press) after blending, thereby compressing the material into tablet form. As used herein, a tablet may be of a conventional elongated shape with a rounded rectangular cross-section, a spherical shape, a disc pellet, and the like. The material is compressed into a tablet shape having a hardness preferably between about 2KP and 6KP, with a preferred value of about 4KP when the tablet is dry. In the present invention, the IR or ER layer or tablet is compressed by wet granulation and has a hardness of 6KP or more.

After preparing the particles or granules, for the particles to be pressed, the material may be dried under sufficient conditions to obtain granules having a moisture content preferably not greater than 0.5% by weight. In the present invention, the LOD (loss on drying) range of IR and ER particles results in a moisture content after drying of 1.0% to 3.0%. The material may be dried at a preferred temperature of about 50 ℃. The drying temperature ranges from about 40 ℃ to 50 ℃, preferably for a suitable length of time (e.g., 12-16 hours) to remove liquids such as solvents and/or water. Drying time was 12-16 hours at laboratory level. On an industrial scale, the drying time can be shorter, such as about 0.5 to 2 hours using a fluidized bed dryer.

In a bilayer tablet, one layer may be deposited onto another layer, e.g., a layer of IR material may be deposited or attached to the ER layer, or vice versa. Similarly, dosage forms having an ER layer sandwiched between two layers of IR material can be formed in the same manner. Similarly, a coating of IR material can be deposited onto the core to form an ER tablet in which the IR layer coats the ER core, such that the tablet can provide immediate release and sustained release for treatment and symptom relief in a patient.

Apparatus and methods for forming tablets having multiple layers or tablets having a coating on a solid core during tablet manufacture are well known in the art. For example, an immediate release layer on a delayed release core can be achieved by a variety of granulation methods. Alternatively, bilayer tablets may be prepared using a bilayer tablet press. One method of forming a bilayer tablet is to laminate the granules or particles (e.g., ER material) for one layer into a layer and then to laminate the granules or particles (e.g., IR material) for the other layer onto it to form a bilayer tablet-like structure. To form a three-layer tablet, a third layer (e.g., an IR layer) can be pressed onto a selected side (e.g., the ER side) of the two-layer tablet-like structure.

Generally, for the active ingredient of the complete tablet of the present invention, the APAP in the core of the tablet ER is from about 30 to 90% by weight, preferably from about 40 to 80% by weight, more preferably from about 50 to 70% by weight. On the other hand, tramadol is typically present in the core of the ER tablets in an amount of about 30 to 100% by weight, preferably about 50 to 90% by weight, more preferably about 60 to 80% by weight. A balance of the active ingredients APAP and tramadol may be present in the IR layer adjacent to the ER layer, resulting in a rapid rise in serum levels of the drug, thereby achieving a therapeutic effect.

Procedure and apparatus

Representative exemplary equipment and procedures that may be used to prepare, evaluate and use the dosage forms of the present invention are set forth below. Lambda carrageenan is mentioned as an illustrative example. Matrix tablets were prepared by wet granulation. The detailed composition of the different formulations is given in the table provided below. Generally, in the process of preparing the dosage form, tramadol hydrochloride is dissolved in 60% ethanol solution (1: 1.5, w/v) and a complex is prepared by slowly adding lambda carrageenan to the resulting tramadol hydrochloride solution and mixing in a wide-mouth container using a stirrer. The premixed APAP/HPMC powder and the composite were then mixed to obtain a homogeneous wet paste. The paste was sieved through a 1.0mm mesh screen and then dried at 45 ℃ overnight. The dried granules are sieved through a 1.0mm mesh screen and then mixed with a matrix-forming polymer and other excipients, including magnesium stearate. These granules were compressed into tablets weighing approximately 600mg per tablet using a rotary tablet press equipped with 19.5mm by 8.5mm oval punches and die holders. The compression force was about 20KN and the tablet hardness and thickness were about 7-10KP and 3.9mm, respectively. All formulations were stored in air tight containers at room temperature for further study.

The active ingredients and excipients were mixed and kneaded using a K5SS mixer (Kitchen Aid, USA). The compounds were granulated and sieved using an AR400 type FGS (Erweka, Germany) granulator. Separately compressed using a ZP 198 rotary tablet press (Shanghai Tianhe Pharmaceutical Machinery co., ltd., China). In vitro dissolution testing of the pellet was performed using the VK7000(VANKEL, Germany) dissolution system and quantitative analysis was performed using LC-10A HPLC of SHIMADZU. The solubility tester can be used for both the USP I method (basket method) and the USP II method (paddle method). A description of The USP method regarding solubility can be found in "solubility" in The United States Pharmacopeia, 30th ed., pp.277-284, The United States Pharmacopeia Convention, Rockville, MD (2007) (United States Pharmacopeia 30th edition, page 277-284, United States Pharmacopeia Committee (Rockville, MD) (2007)). It is known in the art that solubility tests such as USP I and USP II make reasonable predictions of the in vivo solubility of a drug in the gastrointestinal tract of a patient. Due to the successful in vitro/in vivo correlation, the FDA has increased USP solubility as one of the tests required for the development of oral formulations. See, e.g., (1) Dressman, Jennifer b.; amidon, Gordon L.; reppas, christos; shah, Vinod P, Abstract of "resolving stabilizing as a proteinaceous tool for oral drug adsorption: immediatate release desk forms ", Pharmaceutical Research (1998), 15(1), 11-22, Plenum Publishing Corp. (Dressman, Jennifer B., Amidon, Gordon L., Reppas, Christos, Shah, Vinod P.," solubility test as a predictor for oral drug absorption "-Summy of immediate release dosage forms" [ Abstract of Pharmaceutical Research ], [ journal of Pharmaceutical Research ], [ volume 15, pages 11-22, Plenum Publishing Corp. ]); (2) shah, Vinod P., Abstract of "The role of dissolution testing in The regulation of pharmaceuticals: the FDA permselectivity Testing, (2005), 81-96, Taylor & Francis, Boca Raton, Florida (Shah, Vinod P., "Effect of solubility Testing in Pharmaceutical regulations": FDA View "Abstract," drug solubility Testing, "2005, pp.81-96, Taylor & Francis (Boca Raton, Florida)); and (3) Uppoor, V.R.S., Abstract of "Regulation perspectives on in vitro (disorder)/in ViVo (bioavailability) coatings", Office of Clinical pharmacy and Biopharmacy, FDA, CDER, Rockville, MD, USA, Journal of Controlled Release (2001), 72(1-3), 127-fold 132, Elsevier Science Ireland Lp. (Poor, V.R.S., "Regulation of in vitro (solubility)/in ViVo (bioavailability) relevance" Abstract of MD ", Clinical Pharmacology and biopharmaceutical Office, FDA, CDER (Rockville, USA)," J.P.M.P.72, pp.1-3, Iresel 132, Lseville 132).

Typical carrageenans are lambda carrageenan. Lambda-carrageenan (VISCARIN)GP109、VISCARINGP209) from FMC BioPolymers. HPMC 2910 (METHOCEL)K4M)、HPMC 2208(METHOCEL^TM E5、METHOCEL^TME15) And polyethylene oxide (POLYOX)WSR N12K) was provided by COLORCON.

In vitro drug release studies of pre-formed matrix tablets were performed according to USP II method (paddle method) at 50-100rpm/900ml, 37 ± 0.5 ℃ and dissolution medium (pH 1.2, pH 4.0, pH 6.8 buffer and distilled water, prepared according to USP) using a VK7000 dissolution system for a period of 12 hours. The pH 6.8 buffer had the same composition as USP Simulated Intestinal Fluid (SIF) without enzyme; the pH 1.2 buffer was identical in composition to USP Simulated Gastric Fluid (SGF) without enzyme; the pH 4.0 buffer was prepared with 0.05mol/l acetic acid and 0.05mol/l sodium acetate and adjusted to pH 4.0. Samples of the dissolution medium (pH 1.2, pH 4.0, pH 6.8 buffer and distilled water) were periodically filtered through a 0.45 μm membrane, and the concentrations of both tramadol hydrochloride and APAP in the release medium were determined by HPLC under the following conditions. Xterra RP8 (4.6X 5.0mm, 5 μm, Waters (USA)) was used as a column for HPLC analysis and 0.5% aqueous NaCl/methanol (85/15) solution was used as the mobile phase. The flow rate of the mobile phase was 1ml/min and the injection volume was 10. mu.l. The detection wavelength was set at 275nm using a SHIMADZU SPD-10A ultraviolet detector as the detector.

The drug content in the sample was calculated using a suitable calibration curve consisting of reference standards. Drug solubility for a given time period was plotted as percent release versus time. The solubility data is fitted according to the following well-known exponential equation (Korsmeyer's equation in mathematical modeling) which is used in the art to describe drug release behavior in polymer systems.

M_t/M_∞＝ktⁿ

Wherein M is_t/M_∞A drug release fraction at time t; k is the release rate constant for the combination of the macromolecular polymer system and the drug, and the size "n" of the release index is an index indicative of the diffusion of the drug release mechanism. For the n value of the tablet, n-0.45 indicates classical Fickian (Case I, diffusion drug controlled release), 0.45 < n < 0.89 indicates non Fickian (irregular drug diffusion and polymer erosion release), n-0.89 indicates Case II (zero order erosion controlled release), and n > 0.89 indicates hypercaseAnd (3) releasing II. Irregular delivery (non-Fickian) refers to a combination of both diffusional and erosive controlled drug release.

Model-independent methods (i.e., Dissolution Efficiency (DE) and Mean Dissolution Time (MDT)) were also used to compare the difference in the degree and rate of drug release among the prepared formulations and convert the curve difference to a single value:

it is defined as the area under the dissolution curve up to a particular time t, expressed as a percentage of the area of the rectangle described by 100% dissolution over the same time. MDT is a measure of dissolution rate: the larger the MDT, the smaller the release rate.

Where i is the lysis sample number variable, n is the lysis sample number, t_midIs the time midway between sampling times i and i-1, and Δ M is the amount of drug dissolved between i and i-1.

Examples of the invention

In the following examples tramadol hydrochloride, i.e. racemic cis- (2- (dimethylaminomethyl) -1- (3-methoxyphenyl) -cyclohexan-1-ol, C, was used₁₆H₂₅NO₂) HCl to form a complex. In the optical rotation test performed on tramadol hydrochloride, there was no rotation in linearly polarized light. However, since complexation is an interaction of the cationic properties of tramadol with carrageenan having a sulfate group, it is expected that other enantiomers of tramadol hydrochloride may be similarly complexed with carrageenan.

Example 1: preparation of tramadol Complex

First, 1 gram of tramadol hydrochloride was dissolved in 2ml of deionized water. The resulting drug solution has an acidic pH. Then, 0.8g of lambda carrageenan (VISCARINGP-109, from FMC) was added to the drug solution and ground using a set of mortar/pestles for about 5 minutes to form a tramadol complex paste. The paste was dried in an oven at 40 ℃ overnight. The dried complex was then ground using a set of mortar/pestles and subsequently sieved through a 40 mesh screen. The tramadol content of the complex was determined using HPLC. The target weight ratio of tramadol to carrageenan was 1.0/0.8.

Example 2: preparation of tramadol Complex

In this example the complex preparation procedure of example 1 was repeated except that the ratio of tramadol to carrageenan was 1.01/1.0.

Example 3: preparation of tramadol Complex

In this example the complex preparation procedure of example 1 was repeated except that the ratio of tramadol to carrageenan was 1.01/1.25.

Example 4: release of complex and non-complex tramadol

First, the excipients listed in table 2 were sieved through a 40 mesh screen. The tramadol complex or free tramadol prepared as per example 1 was then dry blended with those sieved excipients according to the compositions shown in table 2. Each portion of the dry blended material in an amount of 600mg was compressed into tablets using an 9/32 inch die at a compression pressure of about 1 metric ton. A pressure of 1 metric ton corresponds to 57 MPa.

Table 2: compositions A and B (% by weight)

Components	A	B
			Tramadol hydrochloride	112.5
APAP	54.2	54.2
			HPMC K4M	15.0	15.0
MCC	17.3	7.3
			Magnesium stearate	1.0	1.0
Example 1 complexes		22.5

The release profiles of both tramadol and APAP were determined using USP I method in simulated intestinal fluid (standard pH 6.8USP, no enzyme) with a stirring speed of 50 rpm. The concentration of tramadol and APAP in the release medium was determined using HPLC method (Waters XTerra RP8, 5 μm, 4.6X 50 mm; mobile phase 85: 15(v/v) 0.5% NaCI aqueous solution: MeOH). Figure 2 shows the release profile of the APAP/tramadol combination in a matrix in which tramadol is complexed and non-complexed. The curve with black circle data points is the APAP data for formulation a, the open circles are the tramadol data for formulation a, the black triangles are the APAP data for formulation B, and the open triangles are the tramadol data for formulation B. This data indicates that tramadol is released at a much faster rate than APAP, its T₈₀(defined as the time to release 80% of the drug) was 7.3 hours and 17.7 hours, respectively. There is a difference in the duration of release, T, between the two drugs₈₀The ratio was 2.4. For formulation B, where tramadol was complexed with carrageenan, the release duration difference was significantly reduced. T is₈₀The ratio decreased from 2.4 to 1.4, p value < 0.0001. Thus, complexing with carrageenan delays the release of tramadol. See table 1 above.

Example 5: effect of HPMC

This example repeats the tablet preparation procedure and release method shown in example 4, except that the composition of the tablet is varied to give a wide range of release durations. Table 3 shows the composition of the tablets used.

Table 3: compositions C, D and E: different HPMC K4M contents (weight)Volume%)

Components	C	D	E
				Example 1 complexes	22.5	22.5	22.5
APAP	54.2	54.2	54.2
				HPMC K4M	10.0	5.0	0.0
Lactose	12.3	17.3	22.3
				Magnesium stearate	1.0	1.0	1.0

Fig. 3, 4 and 5 show the release profiles of formulations C, D and E, respectively, with varying amounts of hydroxypropylmethylcellulose K4M (HPMC K4M). Black dots are APAP data and open circles are tramadol data. T of APAP is plotted in FIG. 6₈₀And the duration ratio of tramadol. Black dots are APAP data and open circles are tramadol data. FIG. 6 shows that HPMC content greatly affects the duration of APAP release (HPMC content increase, T) for formulations containing tramadol complexes₈₀Increased) but has no significant effect on the duration ratio.

Example 6: effect of Compound tramadol

Table 4 compositions F (non-complexed) and G (complexed) showing the% by weight

Components	F	G
			Tramadol hydrochloride		12.5
APAP	54.2	54.2
			HPMC E5	5.0
HPMC K4M		10.0
			Lactose	11.7	22.3
Magnesium stearate	1.0	1.0
			Example 3 complexes	28.1

[0116] The preparation procedure was the same as described in example 4 above, using formulations F and G according to table 4. Fig. 7a and 7b show the release profiles of tramadol and APAP in compositions F and G, respectively. Black dots are APAP data and open circles are tramadol data. Both formulations have similar APAP T₈₀The curves, and the tramadol release profile, are much different. After compounding (formulation F), a simultaneous release of tramadol and APAP was achieved with a release duration ratio of 1.1. Further, the diffusion release index of the complex tramadol was 0.731 compared to the diffusion release index (n) of the non-complex tramadol 0.502. An increase in the value of n indicates that tramadol release becomes closer to zero order (constant rate) delivery.

Example 7: quick release material

The same tablet preparation procedure of example 4 was repeated in this example except that the formulation was of an Immediate Release (IR) material according to table 5. The ingredients were passed through a 40 mesh screen prior to dry blending to ensure uniform mixing. Immediate release tablets were prepared using 0.75 inch x 0.32 inch caplet dies at a pressure of about 1 metric ton (corresponding to 57Mpa) provided by a CAVER tablet press, where 365.2mg of the composition was compressed into IR tablets. Each IR tablet contained 325mg of APAP. The tablets showed rapid disintegration with more than 95% of the APAP dissolved in Simulated Gastric Fluid (SGF) in less than 15 minutes (i.e., standard ph1.5 USP, no enzyme, dissolution completed according to USP II method standard procedure). Thus, the results indicate that IR materials can be formed that should release APAP quickly. The material can be used as an IR layer attached to an extended release composition comprising APAP and a complex tramadol as shown in fig. 1A, fig. 1B, and fig. 1C. As an outer layer of the tablet, it should disintegrate and release the drug similarly rapidly. In this prior experiment, the IR layer 22 contained no tramadol, but APAP was the only active analgesic ingredient. However, because the IR material dissolves too quickly, there is no reason to believe that inclusion of tramadol will significantly prolong the release time. The IR layer containing APAP and tramadol should dissolve in a few minutes compared to the ER material (release APAP and tramadol in a few hours).

Table 5: composition of quick release material

Example 8: effect of HPMC E5 on hardness

Formulation F-No.01A-03A was prepared using various HPMC E5 ratios according to the formulation given in Table 6A to demonstrate the effect of HPMC E5 on tablet compressibility. The higher the HPMC E5 content, the greater the tablet hardness. Thus, the addition of 10mg of HPMCE5 to ER layer granules can be used to prepare tablets of suitable hardness (e.g., about 6KP to 12 KP).

Table 6A: for indicating HPMC E5 composition of influence on compressibility。

Ingredients (mg)	F-No.01A	F-No.02A	F-No.03A
				Tramadol hydrochloride	56.25	56.25	56.25
APAP	390	390	390
				λ-C(GP-109)	70.4	70.4	70.4
HPMC E5	0	5	10
				Magnesium stearate	5.2	5.3	5.3
Total of	521.85	526.95	531.95
Hardness (KP)	2-5	6-9	7-11

Example 9: other examples of composite matrix tablets

Matrix tablets were prepared by wet granulation. The detailed composition of the various formulations is given in table 6B and table 6C. Tramadol hydrochloride was dissolved in 60% ethanol solution (1: 1.5, w/v) and the complex was prepared by slowly adding lambda carrageenan to the resulting tramadol hydrochloride solution and mixing in a wide-mouth container using a stirrer. The premixed APAP/HPMC powder and the composite were then mixed to give a homogeneous wet paste. The paste was sieved through a 1.0mm mesh screen and then dried at 45 ℃ overnight. The dried granules are sieved through a 1.0mm mesh screen and then mixed with a matrix-forming polymer and other excipients, including magnesium stearate. These granules were compressed into tablets weighing approximately 600mg per tablet using a rotary tablet press equipped with 19.5mm by 8.5mm oval punches and die holders. The compression force was about 20KN and the tablet hardness and thickness were about 7-10KP and 3.9mm, respectively. All formulations were stored in air tight containers at room temperature for further study. The tablet preparation method may also be adapted to prepare tablets containing the ingredients in the following examples by adding appropriate excipients.

Table 6B: compositions of formulations F.No.1 to F.No.5

Ingredients (mg)	F-No.1	F-No.2	F-No.3	F-No.4	F-No.5
						APAP	390	390	390	390	390
Tramadol hydrochloride	56.25	56.25	56.25	56.25	56.25
						λ-C(GP-109)	70.4	70.4	70.4	70.4	70.4
λ-C(GP-209)	0	0	0	0	0
						HPMC E5	10	0	0	10	10
HPMC E15		0	0	0	0
						POLYOX WSR N12K	0	0	0	67.35	33.675
HPMC K4M	67.35	50	50	0	33.675
						Lactose	0	27.35	0	0	0
AEROSIL 200	0	0	27.35	0	0
						Magnesium stearate	6	6	6	6	6
Total weight of	600	600	600	600	600

[0129] Table 6C: compositions of formulations F.No.6 to F.No.12

Example 10: extended release excipient

Hydrophilic polymers such as polyethylene oxide (PEO) and Hydroxypropylmethylcellulose (HPMC) can be used as excipients for modification of the release tablet formulation. The tablets may be prepared by the method of example 9 above, as would be understood by one skilled in the art. Upon contact with liquid, these polymers should hydrate and swell, forming a hydrogel layer that controls further penetration of the liquid into the tablet matrix and dissolution of the drug therefrom. Thus, drug release from such polymer matrices can be achieved by diffusion, erosion, or a combination of both. ER layer matrix tablets were formulated with various levels of HPMC and PEO and lambda carrageenan/tramadol hydrochloride complex to achieve release durations of about 10-12 hours for twice daily dosing, see table 7 (including table 7A for APAP and table 7B for tramadol hydrochloride). The PEO used was POLYOX WSR N12K from DOW Chemicals. For POLYOX WSR N-12K-NF, the Molecular Weight (MW) was about 1,000,000, and the viscosity of a 2% solution at 25 ℃ ranged from 400 to 800 centipoise. Table 7 lists the dissolution parameters for each matrix tablet formulation from different empirical equations. As shown in the table, the correlation coefficient values (R) of all preparations²) Are sufficiently high (> 0.97) to evaluate the dissolution behavior of the drug by Korsmeyer model and find that the "n" and k values vary with the type and concentration of the polymer. The values of the release index "n" determined for the various scaffolds varied from 0.43 to 0.88 for APAP and 0.46 to 0.66 for tramadol hydrochloride, indicating a combined effect of diffusion and erosion mechanisms. When HPMC K4M was used alone as a release-delaying agent in F-No.1, the tablet hardness was relatively low (less than 3KP), which caused tableting difficulty. However, milk is added to the formulationSugar or AEROSIL 200 as tablet filler can supplement suitable tabletting properties (F-No. 2)& 3)。

Table 7A: in vitro release and dissolution parameters of APAP

Table 7B: in vitro drug release and dissolution parameters of tramadol hydrochloride

When HPMC K4M was used alone as a release-delaying agent in F-No.1, the tablet hardness was relatively low, which caused tablet compression difficulty. However, the addition of lactose or AEROSIL 200 to the formulation as a tablet filler can supplement the appropriate tabletting properties (F-Nos. 2 & 3). The effect of using PEO alone as an extended release agent and HPMC K4M in combination with PEO was also tested (F-Nos. 4 & 5). Dissolution was accomplished in buffer solution (simulated intestinal fluid, without enzyme) at pH 6.8 with a stirring speed of 50 rpm. FIGS. 8 and 9 show the percent dissolution of F-Nos. 2-5 as a function of time.

Assuming that the IR layer contents of the different matrix tablet formulations (F-nos. 2-5) were (a) APAP and (b) tramadol hydrochloride, their simulated release profiles at a stirring speed of 50rpm in pH 6.8 buffer are shown in fig. 10 and 11 (compared to fig. 8 and 9, which are data assuming no IR layer). Data are presented as mean ± standard deviation (n ═ 3). The diamond data points represent the F-No.2 data. The circular data points represent the F-No.3 data. The triangle data points represent the F-No.4 data. The square data points represent the F-No.5 data. As shown in example 4 above, an IR material can be formed that should rapidly release APAP to rapidly increase the amount of active ingredient released. Similarly, IR materials with fast release of APAP and tramadol were also formed. It has been demonstrated that if a layer of IR material is used to form a bilayer structure with a layer of ER material, the release of APAP and tramadol can be approximately consistent by assuming negligible release times for APAP and tramadol. The structures of fig. 1B and 1C should similarly release drug rapidly from the IR layer. Fig. 10 and 11 show simulated release profiles assuming tablets with an ER layer of the compositions of fig. 8 and 9, and an IR layer associated with the ER material, either as an outer layer or as one layer of a bilayer structure. Cumulative percent release is calculated as the percentage of the total amount of APAP (and tramadol) released in the overall (e.g. bilayer) tablet. Figures 10 and 11 show that for the formulations, the cumulative percent release of APAP in IR/ER (e.g. bilayer) tablets is very close to that of tramadol. Thus, a synergistic extended release of APAP and tramadol hydrochloride may be achieved by complexation.

The results also show that the combined use of PEO and HPMC K4M as a sustained release agent (F-No.5) shows the minimum DE% and maximum MDT among the above scaffolds, indicating a higher drug release-delaying ability.

Use of PEO

Formulations F-No.5 and F-No.6 show that the advantages of using HPMC K4M and PEO are a smaller DE% and a larger MDT. (F-No.6) contains HPMCK4M and PEO in a ratio of 1: 1. Figure 12 shows a comparison of the cumulative release profiles of APAP and tramadol hydrochloride. Fig. 13 shows the simulated release profile of the bilayer tablet of F-No.6 with an IR outer layer and an ER core, calculated from the data of fig. 12. In fig. 12 and 13, the diamond-shaped data points represent APAP data. The square data points represent tramadol data. The release of APAP and tramadol hydrochloride in FIG. 12 clearly follows the Korsmeyer model (correlation R)²Equal to 0.9967 and 0.9977, respectively). From the release indices (n is 0.7739 and 0.5694 for APAP and tramadol hydrochloride, respectively), the release mechanism appears to be an irregular transmission (non Fickian). The data show a substantially constant release rate suitable for delayed release. Extended release dosage forms capable of achieving a constant release rate are likely to reflect the sum of both drug diffusion and polymer erosion. Because after the dissolution medium is put into the frameworkBoth swelling and erosion occur simultaneously, resulting in a substantially constant release. In such cases, constant release occurs because the increased diffusion path length of swelling is offset by continued erosion of the scaffold.

Different grades of lambda carrageenan

Figure 14 shows the cumulative amount of APAP released and figure 15 shows the cumulative amount of tramadol hydrochloride over time for extended release formulations F-No.7 and F-No.8, which contain different grades of lambda carrageenan. The diamond data points represent the F-No.7 data. The square data points represent the F-No.8 data. No different grades of lambda carrageenan (VISCRIN) were observedGP-109 and VISCARINGP-209), indicating that there is little difference in their complexing ability with tramadol hydrochloride. Figures 16 and 17 show the cumulative drug release of the simulated bilayer tablet calculated from the data of figures 15 and 15, respectively. Similarly, the release profile of tramadol hydrochloride is very close to that of APAP, indicating that a bilayer dosage form with extended release cores for formulations F-No.7 and F-No.8 can produce a synergistic extended release of both drugs.

Effect of HPMC K4M

The effect of the delayed release on the release profile was studied by fixing the amount of PEO (30mg) while varying the proportion of HPMC K4M and formulating F-No.7, F-No.9 and F-No.10 as ER materials. All formulations showed release over 10-12 hours. FIG. 18 shows the cumulative release profile of APAP, and FIG. 19 shows the cumulative amount profile of tramadol hydrochloride over time in extended release formulations F-No.7, F-No.9 and F-No. 10. Figures 20 and 21 show the cumulative drug release of the simulated bilayer tablet calculated from the data of figures 18 and 19, respectively. The diamond data points represent the F-No.7 data. The square data points represent the F-No.9 data. The triangle data points represent the F-No.10 data. The results show that increasing HPMC K4M content slightly delayed drug release. Similarly, the release profile of tramadol hydrochloride is very close to that of APAP, indicating that a bilayer dosage form with extended release cores for formulations F-No.7, F-No.9 and F-No.10 can produce a synergistic extended release of both drugs.

Effect of PEO

The effect of the delayed release on the release profile was studied by fixing the amount of HPMC K4M (20mg) while varying the proportion of PEO and formulating F-No.10, F-No.11 and F-No.12 as ER materials. All formulations showed release over 10-12 hours. FIG. 22 shows the cumulative release profile of APAP, and FIG. 23 shows the cumulative amount profile of tramadol hydrochloride in the delayed release formulations F-No.10, F-No.11 and F-No.12 over time. Figures 24 and 25 show the cumulative drug release of the simulated bilayer tablet calculated from the data of figures 22 and 23, respectively. The diamond data points represent the F-No.11 data. The square data points represent the F-No.10 data. The triangle data points represent the F-No.12 data. The results indicate that increasing PEO content slightly delayed drug release. Similarly, the cumulative release profile of tramadol hydrochloride is very close to that of APAP, indicating that a bilayer dosage form with extended release cores for formulations F-No.10, F-No.11 and F-No.12 can produce a synergistic extended release of both drugs.

Influence of pH

To investigate the effect of the pH of the dissolution fluid on the rate of drug release from the hydrophilic matrix, the dissolution rate of formulation F-No.10 at 50rpm was investigated with a buffer of pH 1.2, pH 4.0, pH 6.8 and distilled water. Figures 26 and 27 show data for APAP and tramadol hydrochloride, respectively. The diamond data points represent pH 1.2 data. The square data points represent 4.0 data. The triangle data points represent pH 6.8 data. The circular data points represent Distilled Water (DW) data. For formulation F-No.10, the release rates of both APAP and tramadol hydrochloride were faster at acidic pH, consistent with lower MDT values and higher DE% values under acidic conditions. This result can be attributed to erosion or disintegration of the surface of the matrix tablet prior to gel layer formation around the tablet core in acidic media, resulting in faster drug release. The pH 6.8 curve is slower than the other curves. All ER samples released slowly over the first hour, indicating that such formulations released only a small fraction of the drug as the tablet passed through the stomach. Fig. 28 and 29 show the cumulative drug release of simulated bilayer tablets in buffer and distilled water at different pH, calculated from the data of fig. 26 and 27, respectively. Again, the results indicate that dosage forms can be formulated for synergistic release of APAP and tramadol.

Effect of stirring speed (rpm)

Exemplary ER materials prepared from formulation F-No.7 were studied by dissolution at 50rpm, 75rpm, and 100rpm agitation speeds. Figures 30 and 31 show data for APAP and tramadol hydrochloride, respectively. The diamond data points represent 50rpm data. The square data points represent 75rpm data. The triangle data points represent 100rpm data. At higher rpm, the overall rate of drug release from the matrix was significantly higher, as determined by F-No.7 having a smaller MDT (APAP of 4.33h, tramadol hydrochloride of 3.21h) and a higher DE (APAP of 64.41%, tramadol hydrochloride of 68.24%) at 100rpm than at 50rpm, 5.40h for APAP and 4.28h for tramadol hydrochloride, 47.92% for APAP and 60.87% for tramadol hydrochloride. Generally, hydrophilic polymers can create a hydrogel layer when contacted with a liquid; drug dissolution is manifested as a combination of diffusion and erosion, with drug diffusion predominating. However, higher rpm's will result in more erosion of the matrix than hydration of the polymer, which in turn promotes more diffusion and dissolution of the drug. Fig. 32 and 33 show the cumulative drug release of the simulated bilayer tablets calculated from the data of fig. 30 and 31, respectively. Again, the results indicate that dosage forms can be formulated for synergistic release of APAP and tramadol.

In vitro delayed release of bilayer tablet

Based on the above results, a bilayer tablet having an IR layer and a compressed tramadol hydrochloride complex and an APAP layer was prepared according to the composition of formulation F-No.13 shown in Table 8, by the method of example 9, to form an ER layer and deposit an IR layer thereon. This tableting operation is accomplished by using a bi-layer tablet press to laminate the IR layer and the ER layer together while feeding the IR and ER tabletting materials simultaneously to the bi-layer tablet press. Many tablet presses for compressing materials to form bi-or multi-layer tablets are known and commonly used to prepare tablets. One skilled in the art can prepare bilayer tablets of the present invention using a typical tablet press, such as the Carver press. Tablets of formulation F-No.13 were prepared in a pilot 38kg batch. Table 8 also shows the composition of the IR layer immediately adjacent to the ER material layer. As shown in table 8, the tablet cores with the IR and ER layers were also provided with an optional coating.

TABLE 8

Table 9 shows the actual manufacturing data for three pilot batches used to make formulation F-No.13 bilayer tablets. The formulations used for the three pilot production batches produced tablets that met the acceptance criteria and represent a class of long-lasting, durable products. Water and/or ethanol were added while mixing the other ingredients of the respective layers shown in the table. The mixed materials are then pressed to form the respective layers. Water and ethanol were removed during the drying of the dried tablets. These tablets also matched tablet performance evaluated at the laboratory level and at the formulation development stage.

Table 9: actual quantities for three preparation batches

^*Moisture is removed during the drying process and does not appear in the finished product.

^*Moisture is removed during granulation and does not appear in the finished product.

^**Ethanol is removed during the granulation process and does not appear in the finished product.

^***The values were adjusted because of losses that occur during the coating process. The actual amount required for the batch included a 20% allowed excess (3kg- - - → 3.6 kg).

^****Moisture is removed during the coating process and does not appear in the finished product.

The IR layer was prepared using a fluid bed granulation preparation method and the ER layer was prepared using a high shear mixer granulation method, followed by drying, sieving and mixing steps and subsequent tableting. Finally, the tablet is subjected to film coating. The main equipment used in the preparation process is summarized as follows: and (3) granulating: high shear mixing granulator, fluidized bed granulator; and (3) drying: a fluidized bed granulator; grinding: vibrating screen; mixing: a V-shaped mixer; a tablet press: a TMI bi-layer tablet press; coating: high-efficient capsule machine. Fig. 35 shows a flow chart of a manufacturing process for a tablet.

In preparing the IR particles, a binder solution is first prepared. The IR material (APAP, tramadol hydrochloride, powdered cellulose, pregelatinized starch, sodium starch glycolate) was transferred to a fluid bed granulator and pre-mixed. The desired amount of binder solution is sprayed onto the material and granules of the material are formed using a fluid bed granulator. The granules are dried and passed through a sieve mill with magnesium stearate to achieve the desired particle size. The resulting IR particles were mixed using a V-blender. In the preparation of ER granules, tramadol hydrochloride is dissolved in a 60% ethanol solution and lambda carrageenan is added to form a complex. APAP was premixed with HPMC E15 in a SuperMixer granulator. The tramadol complex paste and APAP/HPMC E15 were granulated together using a high shear mixer. The wetted particles are passed through a screen to achieve the desired particle size. The granules were dried in a fluid bed dryer. The dried granules, along with other agents (HPMC K4M, POLYOX) and magnesium stearate, were passed through a screen and then mixed to form an ER blend. The IR blend and ER blend were compressed into tablets at a weight of about 925.8mg using a suitable bi-layer tablet press (e.g., TMI bi-layer tablet press or equivalent) and an impression tablet die (49 sets of upper and lower dies). Three batches of tablets were prepared. The dimensions of the punches in the die used to prepare the tablets are characterized by: length 19.05mm, width 7.62mm, curve radius 5.5 mm. A coating fluid (liquid) was prepared by mixing an appropriate amount of OPADRY yellow YS-1-6370-G in purified water. The tablets to be coated (tablet cores) are loaded into a coating pan. The tablet cores are heated in a coating pan and coated with a coating fluid using a suitable coating machine, such as a high-efficiency coating machine or equivalent. After spraying, the pan was kept rotating to ensure the tablets were dry. Caroba wax is sprayed throughout the rotating tablet bed. The coating fluid may be a solution in which all the ingredients are sufficiently dissolved in the solvent, or it may contain some particulate ingredients dispersed in the fluid. Coating fluids are well known in the art, and those skilled in the art will appreciate which alternatives may be used in accordance with the examples disclosed herein.

The main equipment used in the tablet preparation process is summarized as follows:

1. and (3) granulating: high shear mixing granulator (Supermixer: 30kg)

Fluid bed granulator (Glatt WSG 30: 30kg)

2. And (3) drying: fluid bed granulator (Glatt WSG 30: 30kg)

3. Grinding: vibrating screen

4. Mixing: v-shaped mixer (100L)

5. A tablet press: TMI tablet press

6. Coating: coating pan (30kg)

Table 10 shows the parameters of the above equipment used to make the tablets in batches 001, 002 and 003. During drying, the tablets are dried to a target post-drying moisture weight percent (MafD) of 1 wt% to 3 wt%. One skilled in the art would know how to prepare tablets using the above equipment under the parameter conditions of table 10. In table 10, the "set" parameter values are for each batch and may be slightly different (as shown in the table).

Table 10: process parameters of the apparatus

Table 11 shows the particle size distribution based on mesh of Immediate Release (IR) granules for batches 001, 002 and 003 extended release tablets.

Table 11: particle size distribution (% by weight) of IR particles

The weight of the final tablet was about 951 mg/tablet. Tablets were prepared weighing about 114 kg/batch.

In the above F-No.13 tablet, the IR layer was about 3.14mm thick, the ER layer was about 3.82mm thick, and the total thickness was 6.96 mm. Under the above conditions, the hardness of the plain tablets was 8.5. + -. 1KP on average, and the friability was less than 1% (0.23%). FIG. 34 shows the dissolution profile of F-No.13 (coated tablet). The diamond data points represent APAP data. The square data points represent tramadol data. The relative standard deviation (CV) values for all assay points (n-6) were less than 7%. From the first hour to the twelfth hour, the cumulative weight percent release of APAP was very close (by less than 10%) to that of tramadol. From the second hour to the eighth hour, the difference is less than 5%. The results indicate that the multi-layered dosage forms prepared provide a synergistic release of APAP and tramadol. In this example, the release rates of tramadol and APAP are very close. APAP T on tramadol₆₀、T₇₀、T₈₀、T₉₀The ratio is less than 2, in fact less than 1.5 and substantially close to 1. It is apparent from the release rate experimental results that in a bilayer tablet, the IR layer will disintegrate (within minutes, e.g. 15 minutes) and release the drug rapidly. The drug release time of the IR layer is extremely short compared to the release time of the ER layer of 8 hours or more. Thus, it is reasonable to assume that the drug release rate of the ER layer in a bilayer tablet is similar to the drug release rate of the ER layer in an in vitro dissolution test (in which only the ER layer is tested). Since the ER layer of F-No.13 is nearly identical to that of F-No.7, the release index n of APAP in the ER layer will be about 0.75 and that of tramadol about 0.6.

It has been found that the combination of tramadol with an anionic polymer, preferably carrageenan, to form a delayed release layer in a tablet provides non-Fickian and/or Case II erosion controlled release and thus enables synergistic release with APAP. To compare the properties of the different tablets, MDT, T are preferably determined by in vitro tests using USP II (Paddle) apparatus in the following manner₈₀And the release index n in the Korsmeyer equation. The paddle is 25mm away from the inner bottom surface of the container. The dissolution medium was phosphate buffered saline pH 6.8 prepared according to USP method (USP SIF, enzyme free) and dissolution was completed at 50rpm/900ml, 37. + -. 0.5 ℃. Collecting dissolution medium samples at regular intervals, filtering with 0.45 μmembrane filter, and releasingThe concentration of tramadol hydrochloride and APAP in the medium were both determined by HPLC using aqueous buffer/methanol solution as mobile phase. The mobile phase (pH 2.7 buffer: methanol 73: 27) was filtered through a 0.45 micron Millipore filter (HAWP 04700) or equivalent device and degassed by sparging with helium. Dissolution standard (100%) 37.5/325mg was prepared as follows: add 36.11/pure mg (. + -. 1%) acetaminophen to a 50ml volumetric flask, pour 10.0ml tramadol hydrochloride stock solution, dissolve with pH 6.8 phosphate buffer and dilute to volumetric flask volume. A tramadol hydrochloride stock solution was prepared as follows: 41.66/pure mg (. + -. 1%) tramadol hydrochloride was weighed into a 100ml volumetric flask, dissolved with pH 6.8 phosphate buffer and diluted to volumetric flask volume. HPLC chromatographic column is SUPELCO LC-8-DB 150 × 4.6 mm; 5 μm. The injection volume was 10. mu.l, the flow rate was 2.5ml/min, and the run time was 16 minutes; APAP retention time: about 1.2 min; tramadol hydrochloride retention time: about 4.0 min. The detector is a Waters 490 programmable UV detector or equivalent (APAP 280nm-1.0 AUFS; tramadol hydrochloride 215nm-0.5 AUFS). The column temperature was about 35 ℃. The USP II method is a standard method. The USP II method is known to those skilled in the art by reference to the pharmacopoeia.

The percentage of the drug labeled amount (designated La) in the sample can be calculated by the following formula

Wherein A is_samThe peak area of tramadol hydrochloride or acetaminophen used for the sample,

A_stdthe peak area for tramadol hydrochloride or acetaminophen used for the standards,

C_stdstandard concentrations, expressed in mg/ml,

C_t100expressed in mg/ml at a concentration of 100% of theory,

la ═ labeled amount of tramadol hydrochloride or APAP.

In the present invention, the release index n of tramadol from the Korsmeyer equation can be obtained to be greater than about 0.45, even greater than 0.7, and even greater than 0.85 for the ER layer. Preferably, the APAP release index n is about 0.46 to 1, more preferably about 0.6 to 0.9, more preferably about 0.6 to 0.8. Preferably, the release index n of tramadol is from about 0.46 to 0.7, more preferably from about 0.5 to 0.7, more preferably from 0.5 to 0.65.

The T of APAP to tramadol in the double-layer tablet can also be realized₈₀The ratio is close to 1. Preferably, T₈₀The ratio is about less than 2, preferably about less than 1.5, and still more preferably between about 1.5 and 1. More preferably T₈₀The ratio is between 0.9 and 1.1. Also preferred is T₈₀For about 8 to 12 hours, more preferably for about 10 to 12 hours. Table 12 shows T of F-No.13₈₀And (4) data.

Table 12: t of F-No.13 tablet ₈₀ Data of

Time of day	1	2	3	4	5	6	7	8	9	10	11	12
													T80	1.096	1.009	1.007	0.997	0.995	0.998	1.002	1.010	1.021	1.032	1.042	1.047

In vivo extended release of bilayer tablet

The relative bioavailability and other pharmacokinetic properties of the extended release tablets (prepared according to the pilot formulation described in table 9) and the brand formulation tramadol/APAP combination (ULTRACET) were compared in korean healthy male volunteers. ULTRACET tablets contain 37.5mg tramadol hydrochloride and 325mg APAP. Such ULTRACET tablets are commercially availableAnd (4) obtaining. The inactive ingredients in the tablet are powdered cellulose, pregelatinized corn starch, sodium starch glycolate, starch, purified water, magnesium stearate, OPADRYLight Yellow and carnauba wax. Label description and use of ULTRACET tablets can be found for example in USFDA NDA No.021123 (this label was approved in 2004 at 4 months and 16 days,OMP 2003), which is incorporated herein by reference in its entirety.

Multiple dose, double treatment, two cycle, two-sequence randomized crossover studies were performed on korean healthy male volunteers under fasted conditions, with an elution period of 4 days between study cycles as shown in table 13 below.

Watch 13

Sequence of	Number of people N	First period (4 days)	Second cycle (4 days)
				Sequence 1(AB)	6	ULTRACET(A)	ER tablet (B)
Sequence 2(BA)	6	ER tablet (B)	ULTRACET(A)

After screening, at the beginning of the dosing sequence, each was dosed with the selected drug for 4 days according to a first cycle, followed by a 4 day elution period without dosing, followed by a 4 day dosing according to a second cycle. Individuals were followed 4 days after dosing and blood sample data was recorded for the individuals. During the sequential dosing period, commercially available ULTRACET tablets (identified as a in table 13) and ER tablets (identified as B in table 13) were orally administered 14 times (6 hours apart) and 7 times (12 hours apart), respectively, according to table 13. Blood samples were taken at preset time intervals after dosing.

The bioavailability of the drug in the tablets was determined using the data in table 13. As used herein, the term "bioavailability" refers to the rate and extent of absorption of an active ingredient or active moiety from a drug product and onset at the site of action. The rate and extent is determined by pharmacokinetic parameters such as the peak blood or plasma concentration (C) of the drug_max) And area under the blood or plasma drug concentration-time curve (AUC).

In pharmacokinetics, the term "AUC" refers to the area under the curve, which is obtained by plotting the serum concentration of the beneficial agent in a subject versus time, as measured from the time of initiation of administration to the time "t" after initiation of administration. AUC for steady state administration_ssIs the area under the curve when a dosing cycle of sustained periodic dosing is taken. AUC can be obtained by analyzing patient serum samples.

As used herein, the term "C_max"refers to the peak blood or plasma concentration of the drug. Time "t_max"refers to the time to reach the peak blood or plasma concentration of the drug. The term "t_1/2"is the half-life and refers to the time it takes for the drug plasma concentration to decay by half.

Plasma APAP/tramadol concentrations were determined using a validated LC/MS/MS method. A plasma concentration-time curve was generated for each volunteer, with the main parameter (C) on the first day after administration_max、T_max、AUC_0-12hr) And minor parameters of the steady-state phase (C)_max(ss)、T_max(ss)、AUC_0-12h，ssAnd t_1/2) Using WINNONLIN5.2.1(Pharsight Co, CA, USA) by non-compartmental analysis. For example, bioequivalence is defined by regulatory requirements set by korea and the U.S. food and drug administration (bioequivalence acceptance range 0.80-1.25). To achieve bioequivalence to the commercial ULTRACET tablet, the mean steady state C of the novel ER tablet against ULTRACET tablets of the same dose strength at a ═ 0.05_maxThe 90% Confidence Interval (CI) of the ratio of (a) needs to be within 80% to 125% (i.e. 0.8 to 1.25); while the mean AUC of the novel ER tablets versus the commercial ULTRACET tablets_ssThe 90% Confidence Interval (CI) of the ratio of (a) needs to be within 80% to 125%.

A total of 12 volunteers completed the study. The average age of the volunteers was 24.4 + -5.2 years and the average body weight was 65.1 + -6.0 kg. Tables 14 and 15 below show the mean values of pharmacokinetic parameters (+ standard deviation) for tramadol after administration of commercially available ULTRACET tablets and ER tablets of the invention.

Table 14: pharmacokinetic parameters of tramadol

¹⁾Median [ min-max ]]

Table 15: c of tramadol _max，ss 、AUC _0-12h，ss Comparison

¹⁾Arithmetic mean ± standard deviation;

²⁾logarithmic transformation geometric mean ± standard deviation;

³⁾geometric mean ratio of ER to ULTRACET. The arithmetic value is obtained from the actual individual data. Bioequivalence, however, was determined by the difference in geometric means at 90% confidence intervals, thus converting the geometric means from the arithmetic mean.

Figure 36 shows in part the mean plasma concentration-time profile of tramadol following multiple oral administrations of ULTRACET tablets and ER tablets of the invention. Error bars in the figure indicate standard deviations. The curve with the filled circle data points represents ER data, showing a peak occurring approximately every 12 hours. The curve with open circle data points represents ULTRACET data, showing a peak occurring approximately every 6 hours.

Tables 16 and 17 below show the mean values (+ standard deviation) of the pharmacokinetic parameters of APAP after administration of the commercially available ULTRACET tablets and the ER tablets of the invention.

Table 16: pharmacokinetic parameters of APAP

¹⁾Median [ min-max ]]

Table 17: c of APAP _max，ss 、AUC _0-12h，ss Comparison

¹⁾Arithmetic mean ± standard deviation;

²⁾logarithmic transformation geometric mean ± standard deviation;

³⁾geometric mean ratio of ER to ULTRACET.

Figure 37 shows in part the mean plasma APAP concentration-time profiles after multiple oral administrations of ULTRACET tablets and ER tablets of the invention. Error bars in the figure indicate standard deviations. The curve with the filled circle data points represents ER data, showing a peak occurring approximately every 12 hours. The curve with open circle data points represents ULTRACET data, showing a peak occurring approximately every 6 hours.

Analysis of the variance data (including the data of figures 36 and 37) from the in vivo studies described above shows that the formulation, period or sequence has no significant effect on the pharmacokinetic parameters studied. C_max，ssAnd AUC_0-12h(ss)The 90% confidence intervals for the treatment ratios of the values were 0.87 and 0.95 for tramadol and 0.85 and 0.94 for APAP. All data were in the standard bioequivalence acceptance range of 0.80 to 1.25. In this in vivo study conducted on a selected population of healthy volunteers, ULTRACET tablets and C of a novel extended release formulation were marketed_max，ssAnd AUC_0-12h，ssThey were not statistically significantly different and were found to be bioequivalent. Furthermore, both formulations were well tolerated. No adverse events were recorded in this study. Thus, the novel ER formulations of the present invention are shown to be bioequivalent in vivo to commercially available ULTRACET tablets and thus can provide effective therapeutic efficacy for human pain treatment in the same bioequivalent manner as commercially available ULTRACET tablets.

The practice of the present invention will employ, unless otherwise indicated, conventional methods employed in the development of pharmaceutical products by those skilled in the art. Embodiments of the present invention have been described in detail. The examples are intended to illustrate all aspects of the invention, but not to limit the invention. It is understood that various combinations and permutations of the various parts and components of the disclosed embodiments may be employed by those skilled in the art without departing from the scope of the invention. It is also contemplated that other bioactive agents and other excipients may be included in the formulation. Where it is described that certain materials contain certain ingredients, it is also contemplated that materials consisting essentially of these ingredients may also be prepared.

Claims (30)

1. A pharmaceutical composition comprising acetaminophen and a complex tramadol material, and exhibiting a synergistic sustained release upon dissolution resulting in a synergistic tramadol cumulative release and acetaminophen cumulative release over time.

2. The pharmaceutical composition of claim 1, wherein the complex tramadol material is complexed using carrageenan.

3. The pharmaceutical composition of claim 1, wherein the complex tramadol material is complexed using carrageenan and a tramadol salt.

4. The pharmaceutical composition according to claim 1, wherein the period of sustained release is 4 to 12 hours throughout the period of both tramadol and acetaminophen.

5. The pharmaceutical composition of claim 1, wherein the sustained release has a period of 10 hours or more for both the tramadol material and the acetaminophen.

6. The pharmaceutical composition according to claim 1, wherein in the sustained release, when the weight percentage of cumulative release of tramadol is 40 weight%, the weight percentage of cumulative release of acetaminophen is less than 25 weight% different from the weight percentage of cumulative release of tramadol.

7. The pharmaceutical composition according to claim 1, wherein in the sustained release, starting from when the weight percentage of cumulative release of tramadol is 40 weight%, the weight percentage of cumulative release of acetaminophen is never more than 20 weight% unlike the weight percentage of cumulative release of tramadol.

8. The pharmaceutical composition according to claim 1, wherein in the sustained release, starting from when the weight percentage of cumulative release of tramadol is 40 weight%, the weight percentage of cumulative release of acetaminophen is never more than 10 weight% unlike the weight percentage of cumulative release of tramadol.

9. The pharmaceutical composition according to claim 1, wherein in the sustained release, after the first hour in sustained release for at least 12 hours, the weight percent cumulative release of acetaminophen is never greater than 10 weight percent, unlike the weight percent cumulative release of tramadol.

10. The pharmaceutical composition of claim 1, wherein the sustained release cumulative release is measured in vitro by the United states Pharmacopeia apparatus II (USP II) paddle method at 37 ℃, 50rpm/900ml in an enzyme-free simulated intestinal fluid dissolution medium at pH 6.8.

11. The pharmaceutical composition of claim 1, comprising a layer of an extended release composition comprising acetaminophen and the complex tramadol material attached to an immediate release layer comprising acetaminophen and tramadol material that is mostly uncomplexed.

12. The pharmaceutical composition of claim 1, comprising a layer of an extended release composition attached to an immediate release layer, the extended release composition comprising a disintegrant, acetaminophen and the complex tramadol material that is a complex of lambda carrageenan and tramadol hydrochloride, the immediate release layer comprising a hydrophilic polymeric retarding agent, acetaminophen and tramadol material that is mostly uncomplexed.

13. The pharmaceutical composition of claim 12, wherein the hydrophilic polymeric delay agent is a member selected from the group consisting of polysaccharides or derivatives thereof, agar, agarose, gums; and the extended release composition comprises hydroxypropyl methylcellulose and a filler.

14. The pharmaceutical composition of claim 1, comprising a layer of an extended release composition adjacent to an immediate release layer, the extended release composition comprising a disintegrant carrier, acetaminophen and the complex tramadol material that is a complex of lambda carrageenan and tramadol hydrochloride, the immediate release layer comprising a hydrophilic polymeric retarding agent, acetaminophen and tramadol material that is mostly uncomplexed.

15. The pharmaceutical composition according to claim 14, wherein in the extended release composition the weight ratio of acetaminophen to tramadol material in the complex tramadol material is from 1: 1 to 20: 1.

16. The pharmaceutical composition according to claim 14, wherein in the extended release composition the weight ratio of acetaminophen to tramadol material in the complex tramadol material is from 5: 1 to 10: 1.

17. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprising acetaminophen and the complex tramadol material is a layer, and both acetaminophen and tramadol in the layer are released in a non-Fickian manner.

18. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprising acetaminophen and the complex tramadol material is a layer, and both acetaminophen and tramadol in the layer are released in this manner: the release index n of tramadol in the Korsmeyer equation is about 0.5 to 0.7, while the release index n of acetaminophen is 0.6 to 0.9.

19. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprising acetaminophen and the complex tramadol material is a layer, and both acetaminophen and tramadol in the layer are released in this manner: t of paracetamol₈₀T with tramadol₈₀Is between 0.9 and 1.1, T₈₀For 8 hours or more.

20. A method of making a pharmaceutical composition dosage form comprising:

forming a composite tramadol material;

forming a tableted form comprising the complex tramadol material and acetaminophen, which exhibits a synergistic sustained release upon dissolution in use, resulting in a synergistic tramadol cumulative release and acetaminophen cumulative release over time.

21. The method of claim 20, comprising forming the composite tramadol material using a tramadol salt and carrageenan.

22. The method of claim 20, comprising using a tramadol salt and carrageenan to form the composite tramadol material as a paste, drying the paste and thereby forming granules.

23. The method of claim 20, comprising using tramadol salt and carrageenan to form the complex tramadol material as a paste, drying the paste, thereby forming granules, and compressing the granules to form the compressed tablet form.

24. The method of claim 20, comprising forming the complex tramadol material using a tramadol salt and lambda carrageenan, thereby forming granules, compressing the granules to form the compressed tablet form, and forming an additional layer on the compressed tablet form, the additional layer comprising a hydrophilic polymeric retarding agent, acetaminophen, and a mostly uncomplexed tramadol material.

25. The method of claim 24, comprising using acetaminophen and the tramadol material in a weight ratio of 1: 1 to 20: 1 to form the compressed tablet form.

26. The method of claim 24, comprising using acetaminophen and the tramadol material in a weight ratio of 5: 1 to 10: 1 to form the compressed tablet form.

27. The method of claim 24, such that in the sustained release when the wt% cumulative release of tramadol is 40 wt%, the wt% cumulative release of acetaminophen is less than 25 wt% different than the wt% cumulative release of tramadol.

28. The method according to claim 24, wherein in the sustained release, starting from when the weight percent cumulative release of tramadol is 40 weight percent, unlike the weight percent cumulative release of tramadol, the weight percent cumulative release of acetaminophen is never greater than 20 weight percent.

29. The method of claim 20, comprising using at least two different hydroxypropyl methylcelluloses to prepare the compressed tablet form.

30. Use of a complex tramadol material in the manufacture of a medicament for treating pain, wherein the medicament comprises a complex tramadol material and acetaminophen, and the medicament exhibits a synergistic sustained release of tramadol and acetaminophen upon oral administration of the medicament to a patient, resulting in a synergistic cumulative release of tramadol and cumulative release of acetaminophen over time.