HK1054698B - Controlled release hydrocodone formulations - Google Patents
Controlled release hydrocodone formulations Download PDFInfo
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- HK1054698B HK1054698B HK03107106.3A HK03107106A HK1054698B HK 1054698 B HK1054698 B HK 1054698B HK 03107106 A HK03107106 A HK 03107106A HK 1054698 B HK1054698 B HK 1054698B
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Description
Background
Since the drug therapy is difficult to cure pain, especially chronic pain, opioid analgesics are ideal controlled release drug formulations. The present invention relates to a solid oral controlled release dosage form for the treatment of pain.
The goal of all controlled (sustained) release formulations is to provide a more sustained drug pellet effect after administration than an immediate release dosage form. Such a long-acting effect has many therapeutic benefits compared to the short-acting effect of an immediate release formulation. This allows the treatment to be continued without disturbing the patient's sleep, for example in the treatment of moderately to severely painful patients (e.g. post-operative patients, cancer patients, etc.), or for patients who are awake with migraines, or for debilitating patients who are at risk of dreaming.
Rapid-acting drug therapy unless carefully timed administration is performed to maintain a stable effective plasma concentration of the drug, the plasma levels of the active drug will peak to valley due to rapid absorption, systemic excretion and metabolic inactivation of the compound, thus causing problems in maintaining the therapeutic effect on the patient. Another advantage of long acting drugs is improved patient compliance because it avoids patients forgetting to administer the drug.
The preparation of compositions which release the contained pharmaceutically active substances slowly after oral administration to humans and animals is a known technique in the pharmaceutical industry. Such sustained release compositions are used to delay absorption of the drug until it reaches a specific site in the digestive tract. The controlled release of the drug in the digestive tract maintains the blood concentration of the drug at a desired level for a longer period of time than administration of conventional immediate release dosage forms.
The prior art relating to the preparation and use of compositions for the slow release of active compounds from carriers has all involved the release of the active substance into the physiological fluids of the digestive tract. However, it is known that the active substance present in the gastrointestinal fluids alone does not ensure its bioavailability by itself.
In order to be absorbed, the active drug must be in solution. The time required for a unit dosage form to release an amount of active agent can be measured under standard conditions and is expressed as the proportion of the amount of active agent that is released from the unit dosage form over a particular period of time. Physiological intestinal gastric fluid is the medium for determining dissolution time. The prior art recognizes that many tests are available to determine the dissolution time of a pharmaceutical composition, and these tests are discussed in various official pharmacopoeias around the world.
While there are many factors that affect the dissolution of a drug from its carrier, the time over which the active drug is dissolved from a particular composition is relatively stable and reproducible by experimentation. Factors that influence dissolution time include the surface area of the drug in contact with the solvent medium, the pH of the solution, the solubility of the drug in a particular solvent, and the driving force for the saturation concentration of the substance in the solvent. Thus, as the active agent is absorbed at the tissue site and eliminated from the solvent, its dissolution concentration dynamically remains steady. Under physiological conditions, the saturation level of solute is replenished by the reserve in the dosage form, thereby maintaining a relatively uniform and constant dissolution concentration in the solvent to achieve stable absorption.
Trans-tissue transport at the site of absorption of gastrointestinal tissue is influenced by the Donnan osmotic equilibrium force on both sides of the membrane, since the direction of the driving force is the difference in the concentration of the active substance on both sides of the membrane, i.e. the difference in the amount of active substance dissolved in the gastrointestinal fluid and in the blood. Since blood concentrations are constantly changing due to dilution, circulation changes, tissue storage, metabolic conversion and systemic excretion, the flow of active substances is from the gastrointestinal tract into the blood.
Various techniques have been used to prepare controlled release dosage forms. Specifically, coated pellets, tablets and capsules slowly release the active drug by selective disintegration of their coating or by admixture with a specific matrix to affect drug release, as is known in the art. Certain controlled release formulations achieve sequential release over a predetermined period of time following administration of a single dose of the active compound.
Examples of controlled release opioid formulations described in the patent literature include: U.S. Pat. Nos. 4,990,341 and 4,844,909(Goldie et al), both assigned to the assignee of the present invention, wherein the in vitro dissolution rates of the hydromorphone composition dosage forms are as follows, as measured by 37 ℃, 900ml buffer (pH1.6-7.2), USP paddle or basket method at 100 rpm: 12.5-42.5 wt% hydromorphone after 1 hour, 25-55 wt% after 2 hours, 45-75 wt% after 4 hours, 55-85 wt% after 6 hours, an in vitro release rate within the pH range of 1.6-7.2 independent of pH, and a peak in vivo hydromorphone plasma concentration occurring between 2-4 hours after administration. The hydromorphone formulations described above provide pain relief for at least 12 hours.
There is a great need for sustained release dosage forms of other opioid analgesics that are useful for the treatment of moderate pain. Moreover, there is a great need for controlled release dosage forms whose pharmacokinetic profile provides optimal analgesic efficacy.
Summary of The Invention
One of the purposes of the invention is to obviously improve the analgesic effect on patients with moderate pain.
It is also an object of the present invention to provide a bioavailable hydrocodone preparation that can significantly improve analgesic efficiency and efficacy.
It is also an object of the present invention to provide a bioavailable controlled release hydrocodone formulation having a significantly longer duration of analgesic effect than an immediate release hydrocodone formulation but a rapid onset of action.
It is also an object of the present invention to provide oral controlled release opioid formulations suitable for twice daily administration which exhibit early onset of action, relatively flat plasma profiles after reaching peak concentrations between administrations, and a C for opioid plasma levels12/CmaxThe ratio of the total weight of the powder to the total weight of the powder is 0.55-0.85, and the powder can effectively relieve pain of patients. In other embodiments, C of the dosage form12/CmaxThe ratio of the ratio is 0.65-0.75.
The above and other objects can be accomplished by the features of the present invention which in certain embodiments provides a solid oral controlled release dosage form comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof and a sufficient amount of a controlled release material to render the dosage form suitable for twice daily administration, wherein the dosage form provides a time to peak plasma concentration of hydrocodone in vivo after a time of about 2 to about 8 hours (Tmax) after a peak plasma concentration of hydrocodone in vivo has occurred and a C after the peak plasma concentration has been reached after a single administration to a human patient12/CmaxThe ratio of the ratio is 0.55-0.85.
In some preferred embodiments, the following is measured by the USP basket method: at 37 ℃, the in vitro release rate of the hydrocodone or the salt thereof after 1 hour of the controlled release formulation is measured to be 18 to 42.5wt percent in 700ml Simulated Gastric Fluid (SGF) at 100rpm for 55 minutes and then transferred into 900ml Simulated Intestinal Fluid (SIF).
In some preferred embodiments, the following is measured by the USP basket method: at 37 ℃, 900ml of buffer solution with pH1.2-7.5, 100rpm, said hydrocodone dosage form having an in vitro dissolution rate of hydrocodone or a pharmaceutically acceptable salt thereof of: after 2 hours, the weight is about 25 to 65 wt%, after 4 hours, the weight is 45 to 85 wt%, and after 8 hours, the weight exceeds 60 wt%. Although the rate of in vitro release may be pH independent or pH dependent, as desired, in a preferred embodiment of the invention, the release of hydrocodone is pH independent.
In some preferred embodiments, there is provided a controlled release dosage form comprising a therapeutically effective amount of hydrocodone which provides a plasma concentration of hydrocodone of at least 5 to 6ng/ml at 12 hours after administration and at least 8ng/ml at 2 to 8 hours after administration.
In other preferred embodiments of the present invention, there is provided a twice daily oral controlled release dosage form of hydrocodone having a Cmax which is lower than that of an equivalent immediate release hydrocodone reference preparation (e.g., a reference preparation of equivalent immediate release hydrocodone)) 50% of Cmax, and can effectively relieve pain within the administration interval of 12 hours.
In other preferred embodiments of the present invention, there is provided a twice-daily oral controlled release dosage form of hydrocodone that achieves a Cmax of 80% in a time period approximating that of an equivalent dose of an immediate release hydrocodone reference preparation (e.g., a reference preparation of hydrocodonePreferably about 90 to about 150%, more preferably about 90 to about 110%. Preferably, the time required for the controlled release dosage form to achieve a Cmax of 80% hydrocodone is about 0.5 to 1.5 hours, more preferably 0.8 to 1.2 hours. In other embodiments, the time required for the controlled release dosage form to achieve a Cmax of 80% hydrocodone is about 0.75 to 2.0 hours, preferably 0.9 to 1.5 hours.
In other preferred embodiments of the present invention, there is provided a twice-daily oral controlled release dosage form of hydrocodone that achieves a Cmax of 90% in a time period approximating that of an equivalent dose of an immediate release hydrocodone reference preparation (e.g., a reference preparation of hydrocodoneOf 150-. Preferably, the time required for the controlled release dosage form to achieve a Cmax of 90% hydrocodone is about 1.5 to 2.5 hours, more preferably 1.8 to 2.2 hours. In other embodiments, the time required for the controlled release dosage form to achieve a Cmax of 90% hydrocodone is about 1.5 to 4.0 hours, preferably about 1.8 to 2.5 hours.
In other preferred embodiments of the present invention, there is provided a twice daily oral controlled release dosage form of hydrocodone which maintains plasma concentrations at 80% Cmax for a period of time up to about 0.5 to 10 hours, preferably 1 to 9 hours or 4 to 8 hours.
In other preferred embodiments of the present invention, there is provided a twice daily oral controlled release dosage form of hydrocodone that maintains plasma concentrations at 90% Cmax for a period of time up to about 1 to 6.5 hours, preferably 2 to 5 hours or 2 to 6.5 hours.
In other preferred embodiments of the present invention, there is provided a twice daily oral controlled release dosage form of hydrocodone, having a mean in vivo absorption rate from administration to Tmax of 1.5 to 5 mg/hr and a mean absorption rate from Tmax to the end of the administration period of less than 0.5 mg/hr, based on an oral dosage form containing 15mg hydrocodone ditartrate. Preferably, the oral dosage form comprises 15mg hydrocodone bitartrate, wherein the average in vivo absorption rate is from about 2 to about 4 mg/hr from administration to Tmax and from about 0.08 to about 0.4 mg/hr at the end of the administration period from Tmax to 12 hours.
In other preferred embodiments of the present invention, there is provided a twice daily oral controlled release dosage form of hydrocodone having an absorption rate from about 55 to about 85% of the elimination rate from Tmax to a period of 12 hours after administration.
Preferably, the Tmax of these and other embodiments of the invention is 3 to 4 times later than that of an equivalent dose of an immediate release hydrocodone reference preparation. Preferably, the Tmax of the sustained release formulation occurs at about 2 to 8 hours, about 3 to 7 hours, or 4 to 6 hours after oral administration.
The invention also relates to hydrocodone preparations comprising: the hydrocodone Cmax is less than about 50%, preferably less than about 40%, of the equivalent immediate release reference product.
For example, it was a surprising discovery of the present invention that when hydrocodone is formulated in the delivery systems described in U.S. Pat. Nos. 4,861,598 and 4,970,075, the percentage of hydrocodone Cmax in such systems relative to an immediate release reference product is lower than that of oxycodone formulated in the same delivery system. Although oxycodone and hydrocodone controlled release formulations showed similar dissolution profiles in vitro, the above was quite evident.
When the present invention is formulated with the delivery system described in us patent 4,861,598 and 4,970,075, the percentage of Cmax of the system relative to the immediate release reference product is less than 50%, preferably less than 40%, and oxycodone is greater than 50%.
For the purposes of the present invention, "hydrocodone" includes hydrocodone free base, and pharmaceutically acceptable salts and complexes thereof.
The "USP paddle or basket method" is the method described in US pharmacopoeia XXII (1990).
For the purposes of the present invention, "pH-dependent" means a characteristic that varies with the surrounding pH (e.g. dissolution).
For the purposes of the present invention, "pH independent" means a property that is not affected by the surrounding pH (e.g. dissolution).
For the purposes of the present invention, "bioavailability" refers to the degree to which a drug (e.g., hydrocodone) is absorbed in a unit dosage form.
For purposes of the present invention, "controlled release" means that the rate of release of the drug (e.g., hydrocodone) is such that the blood (e.g., plasma) concentration remains within the therapeutic range for at least about 12 hours, but below toxic concentrations.
"Cmax" means the highest plasma concentration achieved during the dosing interval.
"Tmax" means the time required to reach the maximum plasma concentration (Cmax).
“T1/2(absorption) "means the time required for half of the absorbable dose of opioid to transport into the plasma.
By "steady state" is meant that the plasma concentration achieved by a given drug is maintained above the minimum therapeutic concentration of the drug, below the minimum toxic plasma concentration, by continuous administration. In the case of opioid analgesics, the minimum therapeutic concentration may be determined to some extent by the degree of pain relief achieved for a particular patient. Those skilled in the medical arts will appreciate that pain levels are highly subjective and vary widely from patient to patient.
For the purposes of the present invention, "maintenance therapy" and "long-term therapy" refer to drug therapy administered to a patient after the patient has reached the above-mentioned steady state via opioid analgesic administration.
The "minimum analgesically effective concentration" or "MEAC" of an opioid such as hydrocodone is very difficult to determine. However, there is generally a minimum analgesically effective plasma concentration of hydrocodone below which there is no analgesic effect. Although there is an indirect correlation between, for example, hydrocodone plasma levels and analgesic effects, higher, more sustained plasma levels are generally associated with better analgesic effects. There is a lag period between the time when the plasma level of hydrocodone reaches its maximum and the time when the effect of the drug reaches its maximum. This is true for all opioid analgesics that treat pain.
The calculated value relates to absorption, distribution and elimination and depends to some extent on the dosage form containing the active ingredient.
In the present invention, unless otherwise indicated, "a patient" means that the discussion (or claims) is in the context of pharmacokinetics of a single patient.
By "patient population" is meant a representation that the discussion (or claims) made is the pharmacokinetic profile of at least two patients.
"breakthrough pain" refers to the pain experienced by the patient despite the patient being administered a generally effective amount of the sustained release solid oral dosage form of the present invention containing hydromorphone.
"rescue" refers to the dosage of analgesic administered to a patient experiencing breakthrough pain.
"effective analgesia" refers to both the objective assessment of a physician's response to a patient receiving an analgesic treatment and the subjective assessment of treatment by a patient receiving such treatment. One skilled in the art will recognize that effective analgesia depends on many factors, including individual patient variability.
For the purposes of the present invention, a "reference preparation for immediate release of hydrocodone" is an equivalent doseHydrocodone (available from UCBPharma, Inc), or other hydrocodone or a pharmaceutically acceptable salt thereof in an immediate release drug product.
In the present invention, both the controlled release and immediate release formulations are dose proportional. In such formulations, the increase in pharmacokinetic parameters (e.g., AUC and Cmax) from one dose intensity to another dose intensity is linear. Thus, the pharmacokinetic parameters for a particular dose can be derived from the parameters for other doses of the formulation.
In the present invention, unless otherwise specified, the pharmacokinetic parameters are based on a single administration of a hydrocodone preparation to a patient. Pharmacokinetic parameters based on patient population will be expressed as "average" numbers.
"first administration" refers to one administration to a patient or group of patients at the beginning of treatment.
Surprisingly, the controlled release oral solid dosage form of the present invention provides a savings in the amount of opioid. The daily dose of the controlled release oral solid dosage form can be greatly lower than that of the conventional quick release product, but the analgesic effect is not different. Better results are obtained with the controlled release oral solid dosage form of the invention over a comparable daily dose compared to conventional immediate release products.
Brief Description of Drawings
The drawings are intended to illustrate embodiments of the invention and not to limit the scope of the invention as claimed.
Figure 1 shows the mean hydrocodone plasma concentration for examples 1, 2, 3 and an equivalent dose of immediate release hydrocodone.
Figure 2 shows the average hydrocodone plasma concentrations of examples 1, 2 and 3 compared to the controlled release oxycodone samples prepared according to the method of example 4 and the controlled release morphine samples prepared according to the method of example 5.
Figure 3 shows the percent absorption of hydrocodone for examples 1, 2, 3 and an equivalent dose of immediate release hydrocodone over various periods of time.
Detailed Description
The above-described embodiments of the present invention may be practiced with a variety of controlled release formulations known in the art. Such as the controlled release dosage forms described in U.S. patents 4,861,598 and 4,970,075.
In some embodiments of the invention, the formulation comprises an effective amount of an opioid in an immediate release dosage form. The amount of immediate release dosage form opioid contained is effective to shorten the time required to reach the maximum concentration of opioid in the blood (e.g., plasma), resulting in a decrease in Tmax to, for example, 2-5 hours or 2-4 hours. It has been found that inclusion of an effective amount of an immediate release opioid as described above in a unit dosage form provides significant relief to the patient of more intense pain. In such embodiments, the effective amount of the immediate release opioid may be coated onto the matrix of the present invention. For example, where extended release of the opioid from the formulation is achieved by a controlled release coating, the immediate release layer may be coated over the controlled release coating. On the other hand, when the opioid is incorporated in a controlled release matrix, the immediate release layer may be coated on the surface of the matrix. If multiple sustained release matrices (e.g., multiparticulate systems of pellets, prills, beads, etc.) containing an effective unit dose of the opioid are contained within a hard gelatin capsule, the immediate release portion of the opioid dose may be incorporated into the gelatin capsule in powder or granular form. Alternatively, the gelatin capsule itself may be coated with an immediate release layer of the opioid. Those skilled in the art will recognize that there are other ways to incorporate an immediate release portion of an opioid into a unit dose. These should be considered as being encompassed by the claims that follow.
One of the advantages of the opioid dosage forms of the present invention is that the therapeutic concentrations are substantially achieved without a significant increase in the intensity and/or extent of concomitant side effects such as nausea, vomiting or lethargy that often accompany high blood levels of opioids. There is also evidence that the risk of drug addiction may be reduced by using the dosage forms of the present invention.
Active substance
The controlled release oral dosage form of the invention preferably comprises from about 0.5 to 1250mg hydrocodone or an equivalent amount of a pharmaceutically acceptable salt thereof, and in a preferred embodiment may be from about 5 to 60mg, for example 15 mg. Suitable pharmaceutically acceptable salts of hydrocodone include: hydrocodone bitartrate, hydrocodone bitartrate hydrate, hydrocodone hydrochloride, hydrocodone p-toluenesulfonate, hydrocodone phosphate, hydrocodone thiosemicarbazone, hydrocodone sulfate, hydrocodone trifluoroacetate, hydrocodone hemihydrate, hydrocodone pentafluoropropionate, hydrocodone p-nitrohydrazone, hydrocodone o-methyloxime, hydrocodone semicarbazone, hydrocodone hydrobromide, hydrocodone mucate, hydrocodone oleate, hydrocodone dihydrogen phosphate, hydrocodone hydrogen phosphate, hydrocodone inorganic acid salt, hydrocodone organic acid salt, hydrocodone acetate trihydrate, di (heptafluorobutyric acid) hydrocodone, di (methylcarbamic acid) hydrocodone, di (pentafluoropropionic acid) hydrocodone, di (pyridinecarboxylic acid) hydrocodone, di (trifluoroacetic acid) hydrocodone, hydrocodone hydrochloride, and hydrocodone sulfate pentahydrate. Hydrocodone bitartrate is preferred in the present invention.
The dosage form of the present invention may also contain one or more additional drugs which act, with or without synergism, with the hydrocodone analgesic of the invention. Examples of such drugs include: non-steroidal anti-inflammatory drugs, such as ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubfen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, moraprofen, trioxofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, thiofenac, zidometacin, acemetacin, fentiazac, clidanac, oxepirac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, sudoxicam or isoxicam. Such non-steroidal anti-inflammatory drugs also include cyclooxygenase inhibitors such as celecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxicam, 6-methoxy-2-naphthylacetic acid (6-MNA), Vioxx (MK-966), nabumetone (a prodrug of 6-MNA), nimesulide, NS-398, SC-5766, SC-58215 and T-614, amantadine (1-aminoadamantane) and memantine (3, 5-dimethylaminoadamantanone), mixtures thereof, and pharmaceutically acceptable salts thereof.
Other additional agents include nontoxic NMDA receptor antagonists such as dextrorphan, dextromethorphan, 3- (1-naphthyl) -5- (phosphonomethyl) -L-phenylalanine, 3- (1-naphthyl) -5- (phosphonomethyl) -DL-phenylalanine, 1- (3, 5-dimethylphenyl) naphthalene and 2- (3, 5-dimethylphenyl) naphthalene, 2SR, 4RS-4- (((1H-tetrazol-5-yl) methyl) oxy) piperidine-2-carboxylic acid; 2SR, 4RS-4- (((((1H-tetrazol-5-yl) methyl) oxy) methyl) piperidine-2-carboxylic acid; e and Z2SR-4- (O- (1H-tetrazol-5-yl) methyl) methanoximino) piperidine-2-carboxylic acid; 2SR, 4RS-4- ((1H-tetrazol-5-yl) thio) piperidine-2-carboxylic acid; 2SR, 4RS-4- (5-mercapto-1H-tetrazol-1-yl) piperidine-2-carboxylic acid; 2SR, 4RS-4- (5-mercapto-2H-tetrazol-2-yl) piperidine-2-carboxylic acid; 2SR, 4RS-4- (5-mercapto-1H-tetrazol-1-yl) piperidine-2-carboxylic acid; 2SR, 4RS-4- (5-mercapto-2H-tetrazol-2-yl) piperidine-2-carboxylic acid; 2SR, 4RS-4- (((1H-tetrazol-5-yl) thio) methyl) piperidine-2-carboxylic acid; 2SR, 4RS-4- ((5-mercapto-1H-tetrazol-1-yl) methyl) piperidine-2-carboxylic acid; or 2SR, 4RS-4- ((5-mercapto-2H-tetrazol-2-yl) methyl) piperidine-2-carboxylic acid; mixtures thereof, and pharmaceutically acceptable salts thereof.
Other suitable additional medicaments that may be included in the formulations of the present invention include: acetaminophen, aspirin, neuroactive steroids (such as those described in U.S. patent application 09/026,520(1998 application 2/20)) and other non-opioid analgesics.
For example, if a second drug (other than an opioid) is included in the formulation, the drug may be in a controlled release dosage form or an immediate release dosage form. The additional drug may be contained in a controlled release matrix with the opioid; contained in a controlled release coating; included in the formulation as another controlled release layer or immediate release layer; or in the form of powder, granules, etc. together with the matrix according to the invention in gelatin capsules.
In some embodiments of the present invention, a controlled release unit dosage form hydrocodone formulation for administration comprises an effective amount of an immediate release dosage form hydrocodone. The immediate release hydrocodone is present in an amount effective to shorten the time required to achieve a Cmax of hydrocodone in blood (e.g., plasma). In such embodiments, an effective amount of immediate release hydrocodone may be coated outside the matrix of the present invention. For example, if a delayed release of hydrocodone is achieved by a controlled release coating, an immediate release layer may be coated over the controlled release coating. On the other hand, if hydrocodone is contained in a controlled release matrix, the immediate release layer can be coated outside the matrix. If multiple sustained release matrices (e.g., multiparticulate systems of pellets, prills, beads, etc.) containing an effective unit dose of the opioid are contained within a hard gelatin capsule, the immediate release portion of the opioid dose may be incorporated into the gelatin capsule in powder or granular form. Alternatively, the gelatin capsule itself may be coated with an immediate release layer of the opioid. One skilled in the art will recognize that there are other ways to incorporate the immediate release hydrocodone portion into a unit dose. These should be considered as being encompassed by the claims that follow. It has been found that significant relief from severe pain in patients can be obtained by incorporating an effective amount of immediate release hydrocodone in a unit dosage form.
Dosage forms
The controlled release dosage form may optionally comprise a controlled release material incorporated into the matrix with the hydrocodone or coated as a slow release coating over a drug-containing matrix (so-called "matrix includes pellets, granules, spheres, tablets, cores and the like). The controlled-release material may be either hydrophobic or hydrophilic as necessary. The oral dosage form of the present invention may be, for example, granules, pellets (hereinafter collectively referred to as "multiparticulates"). The multiparticulates may be encapsulated in an amount sufficient to provide the desired dose of opioid effectively over a period of time, or incorporated into a variety of other suitable oral solid dosage forms, such as compressed tablets. Alternatively, the oral dosage forms of the present invention may be formed into a core and then coated with a controlled release coating, or formed into tablets containing the drug, controlled release material and optionally other ingredients (e.g., diluents, binders, pigments, lubricants, etc.) in a matrix.
Controlled release matrix formulations
In some embodiments of the invention, the controlled release formulation is made from a matrix (e.g., a matrix tablet) comprising the controlled release material described above. Dosage forms containing a controlled release matrix have an opioid in vitro dissolution rate within the preferred range and have a pH-dependent or pH-independent dissolution profile. The materials suitable for inclusion in the controlled release matrix depend on the method of forming the matrix. The oral dosage form may comprise 1-80 wt% of at least one hydrophilic or hydrophobic controlled release material.
Suitable controlled release materials for inclusion in the controlled release matrix of the present invention include, but are not limited to, hydrophilic and/or hydrophobic materials such as gums, cellulose ethers, acrylic resins, protein derived materials, waxes, shellac and fats and oils such as hydrogenated castor oil, hydrogenated vegetable oil and the like. However, any pharmaceutically acceptable hydrophobic or hydrophilic controlled release material can be used in the present invention so long as controlled release of the opioid is achieved. Preferred controlled release polymers include alkyl celluloses, such as ethyl cellulose, acrylic and methacrylic acid polymers and copolymers, cellulose ethers, especially hydroxyalkyl celluloses (especially hydroxypropyl methylcellulose) and carboxyalkyl celluloses. Preferred acrylic and methacrylic polymers and copolymers include methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), methacrylic acid-alkylamine copolymers, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), polymethacrylates, polyacrylamides, poly (methacrylic anhydride) and glycidyl methacrylate copolymers. Certain preferred embodiments utilize the controlled release material mixtures described above in the matrices of the present invention.
The matrix may also comprise a binder. In such embodiments, the binder desirably contributes to the controlled release of hydrocodone from the controlled release matrix.
Preferred hydrophobic binders are water-insoluble substances which have a pronounced tendency to be hydrophilic and/or hydrophobic to a greater or lesser extent. Preferably, the hydrophobic binders useful in the present invention have a melting point of about 30 to about 200 deg.C, more preferably about 45 to about 90 deg.C. When the hydrophobic substance is a hydrocarbon, the melting point is preferably between 25 and 90 ℃. In long chain hydrocarbons (C)8-50) Among them, fatty alcohols are preferred. The oral dosage form of the invention may contain up to 80% by weight of at least one digestible long chain hydrocarbon.
Preferably, the oral dosage form contains up to 80% by weight of at least one polyalkylene glycol. Specifically, the hydrophobic binder may comprise a natural or synthetic wax, a fatty alcohol (such as lauryl, myristyl, stearyl, cetyl, or preferably cetostearyl alcohol), a fatty acid (including, but not limited to, fatty acid esters, fatty acid glycerides (mono-, di-, or tri-esters), hydrogenated fats, hydrocarbons, common waxes, stearic acid, stearyl alcohol, and hydrophobic and hydrophilic materials having a hydrocarbon backbone.
Preferred hydrophobic binders useful in the present invention include digestible long chain (C)8-50In particular C12-40) Saturated or unsaturated hydrocarbons, such as fatty acids, fatty alcohols, glycerol fatty acid esters, mineral and vegetable oils, natural and synthetic waxes and polyalkylene glycols. Hydrocarbons having melting points of about 25-90 c are preferred. Among long chain hydrocarbon binders, fatty alcohols are preferred in some embodiments. The oral dosage form of the invention may contain up to 80% by weight of at least one digestible long chain hydrocarbon.
In some preferred embodiments, the matrix formulation comprises a mixture of two or more hydrophobic binders. If another hydrophobic binder is present, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols and mixtures thereof. Examples thereof include cerulean wax, carnauba wax, stearic acid, and stearyl alcohol. The above is not exhaustive.
A specific preferred controlled release matrix comprises at least one water-soluble hydroxyalkyl cellulose, at least one C12-36(C14-22More preferably) fatty alcohols, and optionally at least one polyalkylene glycol. The hydroxyalkyl cellulose is preferably C1-6Hydroxyalkyl celluloses, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, and especially hydroxyethyl cellulose. The amount of the at least one hydroxyalkyl cellulose present in the oral dosage form of the present invention will depend upon such factors as the precise rate of opioid release desired. The fatty alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. However, in a particularly preferred embodiment of the oral dosage form of the present invention, the at least one fatty alcohol is cetyl alcohol or cetearyl alcohol. The amount of fatty alcohol present in the oral dosage form of the present invention depends, as previously mentioned, on the exact rate of opioid release required and on whether the oral dosage form contains at least one polyalkylene glycol. If no polyalkylene glycol is present, the oral dosage form preferably comprises 20-50 wt% fatty alcohol; if a polyalkylene glycol is present, the sum of the fatty alcohol and polyalkylene glycol content is preferably from 20 to 50% by weight of the total dosage form.
In a preferred embodiment, for example, the ratio of the at least one hydroxyalkyl cellulose or acrylic resin to the at least one fatty alcohol/polyalkylene glycol determines to a considerable extent the rate of release of the opioid from the formulation. The ratio of hydroxyalkyl cellulose to fatty alcohol/polyalkylene glycol is from 1: 2 to 1: 4, preferably from 1: 3 to 1: 4.
The polyalkylene glycol may be, for example, polypropylene glycol or preferably polyethylene glycol. The number average molecular weight of the at least one polyalkylene glycol is preferably from 1,000 to 15,000, more preferably from 1,500 to 12,000.
Another suitable controlled release matrix comprises alkylcellulose (especially ethyl)Cellulose), C)12-36Fatty alcohols and optionally polyalkylene glycols.
In addition to the above components, the controlled release matrix may contain suitable amounts of other materials such as diluents, lubricants, binders, granulation aids, pigments, flavors and glidants commonly used in the pharmaceutical industry.
To facilitate the preparation of the solid controlled release oral dosage form of the present invention, another aspect of the invention is a method of preparing the same, comprising mixing an opioid or salt thereof into a controlled release matrix, which may be carried out as follows:
(a) making particles comprising at least one of the above hydrophobic and/or hydrophilic substances (e.g., water-soluble hydroxyalkyl cellulose) and hydrocodone;
(b) mixing particles containing at least one hydrophobic and/or hydrophilic substance with at least one C12-36Mixing fatty alcohol;
(c) optionally, the granules are compressed and shaped.
The above granules can be prepared by various methods well known in the pharmaceutical formulation industry. For example, in a preferred method, the particles are formed by wet hydroxyalkyl cellulose/opioid granulation with water. In a particularly preferred embodiment of the process, the amount of water added during wet granulation is 1.5 to 5 times, more preferably 1.75 to 3 times the dry weight of the opioid.
The matrices of the invention may also be prepared by the melt-pelleting technique. At this point, the finely divided opioid is mixed with a binder (again in particulate form) and optionally other inert ingredients, and the mixture is then formed into particles (granules, pellets) by mechanical action, for example, in a high shear mixer. Then, pellets (granules, pellets) having a prescribed size are screened. The binder is preferably in the form of particles and has a melting point above 40 ℃. Suitable binders include, for example, hydrogenated castor oil, hydrogenated vegetable oil, other hydrogenated fats, fatty alcohols, fatty acid esters, fatty acid glycerides, and the like.
Controlled release matrices can also be prepared by, for example, melt granulation (granulation) or melt extrusion techniques. Melt granulation techniques generally involve melting a hydrophobic binder (e.g., a wax), which is usually in a solid state, to incorporate the drug powder. To obtain a controlled release dosage form, it may be desirable to incorporate a hydrophobic controlled release material (e.g., ethylcellulose or a water-soluble acrylic polymer) into a molten waxy hydrophobic binder. Controlled release formulations prepared by melt granulation techniques can be found in U.S. patent 4,861,598, assigned to the assignee of the present invention.
The additional hydrophobic adhesive may comprise one or more water-insoluble waxy thermoplastic materials possibly mixed with another waxy thermoplastic material of slightly lower hydrophobicity. To achieve controlled release, the various waxy materials in the formulation must not substantially degrade or dissolve in gastrointestinal fluids during the initial stages of release. Useful water-insoluble waxy binders are those having a solubility in water of less than 1: 5,000 (w/w).
In addition to the above components, the controlled release matrix may also contain suitable amounts of other substances, as required, such as diluents, lubricants, binders, granulation aids, pigments, flavors and glidants (glidants), which are generally used in the pharmaceutical industry, in a total amount of about 50% by weight of the total amount of granules. The amount of these additional materials should be sufficient to produce the desired effect on the desired formulation. Specific examples of pharmaceutically acceptable carriers and excipients used to formulate oral dosage forms can be found inA handbook of pharmaceutical excipients,American Pharmaceutical Association(1986)。
preparing a suitable melt-extruded substrate of the present invention comprises: the opioid analgesic is mixed with the controlled release material, preferably a binder, to form a homogeneous mixture. The homogeneous mixture is then heated until it is at least softened to enable extrusion. The mixture is then extruded, for example, using a twin-screw extruder to form strands. The extrudate is then cooled and cut into multiparticulates by methods known in the art. The multiparticulates are then divided into unit doses. The diameter of the extrudate is preferably from 0.1 to 5mm and should achieve controlled release of the active agent over a period of about 8 to 24 hours.
An alternative method of preparing the melt-extruded formulation of the present invention comprises directly metering the hydrophobic controlled release material, active drug and optional binder into an extruder; heating the homogeneous mixture; extruding the homogeneous mixture into a strip; cooling the ribbon containing the homogeneous mixture; cutting the mixture into granules of about 0.1-12mm in size; dividing the particles into unit doses. In this section, a relatively continuous production process can be achieved.
The plasticizers described hereinbefore may be incorporated in the melt-extruded matrix. The plasticizer is preferably 0.1 to 30 wt% of the matrix. The controlled release matrix of the invention can also comprise talc, monosaccharide or polysaccharide, pigment, essence, lubricant and other pharmaceutical excipients. Their content depends on the properties to be obtained.
The thickness of the extruded strands can be varied by adjusting the diameter of the extruder orifices. Further, the extrusion port of the extruder is not necessarily circular but may be oval, rectangular, or the like. The extruded strands can be cut into pellets using a hot wire cutter or guillotine. The melt extrusion type multiparticulate system may be in the form of pellets, prills or granules depending on the extrusion orifice of the extruder. For purposes of the present invention, "melt-extruded multiparticulates" and "melt-extruded multiparticulate systems" and "melt-extruded particles" both refer to a collection of unit entities, preferably all of similar size and/or shape, and containing one or more active agents and one or more excipients, and preferably comprising a hydrophobic controlled release material. Preferably, the melt-extruded multiparticulates have a particle size of from about 0.1 to about 12mm in length and from about 0.1 to about 5mm in diameter. Further, it is to be understood that the melt-extruded multiparticulates can be in various geometric shapes of the above size, such as beads, seeds, pellets, and the like. Alternatively, the extrudate can be cut directly into active drug unit dosage forms of the desired length without undergoing a spheronization process.
In a preferred embodiment, the oral dosage form is prepared by encapsulating an effective amount of melt-extruded multiparticulates. For example, a plurality of melt-extruded multiparticulates can be loaded into a gelatin capsule in an amount sufficient to provide an effective controlled release dosage when ingested and exposed to gastric fluid.
In another preferred embodiment, a suitable amount of the multiparticulate extrudate is compressed into an oral tablet by standard conventional tableting techniques. Techniques and formulations for the manufacture of tablets (compressed or molded tablets), capsules (hard, soft gelatin capsules) and pills can also be found inRemington pharmaceuticals(edit: Arthur Osol), 1553-1593 (1980).
In another preferred embodiment, the extrudate can be formed into tablets as described in U.S. patent 4,957,681(Klimesch et al).
Optionally, the controlled release matrix multiparticulate system or the tablet or gelatin capsule may be coated with a controlled release coating as described previously. The coating preferably comprises a sufficient amount of hydrophobic and/or hydrophilic controlled release material to provide a weight gain of about 2-25 wt%, however, the coating will depend to a greater extent on such factors as the physical characteristics of the particular opioid analgesic being used and the desired rate of release.
The dosage form of the present invention may also comprise a blend of melt-extruded multiparticulates comprising one or more opioid analgesics. Moreover, the dosage form may also include an amount of an immediate release drug to achieve immediate therapeutic effect. The immediate release drug may be other pellets contained within a gelatin capsule or coated over beads or melt-extruded multiparticulates. The unit dosage form of the present invention may further comprise, for example, a mixture of controlled release beads and matrix multiparticulates to achieve the desired effect.
Preferably, the controlled release dosage form of the present invention provides for the slow release of the therapeutically active agent upon ingestion and subsequent contact with gastric and intestinal fluids. The controlled release profile of the melt-extruded formulations of the present invention can be varied by, for example, varying the amount of controlled release material, varying the ratio of plasticizer content to other matrix components, hydrophobic materials, adding other ingredients or excipients, varying the manufacturing process, etc.
In other embodiments of the invention, the melt-extruded formulation is prepared without a therapeutically active drug, which is added to the extrudate after extrusion. Such formulations are generally prepared by mixing the therapeutically active drug with an extruded matrix material and then compressing the mixture into a sustained release dosage form. Such formulations are suitable where the therapeutically active drug is sensitive to the temperature required to soften the hydrophobic material and/or the sustained release material.
A typical melt extrusion production system suitable for the present invention comprises: suitable extruders drive motors with adjustable speed but constant torque, with on-off control and galvanometers. In addition, the production system should have a temperature control platform including temperature sensors, cooling mechanisms and temperature display mechanisms mounted along the entire length of the extruder. In addition, the production system should include an extruder, such as a twin screw extruder, having two counter-rotating intermeshing screws located in a barrel having an orifice or die at the exit of the barrel. The material is fed from a hopper, moved along a barrel by a screw, forced through a die to form a rod, and then transported, for example, by a conveyor belt to cool and to a pellet mill or other suitable machine to form the extruded rod into a multi-pellet system. The pellet mill may be comprised of rollers, fixed blades, rotary cutters, and the like. Suitable equipment and systems are available from c.w. brabender Instruments, inc, South hacksenack, New Jersey, et al. Other suitable devices are known to those of ordinary skill in the art.
The invention also relates to a process for the preparation of melt-extruded multiparticulates which requires control of the air content in the extrudate. By controlling the air content in the extrudate, we have surprisingly found that the rate of release of the therapeutically active drug from, for example, a multiparticulate extrudate is significantly altered. In some of the examples, we have surprisingly found that the pH dependence of the extruded product is also altered.
Thus, in another aspect of the invention, air is substantially excluded during extrusion to produce a melt extrusion product. This can be achieved, for example, by using a Leistritz extruder with a vacuum mechanism. Surprisingly, the extruded multiparticulates of the present invention made using a Leistritz extruder under vacuum have significantly different physical properties. Specifically, the extrudate is substantially free of porosity as observed, for example, with a scanning electron microscope providing a Scanning Electron Micrograph (SEM). While this is contrary to general imagination, we have found that such substantially non-porous formulations release the therapeutically active agent more rapidly than formulations prepared without vacuum. SEM of extruded multiparticulates under vacuum appeared very smooth with multiparticulates having a higher fastness than those prepared without vacuum. It has been found that, at least in part of the formulation, the pH dependence of the extruded multiparticulates formed by vacuum extrusion is higher than that of an equivalent formulation prepared without vacuum.
Method for preparing substrate beads
The controlled-release formulation of the present invention may be prepared in the form of a matrix bead formulation. The matrix beads comprise a sphering agent and hydrocodone.
Hydrocodone is preferably present in an amount of about 0.01 to 99 wt%, preferably 0.1 to 50 wt%, based on the weight of the matrix beads.
The nodulariser which may be used to prepare the matrix beads of the invention includes various known nodularisers, preferably cellulose derivatives, especially microcrystalline cellulose. A suitable microcrystalline cellulose is, for example, Avicel PH 101 (trade mark, FMCCorporation). The spheronizing agent preferably comprises about 1 to 99 wt% of the matrix beads.
In addition to the active ingredient and the spheronizing agent, the spheroids may also contain a binder. Suitable binders, for example low-viscosity water-soluble polymers, are well known to the person skilled in the pharmaceutical industry. However, preferred are water-soluble hydroxy lower alkyl celluloses, such as hydroxypropyl cellulose.
In addition to the opioid analgesic and the spheronizing agent, the matrix bead formulations of the present invention also contain the aforementioned controlled release materials, preferably acrylic and methacrylic acid polymers or copolymers, and ethyl cellulose. When included in the formulation of the present invention, the controlled-release material is present in an amount of about 1 to 80 wt% of the matrix beads. Preferably, the controlled release material is present in the matrix bead formulation in an amount sufficient to achieve controlled release of the opioid analgesic from the beads.
The matrix bead preparation may also contain medicinal processing aids such as adhesive and diluent. Their content in the adjuvant depends on the properties which the desired formulation exhibits.
A controlled release coating comprising the aforementioned controlled release material may be coated on the outside of the matrix beads. The controlled release coating provides a weight gain of the raw matrix beads of about 5-30%. The amount of controlled release coating depends on many factors, such as the composition of the matrix beads, and the chemical and/or physical properties of the opioid analgesic (i.e., hydrocodone).
The matrix beads are typically prepared by mixing together the spheronizing agent and the opioid analgesic, for example, by wet granulation. The resulting particles are then spheronized into matrix beads. The matrix beads are then optionally over-coated with a controlled release coating using the methods previously described.
Another method of preparing matrix beads is, for example: (a) preparing a granulate comprising at least one water-soluble hydroxyalkyl cellulose and an opioid or salt thereof; (b) mixing the hydroxyalkyl cellulose-containing granules with at least one C12-36Mixing fatty alcohol; and (c) optionally tabletting and shaping the granulate. Preferably, the granules are prepared by wet granulation of the hydroxyalkyl cellulose/opioid with water. In a particularly preferred embodiment of the process, the amount of water added in the wet granulation step is from 1.5 to 5 times, more preferably from 1.75 to 3.5 times the weight of the opioid.
In another embodiment, the spheronizing agent may be spheronized with the active ingredient. The nodulizer is preferably microcrystalline cellulose. A suitable microcrystalline cellulose is, for example, Avicel PH 101 (trade Mark, FMC Corporation). In such embodiments, the pellets may contain a binder in addition to the active ingredient and the spheronizing agent. Suitable binders, such as low viscosity water-soluble polymers, are well known to those skilled in the pharmaceutical industry. However, preferred are water-soluble hydroxy lower alkyl celluloses, such as hydroxypropyl cellulose. Additionally (or alternatively), the pellet may comprise a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethylcellulose. In such embodiments, the extended release coating typically comprises a mixture of water-insoluble materials, such as (a) waxes alone or in admixture with fatty alcohols; or (b) shellac or zein.
Controlled release bead formulations
In a particularly preferred embodiment, the oral dosage form is an effective amount of controlled release pellets contained within a gelatin capsule.
In another preferred embodiment of the present invention, the controlled release dosage form is a pellet containing an active ingredient coated with a controlled release coating containing a controlled release material. "pellets" in the pharmaceutical industry means spherical particles having a diameter of about 0.1 to 2.5mm, in particular between 0.5 and 2 mm.
Preferably, the pellets are coated with a film of a controlled release material which provides controlled release of the opioid or salt thereof in an aqueous medium. The coating is preferably selected to achieve the in vitro release rate characteristics described above (e.g., a release rate of at least about 12.5% after 1 hour). The controlled release coating formulation of the present invention should form a firm and continuous film that is smooth, aesthetically pleasing, able to carry pigments and other coating additives, non-toxic, inert, and non-tacky.
Coating film
The formulations of the present invention may optionally be coated with one or more coatings suitable for modifying the release or protecting the formulation. In one embodiment, the purpose of the coating is to achieve a pH-dependent or pH-independent release upon contact with e.g. gastrointestinal fluids. If a pH independent release is desired, the coating is designed to maintain an optimal release profile in the surrounding fluid (e.g., gastrointestinal fluids) regardless of pH changes. Another preferred embodiment is a pH-dependent coating which releases the opioid at a desired site in the gastrointestinal tract, such as the stomach or small intestine, so that the resulting absorption profile provides analgesia to the patient for at least 12 hours, and more preferably 24 hours. It can also be formulated to release one portion of the dose in one part of the gastrointestinal tract, e.g. the stomach, and then the remainder in another part, e.g. the small intestine.
The formulation of the present invention employing a pH-dependent coating may also produce a repetitive effect, whereby the unprotected drug is coated outside the enteric coating for release in the stomach, and the remainder protected by the enteric coating is released in the later digestive tract. The pH-dependent coating useful in the present invention contains controlled release materials such as shellac, Cellulose Acetate Phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate, methacrylate copolymers, zein and the like.
Another preferred embodiment of the present invention is a stabilized solid controlled release dosage form comprising an opioid coated with a hydrophobic controlled release material selected from the group consisting of: (i) an alkyl cellulose; (ii) an acrylic polymer; (iii) mixtures thereof. The coating may be formed from an organic or aqueous solution or dispersion.
In some preferred embodiments, the controlled release coating is formed from an aqueous dispersion of a hydrophobic controlled release material. The opioid-containing coated matrix (e.g., tablet core or inert pharmaceutical beads or pellets) is then solidified to a matrix having stable dissolution characteristics. The end-point of cure can be determined by comparing the dissolution profile of the dosage form immediately after curing to the dissolution profile of the dosage form after exposure to accelerated storage conditions (e.g., 40 ℃, 75% relative humidity for at least one month). Such formulations are described in U.S. Pat. Nos. 5,273,760 and 5,286,493, both assigned to the assignee of the present invention. Other controlled release formulations and coatings that may be used in the present invention also include those described in U.S. Pat. Nos. 5,324,351,5,356,467 and 5,472,712.
In a preferred embodiment, the controlled release coating contains a plasticizer.
In some embodiments, it may be necessary to coat the opioid analgesic containing matrix with a sufficient amount of an aqueous dispersion containing an alkylcellulose or acrylic polymer to increase the weight by about 2-50 wt% (e.g., about 2-25%), thereby obtaining a controlled release formulation. This outer coating will depend more or less on the physical properties of the therapeutically active agent, the desired release rate, whether the aqueous dispersion contains a plasticizer and the manner in which it is mixed.
Alkyl cellulose polymers
Cellulosic materials and polymers, including alkyl celluloses, are suitable controlled release materials for coating matrices such as beads, tablets, and the like in the present invention. For example, one of the preferred alkyl cellulose polymers is ethyl cellulose, but one skilled in the art will recognize that other cellulose and/or alkyl cellulose polymers may be used alone or in combination as all or part of the hydrophobic coating of the present invention.
A commercially available aqueous dispersion of ethyl cellulose is(FMC Corp.，Philadelphia，Pennsylvania，USA)。The preparation method comprises the following steps: ethylcellulose is first dissolved in a water-immiscible organic solvent and then emulsified in water in the presence of surfactants and stabilizers. After homogenization to submicron droplets, the organic solvent is evaporated in vacuo to form a pseudolatex. During the manufacturing process, no plasticizer is added to the pseudolatex. Therefore, it is necessary to first coat the coating with a coating solutionMixed well with a suitable plasticizer.
Another commercially available aqueous ethylcellulose dispersion is(Colorcon, Inc., West Point, Pennsylvania, USA). The product is manufactured by adding the plasticizer to the dispersion. The polymer hot melt, plasticizer (dibutyl sebacate) and stabilizer (oleic acid) are first prepared as a homogeneous mixture and then rendered alkalineThe solution is diluted to give an aqueous dispersion which can be added directly to the substrate.
Acrylic polymer
In other embodiments of the present invention, the controlled release coating containing the controlled release material is a pharmaceutically acceptable acrylic polymer, including but not limited to: acrylic and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, poly (acrylic acid), poly (methacrylic acid esters), alkylolamide copolymers of methacrylic acid, poly (methyl methacrylate), polymethacrylates. Poly (methyl methacrylate) copolymers, polyacrylamides, aminoalkyl methacrylate copolymers, poly (methacrylic anhydride) and glycidyl methacrylate copolymers.
In some embodiments, the acrylic polymer comprises one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers are well known in the art and can be found in the fully polymerized copolymers of acrylates and methacrylates containing small amounts of quaternary ammonium groups as described in NF XVII.
In order to obtain the desired dissolution profile, it may be necessary to add two or more ammonium methacrylate copolymers with different physical properties, such as different molar ratios of quaternary ammonium groups to neutral (meth) acrylate.
Some methacrylate-based polymers may be used to prepare the pH-dependent coating of the present invention. For example, there is a family of copolymers synthesized from diethylaminoethyl methacrylate and other neutral methacrylates, also known as methacrylic acid copolymers or polymethacrylates, commercially available from Rohm Tech, IncThere are severalOf different types. For example, Eudragit E is a methacrylic acid copolymer that swells and dissolves in acidic media. Eudragit L is a methacrylic acid copolymer which does not swell at pH5.7 or less and dissolves at pH6 or more. Eudragit S is a methacrylic acid copolymer which does not swell at pH6.5 or less and dissolves at pH7 or more. Eudragit RL and Eudragit RS are swellable in water and the amount of water absorbed is pH dependent, however, dosage forms coated with Eudragit RL and Eudragit RS are pH independent.
In some preferred embodiments, the acrylic coating comprises Rohm PharmaRL30D andRS30D a mixture of these two acrylic resins.RL30D andRS30D is a low quaternary ammonium content acrylate and methacrylate copolymer wherein the molar ratio of quaternary ammonium groups to the remaining neutral (meth) acrylate is in the rangeRL30D is 1: 20 inRS30D is 1: 40. The average molecular weight is about 150,000. RL (high permeability) and RS (low permeability) represent permeability.The RL/RS mixture is insoluble in water and digestive juices. However, the coatings formed from them maySwell in aqueous and digestive fluids and are permeated.
Can use the inventionThe RL/RS dispersion is mixed homogeneously in any desired ratio to produce a controlled release formulation having a desired dissolution profile. For example, a desired controlled release formulation can be made from the following composition: 100 percentRL，50％ RL：50％ RS, and 10%RL：90％ And RS. Of course, those skilled in the art will recognize that other acrylic polymers may be used, for exampleL。
Plasticizer
In embodiments where the coating comprises an aqueous dispersion of a hydrophobic controlled release material, the addition of an effective amount of a plasticizer to the aqueous dispersion will further improve the physical properties of the controlled release coating. For example, since ethylcellulose has a high glass transition temperature and does not form a tough film under ordinary coating conditions, it is preferable to use it as a coating material after adding a plasticizer to a coating agent containing ethylcellulose. Generally, the amount of plasticizer in the coating solution depends on the concentration of the film forming agent, for example, generally about 1-50% by weight of the film forming agent. However, the concentration of plasticizer can only be determined accurately after testing with specific coating solutions and coating methods.
Examples of suitable plasticizers for ethylcellulose include water-insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin, although other water-insoluble plasticizers (e.g., acetylated monoglycerides, phthalate esters, castor oil, etc.) may also be employed. Triethyl citrate is a particularly good plasticizer for the aqueous ethylcellulose dispersion of the present invention.
Examples of plasticizers suitable for use in the acrylic polymers of the present invention include, but are not limited to: triethyl citrate NF XVI, tributyl citrate and other citric acid esters, dibutyl phthalate and 1, 2-propylene glycol. Still other plasticizers have proven to be enhancedThe elasticity of acrylic films made from RL/RS resin solutions and the like include polyethylene glycol, propylene glycol, diethyl phthalate, castor oil and triacetin. Triethyl citrate is a particularly good plasticizer for the aqueous ethylcellulose dispersion of the present invention.
It has also been found that the addition of a small amount of talc to the controlled release coating reduces the tendency of the aqueous dispersion to stick during processing and acts as a polishing agent.
Preparation of coated bead formulations
After coating a matrix such as inert pharmaceutical beads (e.g., nupariel 18/20 beads) with an aqueous dispersion of hydrophobic material, an amount of the resulting stabilized solid controlled release beads can be encapsulated in gelatin in an amount sufficient to give an effective controlled release dosage when ingested and contacted with a surrounding fluid such as gastrointestinal fluid or dissolution media.
The stabilized release bead formulations of the present invention release opioid analgesics slowly, e.g., upon ingestion and subsequent contact with gastric and intestinal fluids. The controlled release curve of the preparation can be changed by changing the coating amount of the hydrophobic controlled release material aqueous dispersion, changing the mode of adding the plasticizer into the hydrophobic controlled release material aqueous dispersion, changing the proportion of the plasticizer relative to the hydrophobic controlled release material, adding other components or excipients, changing the manufacturing method and the like. The dissolution profile of the final product can also be modified by, for example, increasing or decreasing the thickness of the controlled release coating.
The preparation of the matrix coated with the therapeutically active drug may be, for example: the therapeutically active drug is dissolved in water and then sprayed onto a substrate (e.g., nu pariel 18/20 beads) with a Wuster cannula (insert). Optionally, other ingredients may be added prior to coating the beads to promote adhesion of the opioid to the beads, or to impart color to the solution, etc. For example, a solution containing hydroxypropylmethylcellulose or the like with or without a pigment (e.g., a pigment, a coloring agent, a coloringProducts of Colorcon, Inc), mixed (e.g., for about 1 hour) and then added to the substrate. The resulting coated substrate may then be further coated with a release agent to separate the therapeutically active agent from the hydrophobic controlled release coating.
One suitable release agent comprises hydroxypropyl methylcellulose. However, various film formers known in the art may be used. Preferably, the release agent does not affect the dissolution rate of the final product.
The matrix may then be coated with an aqueous dispersion of the hydrophobic controlled release material. The aqueous dispersion of hydrophobic controlled release material preferably further comprises an effective amount of a plasticizer, such as triethyl citrate. Can also be usedOrAnd the like, preparing an aqueous dispersion of ethyl cellulose. If adopted, theIt is not necessary to additionally add a plasticizer. Alternatively, it is also possible to useSuch as aqueous preformed acrylic polymer dispersions.
Preferably, the coating solution of the present invention contains a pigment in addition to the film former, plasticizer and solvent system (i.e., water) to make the product aesthetically pleasing and easily distinguishable. The pigment may be added to the therapeutically active agent solution without the addition of the aqueous dispersion of hydrophobic material, or both. For example, an opacifier such as aluminum lake and titanium dioxide can be ground using an alcohol or propylene glycol formulated pigment dispersion, the pigment can be added to the water-soluble polymer solution using shear forces, and then the plasticized pigment can be added using low shear forcesThereby adding pigmentPigments may also be incorporated into the formulations of the present invention by any of a variety of suitable methods. Suitable ingredients for imparting color to the formulation when acrylic polymers are employed include titanium dioxide and pigments such as iron oxide pigments. However, the addition of pigments may increase the retarding effect of the coating.
The aqueous dispersion of plasticized hydrophobic controlled release material can be sprayed onto a substrate containing a therapeutically active drug using a variety of suitable known spray equipment. One of the preferred processes employs a Wurster fluidized bed system in which a gas stream injected from below fluidizes the core material and dries while spraying the acrylic polymer coating. Preferably, the aqueous dispersion of hydrophobic material is applied in an amount sufficient to achieve a predetermined controlled release of the therapeutically active agent when contacted with an aqueous solution such as gastric fluid, and plasticized in view of the physical properties of the therapeutically active agentThe addition mode of the agent and the like. After coating with the hydrophobic controlled-release material, a film-forming agent, such asThe purpose of this coating layer is to substantially eliminate bead aggregation.
The release of the therapeutically active agent from the controlled release formulation of the present invention may also be influenced, e.g. adjusted to a desired release rate, by the addition of one or more release-modifying agents or by providing one or more pathways through the coating. The ratio of hydrophobic controlled release material to water soluble material depends on factors such as the desired release rate and the solubility of the selected material.
The release modifier has a pore-forming effect and may be an organic or inorganic substance, including those that may be dissolved, extracted or exuded from within the coating in the environment of use. The porogen may comprise one or more hydrophilic materials, such as hydroxypropyl methylcellulose.
The controlled release coating of the present invention may also contain corrosion promoters such as starches and gums.
The controlled release coating of the present invention may further comprise a material that forms a microporous layer in an environment of use, such as a polycarbonate, e.g., a linear carbonate polyester, in which carbonate groups are repeatedly present on the polymer chain.
The release-modifying agent may also comprise a semipermeable polymer. The release-modifying agent in some preferred embodiments is selected from the group consisting of hydroxypropyl methylcellulose, lactose, metal stearates, and mixtures thereof.
The controlled release coating of the present invention may further comprise an exudation mechanism consisting of at least one pathway, a pore, etc. The vias may be formed using the methods described in the following U.S. patents: U.S. Pat. nos. 3,845,770, 3,916,889, 4,063,064, and 4,088,864. The passages may be of various shapes, such as circular, triangular, square, oval, irregular, and the like.
Another method of producing a 24 hour controlled release bead formulation is powder coating. U.S. patent 5,411,745, assigned to the assignee of the present invention, is a process for preparing 24-hour morphine formulations by powder coating techniques using a processing aid consisting essentially of very fine lactose hydrate. The powder coating beads were prepared as follows: an aqueous binder solution was sprayed onto inert beads to form a tacky surface, and morphine sulfate and very fine lactose hydrate mixture powders were then sprayed onto the tacky beads. The beads are then dried and coated with the hydrophobic material described previously to achieve the desired release of the drug in the surrounding liquid in the final product. Then, a proper amount of controlled release beads were encapsulated to form a finished dosage form that maintained the effective plasma concentration of morphine over about 12 hours.
Detailed description of the preferred embodiments
The following examples illustrate aspects of the invention. They are only intended to illustrate the invention and do not limit the scope of the invention.
Example 1
Hydrocodone sustained release tablets were prepared according to the formula of table I:
TABLE I
| Composition (I) | Unit content (mg) | Lot size (g) |
| Hydrocodone bitartrate | 15.0 | 150.0 |
| Spray-dried lactose | 56.0 | 560.0 |
| Polyvinylpyrrolidone | 4.0 | 40.0 |
| Eudragit RS30D (solid) | 10.0 | 100.0 |
| Glycerol triacetate | 2.0 | 20.0 |
| Stearyl alcohol | 20.0 | 200.0 |
| Talc | 2.0 | 20.0 |
| Magnesium stearate | 1.0 | 10.0 |
| Total amount of | 110.0 | 1100.0 |
The preparation process comprises the following steps:
1. retarder dispersion: eudragit RS30D was mixed with triacetin using a lightnin mixer.
2. The stearyl alcohol was melted.
3. The retarder dispersion was sprayed onto hydrocodone bitartrate, spray dried lactose and polyvinylpyrrolidone using a fluid bed granulator.
4. The whole batch was dried on a stainless steel pan for 15 minutes or to constant weight.
5. Molten stearyl alcohol was added to the batch with a Hobart mixer.
6. Wax granulation was dried on a stainless steel pan for 30 minutes or until the granulation temperature reached 35 ℃ or below.
7. The cooled granulated product was milled with a CoMil.
8. Talc and magnesium stearate were added as lubricants using a Hobart mixer.
9. The granulated product was compressed into tablets with a tablet press.
The tablet dissolution rate was then determined as follows:
1. the instrument comprises the following steps: USP method I (rotating basket method), 100 rpm.
2. Medium: 700ml SGF, 55 min, then 900ml enzyme free SIF
3. Sampling time: 1, 2, 4,8 and 12 hours
4. The analysis method comprises the following steps: high performance liquid chromatography.
Dissolution parameters are shown in table II:
TABLE II
| Time (hours) | Percentage of dissolution |
| 1 | 39.7 |
| 2 | 51.5 |
| 4 | 67.4 |
| 8 | 86.4 |
| 12 | 96.1 |
The Cmax and Tmax of example 1(CR) and an immediate release reference standard (IR) were then obtained in a bioavailability test comparing the difference between 15mg hydrocodone administered to healthy human subjects as an immediate release formulation (lortab7.5mg × 2) and as the CR formulation described above, and the results are shown in table III:
TABLE III
| Pharmacokinetic data | Hydrocodone bitartrate |
| Cmax (ng/ml) IR reference product | 35.4 |
| Cmax (ng/ml) CR product | 13.4 |
| Cmax(CR)/Cmax(IR) | 38％ |
| Tmax (h) IR reference product | 1.32 |
| Tmax (h) CR products | 4.07 |
Example 2
A hydrocodone sustained release tablet was prepared according to the formulation of table IV:
TABLE IV
| Composition (I) | Unit content (mg) | Lot size (g) |
| Hydrocodone bitartrate | 15.0 | 150.0 |
| Spray-dried lactose | 51.0 | 510.0 |
| Polyvinylpyrrolidone | 4.0 | 40.0 |
| Eudragit RS30D (solid) | 10.0 | 100.0 |
| Glycerol triacetate | 2.0 | 20.0 |
| Stearyl alcohol | 25.0 | 250.0 |
| Talc | 2.0 | 20.0 |
| Magnesium stearate | 1.0 | 10.0 |
| Total amount of | 110.0 | 1100.0 |
The procedure was as in example 1.
Dissolution parameters were obtained according to the method of example 1 and are shown in table V:
TABLE V
| Time (hours) | Percentage of dissolution |
| 1 | 36 |
| 2 | 45.8 |
| 4 | 60.5 |
| 8 | 78.9 |
| 12 | 90.4 |
Example 3
Hydrocodone sustained release capsules were prepared according to the formula of table VI:
TABLE VI
| Composition (I) | Unit content (mg) | Lot size (g) |
| Hydrocodone bitartrate | 15.0 | 320.0 |
| Eudragit RSPO | 76.0 | 1520.0 |
| Eudragit RLPO | 4.0 | 80.0 |
| Stearyl alcohol | 25.0 | 500.0 |
| Total amount of | 120.0 | 2400.0 |
The preparation method comprises the following steps:
1. mixing stearyl alcohol, Eudragit RLPO, hydrocodone bitartrate and Eudragit RSPO by milling with a Hobart mixer.
2. Extrusion granulation product: using a powder feeder, a melt extruder (equipped with a 6X 1mm die), a conveyor belt, Lasermike and a pelletizer, the following conditions were set forth:
| region 1 | 10℃ |
| Zone 2 | 20℃ |
| Zone 3 | 120℃ |
| Zone 4 | 120℃ |
| Zone 5 | 120℃ |
| Zone 6 | 120℃ |
| Zone 7 | 95℃ |
| Zone 8 | 95℃ |
| MGA | 120℃ |
| Die head | 117℃ |
Powder feed rate: 40 g/min; screw speed: 185 rpm; vacuum degree: 980mBar conveyor belt: so that the diameter of the extrudate is 1mm
A pelleting machine: cutting into 1mm long pellets
3. The pellets were screened with 16 and 20 mesh. The material that passed through mesh 16 and was retained on mesh 20 was collected.
4. The pills are filled into No. 2 gelatin capsules. The range is as follows: NLT114mg, NMT126 mg.
Dissolution parameters were then obtained as in example 1. The results are shown in Table VII:
TABLE VII
| Time (h) | Percentage of dissolution |
| 1 | 23.9 |
| 2 | 34.7 |
| 4 | 51.7 |
| 8 | 74.6 |
| 12 | 85.2 |
Example 4
Oxycodone sustained release tablets were prepared according to the formulation of table VIII:
TABLE VIII
| Composition (I) | Unit content (mg) | Lot size (g) |
| Oxycodone hydrochloride | 20.0 | 22.0 |
| Spray-dried lactose | 59.25 | 65.175 |
| Polyvinylpyrrolidone | 5.0 | 5.5 |
| Eudragit RS30D (solid) | 10.0 | 11.0 |
| Glycerol triacetate | 2.0 | 2.2 |
| Stearyl alcohol | 25.0 | 27.5 |
| Talc | 2.5 | 2.75 |
| Magnesium stearate | 1.25 | 1.375 |
| Opadry pink Y-S-14518A | 4.0 | 4.26 |
| Total amount of | 129.0 | 141.76 |
The method comprises the following steps:
1. and (3) granulation: the Eudragit/triacetin dispersion was sprayed on oxycodone hydrochloride, spray dried lactose and polyvinylpyrrolidone using a fluid bed granulator.
2. Grinding: the granulated product is discharged and passed through a mill.
3. Waxing: the stearyl alcohol was melted and added to the milled granulation using a mixer. And (4) allowing it to cool.
4. Grinding: the cooled particles were passed through a mill.
5. Lubrication: talc and magnesium stearate were added to the granules as lubricants using a blender.
6. Tabletting: the granules are compressed into tablets using a tablet press.
7. Coating: wrapping a layer of water-based film outside the tablet.
Then, the tablets were subjected to dissolution testing as follows:
1. the instrument comprises the following steps: USP type II (Paddle method), 150rpm
2. Medium: 700ml SGF was used for the first hour, and then phosphate buffer was added to 900ml, pH 7.5.
3. Sampling time: 1, 2, 4,8, 12, 18 and 24 hours
4. The analysis method comprises the following steps: high performance liquid chromatography
Dissolution parameters are shown in table IX:
TABLE VII
| Time (h) | Percentage of dissolution |
| 1 | 45 |
| 2 | 55 |
| 4 | 70 |
| 8 | 87 |
| 12 | 96 |
| 18 | 101 |
| 24 | 102 |
The Cmax and Tmax were then obtained from the bioavailability study for example 4 and the standard immediate release reference samples, see table X:
table X
| Pharmacokinetic data | Oxycodone hydrochloride |
| Cmax (ng/ml) IR reference product | 38.2 |
| Cmax (ng/ml) CR product | 21.7 |
| Cmax(CR)/Cmax(IR) | 57％ |
| Tmax (h) IR reference product | 1.10 |
| Tmax (h) CR products | 2.62 |
Example 5
Morphine sustained release tablets were prepared according to the formulation of table XI:
TABLE XI
| Composition (I) | Unit content (mg) | Lot size (g) |
| Morphine sulfate | 30.0 | 138.0 |
| Spray-dried lactose | 70.0 | 322.0 |
| Hydroxyethyl cellulose | 10.0 | 46.0 |
| Cetostearyl alcohol | 35.0 | 161.0 |
| Talc | 3.0 | 13.8 |
| Magnesium stearate | 2.0 | 9.2 |
| Opadry YS-1-4729 | 5.0 | 23.0 |
| Total amount of | 155.0 | 713.0 |
The method comprises the following steps:
1. and (3) granulation: water was added to morphine sulfate, spray dried lactose and hydroxyethyl cellulose in a mixer and dried using a fluid bed granulator.
2. Screening: discharging the granules and sieving.
3. Waxing: cetearyl alcohol was melted and added to the milled granules using a mixer. And (4) allowing it to cool.
4. Screening: the cooled granules were sieved.
5. Lubrication: talc and magnesium stearate were added to the granules as lubricants using a blender.
6. Tabletting: the granules are compressed into tablets using a tablet press.
7. Coating: the tablets are coated with an aqueous film.
Dissolution testing of the tablets was performed as follows:
1. the instrument comprises the following steps: USP method I (rotating basket method), 50rpm
2. Medium: 900ml of pure water, 37 deg.C
3. Sampling time: 1, 2, 3, 4 and 6 hours.
4. The analysis method comprises the following steps: UV detection at 285nm and 305nm using a 5cm cell, 2-point method.
The dissolution parameters are shown in Table XII:
TABLE XII
| Time (h) | Percentage of dissolution |
| 1 | 34.2 |
| 2 | 49.9 |
| 3 | 64.2 |
| 4 | 75.5 |
| 6 | 90.3 |
The Cmax and Tmax were then determined by bioavailability studies for example 5 and a standard immediate release reference sample:
TABLE XIII
| Pharmacokinetic data | Morphine sulfate |
| Cmax (ng/ml) IR reference product | 22.1 |
| Cmax (ng/ml) CR product | 12 |
| Cmax(CR)/Cmax(IR) | 54％ |
| Tmax (h) IR reference product | 0.98 |
| Tmax (h) CR products | 2.09 |
Example 6
Comparing the pharmacokinetic parameters of examples 1, 4 and 5, it was unexpectedly found that, although the dissolution of the hydrocodone hydrochloride controlled release tablet of example 1 was very similar to the controlled release oxycodone tablet of example 4 and the morphine sulfate controlled release tablet of example 5, the ratio of Cmax of hydrocodone formulation CR to IR was 38%, while the oxycodone and morphine tablets were above 50%. The results of the comparison are shown in Table XIV:
TABLE XIV
| Pharmacokinetic parameters | Hydrocodone bitartrate | Oxycodone hydrochloride | Morphine sulfate |
| Cmax (ng/ml) IR reference product | 35.4 | 38.2 | 22.1 |
| Cmax (ng/ml) CR product | 13.4 | 21.7 | 12 |
| Cmax(CR)/Cmax(IR) | 38％ | 57％ | 54％ |
| Tmax (h) IR reference product | 1.32 | 1.10 | 0.98 |
| Tmax (h) CR products | 4.07 | 2.62 | 2.09 |
Example 7
Single dose, 4 treatments, open label (open tablets) pharmacokinetic comparisons were performed on fasted normal volunteers with the controlled release hydrocodone formulations of examples 1, 2, 3 and two immediate release (hydrocodone bitartrate 7.5 mg/acetaminophen 500mg) tablets. The plasma concentrations of each formulation are shown in tables 15-18:
pharmacokinetic parameters are shown in table 19:
watch 19
a: geometric means (0, last) of AUC and Cmax, Tmax, W50, T1/2(abs) (half-life of absorption) and T1/2(elim) (half-life of elimination) were arithmetic means.
b: the ratios and 90% CI are based on least squares means.
c: ratio (%): (test average/reference average) × 100, based on the least squares average.
Example 8
Hydrocodone sustained release tablets were prepared according to the formulation of table XX:
table XX
| Composition (I) | mg/tablet | kg/batch |
| Hydrocodone bitartrate | 15 | 15.0 |
| Calcium hydrogen phosphate | 31 | 31.0 |
| Glycerol behenate | 10 | 10.0 |
| Stearyl alcohol | 22 | 22.0 |
| Microcrystalline cellulose | 31 | 31.0 |
| Magnesium stearate | 1.0 | 1.0 |
| Opadry purple-1-10371-A | 5.0 | 5.0 |
| Pure water | N/A1 | 28.331 |
| 115.0mg | 115.0kg |
1: is evaporated during processing and is not included in the final product
The method comprises the following steps:
1. grinding: the stearyl alcohol flakes were passed through a mill.
2. Mixing: hydrocodone bitartrate, calcium hydrogen phosphate, glycerol behenate, stearyl alcohol and microcrystalline cellulose were mixed using a suitable mixer.
3. Extrusion molding: the combined materials were continuously fed into a twin screw extruder and the extruder temperature was increased to soften and form the extrudate.
4. And (3) cooling: the extrudate is cooled on a conveyor belt.
5. Grinding: the cooled extrudate is passed through a mill to obtain particles of the desired size.
6. Mixing: the milled extrudate was mixed with magnesium stearate.
7. Tabletting: the resulting granules are compressed into tablets using a tablet press.
8. Coating: opadry was dispersed in purified water to prepare a coating film solution, which was coated on the tablets.
The tablet test was performed as follows:
1. the instrument comprises the following steps: USP type I (rotating basket method), 100 rpm.
2. Medium: 700ml SGF (without enzyme) was initially obtained for 55 minutes, and phosphate buffer was added to 900ml, pH 7.5.
3. Sampling time: 1, 2, 4,8 and 12 hours.
4. The analysis method comprises the following steps: high performance liquid chromatography.
The dissolution parameters are shown in table XXI:
TABLE XXI
| Time (h) | Percentage of dissolution |
| 1 | 22 |
| 2 | 37 |
| 4 | 58 |
| 8 | 84 |
| 12 | 99 |
Example 9
Three-way cross-drug pharmacokinetic comparisons were performed as follows: single dose 15mg hydrocodone controlled release tablets were administered to fed and fasted normal volunteers (example 8); volunteers with normal fasting state were given 15mg hydrocodone immediate release dose (2X 7.5 mg/tablet), Q6H, more than 2 times.
The Cmax and Tmax of example 8 and the standard immediate release reference tablets were then obtained by bioavailability studies, see tables XXII and XXIII:
TABLE XXII
| Pharmacokinetic data (open web) | Hydrocodone bitartrate |
| Cmax (ng/ml) IR reference product (adjusted dose) | 43.16 |
| Cmax (ng/ml) CR product | 17.87 |
| Cmax(CR)/Cmax(IR) | 41％ |
| Tmax (h) IR reference product | 6.42 |
| Tmax (h) CR products | 4.04 |
TABLE XXIII
| Pharmacokinetic data | Hydrocodone bitartrate 15mg CR tablet (fasting) | Hydrocodone bitartrate 15mg CR tablet (fed) | Hydrocodone bitartrate 2X 7.5mg IR tablet (empty stomach) |
| Cmax(ng/ml) | 17.87 | 19.23 | 21.58 |
| C12 hours | 11.06 | 12.84 | |
| C12 hours/Cmax | 62％ | 67％ | |
| Tmax(h) | 4.04 | 4.81 | 6.42 |
| AUC | 267.43 | 277.58 | 229.33 |
Claims (17)
1. A solid controlled release oral dosage form comprising 15-60mg hydrocodone bitartrate dispersed in a controlled release matrix comprising up to 80 wt.% of a fatty alcohol and 1-80 wt.% of at least one hydrophobic controlled release material of the dosage form;
the chain length of the fatty alcohol is C12-C40The melting point is 25-90 ℃, and the hydrophobic controlled release material is selected from Eudragit RS, Eudragit RL and the mixture thereof;
c of the dosage form after first administration to a human patient12/CmaxThe ratio of (A) to (B) is 0.55-0.85, and the dosage form has a therapeutic effect lasting for at least 12 hours.
2. The dosage form of claim 1, said matrix being in the form of a plurality of particles.
3. The dosage form of claim 2, the multiparticulates being compressed into a tablet.
4. The dosage form of claim 2, wherein the multiparticulates are contained within a pharmaceutically acceptable capsule.
5. The dosage form of any one of claims 1-4, as determined according to the USP basket method: the in vitro release rate of bitartrate hydrocodone was 18-42.5 wt% after 1 hour at 37 deg.C, 700ml Simulated Gastric Fluid (SGF), 100rpm, 55 min, and then 900ml Simulated Intestinal Fluid (SIF).
6. The dosage form of claim 1, as determined according to the USP basket method: 900ml of an aqueous buffer solution having a pH of 1.2 or pH of 7.5 at 37 ℃ with a hydrocodone bitartrate release rate of 45 to 85 wt.% in vitro after 4 hours.
7. The dosage form of any of claims 1-4 and 6, which provides a hydrocodone Tmax at 2 to 8 hours after oral administration to a patient.
8. The dosage form according to any of claims 1 to 4 and 6, having a mean plasma concentration of hydrocodone between 2 and 9 hours after oral administration of a dosage form containing 15mg hydrocodone bitartrate of 7.39ng/ml and 10.1ng/ml and 8.49ng/ml at 12 hours after oral administration.
9. The dosage form of any one of claims 1-4 and 6, which provides a time to reach 80% mean hydrocodone Cmax of 0.5 to 1.5 hours.
10. The dosage form of any one of claims 1-4 and 6, which provides a time to reach a mean hydrocodone Cmax of 90% from 1.5 to 2.5 hours.
11. The dosage form of claim 1, wherein said matrix is extruded.
12. The dosage form of claim 1, said C12-C40The fatty alcohol is selected from the group consisting of lauryl alcohol, myristyl alcohol and stearyl alcohol.
13. The dosage form of claim 1, comprising 15mg hydrocodone bitartrate.
14. A method of making a solid controlled release oral dosage form comprising:
forming a matrix comprising up to 80% by weight of the dosage form of a fatty alcohol and 1-80% by weight of at least one hydrophobic controlled release material;
the chain length of the fatty alcohol is C12-C40The melting point is 25-90 ℃, and the hydrophobic controlled release material is selected from Eudragit RS, Eudragit RL and the mixture thereof;
dispersing hydrocodone bitartrate in a matrix of controlled release material whereby an analgesically effective amount of 15 to 60mg hydrocodone bitartrate is incorporated into said controlled release material to form a dosage form suitable for twice daily administration to a human patient;
the dosage form is administered to human for the first time12A ratio/Cmax of 0.55 to 0.85, the therapeutic effect lasting for at least 12 hours.
15. The method of claim 14, wherein the step of forming a matrix comprises forming a matrix by extrusion.
16. The method of claim 14Method of C12-C40The fatty alcohol is selected from the group consisting of lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol and cetearyl alcohol.
17. A dosage form according to claim 1, which dosage form provides a Cmax of hydrocodone or a salt thereof which is less than 50% of the Cmax of an equivalent dose of an immediate release reference preparation of hydrocodone.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16254199P | 1999-10-29 | 1999-10-29 | |
| US60/162,541 | 1999-10-29 | ||
| PCT/US2000/029953 WO2001032148A1 (en) | 1999-10-29 | 2000-10-30 | Controlled release hydrocodone formulations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1054698A1 HK1054698A1 (en) | 2003-12-12 |
| HK1054698B true HK1054698B (en) | 2013-06-14 |
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