CA1312016C - Osmotic continuous dispensing oral delivery system containing a moderately water-soluble metoprolol salt having improved core composition and use thereof - Google Patents
Osmotic continuous dispensing oral delivery system containing a moderately water-soluble metoprolol salt having improved core composition and use thereofInfo
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- CA1312016C CA1312016C CA000551655A CA551655A CA1312016C CA 1312016 C CA1312016 C CA 1312016C CA 000551655 A CA000551655 A CA 000551655A CA 551655 A CA551655 A CA 551655A CA 1312016 C CA1312016 C CA 1312016C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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Abstract
4-16168/=/CGC 1232 OSMOTIC CONTINUOUS DISPENSING ORAL DELIVERY SYSTEM CONTAINING A
MODERATELY WATER-SOLUBLE METOPROLOL SALT HAVING IMPROVED CORE
COMPOSITION AND USE THEREOF
ABSTRACT OF THE DISCLOSURE
An osmotic dispensing oral delivery system containing a moderately water-soluble metoprolol salt for total delivery of between about 50 and about 500 mg of metoprolol wherein from about 60 up to about 90 percent of said metoprolol is released in the gastro-intestinal tract at a substantially continuous rate of about 5 to about 12 percent by weight per hour comprising:
a) a semipermeable shaped wall membrane substantially imper-meable to said salt and permeable to gastrointestinal fluid, b) a core compartment within and defined by said wall, said core containing a solid osmotically active composition comprising: about 7.5 to about 15 percent by weight poly-N-vinylpyrrolidone; up to about 5 percent by weight of a tabletting lubricant; and about 92.5 to about 80 percent by weight of said metoprolol salt, based on the core composition weight and c) at least one passageway in the wall, for dispensing the metoprolol salt, in communication with said core compart-ment and the external environment, and a method of use thereof in conditions responsive to beta1-adrenoreceptor blocking agents.
MODERATELY WATER-SOLUBLE METOPROLOL SALT HAVING IMPROVED CORE
COMPOSITION AND USE THEREOF
ABSTRACT OF THE DISCLOSURE
An osmotic dispensing oral delivery system containing a moderately water-soluble metoprolol salt for total delivery of between about 50 and about 500 mg of metoprolol wherein from about 60 up to about 90 percent of said metoprolol is released in the gastro-intestinal tract at a substantially continuous rate of about 5 to about 12 percent by weight per hour comprising:
a) a semipermeable shaped wall membrane substantially imper-meable to said salt and permeable to gastrointestinal fluid, b) a core compartment within and defined by said wall, said core containing a solid osmotically active composition comprising: about 7.5 to about 15 percent by weight poly-N-vinylpyrrolidone; up to about 5 percent by weight of a tabletting lubricant; and about 92.5 to about 80 percent by weight of said metoprolol salt, based on the core composition weight and c) at least one passageway in the wall, for dispensing the metoprolol salt, in communication with said core compart-ment and the external environment, and a method of use thereof in conditions responsive to beta1-adrenoreceptor blocking agents.
Description
:~3~2~
4 16168/=/CGC 1232 OSMOTIC CONTINUOUS DISPENSING ORAL DELIVERY SYSTE~I CONTAINING A
MODEl~TELY WATER-SOLUBL~ METOPROLOL SA T HAVING IMPROVED CORE
COMPOSITION AND VSE THEREOF
BACKGROUND OF TIIE INVENTION
Osmotic delivery systems Eor the oral administration of drugs are well known in the art. These systems dispense -the active agent in a controlled and continuous manner over a prolonged period of time to produce a desired beneficial effect. Such systems are typically represented by U.S. 3,845,770, U.S. 3,916,899, U.S. 4,016,880 and the like.
Experimental osmotic delivery systems employlng metoprolol fumarate contained within a semipermeable cellulosic wall and their in vivo performance have been described in the literature, e.g. Theeuwes e-t al., Br.J.Clin.Pharm. (1985), Vol. 19, pp. 69S~76S;
Godbillon et al., Br.J Clin.Pharm. (1985), Vol. 19, pp. 213S-2185 and Warrington et al., Br.J.Clin.Pharm. (1985), -Vol~ lg, pp. 219S-224S.
Unfortunately, while experimental oral osmotic devices employing a moderately water-soluble metoprolol salt such as metoprolol fumarate (1:1) as the core ingredient can be prepared on a unit basis in the laboratory by simple dip coating a compressed core oE the salt with, for example, a cellulose acetate solution, to obtain a semi-permeable membrane coated core, such a technique is unsuitable for large scale production of uniform quality product. Due to the high friability of the metoprolol salt, a compressed core thereof, alone or with trace amounts of excipients such as poly-N-vinylpyrrolidone, ~3 ~ ~3 ~
is characteristically too fragile to employ in conventional air suspension techniques, such as the Wurster Air suspes~sion technique or the like.
Moreover, the addition of substantial amounts of excipients may be expected to interfere with the release rate characteristlcs of the active agent.
It has now been surprisingly discovered that the normal friability of such cores can be substantially eliminated by employing between about 7.5 and l5 percent by weight poly-N-vinylpyrrolidone in combination with the moderately soluble pharmaceutically accsptable salt of metoprolol.
OBJECTS OF THE INVENTION
It is acco}dingly an object of the invention to provide an osmotic delivery system for a moderately water-601uble pharmaceutically acceptable metoprolol salt comprising a semipermeable membrane wall covering a core compartment containing an osmotically active solid core composition comprising about 7.5 to about 15 percent by weight poly-N-vinylpyrrolidone, up to about 5 percent by weight of a tabletting lubricant; and about 92.5 to about 80 percent by weight of said metoprolol salt, and at least one passageway in the wall, for dispensing the metoprolol salt, in communication with said core compartment and the external environment.
It is another object of the present invention to provide a method of treatment of conditions responsive to beta1-adrenoreceptor blocking agents in man in need of the same by orally administering to man an effective unit dosage amount in the form of such a device.
These and other objects of the instant inventlon are more fully described in the following detailed disclosure.
4 16168/=/CGC 1232 OSMOTIC CONTINUOUS DISPENSING ORAL DELIVERY SYSTE~I CONTAINING A
MODEl~TELY WATER-SOLUBL~ METOPROLOL SA T HAVING IMPROVED CORE
COMPOSITION AND VSE THEREOF
BACKGROUND OF TIIE INVENTION
Osmotic delivery systems Eor the oral administration of drugs are well known in the art. These systems dispense -the active agent in a controlled and continuous manner over a prolonged period of time to produce a desired beneficial effect. Such systems are typically represented by U.S. 3,845,770, U.S. 3,916,899, U.S. 4,016,880 and the like.
Experimental osmotic delivery systems employlng metoprolol fumarate contained within a semipermeable cellulosic wall and their in vivo performance have been described in the literature, e.g. Theeuwes e-t al., Br.J.Clin.Pharm. (1985), Vol. 19, pp. 69S~76S;
Godbillon et al., Br.J Clin.Pharm. (1985), Vol. 19, pp. 213S-2185 and Warrington et al., Br.J.Clin.Pharm. (1985), -Vol~ lg, pp. 219S-224S.
Unfortunately, while experimental oral osmotic devices employing a moderately water-soluble metoprolol salt such as metoprolol fumarate (1:1) as the core ingredient can be prepared on a unit basis in the laboratory by simple dip coating a compressed core oE the salt with, for example, a cellulose acetate solution, to obtain a semi-permeable membrane coated core, such a technique is unsuitable for large scale production of uniform quality product. Due to the high friability of the metoprolol salt, a compressed core thereof, alone or with trace amounts of excipients such as poly-N-vinylpyrrolidone, ~3 ~ ~3 ~
is characteristically too fragile to employ in conventional air suspension techniques, such as the Wurster Air suspes~sion technique or the like.
Moreover, the addition of substantial amounts of excipients may be expected to interfere with the release rate characteristlcs of the active agent.
It has now been surprisingly discovered that the normal friability of such cores can be substantially eliminated by employing between about 7.5 and l5 percent by weight poly-N-vinylpyrrolidone in combination with the moderately soluble pharmaceutically accsptable salt of metoprolol.
OBJECTS OF THE INVENTION
It is acco}dingly an object of the invention to provide an osmotic delivery system for a moderately water-601uble pharmaceutically acceptable metoprolol salt comprising a semipermeable membrane wall covering a core compartment containing an osmotically active solid core composition comprising about 7.5 to about 15 percent by weight poly-N-vinylpyrrolidone, up to about 5 percent by weight of a tabletting lubricant; and about 92.5 to about 80 percent by weight of said metoprolol salt, and at least one passageway in the wall, for dispensing the metoprolol salt, in communication with said core compartment and the external environment.
It is another object of the present invention to provide a method of treatment of conditions responsive to beta1-adrenoreceptor blocking agents in man in need of the same by orally administering to man an effective unit dosage amount in the form of such a device.
These and other objects of the instant inventlon are more fully described in the following detailed disclosure.
2 ~ ~ ~
DETAILED DESC~IPTION OF TH~ INVENTION
One embodiment of the present invention relates -to an osmotic dispensing oral delivery system contalning a moderately water-soluble pharmaceutically acceptable salt of metoprolol for a total delivery of between about 50 and abou-t 500 mg of metoprolol, capable of delivery, upon activation in the gastrointestinal tract, from about 60 up to about 90 percent of said metoprolol salt at a substantially continuous rate of about 5 to about 12 percent by weight of the total weight of said metoprolol salt per hour com-prising a) a semipermeable shaped wall membrane substantially impermeable to said salt and permeable to gastro-intestinal fluid;
b) a core compartment within and defined by said wall, said core being in the Eorm of a solid osmotically active composition comprising about 7.5 to about 15 percent by weight poly-N-vinylpyrrolidone; up to about 5 percent by weight of a tabletting lubricant;
and about 92.5 to about 80 percent by weight of said metoprolol salt, all based on the core composition weight; and c) at least one passageway in the wall in communication with the core compartment and the external environ-ment for dispensing the metoprolol salt into said gastrointestinal tract.
The metoprolol salt containing devlce i8 suitable for treating those conditions in mammals, including man, responsive to beta1-adreno-receptor blocking agents. Preferred indicat:Lons include the treat-ment of those indications for whlch metoprolol and its pharmaceuti-cally acceptable salts are known to be useful, including hyperten-sion, angina pectoris, cardiac arrhythmlas, and in the treatment of hemodynamically stable patients with myocardial infarction to reduce cardiovascular mortality.
~2~ ~
Conventional commercially available metoprolol tartrate has an immediate release profile and is not in a rate controlled continuous dispensing form. On multiple dosing, such non-continuous forms produce fluctuations between peaks and troughs in terms of blood plasma levels as well as the degree of beta-blockade. While more frequent administration of such conventional forms can reduce these fluctuations, it is burdensome to some patients and may lessen compliance. While single daily doses of the conventional metoprolol salt are adequate if the only aim is to reduce blood pressure, a three-times-a-day regimen is advisable for the maintenance phase for the respective indications of myocardial infarction and angina pectoris.
The instant device advantageously provides a once-a-day regimen for all of the above indications for the total release, per unit dose, of between about 60 and about 500 mg of metoprolol wherein Erom about 50 up to about 90 percent of metoprolol is released at a substantially continuous rate of about 5 to about 12 percent by weight per hour.
The pharmaceutically acceptable salt of metoprolol is advantageously moderately water-soluble, such that the salt dissolves in the aqueous environment upon activation in the envlronment oE use, i.e.
the gastrointestinal tract, by aqueous fluid being imbibed by diffusion through the semipermeable shaped wall into the core compartment to continuously form a concentrated osmotically active solution of dissolved metoprolol salt. The concentrated salt, or solute, solution exhibits an osmotic pressure gradient against the aqueous gastrointestinal fluid and is released through one or more passageways in the wall in communication with both the core compart-ment and the external environment, to dispense the metoprolol salt at a controlled, preferably generally constant rate Izero orderJ.
The influx rate of aqueous Eluid from the aqueous environment through the semipermeable wall is controlled by the continuous dissolution of the metoprolol salt containing composition in the ~ 3 ~
core of the device. Accordingly, the metoprolol salt chosen is advantageously one which processes only limited or moderate solubi-lity in the imbibed aqueous fluid, such that the metop}olol salt is released in a slow and continuous manner a prolonged time by maintaining the rate of internal dissolution of the core composi-tion.
Preferably, the pharmaceutically acceptable metoprolol salt exhibits useful properies for formulations in oral osmotic systems ad has a solubility in water between about 0.1 to about 0.6 grams per cubic centimeter in water at about 37~C and the solubility can be deter-mined simply by placing the salt in water and diluting until complete solution. Suitable metoprolol salts include lower alka-noate salts of metoprolol salts and mono-or di-metoprolol salts of lower alkylene dicarboxylates, especially metoprolol fumarate (1:1) and metoprolol maleate (1:1). Most preferred is the metoprolol fumarate (1:1).
The semipermeable wall membrane is prepared from a material which can form films and is inert to the metoprolol salt drug or host, is pharmaceutically acceptable and is permeable to the external gastrointestinal fluid while essentially being impermeable to the metoprolol salt drug in the device. This selectively permeable membrane forming the wall is insoluble in the gastrointestinal tract and non-erodible or it can be bioerodible after a predetermined period with bioerosion corresponding to the end of the active drug release period. In each instance it is permeable to the gastro-intestinal solvent but not to the metoprolol salt solute and is suitable for construction of the osmotic powered device. Typical materials for forming the wall include membranes known to the art as present in osmosis and reverse osmosis membranes7 such as commer-cially available unplasticized cellulose acetate, plastici~ed cellulose triacetate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate cellulose acetate ethyl carbamate7 cellulose acetate phthalate7 cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, ~ 3 ~
cellulose acetate ethyl carbonate, cellulose acetate methyl sulfonate, cellulose acetate butyl sulfonate, cellulose ethers, cellulose acetate propionate, poly(vinyl methyl) ether polymers, cellulose acetate octate, cellulose acetate laurate, methyl cellulose, triacetate oE locust bean gum, cellulose acetate with acetylated hydroxyethyl cellulose, hydroxylated ethylenevinylacetate, osmotic membranes made from polymeric epoxides, alkylene oxide-alkyl glycidyl ethers, polyurethanes, polyglolic acid, and polycation-polyanion membranes known in the art. Generally such membranes have a fluid permeability of between about 0.01 to lO cm3/cm2 x hour or day or higher at atmospheric pressure against a saturated product solution at about 30C, and simultaneously possess a high degree of impermeability to the metoprolol salt solution.
Preferred semipermeable membrane materials include polyurethanes, methyl cellulose, cellulose acetate, e-thyl cellulose, and cellulose acetate butyrate. Most preferred is cellulose acetate.
Suitable tabletting lubricants include, for example, those lubricants known in the art such as silica, talc, magnesium stearate and high molecular weight polyethylene glycol. Preferred is magnesium stearate.
The preferred amount is between about l and about 5, most praferably between about 2 and about 4, percent by weight, based upon the total core weight.
The poly-N-vinylpyrrolidone (PVP, Povidone) constituent is well known in the art, water soluble and has an average molecular weight between about 10,000 and about 700,000, preEerably between 10,000 and 100,000. Prefer-red is povidone USP, commercially available through GAF Corp. under the tradename Plasdone~. The amount oE poly-N-vinylpyrrolidone, as stated above, is between about 7.5 and about 15 percent by weight, based upon the total core weight.
~L 3 ~
Preferably, the amount of poly-N-vinylpyrrolidone present in the core formulation is about 8.5 and about 13 percent by weight.
Preferably~ PLASDONE K-30 (GAF Corp.) of a molecular welght of 40,000 ls used.
The amount of the metoprolol salt, as metoprolol present in the core, can vary widely but is preferably between about 50 to about SOO mg per unit tablet device. Most preferably, the core contains between about 60 to about 200 mg of metoprolol salt.
The core compartment i8 advantageously in the form of a tablet which is film coated with the semipermeable membrane to form the wall. The core composition is advantageously prepared by combining the moderately water-soluble ~alt of metoprolol with the poly-N-vinyl-pyrrolidone, either by d{y blending and granulating in the presence of a water-ethanol mixture or by mixing said salt with an aqueous ethanolic solution of poly-N-vinylpyrrolidone, and subsequently granulating the mixture, and then drying the granulation and milling the same and optionally blending the dried milled granules with a tabletting lubricant, and compressing the resulting granules into tablets to form the core. The cores have advantageous properties useful for formulation such as hardness between about 8-25 S.C.U.
units (Strong Cobb Units) and Eragibility being less than 1.5 %, aspecially less than 1 %.
The core tablat is than subsequently coated with a semipermeable film-forming solution by using conventional coating methods, e.g.
air suspension techniques, such as the Wurster Air suspension technique, to obtain a core tablet coated with the semipermeable wall material. The resulting device is provided with at least one passageway to osmotically release the metoprolol salt, as a concen-trated or saturated solution, from the core to tha gastrointestinal tract at a controlled rate. The passageway(s) can be formed, in situ, by using a heterogeneous solution to coat the core tablet ~ 3 ~
containing the semipermeable membrane film-forming solution and a water or gastrointestinal fluid soluble material, whereby in the environment of use passageways are formed by erosion with aqueous solvent in situ, or the semipermeable shaped wall can be drilled, either mechanically or by use of a laser, to form the passageway or passageways.
The passageway orifice siæe will vary depending upon the size of the core 7 exact desired releaso profile, and the number of passageways.
Where one passageway is present, the orifice size can vary, for example, between about 0.1 mm and about 0.8 mm.
Generally, the film-forming semipermeable wall material is applied to the tablet core in the form of an organic solvent containing solution. Suitable solvents include, for example, dioxane, diethyl ether, lower alkanols, such as methanol or ethanol, and halogenated lower alkanes, such as chloroform, methylchloride and methylene chloride, or mlxtures thereof. The amount of semipermeable membrane material employed per unit dose will vary dependent upon, for example, the permeability characteristics of the membrane material.
For example, using cellulose acetate as the film-forming material, between about 4 and about 20 percent by weight, preferably between about 10 and about 20 percent by weight based upon the total weight of the device, may be employed.
The following examples are merely illustrative of the present invention and should not be considered as limiting the scope of the present invention. All parts ~re by weight unless otherwise speci-fied.
xample 1:
To 95.37 parts by weight metoprolol fumarate (1:1) there is added 8.10 parts by weight povidone USP and the mixture is milled to a powder and granulated with an ethanol/water mixture (70t30). The granulation mixture is then dried9 sized and 1.53 parts by weight magnesium stearate NF mixed therewith. The resulting particulate product is compressed into core tablets containing a total weight per tablet of 105 mg, containing 7.7 weight percent povidone, 1.5 weight percent magnesium stearate, and remainder metoprolol fumarate (1:1). The core tablets exhibited the following charactsristics:
Hardness (SC~: 9-11 Friability (percentage of tablets broken): 0.2 Disintegration time (min): 9 Example 2:
To illustrate the fragility of core tablets containing insuEficient amounts of poly-N-vinylpyrrolidone, the following composition was prepared in identical fashion with Example 1 but with a reduced amount of povidone USP:
Parts by Weight Weight %
Metoprolol fumarate (1:1) 95.37 93.5 Povidone ~SP 5.10 5 Magnesium Stearate NF 1.53 1.5 The core tablets exhibited the following comparative characteristcs.
Ilardness (SCU) : 7-9 Friability (%) : ~.2 Disintegration (min) : 8 Example 3:
Employing the procedure of Example 1, the following core tablets were prepared (parts by weight):
Example 3 4 5 6 Metoprolol Fumarate (1:1) 95.37g5.37 95.37 95.37 Povidone, USP 10.1013.108.1011.10 Magnesium Stearate NF1.53 1.532.53 2.53 % Povidone 9-4 12.0 7.610.2 % Magnesium Stearate 1.~ 1.4 2.4 2.3 Hardness (SCU) 14-15 ll-lo 9-11 8-11 Friability (%) 0.3 0.2 0.2 0.2 Disintegration (min) 7 8 18 15 Example 7:
Core tablets are prepared according to Example 1, containing per tablet 95 mg metoprolol fumarate (1:1), 2.90 mg magnesium stearate NF, and 11.10 mg povidone USP, having a hardness (SCU) of 8-11, a friability of 0.2 % and a disintegration time of about 15 minutes. The core tablets are film coated by air suspension with a methyl alcohol/mathylene chloride solution of cellulose acetate containing about 16 mg cellulose acetate per tablet. The coated tablets are drilled to provide an exit passage orifice having a diameter of about 0.5 mm.
Example 8-Coated tablets are prepared and drilled according to Example 7, but containing tbe following composition per tablet: metoprolol fumarate (1:1), 190.74 mg; povidone USP, 22.20 mg; magnesium stearate, 5.06 mg having a core composition hardness (SCU) of 11-16, a friability of O.Z % and a disintegration time of 27 minutes, which is then coated with approximately 29 mg cellulose acetate and the dried coated tablet drilled to provide an ex:Lt passageway having a diameter of about 0.5 mm. Upon placement in simulated gastric fluid without en~ymes at 37"C, in a U.S.P basket, s~7herein the fluld is stirred at 100 rpm, the ollowing release characteristics are observed:
Average Hoully Average Time IntervalRelease Rate Cumulative Release (Hour~) (mglh) (Percent) -- . _ 0 - 2 17.8 t 2.7 18.7 2 - 4 21.4 + 1.6 1~1.2 4 - 6 19.0 + 0.9 6l.2 6 - 8 17.0 -~ 1.6 79.0 8 - 10 8.3 ~ 1.4 87.7 10 - 12 4.5 ~ 0.7 92.5
DETAILED DESC~IPTION OF TH~ INVENTION
One embodiment of the present invention relates -to an osmotic dispensing oral delivery system contalning a moderately water-soluble pharmaceutically acceptable salt of metoprolol for a total delivery of between about 50 and abou-t 500 mg of metoprolol, capable of delivery, upon activation in the gastrointestinal tract, from about 60 up to about 90 percent of said metoprolol salt at a substantially continuous rate of about 5 to about 12 percent by weight of the total weight of said metoprolol salt per hour com-prising a) a semipermeable shaped wall membrane substantially impermeable to said salt and permeable to gastro-intestinal fluid;
b) a core compartment within and defined by said wall, said core being in the Eorm of a solid osmotically active composition comprising about 7.5 to about 15 percent by weight poly-N-vinylpyrrolidone; up to about 5 percent by weight of a tabletting lubricant;
and about 92.5 to about 80 percent by weight of said metoprolol salt, all based on the core composition weight; and c) at least one passageway in the wall in communication with the core compartment and the external environ-ment for dispensing the metoprolol salt into said gastrointestinal tract.
The metoprolol salt containing devlce i8 suitable for treating those conditions in mammals, including man, responsive to beta1-adreno-receptor blocking agents. Preferred indicat:Lons include the treat-ment of those indications for whlch metoprolol and its pharmaceuti-cally acceptable salts are known to be useful, including hyperten-sion, angina pectoris, cardiac arrhythmlas, and in the treatment of hemodynamically stable patients with myocardial infarction to reduce cardiovascular mortality.
~2~ ~
Conventional commercially available metoprolol tartrate has an immediate release profile and is not in a rate controlled continuous dispensing form. On multiple dosing, such non-continuous forms produce fluctuations between peaks and troughs in terms of blood plasma levels as well as the degree of beta-blockade. While more frequent administration of such conventional forms can reduce these fluctuations, it is burdensome to some patients and may lessen compliance. While single daily doses of the conventional metoprolol salt are adequate if the only aim is to reduce blood pressure, a three-times-a-day regimen is advisable for the maintenance phase for the respective indications of myocardial infarction and angina pectoris.
The instant device advantageously provides a once-a-day regimen for all of the above indications for the total release, per unit dose, of between about 60 and about 500 mg of metoprolol wherein Erom about 50 up to about 90 percent of metoprolol is released at a substantially continuous rate of about 5 to about 12 percent by weight per hour.
The pharmaceutically acceptable salt of metoprolol is advantageously moderately water-soluble, such that the salt dissolves in the aqueous environment upon activation in the envlronment oE use, i.e.
the gastrointestinal tract, by aqueous fluid being imbibed by diffusion through the semipermeable shaped wall into the core compartment to continuously form a concentrated osmotically active solution of dissolved metoprolol salt. The concentrated salt, or solute, solution exhibits an osmotic pressure gradient against the aqueous gastrointestinal fluid and is released through one or more passageways in the wall in communication with both the core compart-ment and the external environment, to dispense the metoprolol salt at a controlled, preferably generally constant rate Izero orderJ.
The influx rate of aqueous Eluid from the aqueous environment through the semipermeable wall is controlled by the continuous dissolution of the metoprolol salt containing composition in the ~ 3 ~
core of the device. Accordingly, the metoprolol salt chosen is advantageously one which processes only limited or moderate solubi-lity in the imbibed aqueous fluid, such that the metop}olol salt is released in a slow and continuous manner a prolonged time by maintaining the rate of internal dissolution of the core composi-tion.
Preferably, the pharmaceutically acceptable metoprolol salt exhibits useful properies for formulations in oral osmotic systems ad has a solubility in water between about 0.1 to about 0.6 grams per cubic centimeter in water at about 37~C and the solubility can be deter-mined simply by placing the salt in water and diluting until complete solution. Suitable metoprolol salts include lower alka-noate salts of metoprolol salts and mono-or di-metoprolol salts of lower alkylene dicarboxylates, especially metoprolol fumarate (1:1) and metoprolol maleate (1:1). Most preferred is the metoprolol fumarate (1:1).
The semipermeable wall membrane is prepared from a material which can form films and is inert to the metoprolol salt drug or host, is pharmaceutically acceptable and is permeable to the external gastrointestinal fluid while essentially being impermeable to the metoprolol salt drug in the device. This selectively permeable membrane forming the wall is insoluble in the gastrointestinal tract and non-erodible or it can be bioerodible after a predetermined period with bioerosion corresponding to the end of the active drug release period. In each instance it is permeable to the gastro-intestinal solvent but not to the metoprolol salt solute and is suitable for construction of the osmotic powered device. Typical materials for forming the wall include membranes known to the art as present in osmosis and reverse osmosis membranes7 such as commer-cially available unplasticized cellulose acetate, plastici~ed cellulose triacetate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate cellulose acetate ethyl carbamate7 cellulose acetate phthalate7 cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, ~ 3 ~
cellulose acetate ethyl carbonate, cellulose acetate methyl sulfonate, cellulose acetate butyl sulfonate, cellulose ethers, cellulose acetate propionate, poly(vinyl methyl) ether polymers, cellulose acetate octate, cellulose acetate laurate, methyl cellulose, triacetate oE locust bean gum, cellulose acetate with acetylated hydroxyethyl cellulose, hydroxylated ethylenevinylacetate, osmotic membranes made from polymeric epoxides, alkylene oxide-alkyl glycidyl ethers, polyurethanes, polyglolic acid, and polycation-polyanion membranes known in the art. Generally such membranes have a fluid permeability of between about 0.01 to lO cm3/cm2 x hour or day or higher at atmospheric pressure against a saturated product solution at about 30C, and simultaneously possess a high degree of impermeability to the metoprolol salt solution.
Preferred semipermeable membrane materials include polyurethanes, methyl cellulose, cellulose acetate, e-thyl cellulose, and cellulose acetate butyrate. Most preferred is cellulose acetate.
Suitable tabletting lubricants include, for example, those lubricants known in the art such as silica, talc, magnesium stearate and high molecular weight polyethylene glycol. Preferred is magnesium stearate.
The preferred amount is between about l and about 5, most praferably between about 2 and about 4, percent by weight, based upon the total core weight.
The poly-N-vinylpyrrolidone (PVP, Povidone) constituent is well known in the art, water soluble and has an average molecular weight between about 10,000 and about 700,000, preEerably between 10,000 and 100,000. Prefer-red is povidone USP, commercially available through GAF Corp. under the tradename Plasdone~. The amount oE poly-N-vinylpyrrolidone, as stated above, is between about 7.5 and about 15 percent by weight, based upon the total core weight.
~L 3 ~
Preferably, the amount of poly-N-vinylpyrrolidone present in the core formulation is about 8.5 and about 13 percent by weight.
Preferably~ PLASDONE K-30 (GAF Corp.) of a molecular welght of 40,000 ls used.
The amount of the metoprolol salt, as metoprolol present in the core, can vary widely but is preferably between about 50 to about SOO mg per unit tablet device. Most preferably, the core contains between about 60 to about 200 mg of metoprolol salt.
The core compartment i8 advantageously in the form of a tablet which is film coated with the semipermeable membrane to form the wall. The core composition is advantageously prepared by combining the moderately water-soluble ~alt of metoprolol with the poly-N-vinyl-pyrrolidone, either by d{y blending and granulating in the presence of a water-ethanol mixture or by mixing said salt with an aqueous ethanolic solution of poly-N-vinylpyrrolidone, and subsequently granulating the mixture, and then drying the granulation and milling the same and optionally blending the dried milled granules with a tabletting lubricant, and compressing the resulting granules into tablets to form the core. The cores have advantageous properties useful for formulation such as hardness between about 8-25 S.C.U.
units (Strong Cobb Units) and Eragibility being less than 1.5 %, aspecially less than 1 %.
The core tablat is than subsequently coated with a semipermeable film-forming solution by using conventional coating methods, e.g.
air suspension techniques, such as the Wurster Air suspension technique, to obtain a core tablet coated with the semipermeable wall material. The resulting device is provided with at least one passageway to osmotically release the metoprolol salt, as a concen-trated or saturated solution, from the core to tha gastrointestinal tract at a controlled rate. The passageway(s) can be formed, in situ, by using a heterogeneous solution to coat the core tablet ~ 3 ~
containing the semipermeable membrane film-forming solution and a water or gastrointestinal fluid soluble material, whereby in the environment of use passageways are formed by erosion with aqueous solvent in situ, or the semipermeable shaped wall can be drilled, either mechanically or by use of a laser, to form the passageway or passageways.
The passageway orifice siæe will vary depending upon the size of the core 7 exact desired releaso profile, and the number of passageways.
Where one passageway is present, the orifice size can vary, for example, between about 0.1 mm and about 0.8 mm.
Generally, the film-forming semipermeable wall material is applied to the tablet core in the form of an organic solvent containing solution. Suitable solvents include, for example, dioxane, diethyl ether, lower alkanols, such as methanol or ethanol, and halogenated lower alkanes, such as chloroform, methylchloride and methylene chloride, or mlxtures thereof. The amount of semipermeable membrane material employed per unit dose will vary dependent upon, for example, the permeability characteristics of the membrane material.
For example, using cellulose acetate as the film-forming material, between about 4 and about 20 percent by weight, preferably between about 10 and about 20 percent by weight based upon the total weight of the device, may be employed.
The following examples are merely illustrative of the present invention and should not be considered as limiting the scope of the present invention. All parts ~re by weight unless otherwise speci-fied.
xample 1:
To 95.37 parts by weight metoprolol fumarate (1:1) there is added 8.10 parts by weight povidone USP and the mixture is milled to a powder and granulated with an ethanol/water mixture (70t30). The granulation mixture is then dried9 sized and 1.53 parts by weight magnesium stearate NF mixed therewith. The resulting particulate product is compressed into core tablets containing a total weight per tablet of 105 mg, containing 7.7 weight percent povidone, 1.5 weight percent magnesium stearate, and remainder metoprolol fumarate (1:1). The core tablets exhibited the following charactsristics:
Hardness (SC~: 9-11 Friability (percentage of tablets broken): 0.2 Disintegration time (min): 9 Example 2:
To illustrate the fragility of core tablets containing insuEficient amounts of poly-N-vinylpyrrolidone, the following composition was prepared in identical fashion with Example 1 but with a reduced amount of povidone USP:
Parts by Weight Weight %
Metoprolol fumarate (1:1) 95.37 93.5 Povidone ~SP 5.10 5 Magnesium Stearate NF 1.53 1.5 The core tablets exhibited the following comparative characteristcs.
Ilardness (SCU) : 7-9 Friability (%) : ~.2 Disintegration (min) : 8 Example 3:
Employing the procedure of Example 1, the following core tablets were prepared (parts by weight):
Example 3 4 5 6 Metoprolol Fumarate (1:1) 95.37g5.37 95.37 95.37 Povidone, USP 10.1013.108.1011.10 Magnesium Stearate NF1.53 1.532.53 2.53 % Povidone 9-4 12.0 7.610.2 % Magnesium Stearate 1.~ 1.4 2.4 2.3 Hardness (SCU) 14-15 ll-lo 9-11 8-11 Friability (%) 0.3 0.2 0.2 0.2 Disintegration (min) 7 8 18 15 Example 7:
Core tablets are prepared according to Example 1, containing per tablet 95 mg metoprolol fumarate (1:1), 2.90 mg magnesium stearate NF, and 11.10 mg povidone USP, having a hardness (SCU) of 8-11, a friability of 0.2 % and a disintegration time of about 15 minutes. The core tablets are film coated by air suspension with a methyl alcohol/mathylene chloride solution of cellulose acetate containing about 16 mg cellulose acetate per tablet. The coated tablets are drilled to provide an exit passage orifice having a diameter of about 0.5 mm.
Example 8-Coated tablets are prepared and drilled according to Example 7, but containing tbe following composition per tablet: metoprolol fumarate (1:1), 190.74 mg; povidone USP, 22.20 mg; magnesium stearate, 5.06 mg having a core composition hardness (SCU) of 11-16, a friability of O.Z % and a disintegration time of 27 minutes, which is then coated with approximately 29 mg cellulose acetate and the dried coated tablet drilled to provide an ex:Lt passageway having a diameter of about 0.5 mm. Upon placement in simulated gastric fluid without en~ymes at 37"C, in a U.S.P basket, s~7herein the fluld is stirred at 100 rpm, the ollowing release characteristics are observed:
Average Hoully Average Time IntervalRelease Rate Cumulative Release (Hour~) (mglh) (Percent) -- . _ 0 - 2 17.8 t 2.7 18.7 2 - 4 21.4 + 1.6 1~1.2 4 - 6 19.0 + 0.9 6l.2 6 - 8 17.0 -~ 1.6 79.0 8 - 10 8.3 ~ 1.4 87.7 10 - 12 4.5 ~ 0.7 92.5
Claims (7)
1. An osmotic dispensing oral delivery system containing a moderately water-soluble pharmaceutically acceptable salt of metoprolol, capable of a total delivery of between about 50 and about 500 mg of metoprolol, wherein upon activation in the gastrointestinal tract of the host, from about 60 up to about 90 percent of said metoprolol salt is delivered at a substantially continuous rate of about 5 to about 12 percent by weight of the total weight of said salt, per hour, comprising:
a) a semipermeable shaped wall membrane substantially impermeable to said salt and permeable to gastrointestinal fluid;
b) a core compartment within and defined by said wall, said core being in the form of a solid osmotically active composition comprising about 7.5 to about 15 percent by weight poly-N-vinyl-pyrrolidone; up to about 5 percent by weight of a tabletting lubricant; and about 92.5 to about 80 percent by weight of said metoprolol salt, all based upon the core composition weight; and c) at least one passageway in the wall in communication with the core compartment and the external environment for dispensing the metoprolol salt into said gastrointestinal tract.
a) a semipermeable shaped wall membrane substantially impermeable to said salt and permeable to gastrointestinal fluid;
b) a core compartment within and defined by said wall, said core being in the form of a solid osmotically active composition comprising about 7.5 to about 15 percent by weight poly-N-vinyl-pyrrolidone; up to about 5 percent by weight of a tabletting lubricant; and about 92.5 to about 80 percent by weight of said metoprolol salt, all based upon the core composition weight; and c) at least one passageway in the wall in communication with the core compartment and the external environment for dispensing the metoprolol salt into said gastrointestinal tract.
2. A system according to claim 1, wherein the core compartment contains 8.5-13 % poly-N-vinylpyrrolidone.
3. A system according -to claim 2, wherein the core compartment contains 8.5-13 % poly-N-vinylpyrrolidone of an average molecular weight of 40,000.
4. A sytem according to claim 1, wherein the salt is metoprolol fumarate (1:1).
5. A system according to claim 1, wherein the wall membrane consists essentially of cellulose acetate.
6. A system according to claim 1, wherein the core contains between about 60 and about 200 mg of metoprolol salt.
7. A system according to claim 1, wherein the lubricant is magnesium stearate.
FO 7.4/RS/gb*
FO 7.4/RS/gb*
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US93082886A | 1986-11-14 | 1986-11-14 | |
| US930,828 | 1986-11-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1312016C true CA1312016C (en) | 1992-12-29 |
Family
ID=25459837
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000551655A Expired - Lifetime CA1312016C (en) | 1986-11-14 | 1987-11-12 | Osmotic continuous dispensing oral delivery system containing a moderately water-soluble metoprolol salt having improved core composition and use thereof |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0271438B1 (en) |
| JP (1) | JP2567427B2 (en) |
| KR (1) | KR960002180B1 (en) |
| AT (1) | ATE75394T1 (en) |
| AU (1) | AU598318B2 (en) |
| CA (1) | CA1312016C (en) |
| DE (1) | DE3778662D1 (en) |
| DK (1) | DK595987A (en) |
| ES (1) | ES2032205T3 (en) |
| GR (1) | GR3005132T3 (en) |
| IE (1) | IE60533B1 (en) |
| NZ (1) | NZ222525A (en) |
| PT (1) | PT86119B (en) |
| ZA (1) | ZA878526B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4892739A (en) * | 1988-04-25 | 1990-01-09 | Ciba-Geigy Corporation | Osmotic continuous dispensing oral delivery system containing a pharmaceutically acceptable active agent having a improved core membrane adhesion properties |
| US4859470A (en) * | 1988-06-02 | 1989-08-22 | Alza Corporation | Dosage form for delivering diltiazem |
| KR100733925B1 (en) * | 2005-03-16 | 2007-07-02 | 주식회사 엘지화학 | ECD control apparatus |
| IL210279A0 (en) | 2009-12-25 | 2011-03-31 | Dexcel Pharma Technologies Ltd | Extended release compositions for high solubility, high permeability acdtive pharmaceutical ingredients |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3916899A (en) * | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
| US4576604A (en) * | 1983-03-04 | 1986-03-18 | Alza Corporation | Osmotic system with instant drug availability |
| GB8503666D0 (en) * | 1985-02-13 | 1985-03-13 | Shell Int Research | Producing 4-(2-methoxyethyl)-phenylglycidyl ether |
| US5019302A (en) * | 1986-03-12 | 1991-05-28 | Washington University Technology Associates, Inc. | Method for granulation |
-
1987
- 1987-11-09 EP EP87810646A patent/EP0271438B1/en not_active Expired - Lifetime
- 1987-11-09 DE DE8787810646T patent/DE3778662D1/en not_active Expired - Lifetime
- 1987-11-09 ES ES198787810646T patent/ES2032205T3/en not_active Expired - Lifetime
- 1987-11-09 AT AT87810646T patent/ATE75394T1/en active
- 1987-11-12 NZ NZ222525A patent/NZ222525A/en unknown
- 1987-11-12 PT PT86119A patent/PT86119B/en not_active IP Right Cessation
- 1987-11-12 CA CA000551655A patent/CA1312016C/en not_active Expired - Lifetime
- 1987-11-13 KR KR1019870012779A patent/KR960002180B1/en not_active IP Right Cessation
- 1987-11-13 AU AU81192/87A patent/AU598318B2/en not_active Ceased
- 1987-11-13 JP JP62285627A patent/JP2567427B2/en not_active Expired - Lifetime
- 1987-11-13 ZA ZA878526A patent/ZA878526B/en unknown
- 1987-11-13 DK DK595987A patent/DK595987A/en not_active Application Discontinuation
- 1987-11-13 IE IE307187A patent/IE60533B1/en not_active IP Right Cessation
-
1992
- 1992-07-10 GR GR920400683T patent/GR3005132T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK595987D0 (en) | 1987-11-13 |
| AU8119287A (en) | 1988-05-19 |
| KR960002180B1 (en) | 1996-02-13 |
| KR880005944A (en) | 1988-07-21 |
| GR3005132T3 (en) | 1993-05-24 |
| PT86119A (en) | 1987-12-01 |
| AU598318B2 (en) | 1990-06-21 |
| PT86119B (en) | 1990-08-31 |
| EP0271438A3 (en) | 1989-07-19 |
| EP0271438B1 (en) | 1992-04-29 |
| ATE75394T1 (en) | 1992-05-15 |
| ZA878526B (en) | 1988-05-16 |
| ES2032205T3 (en) | 1993-01-16 |
| DE3778662D1 (en) | 1992-06-04 |
| IE873071L (en) | 1988-05-14 |
| DK595987A (en) | 1988-05-15 |
| EP0271438A2 (en) | 1988-06-15 |
| IE60533B1 (en) | 1994-07-27 |
| NZ222525A (en) | 1989-12-21 |
| JP2567427B2 (en) | 1996-12-25 |
| JPS63135329A (en) | 1988-06-07 |
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