CA1188614A - Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose - Google Patents
Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcelluloseInfo
- Publication number
- CA1188614A CA1188614A CA000423322A CA423322A CA1188614A CA 1188614 A CA1188614 A CA 1188614A CA 000423322 A CA000423322 A CA 000423322A CA 423322 A CA423322 A CA 423322A CA 1188614 A CA1188614 A CA 1188614A
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- Canada
- Prior art keywords
- tablets
- weight
- methocel
- mixture
- base material
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
SUSTAINED RELEASE THERAPEUTIC COMPOSITIONS BASED ON
HIGH MOLECULAR WEIGHT HYDROXYPROPYLMETHYLCELLULOSE
ABSTRACT
A carrier base material combined with a therapeutically active medicament and shaped and compressed to a solid unit dosage form having a regular and prolonged release pattern upon administration, the carrier base material being one or more hydroxypropylmethylcelluloses or a mixture of one or more hydroxypropylmethylcelluloses and up to 30% by weight of the mixture of methylcellulose, sodium carboxymethylcellulose and/or other cellulose ether, and wherein at least one of the hydroxypropylmethyl-celluloses has a methoxy content of 16-24 weight-%, a hydroxypropoxyl content of 4-32 weight-% and a number average molecular weight of at least 50,000 and wherein the carrier base material constitutes less than about one third of the weight of the solid unit dosage form.
HIGH MOLECULAR WEIGHT HYDROXYPROPYLMETHYLCELLULOSE
ABSTRACT
A carrier base material combined with a therapeutically active medicament and shaped and compressed to a solid unit dosage form having a regular and prolonged release pattern upon administration, the carrier base material being one or more hydroxypropylmethylcelluloses or a mixture of one or more hydroxypropylmethylcelluloses and up to 30% by weight of the mixture of methylcellulose, sodium carboxymethylcellulose and/or other cellulose ether, and wherein at least one of the hydroxypropylmethyl-celluloses has a methoxy content of 16-24 weight-%, a hydroxypropoxyl content of 4-32 weight-% and a number average molecular weight of at least 50,000 and wherein the carrier base material constitutes less than about one third of the weight of the solid unit dosage form.
Description
SUSTAINED RELEASE THERAPEU'rIC COMPOSITIONS BASED ON HIGH
MOLECULAR WEIG`HT HYDROXYPROP~LMETHYLCELLULOSE
BACKGROUND OF THE INVENTION
1. Field of Invention This invention relates to a carrier base material to be combined with a therapeutically active medicament and formed into a solid, shaped dosage unit having a long-lasting and regular incremental release o:E the medicament upon admin~
istration. Specifically, this invention relates to a carrier 10 base material, consisting essentially or predominantly of hydroxypropylmethylcellulose having a chemical structure and molecular weight which renders it sui~able for use, in relatively low concentrations, in sustained release therapeutic compositions.
MOLECULAR WEIG`HT HYDROXYPROP~LMETHYLCELLULOSE
BACKGROUND OF THE INVENTION
1. Field of Invention This invention relates to a carrier base material to be combined with a therapeutically active medicament and formed into a solid, shaped dosage unit having a long-lasting and regular incremental release o:E the medicament upon admin~
istration. Specifically, this invention relates to a carrier 10 base material, consisting essentially or predominantly of hydroxypropylmethylcellulose having a chemical structure and molecular weight which renders it sui~able for use, in relatively low concentrations, in sustained release therapeutic compositions.
2. Description of the Prior Art Hydroxypropylmethylcelluloses are commercially avail-able in various grades, under several tradenames, including Methocel E, F, J and K (registered trademarks and all previously designated as Methocel HG) from The Dow Chemical Co.s U.S.A., HPM, a registered trademark of and from British Celanese Ltd., England, and Metalose SH, a registered trade-mark of and from Shin-Etsu, Ltd., Japan. The various grades available under a given tradename represent differences in methoxyl and hydroxypropoxyl content as well as molecular weight. The methoxyl con~ent ranges from 16.5 to 30 weight-~/O
and the hydroxypropoxyl content ranges from 4 to 32 weight-%, as determined by the method described in ASTM D-2363-72.
-1- ~
, ~ 3~ ~ ~
Commercial designatlons of the various hydroxy-propylmethylcelluloses are based on the viscosities of 2%
aqueous so]utions at 20C. The viscositi.es range :Erom 15 cps to 30,000 cps and represent number average molecular weights ranging from about 10,000 to over 150,000, as calculated from the data in "Handbook of Methocel Cellulose Ether Products" (The Dow Chemical Co., 1974).
A solid unit dosage form consisting of a mixture of a medicament and a carrier base material which is low molecular weight hydroxypropylmethylcellulose Methocel E50, formerly known as Methocel 601~G 50 cps, having a number avera,~e molecular weight of 23,000, a methoxyl content of 28-30 weight-%, and a hydroxypropoxyl content of less than 9 weight-%, rapidly releases the medicament when brought into contact with the aqueous fluids of the mouth or the gastrointestinal tract.
~owever, an effective "sustained release" tablet is produced by admixture of a medicament with a modified Methocel E50, per se or in admixture with other cellulose ethers. As disclosed by Lowey and Stafford (U.S. Patent 3,870,790) and Schor (U.S. Patent 4,226,849), the modification is carried out by exposure of the low molecular weight hydroxypropyl-methylcellulose Methocel ~50 to high humidity or moisture and drying in air.
It has been disclosed in U.S. Patent No. 4,369,172 that effective prolonged release therapeutic compositions may be prepared by using as a carrier base material a hydroxypropylmethylcellulose having a hydroxypropoxyl content of 9-12 weight-%, and a number average molecular weight of less than 50,000) e.g.
Metalose 60S~150. The carrier base material provides sustained release characteristics without treatment or modification.
Christenson and Huber (U.S. Patent 3,590,117) reported that high viscosity grade, i.e. 15,000 cps, hydroxypropylmethylcellulose did not make an acceptable long-lasting troche because the troche would flake off in the mouth rather than dissolve uniformly.
Christenson and Dale (U.S. Patent 3,065,143) disclosed the use of certain high molecular weight hydro-philic gums, including hydroxypropylmethylcelluloses, in the preparation of a "sustained release tablet". The tablet consisted essentially of a mixture of a medicament and at least one third part be weight of the weight of the tablet of a hydrophilic gum which rapidly absorbed water and swelled at 37C to form a "soft mucilaginous gel barrier" on the surface of the tablet when brought into contact with the aqueous fluids of the gastrointestinal tract.
The high molecular weight hydroxypropylmethyl-celluloses disclosed by Christenson and Dale and constituting at least one third of the weigllt of the tablet, include Methocel 60HG 4000 cps, now known as Methocel E4M, having a 28-30 weight-C/O methoxyl content. a 7.5 12 weigh~-% hydroxy-propoxyl content and a number average molecular weight of 93,000, and Methocel 90HG 4000 cps and Methocel 90HG 15,000 cps, now known as Methocel K4M and Methocel K15M, respectively.
The latter have number average molecular weights of 89,000 and 124,000, respectively, and a 19-24 weight-% methoxyl content, and a ~-12 welght-% hydroxypropoxyl content.
The present invention is dlrected ~oward further improvements in carrier base materials containing hydroxy-propylmethylcelluloses for use in the preparation of sustained release solid pharrnaceutical unit dosage forms, particularly with moisture sensitive and/or high dosage medicaments.
SUMMARY OF THE II~VE~ilTIO~
An object of the present inventlon is to provide a carrier material for use in the preparation of orally, bucally or sublingually, etc., administered lozenges and tablets, as well as suppositories and other solid unit dosage forms which have a regular and sustained release pattern for a systemically absorbable medicament or active ingredient incorporated therein.
Another object of the present lnvention is to provide a carrier base having greater stability, greater hardness, lower friability, reduced water solubility and a uniform sustained release pattern from hydroxypropylmethylcellulose, particularly for use with moisture sensi.tive medicaments.
A furtler object of the present invention is to provide a carrier base which comprises less than about 30 weight-% of the weight of the solid unit dosage form, permitting the preparation of smaller units which are easier to administer.
Still another object of the present invention is to provide a carrier base for use with high dosage medicaments in sustained release dosage forms.
It has now been found that these improvements in a carrier base can be achieved by utilizing a high viscosity grade hydroxypropylmethylcellulose having a number average molecular weight above 50,000 and a methoxyl content of 16-24 weight-%, wherein said carrier base constitutes less than about one third of the weight of the sustained release dosage form.
DETAILED DESCRIPTION OF THE INVENTION
10 According to the present invention, it has now been found that important advantages and improvements over prior products containing hydroxypropylmethylcelluloses, as described in U.S. Patents 3,065,143, 3,870,790 and 4,226,~49, can be obtained by utilizing a high viscosity grade hydroxypropyl-mehtylcellulose having a methoxyl content of 16-24 weight-~The hydroxypropylmethylcellulose used in the present invention has a number average molecular weight above 50,00 and a hydroxypropoxyl content of 4-32 weight-%.
The hydroxypropylmethylcelluloses which are effective in the present invention include, but are not limited to, commercially available 4000 and 15,000 cps viscosity grades of Methocel K, i.e. Methocel K4M and Methocel K15M, available from the Dow Chemical Co., U.S.A., and 4000, 15,000 and 30,000 cps viscosity grades of Metalose 90SH, available from Shin-Etsu Ltd., Japan, as well as 5,000, 12,000, 20,000 and 75,000 cps viscosity grades of Methocel J, i.e. Methocel J5M, J12M, J20M and J75M, available from the Dow Chemical Co.
Althougl. U.S. 3,065,143 disclosed that a sustained release tablet required the presence of at least one third of the weight of the tablet of these hydroxypropylmethyl-celluloses, it has surprisingly been found that e:Efectivesustained release can be obtained from solid dosage forms containing as llttle as 5 to about 30 weight-% of these hydroxypropylmethylcelluloses.
Numerous advantages result from the ability to use less than about 30~/O of the carrier base material in a sustained release dosage form. These include the use of smaller tablets which are more economical and are easy to administer. High dosage drugs which normally result in large tablets can be put in smaller sustained-release dosage form.
Cellulose ethers such as the hydroxypropylmethyl-celluloses of the present invention are hydrophilic and tend to ahsorb moisture from the atmosphere. The use of low levels of the cellulose ether in a solid dosage form results in a lower moisture content upon exposure to the atmosphere.
This is particularly important when the active medicament is mo~sture sensitive and undergoes decomposition and/or hydrolysis upon contact with moisture. Typical moisture sensitive drugs include aspirin, phenacetin, procainamide, nikethamide, poly-mixin, barbiturates, idoxuridine, hydantoins, angiotensinamide, nitroglycerin, benzocaine, scopolamine, meperidine, codeine, streptomycin, ascorbic acld, sulfonamide drugs, tolbutamide, antihistamine salts such as chlorpheniramine and brompheni-ramine, phenylephrine, diphenhydramine, diethylcarbamazine, theophylline, caffeine, alkaloi~ salts, adrenocortical steroidesters such as hydrocortisone phosphate, and the like.
The hydroxypropylmethylceIluloses of the present invention may be used without prior humidification or similar treatment and when mixed with an active medicament, the mixture has excellent compressibility and the tablets prepared therefrom are hard and dense,have low friability andprovide sustained release over an extended period. Treatment of the carrier base material by humidification and drying before incorporation in a sustained release tablet has little or no effect on the compressibility of the polymer and the properties of the tablets prepared therefrom.
Sustained release drug forms containing the hydroxy-propylmethylcelluloses of the present invention are stable and the release rate does not change over an extended storage period. The therapeutic compositions of the present invention, in most cases, give a steady, reproducible release of the active medicament.
A hydroxypropylmethylcellulose having a methoxyl content of 16-24 weight-% and a number average molecular weight above 50,000 can be used as the sole carrier base material or can be used in admixture in all proportions with other hydroxy-propylmethylcelluloses of the same structure with a higher or a lower but above 50,000 number average molecular weight, e.g.
a 30/70 or 70/30 mixture of Methocel K~M and Methocel K15M. A
hydroxypropylmethylcellulose having a different structure and a number average molecular weight above 50,000 can also be used in admixture with the high molecular weight hydroxypropyl-methylcellulose having a methoxyl content of 1~-2~ weight-a/O, e.g. a 30/70 or 50/50 mixture of Methocel E4M and Methocel K4M.
The hydroxypropylmethylcelluloses of the present invention can be optionally mixed with about 0 to 30% by weight of the mixture of a hydroxypropyl.methylcellulose with the same or dlfferent structure and a number average molecular weight below 50,000, or methylcellulose, sodium carboxymethyl-cellulose or other cellulose ether.
The active ingredient can be of any type of medication which acts locally in the mouth or systemically, which in the case of the latter, can be administered orally to transmit the active medicament into the gastrointestinal tract and into the blood, fluids and tissues of the body without excessive peak concentrations occurring. Alternatively, the active ingredient can be of any type of medication which acts through the buccal tissues of the mouth to transmit the active ingredient directly into the blood stream thus avoiding first pass liver metabolism and by-passing the gastric and intestinal fluids which have an adverse inactivating or destructive action on many active in-gredients unless they are especially protected against such fluids as by means of an enteric coating or the like. The active ingredient can also be of a type of medication which can be transmitted into the blood circulation through the rectal tissues.
Representative active medicaments include antacids, anti-inflammatory substances, coronary vasodilators, cerebral vasodilators, peripheral vasodilators, anti-infectives, psycho-tropics, antimanics, stimulants, antihistamines, laxatives, decongestants, vi-tamins, gastro-intestinal sedatives, anti-cliarrheal preparations, anti-anginal drugs, vasodilators, antiarrythmics, anti-hypertensive drugs, vasoconstrictors and migraine treatments, anticoagulants and antithrombotic drugs, analgesics, anti-pyretics, hypnotics, sedatives, anti-emetics, anti-nauseants, anticonvulsants, neruomuscular drugs, hyper- and hypoglycaemic agents, thyroid and anti-thyroid preparations, diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, antiobesity drugs, ana~olic drugs, erythropoietic drugs, antiasthmatics, expectorants, cou~h suppressants, mucolytics, antiuricemic drugs, and other drugs or substances acting locally in the mouth, such as topical analgesics, local anaesthetics, etc.
The hydroxypropylmethylcelluloses of the present invention are partucularly effective in the preparation of sustalned release unit dosage forms containing moisture sensitive medicaments such as those named earlier. However, it is to be understood that the invention is applicable to sublingual lozenges, suppositories and compressed tablets, the latter intended to be swallowed in unit dosage form and which upon ingestion according to a prescribed regimen give slow and regular release of active medicament while being protected against normally inactivating gastric Eluids.
The hydroxypropylmethylcellulose having a methoxyl content of 16-2~ weight-%, a number average molecular weight of more than 50,000 and present in a concentration of less than about one-third of the total weight of the dosage form, forms what is called a long-acting, slow dissolving carrier of such a nature that it has a protective, demulcent and buffering effect in the body and causes the active medicament ~ ~ ~~
to exert its optimum therapewtic action iLnmediately and in-crementally for many hours, so that full therapeutic acdvantage can be taken of the entire or substantially the entire amount of active medicament administered. This unexpectedly high degree of efficiency is a particular advantage of the in-vention and minimizes the side effects of the medication.
In making up tablets containing an orally administrable systemi.cally absorbable active component such as one of the neretofore mentioned medicaments, the oral carrier material is thoroughly intermixed with the medicament which is also in powdered or granular form or in solution, and any other needed ingredien-ts which are conventional in tablet making such as magnesium stearate, lactose, starch and, in general, binders, fillers, disintegrating agents and the like. The complete mixture, in an amount sufficient to make a uniform batch of tablets, e.g. 50,000, of which each contains an effective amount of active medicament, is then subjected to tableting in conventional tableting machines at compression pressures of 2,000 to 16,000 lbs/sq.in. and, because of the use of the specific carrier material of this invention in the production of the tablets, a product is obtained which has the desired hardness, low level of friability and a predetermined prolonged action and a regular delayed release pattern so that the medicament is available over a period of 1 to 36 hours, depending on the precise tablet size, hardness and the par-ticular carrier composition. In this way, it is possible to produce sustained or slow continuous release tablets in relatively simple and economical manner on a commercial scale as contrasted with the more elaborate and more complex materials and procedures heretofore employed or proposed.
The moisture content o:E the carrier used in the preparati.on of the sustained release tablets may be in the 0.1-10% range, the lower end of the range being preerable when moisture sensitive medicaments are used. If the moisture con-tent is outside o:E this range, it may be brought within the range by the use of ambient or hot, dry or wet air, using appropriate equipment including static, convection, forced air or vacuum chambers or other equipment well known to those skilled in the art. The moisture content of the carrier during tableting influences the integrity of the tablet obtained under a given compression pressure. ~owever, the moisture content has little or no influence on the sustained release characteristics and plays a minor role as compared to the chemical structure of the carrier and its concentration on the ra~e of release of medicaments. Similarly, while the release rate is governed at least in part by the size of the tablet or other shaped dosage form, as well as by the degree of compression, the chemical structure of the hydroxypropylmethylcellulose superimposes its effect and is the dominant factor in the control of the release rate.
The relea&e pattern of active medicament from the carrier of the present invention can be controlled according to the particular medication and its intended therapeutic effect. For a sublingual lozenge or tablet, the release pattern may be varied from about 15 minutes to 4 hours. For orally administered tablets, the rate of release may be 2-4 hours, 4-8 hours, 8-10 hours, 10-12 hours, 15-18 hours, 20-24 hours, etc., as desired. For vaginal and rectal suppositories, the release pattern ranges from 2 to 36 hours, and can be less where indicated. Predetermined release patterns of unusually reliable and constant characteristics can be secured. This is often very important medically, especially when treating patients having coronary diseases, such as angina pectoris with nitroglycerin, or related problems of circulatory disorders or abnormal blood pressure conditions or psychotropic disorders such as manic depression or schizophrenia. The invention is particularly important also in treating such conditions as ulcerated tissue or mucous lesions and other conditions which arise from local hyperacidity or metabolic dysfunction in the physiological system. The invention is therefore of very versatile and adaptable nature giving it a wide range o~ application and end use.
The following illustrative embodiments of the dis-closures of ~he present invention are non-limiting and variations will be obvious to those skilled in the art.
Examples 1-6 describe the preparation of controlled release 650 mg aspirin tablets.
Controlled release 650 mg aspirin tablets containing 13.2% Methocel K4M were prepared from untreated Methocel K4M
having a moisture content of 2.5% and from treated Methocel K4M
which had been exposed to 85% humidity for 24 hours and then dried in a forced air oven at 120F to a moisture content of 5.0%.
The 650 mg aspirin tablets were prepared from the following ingredients:
Ingredients grams mg/tablet 1 Aspirin (40 mesh) 1300 650 2 Methocel K4M 200 100 15 3 Hydrogenated vegetable oi]
(Lubritab) Registered Trademark 14 7 4 Fumed silica (Cab-O-Sil M-5) Registered Trademark 1 0.5 Ingredients 1 and 2 were mixed, ingredient 3 was added to the blend and, after mixing, was followed by ingred-ient 4. The mixture was blended for 20 minutes and then sub-jected to compression in a tableting machine having a 0.281x0.625 inch punch, under a compression pressure of 4000 psi, to make 2000 capsule shaped tablets bisected on one side. The average weight of the tablets was 760 mg from untreated Methocel K4M
and 750 mg from treated Methocel K4M. The thickness of the tablets was 0.265-0.280 inches from the former and 0.260-0.265 inches from the latter.
The hardness of the tablets was determined on a Penn-walt Stokes hardness tester. The friability was determined in an Erweka Friabilator (Erweka-Apparatebau GmbH, Heuenstamm Kr.
Offenbach/MainJ West Germany) by measuring the weight loss after
and the hydroxypropoxyl content ranges from 4 to 32 weight-%, as determined by the method described in ASTM D-2363-72.
-1- ~
, ~ 3~ ~ ~
Commercial designatlons of the various hydroxy-propylmethylcelluloses are based on the viscosities of 2%
aqueous so]utions at 20C. The viscositi.es range :Erom 15 cps to 30,000 cps and represent number average molecular weights ranging from about 10,000 to over 150,000, as calculated from the data in "Handbook of Methocel Cellulose Ether Products" (The Dow Chemical Co., 1974).
A solid unit dosage form consisting of a mixture of a medicament and a carrier base material which is low molecular weight hydroxypropylmethylcellulose Methocel E50, formerly known as Methocel 601~G 50 cps, having a number avera,~e molecular weight of 23,000, a methoxyl content of 28-30 weight-%, and a hydroxypropoxyl content of less than 9 weight-%, rapidly releases the medicament when brought into contact with the aqueous fluids of the mouth or the gastrointestinal tract.
~owever, an effective "sustained release" tablet is produced by admixture of a medicament with a modified Methocel E50, per se or in admixture with other cellulose ethers. As disclosed by Lowey and Stafford (U.S. Patent 3,870,790) and Schor (U.S. Patent 4,226,849), the modification is carried out by exposure of the low molecular weight hydroxypropyl-methylcellulose Methocel ~50 to high humidity or moisture and drying in air.
It has been disclosed in U.S. Patent No. 4,369,172 that effective prolonged release therapeutic compositions may be prepared by using as a carrier base material a hydroxypropylmethylcellulose having a hydroxypropoxyl content of 9-12 weight-%, and a number average molecular weight of less than 50,000) e.g.
Metalose 60S~150. The carrier base material provides sustained release characteristics without treatment or modification.
Christenson and Huber (U.S. Patent 3,590,117) reported that high viscosity grade, i.e. 15,000 cps, hydroxypropylmethylcellulose did not make an acceptable long-lasting troche because the troche would flake off in the mouth rather than dissolve uniformly.
Christenson and Dale (U.S. Patent 3,065,143) disclosed the use of certain high molecular weight hydro-philic gums, including hydroxypropylmethylcelluloses, in the preparation of a "sustained release tablet". The tablet consisted essentially of a mixture of a medicament and at least one third part be weight of the weight of the tablet of a hydrophilic gum which rapidly absorbed water and swelled at 37C to form a "soft mucilaginous gel barrier" on the surface of the tablet when brought into contact with the aqueous fluids of the gastrointestinal tract.
The high molecular weight hydroxypropylmethyl-celluloses disclosed by Christenson and Dale and constituting at least one third of the weigllt of the tablet, include Methocel 60HG 4000 cps, now known as Methocel E4M, having a 28-30 weight-C/O methoxyl content. a 7.5 12 weigh~-% hydroxy-propoxyl content and a number average molecular weight of 93,000, and Methocel 90HG 4000 cps and Methocel 90HG 15,000 cps, now known as Methocel K4M and Methocel K15M, respectively.
The latter have number average molecular weights of 89,000 and 124,000, respectively, and a 19-24 weight-% methoxyl content, and a ~-12 welght-% hydroxypropoxyl content.
The present invention is dlrected ~oward further improvements in carrier base materials containing hydroxy-propylmethylcelluloses for use in the preparation of sustained release solid pharrnaceutical unit dosage forms, particularly with moisture sensitive and/or high dosage medicaments.
SUMMARY OF THE II~VE~ilTIO~
An object of the present inventlon is to provide a carrier material for use in the preparation of orally, bucally or sublingually, etc., administered lozenges and tablets, as well as suppositories and other solid unit dosage forms which have a regular and sustained release pattern for a systemically absorbable medicament or active ingredient incorporated therein.
Another object of the present lnvention is to provide a carrier base having greater stability, greater hardness, lower friability, reduced water solubility and a uniform sustained release pattern from hydroxypropylmethylcellulose, particularly for use with moisture sensi.tive medicaments.
A furtler object of the present invention is to provide a carrier base which comprises less than about 30 weight-% of the weight of the solid unit dosage form, permitting the preparation of smaller units which are easier to administer.
Still another object of the present invention is to provide a carrier base for use with high dosage medicaments in sustained release dosage forms.
It has now been found that these improvements in a carrier base can be achieved by utilizing a high viscosity grade hydroxypropylmethylcellulose having a number average molecular weight above 50,000 and a methoxyl content of 16-24 weight-%, wherein said carrier base constitutes less than about one third of the weight of the sustained release dosage form.
DETAILED DESCRIPTION OF THE INVENTION
10 According to the present invention, it has now been found that important advantages and improvements over prior products containing hydroxypropylmethylcelluloses, as described in U.S. Patents 3,065,143, 3,870,790 and 4,226,~49, can be obtained by utilizing a high viscosity grade hydroxypropyl-mehtylcellulose having a methoxyl content of 16-24 weight-~The hydroxypropylmethylcellulose used in the present invention has a number average molecular weight above 50,00 and a hydroxypropoxyl content of 4-32 weight-%.
The hydroxypropylmethylcelluloses which are effective in the present invention include, but are not limited to, commercially available 4000 and 15,000 cps viscosity grades of Methocel K, i.e. Methocel K4M and Methocel K15M, available from the Dow Chemical Co., U.S.A., and 4000, 15,000 and 30,000 cps viscosity grades of Metalose 90SH, available from Shin-Etsu Ltd., Japan, as well as 5,000, 12,000, 20,000 and 75,000 cps viscosity grades of Methocel J, i.e. Methocel J5M, J12M, J20M and J75M, available from the Dow Chemical Co.
Althougl. U.S. 3,065,143 disclosed that a sustained release tablet required the presence of at least one third of the weight of the tablet of these hydroxypropylmethyl-celluloses, it has surprisingly been found that e:Efectivesustained release can be obtained from solid dosage forms containing as llttle as 5 to about 30 weight-% of these hydroxypropylmethylcelluloses.
Numerous advantages result from the ability to use less than about 30~/O of the carrier base material in a sustained release dosage form. These include the use of smaller tablets which are more economical and are easy to administer. High dosage drugs which normally result in large tablets can be put in smaller sustained-release dosage form.
Cellulose ethers such as the hydroxypropylmethyl-celluloses of the present invention are hydrophilic and tend to ahsorb moisture from the atmosphere. The use of low levels of the cellulose ether in a solid dosage form results in a lower moisture content upon exposure to the atmosphere.
This is particularly important when the active medicament is mo~sture sensitive and undergoes decomposition and/or hydrolysis upon contact with moisture. Typical moisture sensitive drugs include aspirin, phenacetin, procainamide, nikethamide, poly-mixin, barbiturates, idoxuridine, hydantoins, angiotensinamide, nitroglycerin, benzocaine, scopolamine, meperidine, codeine, streptomycin, ascorbic acld, sulfonamide drugs, tolbutamide, antihistamine salts such as chlorpheniramine and brompheni-ramine, phenylephrine, diphenhydramine, diethylcarbamazine, theophylline, caffeine, alkaloi~ salts, adrenocortical steroidesters such as hydrocortisone phosphate, and the like.
The hydroxypropylmethylceIluloses of the present invention may be used without prior humidification or similar treatment and when mixed with an active medicament, the mixture has excellent compressibility and the tablets prepared therefrom are hard and dense,have low friability andprovide sustained release over an extended period. Treatment of the carrier base material by humidification and drying before incorporation in a sustained release tablet has little or no effect on the compressibility of the polymer and the properties of the tablets prepared therefrom.
Sustained release drug forms containing the hydroxy-propylmethylcelluloses of the present invention are stable and the release rate does not change over an extended storage period. The therapeutic compositions of the present invention, in most cases, give a steady, reproducible release of the active medicament.
A hydroxypropylmethylcellulose having a methoxyl content of 16-24 weight-% and a number average molecular weight above 50,000 can be used as the sole carrier base material or can be used in admixture in all proportions with other hydroxy-propylmethylcelluloses of the same structure with a higher or a lower but above 50,000 number average molecular weight, e.g.
a 30/70 or 70/30 mixture of Methocel K~M and Methocel K15M. A
hydroxypropylmethylcellulose having a different structure and a number average molecular weight above 50,000 can also be used in admixture with the high molecular weight hydroxypropyl-methylcellulose having a methoxyl content of 1~-2~ weight-a/O, e.g. a 30/70 or 50/50 mixture of Methocel E4M and Methocel K4M.
The hydroxypropylmethylcelluloses of the present invention can be optionally mixed with about 0 to 30% by weight of the mixture of a hydroxypropyl.methylcellulose with the same or dlfferent structure and a number average molecular weight below 50,000, or methylcellulose, sodium carboxymethyl-cellulose or other cellulose ether.
The active ingredient can be of any type of medication which acts locally in the mouth or systemically, which in the case of the latter, can be administered orally to transmit the active medicament into the gastrointestinal tract and into the blood, fluids and tissues of the body without excessive peak concentrations occurring. Alternatively, the active ingredient can be of any type of medication which acts through the buccal tissues of the mouth to transmit the active ingredient directly into the blood stream thus avoiding first pass liver metabolism and by-passing the gastric and intestinal fluids which have an adverse inactivating or destructive action on many active in-gredients unless they are especially protected against such fluids as by means of an enteric coating or the like. The active ingredient can also be of a type of medication which can be transmitted into the blood circulation through the rectal tissues.
Representative active medicaments include antacids, anti-inflammatory substances, coronary vasodilators, cerebral vasodilators, peripheral vasodilators, anti-infectives, psycho-tropics, antimanics, stimulants, antihistamines, laxatives, decongestants, vi-tamins, gastro-intestinal sedatives, anti-cliarrheal preparations, anti-anginal drugs, vasodilators, antiarrythmics, anti-hypertensive drugs, vasoconstrictors and migraine treatments, anticoagulants and antithrombotic drugs, analgesics, anti-pyretics, hypnotics, sedatives, anti-emetics, anti-nauseants, anticonvulsants, neruomuscular drugs, hyper- and hypoglycaemic agents, thyroid and anti-thyroid preparations, diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, antiobesity drugs, ana~olic drugs, erythropoietic drugs, antiasthmatics, expectorants, cou~h suppressants, mucolytics, antiuricemic drugs, and other drugs or substances acting locally in the mouth, such as topical analgesics, local anaesthetics, etc.
The hydroxypropylmethylcelluloses of the present invention are partucularly effective in the preparation of sustalned release unit dosage forms containing moisture sensitive medicaments such as those named earlier. However, it is to be understood that the invention is applicable to sublingual lozenges, suppositories and compressed tablets, the latter intended to be swallowed in unit dosage form and which upon ingestion according to a prescribed regimen give slow and regular release of active medicament while being protected against normally inactivating gastric Eluids.
The hydroxypropylmethylcellulose having a methoxyl content of 16-2~ weight-%, a number average molecular weight of more than 50,000 and present in a concentration of less than about one-third of the total weight of the dosage form, forms what is called a long-acting, slow dissolving carrier of such a nature that it has a protective, demulcent and buffering effect in the body and causes the active medicament ~ ~ ~~
to exert its optimum therapewtic action iLnmediately and in-crementally for many hours, so that full therapeutic acdvantage can be taken of the entire or substantially the entire amount of active medicament administered. This unexpectedly high degree of efficiency is a particular advantage of the in-vention and minimizes the side effects of the medication.
In making up tablets containing an orally administrable systemi.cally absorbable active component such as one of the neretofore mentioned medicaments, the oral carrier material is thoroughly intermixed with the medicament which is also in powdered or granular form or in solution, and any other needed ingredien-ts which are conventional in tablet making such as magnesium stearate, lactose, starch and, in general, binders, fillers, disintegrating agents and the like. The complete mixture, in an amount sufficient to make a uniform batch of tablets, e.g. 50,000, of which each contains an effective amount of active medicament, is then subjected to tableting in conventional tableting machines at compression pressures of 2,000 to 16,000 lbs/sq.in. and, because of the use of the specific carrier material of this invention in the production of the tablets, a product is obtained which has the desired hardness, low level of friability and a predetermined prolonged action and a regular delayed release pattern so that the medicament is available over a period of 1 to 36 hours, depending on the precise tablet size, hardness and the par-ticular carrier composition. In this way, it is possible to produce sustained or slow continuous release tablets in relatively simple and economical manner on a commercial scale as contrasted with the more elaborate and more complex materials and procedures heretofore employed or proposed.
The moisture content o:E the carrier used in the preparati.on of the sustained release tablets may be in the 0.1-10% range, the lower end of the range being preerable when moisture sensitive medicaments are used. If the moisture con-tent is outside o:E this range, it may be brought within the range by the use of ambient or hot, dry or wet air, using appropriate equipment including static, convection, forced air or vacuum chambers or other equipment well known to those skilled in the art. The moisture content of the carrier during tableting influences the integrity of the tablet obtained under a given compression pressure. ~owever, the moisture content has little or no influence on the sustained release characteristics and plays a minor role as compared to the chemical structure of the carrier and its concentration on the ra~e of release of medicaments. Similarly, while the release rate is governed at least in part by the size of the tablet or other shaped dosage form, as well as by the degree of compression, the chemical structure of the hydroxypropylmethylcellulose superimposes its effect and is the dominant factor in the control of the release rate.
The relea&e pattern of active medicament from the carrier of the present invention can be controlled according to the particular medication and its intended therapeutic effect. For a sublingual lozenge or tablet, the release pattern may be varied from about 15 minutes to 4 hours. For orally administered tablets, the rate of release may be 2-4 hours, 4-8 hours, 8-10 hours, 10-12 hours, 15-18 hours, 20-24 hours, etc., as desired. For vaginal and rectal suppositories, the release pattern ranges from 2 to 36 hours, and can be less where indicated. Predetermined release patterns of unusually reliable and constant characteristics can be secured. This is often very important medically, especially when treating patients having coronary diseases, such as angina pectoris with nitroglycerin, or related problems of circulatory disorders or abnormal blood pressure conditions or psychotropic disorders such as manic depression or schizophrenia. The invention is particularly important also in treating such conditions as ulcerated tissue or mucous lesions and other conditions which arise from local hyperacidity or metabolic dysfunction in the physiological system. The invention is therefore of very versatile and adaptable nature giving it a wide range o~ application and end use.
The following illustrative embodiments of the dis-closures of ~he present invention are non-limiting and variations will be obvious to those skilled in the art.
Examples 1-6 describe the preparation of controlled release 650 mg aspirin tablets.
Controlled release 650 mg aspirin tablets containing 13.2% Methocel K4M were prepared from untreated Methocel K4M
having a moisture content of 2.5% and from treated Methocel K4M
which had been exposed to 85% humidity for 24 hours and then dried in a forced air oven at 120F to a moisture content of 5.0%.
The 650 mg aspirin tablets were prepared from the following ingredients:
Ingredients grams mg/tablet 1 Aspirin (40 mesh) 1300 650 2 Methocel K4M 200 100 15 3 Hydrogenated vegetable oi]
(Lubritab) Registered Trademark 14 7 4 Fumed silica (Cab-O-Sil M-5) Registered Trademark 1 0.5 Ingredients 1 and 2 were mixed, ingredient 3 was added to the blend and, after mixing, was followed by ingred-ient 4. The mixture was blended for 20 minutes and then sub-jected to compression in a tableting machine having a 0.281x0.625 inch punch, under a compression pressure of 4000 psi, to make 2000 capsule shaped tablets bisected on one side. The average weight of the tablets was 760 mg from untreated Methocel K4M
and 750 mg from treated Methocel K4M. The thickness of the tablets was 0.265-0.280 inches from the former and 0.260-0.265 inches from the latter.
The hardness of the tablets was determined on a Penn-walt Stokes hardness tester. The friability was determined in an Erweka Friabilator (Erweka-Apparatebau GmbH, Heuenstamm Kr.
Offenbach/MainJ West Germany) by measuring the weight loss after
3 minutes rotation.
The release rate was determined by using the release rate apparatus as described in NF XIV, page 935. Five tablets were plac~d into a 100 ml screw cap dissolution vial and 60 ml of a buffered solution of the desired pH, preheated to 37C, was added to the vial. The vial was closed and rotated in the NF
time release apparatus maintained at 40 + 2 rpm. At intervals of one hour, the vial was opened and the supernatant liquid was poured through a screen and collected. The collected liquid was quantitatively transferred to a 100 ml volumetric flask.
The tablets on the screen and the vial were washed with deionized water, the washings being added to the flask. The washed tablets were returned to the vial from the screen with the aid of the next buffered solution and the closed vial was rotated in the bath for the next interval of one hour. The following schedule of buffered solutions was used:
- -Hours pH Hours pH
1 1.2 9 7.5 2 2.5 ~ 10 7.5 3 4.5 ~ 11 7.5
The release rate was determined by using the release rate apparatus as described in NF XIV, page 935. Five tablets were plac~d into a 100 ml screw cap dissolution vial and 60 ml of a buffered solution of the desired pH, preheated to 37C, was added to the vial. The vial was closed and rotated in the NF
time release apparatus maintained at 40 + 2 rpm. At intervals of one hour, the vial was opened and the supernatant liquid was poured through a screen and collected. The collected liquid was quantitatively transferred to a 100 ml volumetric flask.
The tablets on the screen and the vial were washed with deionized water, the washings being added to the flask. The washed tablets were returned to the vial from the screen with the aid of the next buffered solution and the closed vial was rotated in the bath for the next interval of one hour. The following schedule of buffered solutions was used:
- -Hours pH Hours pH
1 1.2 9 7.5 2 2.5 ~ 10 7.5 3 4.5 ~ 11 7.5
4 ~.5 12 7.5 7.0 13 7.5 6 7.0 14 7.5 7 7.5 15 7.5 8 7.5 16 7.5 The solutions separated from the tablets were analyzed for the concentration of medicament released from the tablets.
The procedure was continued until at least 90~/O of the tablet had dissolved and/or essentially all of the medicament had be~n released.
The 650 mg aspirin tablets had the following properties:
- ~ -Example No. 1 ~ 2 _ Methocel K4M Untreated Treated Hardness, kg 7.5-8.5 9.0-10.0 Friabillty, % 0.4 0.26
The procedure was continued until at least 90~/O of the tablet had dissolved and/or essentially all of the medicament had be~n released.
The 650 mg aspirin tablets had the following properties:
- ~ -Example No. 1 ~ 2 _ Methocel K4M Untreated Treated Hardness, kg 7.5-8.5 9.0-10.0 Friabillty, % 0.4 0.26
5 Release rate Cumulative Cumulative Hour ~/O % % %
1 8.9 8.9 10.8 10.8 2 11.6 20.5 ~10.8 21.6 3 10.6 31.1 ~12.0 33.6 4 10.2 41.3 10.7 4~.3 12.~ 53.7 13.5 57.8
1 8.9 8.9 10.8 10.8 2 11.6 20.5 ~10.8 21.6 3 10.6 31.1 ~12.0 33.6 4 10.2 41.3 10.7 4~.3 12.~ 53.7 13.5 57.8
6 8.3 62.0 10.7 68.5
7 13.6 75.6 9.~ 77.9
8 7.5 ~3.1 5.5 83.4
9 3.8 86.9 4.3 87.7 3.0 89.9 3.3 91.0 13 _ _ - 98.1 14 _ 100.9 Although the controlled release tablets prepared with treated and untreated Methocel K4M had comparable properties and reIease rates, the storage stability of the aspirin made with the treated carrier base material was about 18 months while that made with the untreated carrier base materlal was more than 3 years.
t~
Controlled release 650 mg aspirin tablets containing 9.0% Methocel K4M were prepared from treated Methocel K4M which had been exposed to 85% humldity for 24 hours and then dried in a forced air oven at 120F to a moisture content of 5.0% and from treated Methocel K4M which was dried in an oven at 210F
to a moisture content of 2.3%
The 650 mg aspi.rin tablets were prepared from the :Eollowing ingredients:
.. .. _ Treated Treated Dried Methocel Methocel Ingredients grams grams mg/tablet -1 Aspirin (40 mesh)6500 650 650 2 Methocel K4M 650 65 65 3 Lubritab 70 7 7 4 Cab-O-Sil M-5 5 0.5 0.5 The ingredients were mixed in the same manner as in Examples 1-2. The mixture was subjected to compression in a tableting machine having a 0.281x0.625 inch punch under a com-pression pressure of 4000 psi to make 10,000 capsule shaped tablets bisected on one side from the treated Methocel K4M and 1000 capsule shaped tablets from the treated and dried Methocel K4M.
The tablets from the treated Methocel K4M had an average weight of 724 mg and a thickness of 0.250-0.260 inches while the tablets from the treated and dried Methocel K4M had an average weight of 714 mg and a thickness of 0.250-0.260 inches.
The hardness, friability and release rate o:E the 650 mg aspirin tablets were determined as described earlier to give the following results:
__ Example No. 3 Methocel K4M Treated TrQated-Dried Hardness, kg 8.0-10.0 7.0-8.0 Friability, % 0.2 0.48 Release rate Cumulative Cumulative Hour ~ % % %
1 12.5 1205 10.7 10.7 2 12.5 25.0 12.1 22.8 3 12.5 37.5 14.4 37.2 4 12.5 50.0 13.2 50.4 15.4 65.~ 16.7 67.1 6 ~10.5 75.9 12.8 79.9 7 111.0 86.9 11.6 91.5 8 5.~ 92.3 4.9 96.4 9 2.8 95.1 3.1 99.5 ~, - ~:L~
EX~PLE 5 Controlled release 650 mg aspirin tablets containing 2.7% Methocel E4M and 6.3% Methocel K4M were prepared from untreated hydroxypropylmethylcelluloses with moist~re coT~tents in the range o:f 2-3%.
The 650 mg aspirin tablets were prepared from the following ingredients:
IngredienTs grams mg/tablet .
1 Aspirin 650 650
t~
Controlled release 650 mg aspirin tablets containing 9.0% Methocel K4M were prepared from treated Methocel K4M which had been exposed to 85% humldity for 24 hours and then dried in a forced air oven at 120F to a moisture content of 5.0% and from treated Methocel K4M which was dried in an oven at 210F
to a moisture content of 2.3%
The 650 mg aspi.rin tablets were prepared from the :Eollowing ingredients:
.. .. _ Treated Treated Dried Methocel Methocel Ingredients grams grams mg/tablet -1 Aspirin (40 mesh)6500 650 650 2 Methocel K4M 650 65 65 3 Lubritab 70 7 7 4 Cab-O-Sil M-5 5 0.5 0.5 The ingredients were mixed in the same manner as in Examples 1-2. The mixture was subjected to compression in a tableting machine having a 0.281x0.625 inch punch under a com-pression pressure of 4000 psi to make 10,000 capsule shaped tablets bisected on one side from the treated Methocel K4M and 1000 capsule shaped tablets from the treated and dried Methocel K4M.
The tablets from the treated Methocel K4M had an average weight of 724 mg and a thickness of 0.250-0.260 inches while the tablets from the treated and dried Methocel K4M had an average weight of 714 mg and a thickness of 0.250-0.260 inches.
The hardness, friability and release rate o:E the 650 mg aspirin tablets were determined as described earlier to give the following results:
__ Example No. 3 Methocel K4M Treated TrQated-Dried Hardness, kg 8.0-10.0 7.0-8.0 Friability, % 0.2 0.48 Release rate Cumulative Cumulative Hour ~ % % %
1 12.5 1205 10.7 10.7 2 12.5 25.0 12.1 22.8 3 12.5 37.5 14.4 37.2 4 12.5 50.0 13.2 50.4 15.4 65.~ 16.7 67.1 6 ~10.5 75.9 12.8 79.9 7 111.0 86.9 11.6 91.5 8 5.~ 92.3 4.9 96.4 9 2.8 95.1 3.1 99.5 ~, - ~:L~
EX~PLE 5 Controlled release 650 mg aspirin tablets containing 2.7% Methocel E4M and 6.3% Methocel K4M were prepared from untreated hydroxypropylmethylcelluloses with moist~re coT~tents in the range o:f 2-3%.
The 650 mg aspirin tablets were prepared from the following ingredients:
IngredienTs grams mg/tablet .
1 Aspirin 650 650
10 2 Methocel E4M 19.5 19.5 3 Methocel K4M 45.5 45.5 4 Lubritab 7 7 Cab-0-Sil M-5 0.5 0.5 Ingredient 1 was placed in a bag. Ingredients 2 and 3 were added and mixed with ingredient 1. Ingredients 4 and 5 were mixed with the blend of ingredients 1, 2 and 3 for 20 minutes. The mixture was subjected to compression in a tableting machine having a 0.281x0.625 inch punch under a compression pressure of 5000 psi to make 1000 capsule shaped tablets bisected on one side.
The average weight of the tablets was 717 mg and the thickness was 0.250-0.260 inches.
The hardness, friability and release rate of the 650 mg aspirin tablets were determined as described earlier to give the following results:
Hardness, kg 7.0-9.0 Friability, ~/a 0. 78 Release rate Cumulative Hour % %
l 23.1 23.1 2 36.1 59.2 3 19.7 78~9 4 15.5 94.4 5.2 99.6 Controlled release 650 mg aspirln tablets containing 2.7% Methocel E50 and 6.3% Methocel KlSM were prepared from the untreated hydroxypropylmethylcellyloses with moisture contents in the range of 2-3%.
The 650 mg aspirin tablets were prepared from the following ingredients:
Ingredients grams mg/tablet l Aspirin 650 650 2 Methocel E50 l9.$ 19.5 3 Methocel KlSM 45.5 45.5 4 Lubritab 7 7 Cab~0-Sil M-5 0.5 0.5 The ingre~ients weré mixe~ as described in Example 5.
The mixture was tableted under a compression pressure of 5000 psi using a 0.281x0.625 inch punch to make 1000 capsule shaped tablets bisected on one side.
The average weight of the tablets was 717 mg and the thickness was 0.250-0.260 inches.
The hardness, friability and release rate of -the 650 mg aspirin tablets were determined as described earlier to give the following results:
_ 10 ~ardness, kg 7.5_9.0 Friability, % 0.38 Release rate Cumulative Hour % %
1 1~.7 12.7 2 12.7 25.4 3 13.3 38.7 4 12.5 51.2 15.4 66.6 6 13.4 80.0 7 11.8 91.8 8 6.3 98.1 These results demonstrate that effective release rates are obtained from!mixtures of hydroxypropylmethylcelluloses when at least one of the polymers has a molecular weight above 50.000.
Examples 7-12 describe the preparation of controlled release 300 mg theophylline tablets.
EXAMPI.E 7 Controlled release 300 mg theophylline tablets contain-ing 19.4% Methocel K4M were prepared from untrea-ted Methocel K4M having a moisture content of 2.5%.
The 300 mg theophylline tablets were prepared from the following ingredients:
Ingredients grams mg/tablet _ 10 1 Theophylline, anhydrous 350 306 2 Methocel K4M 37.5 75 3 Cab-O-Sil M-5 0.75 1.5 4 Stearic acid 1.75 3.5 .
Ingredients 1 and 2 were mixed, ingredients 3 and 4 were added and the mixture was then blended for 20 minutes.
Tablets were prepared under a compression pressure of 5000 psi using a 0.300 x 0.545 inch punch to make 500 capsule shaped tablets bisected on one side.
The average weight of the tablets was 392 mg and the thickness was 0.180-0.190 inches.
The hardness, friability and release rates of the 300 mg theophylline tablets were determined in the usual manner to give the following results:
'~
Hardness, kg 6.0-8.0 Friability, % 0.2 -Release rate Cumulative Hour % %
1 19.2% 19.2%
2 12.7 31.9 3 12.3 44.2 4 11.0 55.2 ll.0 66.2 6 11.7 77.9 7 10.0 87.9 8 5.6 93.5 9 6.1 99.6 Controlled release 300 mg theophylline tablets con-taining 19.4% Methocel Kl5M were prepared from untreated Methocel Kl5M having a moisture content of 2.0%.
The 300 mg theophylline tablets were prepared from the following ingredients: -"~
Ingredients grams mg/tablet _ 1 Theophylline, anhydrous 153 306 2 Methocel Kl5M 37.5 75 3 Cab-0-Sil M-5 0.75 1.5 5 ~ Stearic acid 1.75 3.5 The ingredients were mixed as described in Example 7 and tableted under a compression pressure of 5000 psi using a 0.300 x 0.545 inch punch to make 500 capsule shaped -tablets bisected on one side.
The average weight of the table~s was 388 mg and the thickness was 0.180-0.190 inches.
The hardness, friability and release rates of the 300 mg theophylline tablets were determined in the usual manner to give the following results:
15 Hardness, kg 7.5-8.5 Friability, % 0.14 Release rate Cumulative Hour % %
1 17.0 17.0 2 12.8 29.8 3 9.7 39.5 4 8.8 48.3 8.2 56.5 (continued) (continued) 8.2 56.5 6 8.0 64.5 7 7.6 72.1 8 7~1 79.2 9 7.7 86.9 5.4 92.3
The average weight of the tablets was 717 mg and the thickness was 0.250-0.260 inches.
The hardness, friability and release rate of the 650 mg aspirin tablets were determined as described earlier to give the following results:
Hardness, kg 7.0-9.0 Friability, ~/a 0. 78 Release rate Cumulative Hour % %
l 23.1 23.1 2 36.1 59.2 3 19.7 78~9 4 15.5 94.4 5.2 99.6 Controlled release 650 mg aspirln tablets containing 2.7% Methocel E50 and 6.3% Methocel KlSM were prepared from the untreated hydroxypropylmethylcellyloses with moisture contents in the range of 2-3%.
The 650 mg aspirin tablets were prepared from the following ingredients:
Ingredients grams mg/tablet l Aspirin 650 650 2 Methocel E50 l9.$ 19.5 3 Methocel KlSM 45.5 45.5 4 Lubritab 7 7 Cab~0-Sil M-5 0.5 0.5 The ingre~ients weré mixe~ as described in Example 5.
The mixture was tableted under a compression pressure of 5000 psi using a 0.281x0.625 inch punch to make 1000 capsule shaped tablets bisected on one side.
The average weight of the tablets was 717 mg and the thickness was 0.250-0.260 inches.
The hardness, friability and release rate of -the 650 mg aspirin tablets were determined as described earlier to give the following results:
_ 10 ~ardness, kg 7.5_9.0 Friability, % 0.38 Release rate Cumulative Hour % %
1 1~.7 12.7 2 12.7 25.4 3 13.3 38.7 4 12.5 51.2 15.4 66.6 6 13.4 80.0 7 11.8 91.8 8 6.3 98.1 These results demonstrate that effective release rates are obtained from!mixtures of hydroxypropylmethylcelluloses when at least one of the polymers has a molecular weight above 50.000.
Examples 7-12 describe the preparation of controlled release 300 mg theophylline tablets.
EXAMPI.E 7 Controlled release 300 mg theophylline tablets contain-ing 19.4% Methocel K4M were prepared from untrea-ted Methocel K4M having a moisture content of 2.5%.
The 300 mg theophylline tablets were prepared from the following ingredients:
Ingredients grams mg/tablet _ 10 1 Theophylline, anhydrous 350 306 2 Methocel K4M 37.5 75 3 Cab-O-Sil M-5 0.75 1.5 4 Stearic acid 1.75 3.5 .
Ingredients 1 and 2 were mixed, ingredients 3 and 4 were added and the mixture was then blended for 20 minutes.
Tablets were prepared under a compression pressure of 5000 psi using a 0.300 x 0.545 inch punch to make 500 capsule shaped tablets bisected on one side.
The average weight of the tablets was 392 mg and the thickness was 0.180-0.190 inches.
The hardness, friability and release rates of the 300 mg theophylline tablets were determined in the usual manner to give the following results:
'~
Hardness, kg 6.0-8.0 Friability, % 0.2 -Release rate Cumulative Hour % %
1 19.2% 19.2%
2 12.7 31.9 3 12.3 44.2 4 11.0 55.2 ll.0 66.2 6 11.7 77.9 7 10.0 87.9 8 5.6 93.5 9 6.1 99.6 Controlled release 300 mg theophylline tablets con-taining 19.4% Methocel Kl5M were prepared from untreated Methocel Kl5M having a moisture content of 2.0%.
The 300 mg theophylline tablets were prepared from the following ingredients: -"~
Ingredients grams mg/tablet _ 1 Theophylline, anhydrous 153 306 2 Methocel Kl5M 37.5 75 3 Cab-0-Sil M-5 0.75 1.5 5 ~ Stearic acid 1.75 3.5 The ingredients were mixed as described in Example 7 and tableted under a compression pressure of 5000 psi using a 0.300 x 0.545 inch punch to make 500 capsule shaped -tablets bisected on one side.
The average weight of the table~s was 388 mg and the thickness was 0.180-0.190 inches.
The hardness, friability and release rates of the 300 mg theophylline tablets were determined in the usual manner to give the following results:
15 Hardness, kg 7.5-8.5 Friability, % 0.14 Release rate Cumulative Hour % %
1 17.0 17.0 2 12.8 29.8 3 9.7 39.5 4 8.8 48.3 8.2 56.5 (continued) (continued) 8.2 56.5 6 8.0 64.5 7 7.6 72.1 8 7~1 79.2 9 7.7 86.9 5.4 92.3
11 2.9 95.2
12 3.7 98.9 _ Controlled release 300 mg theophylline tablets con-taining 17.0% Methocel K4M and 7.3% Methocel K15M were prepared from the untreated polymers, each containing 2.0% moisture.
The 300 mg theophylline tablets were prepared from the following ingredients:
. _ Ingredients grams mg/tablet 1 Theophylline, anhydrous306 306 2 Methocel K4M 70 70 3 Met.hoceI K15M 30 30 4 Cab-0-Sil M-5 1.5 1.5 Stearic acid 3.5 3.5 The ingredients were mixed as described in Example 7, adding the premixed Methocel K4M and Methocel KlSM to the theophylline and, a~ter rllixing, adding the excipient in-gredients 4 and 5. Tablets were prepared under 5000 psi pressure using a 0.300 x 0.545 inch punch to make 1000 capsule shaped tablets having an average weight of 406 mg and a thickness o~ 0.193-0.203 inches.
The hardness, friability and release rates were determined as described earlier to give the following results:
-Hardness, kg 4.0-8.0 10 Friability~ % 0.39 ~elease rate Cumulative Hour % %
1 11.4 11.4 2 6.8 18.2 3 7.5 25.7 7.3 33.0 8.4 ~1.4 6 8.9 50.3 7 8.7 59.0 8 11.7 70.7 9 ~.4 75.1 5.9 81.0 11 6.3 87.3 12 8.4 95.7
The 300 mg theophylline tablets were prepared from the following ingredients:
. _ Ingredients grams mg/tablet 1 Theophylline, anhydrous306 306 2 Methocel K4M 70 70 3 Met.hoceI K15M 30 30 4 Cab-0-Sil M-5 1.5 1.5 Stearic acid 3.5 3.5 The ingredients were mixed as described in Example 7, adding the premixed Methocel K4M and Methocel KlSM to the theophylline and, a~ter rllixing, adding the excipient in-gredients 4 and 5. Tablets were prepared under 5000 psi pressure using a 0.300 x 0.545 inch punch to make 1000 capsule shaped tablets having an average weight of 406 mg and a thickness o~ 0.193-0.203 inches.
The hardness, friability and release rates were determined as described earlier to give the following results:
-Hardness, kg 4.0-8.0 10 Friability~ % 0.39 ~elease rate Cumulative Hour % %
1 11.4 11.4 2 6.8 18.2 3 7.5 25.7 7.3 33.0 8.4 ~1.4 6 8.9 50.3 7 8.7 59.0 8 11.7 70.7 9 ~.4 75.1 5.9 81.0 11 6.3 87.3 12 8.4 95.7
13 4.4 100.1 -Controlled release 300 mg theophylline tablets con-taining 22.4% Methocel K4M were prepared from Methocel K4M
which was exposed to 85% humidity for 24 hours and then dried at 120F to a moisture content of 4.5%.
The 300 mg theophylline tablets were prepared from the following ingredien~.s:
Ingredients grams mg/tablet 1 Theophylline, anhydrous 612 306 2 Methodel K4M 180 90 3 Cab-0-Sil M-5 3 1.5 4 Stearic acid 7 3.5 The ingredients were mixed as described in Example 7.
The resultant r.lixture was tableted under 5000 psi compression pressure using a 0.300 x 0.5~5 inch punch to make 2000 capsule shaped tablets.
The average weight of the tablets was 400 mg and the thickness was 0.185-0.195 inches.
The hardness, friability and release rates of the 300 mg theophylline tablets were determined in the usual manner to give the following results:
Hardness, kg 5.0-7.0 Friability, /O 0.3 ~ . . ... _ .
Release rate Cumulative Hour % %
1 15.7 15.7 2 11.2 26.9 3 9.6 36.5 ~ 10.9 ~7.4 10.5 57.9 6 10.6 68.5 7 15.5 84.0 8 7.0 91.0 Tablets with 300 mg theophylline, containing 19.4%
of low molecular weight Methocel K35 or Methocel K100, were prepared from untrea-ted Methocel K35 having a number average molecular weight of 19,440 or untreated Methocel K100 having a number average molecular weight of 26,880. The moisture contents of the untreated hydroxypropylmethylcelluloses were in the range of 2-3%.
The 300 mg theophylline tablets were prepared from the following ingredients:
.:,, Ingredlents grams mg/tablet 1 Thoephylline, anhydrous 153 306 2 Methocel K35 or K10037.5 75 3 Cab-0-Sil M-5 0.75 1.5 4. Stearic acid 1~75 3.5 -The ingredients were mixed as described in Example 7 and tableted under 5000 psi pressure using a 0.300 x 0.545 inch punch to make 500 capsule shaped tablets bisected on one side.
The average weight of the Methocel K35 tablets was 390 mg while that of the Methocel K100 tablets was 379 mg. The thickness oE the former tablets was 0.180-0.190 inches while that of the latter tablets was 0.175-0.185 inches.
The hardness, friabili-ty and release rates of the 300 mg theophylline tablets were determined as described earlier to give the following results:
Example No. 11 12 MethoceI K35 K100 Hardness, kg 6.5-8.0 5.4-7.5 Friability, % 0.3 0.2 20 Release rate Cumulative ~ Cumulative Hour % % ';~ % %
1 85.7 85.7 92.8 92.8 2 15.4 101.1 2.8 95.6 t~
These results demonstrate that hydroxypropylmethyl-celluloses having a methoxyl content of 19-24 weight-% are ineffective as the sole component of the carrier base when their number average molecular weight is below 5Q,000.
5Examples 13-1.5 describe the preparation of controlled relea.se 80 mg isosorbide dinitrate tablets.
Controlled release 80 mg isosorbide dinitrate tablets containing 13.5% Methocel K4M and 5.8% Methocel K15M were pre-10 pared from the untreated hydroxypropylmethylcelluloses having moisture contents in the range of 2-3%~
The 80 mg isosorbide dinitrate tablets were prepared from the following ingredients:
Ingredients grams mg/tablet -15 1 Isosorbide dinitrate (25% in lactose) 652.8 326.4 2 Methocel K4M 112 56 3 Methocel K15M 48 24 4 Stearic acid 12 6 29 5 Silica gel (Syloid 244) Registered Trademark 6 3 -Intredients 2 and 3 were premixed and added to ingredient 1. After these ingredients were mixed for 15 minutes, a mixture o~ ingredients 4 and 5, which had passed through a 20 mesh sieve, was added and -the resul-tan-t mixture was blended for 20 minutes. The mlxture was tableted under a pressure o~ 5000 psi using a 0.300 x 0.545 inch punch to prepare 2000 capsule shaped bisected tablets.
The average weight of the tablets was 422 mg and the thickness was 0.182-0.192 inches.
The hardness and ~riability o~ the 80 mg isosorbide dinitrate tablets were determined as described earlier. The release rates were determined using solutions having the pH
indicated in the following table.
Hardness, kg 9.0-11.0 Friability) % 0.15 Release rate Cumulatlve ~our pH % %
1 1.5 15.8 15.8 2 4.5 10.6 26.4 3 6.9 10.5 36.9 4 6.9 8.1 45.0 6.9 7.4 52.4 6 6.9 6.6 59.0 7 7.2 8.0 67.0 8 7.2 5.7 72.7 g 7.2 6.7 79.4 7.2 12.9 92.3 11 7.2 6.2 98.5 i~.~
EXAMPLE 1~
Controlled release 80 mg isosorbide dinitrate -tablets containing 5.8% Methocel K4M and 13.5% Methocel KlSM were pre-pared from the untreated hydroxypropylmethylcelluloses having moisture contents in the range of 2-3%.
The 80 mg isosorbide dinitrate tablets were prepared :Erom the following ingredients:
Ingredients grams mg/tablet 1 Isosorbide dinitrate (25% in lactose) 652.8 326.4 2 Methocel K4M 48 24 3 Methocel K15M 112 56 4 Stearic acid 12 6 Syloid 244 6 3 The ingredients were mixed as described in Example 13.
The mixture was tableted under 6000 psi pressure using a 0.300 x 0.545 înch punch to make 2000 capsule shaped tablets.
The average weight of the tablets was 414 mg and the thickness was 0.180-0.190 inches.
The hardness, friability and release rates of the 80 mg isosorbide dinitrate tablets were determined as described in Example 13 and gave the following results:
Hardness, kg 9.0-12.. 0 Friability, % 0.16 Release rate Cumulative Hour % %
1 11.9 11.9 2 7.6 19.5 3 7.3 26.8 4 7.0 33.8 10.4 44.2 6 9.9 54.1 7 7.8 61.9 8 7.1 69.0 9 6.1 75.1 ~.7 79.8 15 11 3.9 83.7 12 3.5 87.2 13 10.3 97.5
which was exposed to 85% humidity for 24 hours and then dried at 120F to a moisture content of 4.5%.
The 300 mg theophylline tablets were prepared from the following ingredien~.s:
Ingredients grams mg/tablet 1 Theophylline, anhydrous 612 306 2 Methodel K4M 180 90 3 Cab-0-Sil M-5 3 1.5 4 Stearic acid 7 3.5 The ingredients were mixed as described in Example 7.
The resultant r.lixture was tableted under 5000 psi compression pressure using a 0.300 x 0.5~5 inch punch to make 2000 capsule shaped tablets.
The average weight of the tablets was 400 mg and the thickness was 0.185-0.195 inches.
The hardness, friability and release rates of the 300 mg theophylline tablets were determined in the usual manner to give the following results:
Hardness, kg 5.0-7.0 Friability, /O 0.3 ~ . . ... _ .
Release rate Cumulative Hour % %
1 15.7 15.7 2 11.2 26.9 3 9.6 36.5 ~ 10.9 ~7.4 10.5 57.9 6 10.6 68.5 7 15.5 84.0 8 7.0 91.0 Tablets with 300 mg theophylline, containing 19.4%
of low molecular weight Methocel K35 or Methocel K100, were prepared from untrea-ted Methocel K35 having a number average molecular weight of 19,440 or untreated Methocel K100 having a number average molecular weight of 26,880. The moisture contents of the untreated hydroxypropylmethylcelluloses were in the range of 2-3%.
The 300 mg theophylline tablets were prepared from the following ingredients:
.:,, Ingredlents grams mg/tablet 1 Thoephylline, anhydrous 153 306 2 Methocel K35 or K10037.5 75 3 Cab-0-Sil M-5 0.75 1.5 4. Stearic acid 1~75 3.5 -The ingredients were mixed as described in Example 7 and tableted under 5000 psi pressure using a 0.300 x 0.545 inch punch to make 500 capsule shaped tablets bisected on one side.
The average weight of the Methocel K35 tablets was 390 mg while that of the Methocel K100 tablets was 379 mg. The thickness oE the former tablets was 0.180-0.190 inches while that of the latter tablets was 0.175-0.185 inches.
The hardness, friabili-ty and release rates of the 300 mg theophylline tablets were determined as described earlier to give the following results:
Example No. 11 12 MethoceI K35 K100 Hardness, kg 6.5-8.0 5.4-7.5 Friability, % 0.3 0.2 20 Release rate Cumulative ~ Cumulative Hour % % ';~ % %
1 85.7 85.7 92.8 92.8 2 15.4 101.1 2.8 95.6 t~
These results demonstrate that hydroxypropylmethyl-celluloses having a methoxyl content of 19-24 weight-% are ineffective as the sole component of the carrier base when their number average molecular weight is below 5Q,000.
5Examples 13-1.5 describe the preparation of controlled relea.se 80 mg isosorbide dinitrate tablets.
Controlled release 80 mg isosorbide dinitrate tablets containing 13.5% Methocel K4M and 5.8% Methocel K15M were pre-10 pared from the untreated hydroxypropylmethylcelluloses having moisture contents in the range of 2-3%~
The 80 mg isosorbide dinitrate tablets were prepared from the following ingredients:
Ingredients grams mg/tablet -15 1 Isosorbide dinitrate (25% in lactose) 652.8 326.4 2 Methocel K4M 112 56 3 Methocel K15M 48 24 4 Stearic acid 12 6 29 5 Silica gel (Syloid 244) Registered Trademark 6 3 -Intredients 2 and 3 were premixed and added to ingredient 1. After these ingredients were mixed for 15 minutes, a mixture o~ ingredients 4 and 5, which had passed through a 20 mesh sieve, was added and -the resul-tan-t mixture was blended for 20 minutes. The mlxture was tableted under a pressure o~ 5000 psi using a 0.300 x 0.545 inch punch to prepare 2000 capsule shaped bisected tablets.
The average weight of the tablets was 422 mg and the thickness was 0.182-0.192 inches.
The hardness and ~riability o~ the 80 mg isosorbide dinitrate tablets were determined as described earlier. The release rates were determined using solutions having the pH
indicated in the following table.
Hardness, kg 9.0-11.0 Friability) % 0.15 Release rate Cumulatlve ~our pH % %
1 1.5 15.8 15.8 2 4.5 10.6 26.4 3 6.9 10.5 36.9 4 6.9 8.1 45.0 6.9 7.4 52.4 6 6.9 6.6 59.0 7 7.2 8.0 67.0 8 7.2 5.7 72.7 g 7.2 6.7 79.4 7.2 12.9 92.3 11 7.2 6.2 98.5 i~.~
EXAMPLE 1~
Controlled release 80 mg isosorbide dinitrate -tablets containing 5.8% Methocel K4M and 13.5% Methocel KlSM were pre-pared from the untreated hydroxypropylmethylcelluloses having moisture contents in the range of 2-3%.
The 80 mg isosorbide dinitrate tablets were prepared :Erom the following ingredients:
Ingredients grams mg/tablet 1 Isosorbide dinitrate (25% in lactose) 652.8 326.4 2 Methocel K4M 48 24 3 Methocel K15M 112 56 4 Stearic acid 12 6 Syloid 244 6 3 The ingredients were mixed as described in Example 13.
The mixture was tableted under 6000 psi pressure using a 0.300 x 0.545 înch punch to make 2000 capsule shaped tablets.
The average weight of the tablets was 414 mg and the thickness was 0.180-0.190 inches.
The hardness, friability and release rates of the 80 mg isosorbide dinitrate tablets were determined as described in Example 13 and gave the following results:
Hardness, kg 9.0-12.. 0 Friability, % 0.16 Release rate Cumulative Hour % %
1 11.9 11.9 2 7.6 19.5 3 7.3 26.8 4 7.0 33.8 10.4 44.2 6 9.9 54.1 7 7.8 61.9 8 7.1 69.0 9 6.1 75.1 ~.7 79.8 15 11 3.9 83.7 12 3.5 87.2 13 10.3 97.5
14 3.0 100.5 Controlled release 80 mg isosorbide dinitrate tablets containing 9.6% Methbcel K4M and 9.6% Methocel E4M were pre-pared from the untreated Methocel K4M containing 2.8%
moisture and the untreated Methocel E4M containing 2.5%
moisture.
The 80 mg isosorbide dinitrate tablets were prepared from the following ingredients:
Ingredients grams mg/tablet _ .
1 Isosorbide dinitrate (25~/o in lactose) 326.4 326.4 2 Methocel K4M 40 40 3 Methocel E4M 40 40 4 Stearic acid 6 6 Syloid 244 3 3 10 The ingredients were mixed as described in Example 13.
The mixture was tableted under 6000 psi pressure to make 1000 capsule shaped tablets, using a 0. 300 x 0.545 inch punch.
The average weight of the tablets was 418 mg and the thickness was 0.189-0.195 lnches.
moisture and the untreated Methocel E4M containing 2.5%
moisture.
The 80 mg isosorbide dinitrate tablets were prepared from the following ingredients:
Ingredients grams mg/tablet _ .
1 Isosorbide dinitrate (25~/o in lactose) 326.4 326.4 2 Methocel K4M 40 40 3 Methocel E4M 40 40 4 Stearic acid 6 6 Syloid 244 3 3 10 The ingredients were mixed as described in Example 13.
The mixture was tableted under 6000 psi pressure to make 1000 capsule shaped tablets, using a 0. 300 x 0.545 inch punch.
The average weight of the tablets was 418 mg and the thickness was 0.189-0.195 lnches.
15 The hardness, friability and release rates of the 80 mg isosorbide dinitrate tablets were determined as described in Example 13 and gave the following results:
Hardness, ~g 6.5-8.5 Friability, % 0. 2 20 Release rate Cumulative Hour % %
1 40~7 40.7 2 11.2 51.9 (continued) `` ~ ~ 34 ~
(continued) 3 7.2 59.1 ~ 7.3 66.4 6.7 73.1 6 5.7 78.8 7 7.9 86.7 8 3.5 90.2 9 6.0 96.2 Examples 16-19 descrlbe the preparation of controlled reIease 300 mg lithium carbonate tablets.
Controlled release 300 mg lithium carbonate tablets containing 24.8% Methocel K15M were prepared Erom Methocel Kl5M
which had been exposed to 85% humidity for 24 hours and then dried in a forced air oven at 120F until the moisture content w~s 5.0%.
The 300 mg lithium carbonate tablets were prepared from ~he following ingredients:
-Ingredients grams mg/tablet 1 Lithium carbonate 300 300 2 Methocel K15M 100 100 3 Cherry flavor 1.2 1.2 4 Magnesium stearate 1.6 1.6 Ingredients 1 and 2 were mi.xed, ingredient 3 was added and mixed in, followed by the addition of ingredient 4.
After mixing for 20 minutes:, the mixture was tableted under 5000 psi compression pressure using a 13/32 inch tool to pre-pare 1000 round, flat faced beveled tablets bisected on oneside.
The average weight of the tablets was 395 mg and the thickness was 0.120-0.140 inches.
The hardness and friability of the 300 mg lithium carbonate tablets were determined as described earlier. The release rates were determined using solutions having the pH
indicated in the following table:
-Hardness, kg 6.0-9.0 Friability, % 0.29 _ 15 Release rate Cumulative Cumulative Hour pH % % Hour pH % %
1 1.2 14.2 14.2 13 7.5 3.6 72.5 2 2.5 11.3 25.5 14 7.5 3.9 76.4 3 ~.5 5.6 31.1 15 7.5 3.5 79.9 ~ 7.0 5.4 36.5 16 7.5 3.3 83.2 7.0 5.3 41.8 17 7.5 4.1 87.3 6 7.5 3.9 45.7 18 7.5 2.7 90.0 7 7.5 4.0 49.7 19 7.5 2.5 92.5 8 7.5 3.3 53.0 20 7.5 2.2 94.7 9 7.5 4.2 57.2 21 7.5 2.1 96.8 (continued) (con~inued) 7.5 4.0 61.2 22 7.5 1.7 98.5 11 7.5 3.7 64.9 23 7.5 1.6 lO0.1 12 7.5 ~i.0 68.9 2~ 7.5 1.2 101.3 EX~PLE 17 Controlled release 300 mg lithium carbonate tablets containing 14.2% Methocel K15M were prepared using Methocel K15M
which had been humidified in an 85% humidity chamber and then dried at 120F to a moisture content of 5.0%.
The 300 mg lithium carbonate tablets were prepared from the ~ollowing ingredients:
Ingredients grams mg/tablet 1 Lithium carbonate 300 300 2 MethoceI ~lSM S0 50 3 Cherry flavor 1O2 1.2 4 Magnesium stearate 1.6 1.6 .
The ingredients were mixed as described in Example 16 and the mixture was tableted under a pressure of S000 psi using an 11/32 inch tool to prepare 1000 round, flat beveled tablets.
The average weight of the tablets was 354 mg and the thic~ne,ss was O.lSS-0.165 inches.
The hardness, friability and release rates of the 300 mg lithium carbonate tablets were determined as described in .
Example 16 and gave the following results:
Hardness, kg 3.8-4.0 Friability, V/~ 0.25 Release rate Cumula-tive Hour % %
1 23.3 23.3 2 11.0 34.3 3 10.5 44.8 4 8.5 53.3 8.3 61.6 6 6.8 68.4 7 7.6 76~0 8 5.4 81.4 9 5.3 86.7 4.3 91.0 11 3.2 94.2 12 4.7 98.9 Controlled release 300 mg lithium carbonate tablets containing 19.9% Methocel K15M were prepared using untreated Methocel K15M having a moisture con-tnet of 1.5%
~'J7~
Tlle 300 mg llthium carbonate -tablets were prepared from the ~ollowing ingredients:
-Ingredients grams mg/tablet .
1 Lithium carbonate 300 300 2 Methocel K15M 75 75 3 Magnesium stearate 0.8 0.8 4 Cab-O-Sil M-5 1.0 1.0 The ingredients were mixed as described in Example 16.
An 11/32 inch flat faced bevel tool was used to prepare 1000 white round tablets under 5000 psi pressure. The average weight of the tablets was 380 mg, the thickness was 0.170-0.180 inches and the hardness was 6.0-6.5 kg.
EXA~IPLE 19 Controlled release 300 mg lithium carbonate tablets containing 19.9% Methocel K4M were prepared using untreated Methocel K4M having a moisture content of 2.0%.
The tablets were prepared from the following ingredients:
-Ingredients grams mg/tablet 20 1 Lithium carbonate 300 300 2Methocel K4M 75 75 3Magnesium stearate 0.8 0.8 4 Cab-0-Sil M-5 1.0 1.0 The ingredients were mi~ed as described in Example 16 and the mixture was compressed using an 11/32 inch flat faced bevel tool to prepare 1000 white round table-~s. The average weight of the 300 mg lithium carbona-te tablets was 376 mg, the thickness was 0.165-0.170 inches and the hardness was 6.0 kg.
Examples 20-22 describe the preparation of controlled re]ease nitroglycerin tablets.
Controlled reIease 6.5 mg nitroglycerin tablets con-taining 24% Methocel K4M were prepared from untreated Methocel K4M having a moisture content of 2.5% as well as from Methocel K4M which had been humidiEied and then dried at 120F to a moisture content of 5.0% as described earlier.
Tl~e 6.5 mg nitroglycerin tablets were prepared from the :Eollowing ingredients:
Untreated Treated Methocel K4M Methocel K4M
Ingredients grams grams mg/tablet _ 1 Nitroglycerin (10% in lactose) 350 195 65 2 Lactose, anhydrous 80 120 40 3 Methocel K4M 70 105 35 4 FDC Red No. 3 0.6 0.9 0.3 Stearic acid 6 9 3 6 Syloid 244 2 3 25 7 Cab-0-Sil M-5 2 Ingredients 1, 2, 3 and 4 were mi~ed together and passed through a 20 mesh sieve. Ingredients 5 and 6, and 7 when used, were mixed, passed through a 20 mesh sieve and then mixed with the mixture of the other ingredients. After 20 minutes of blending, the mixture was compressed using a 9/32 inch tool to prepare 2000 pink, round and concave tablets bisected on one side from the untreated Methocel K4M and 3000 similar tablets from the treated Methocel K4M.
The tablets from the untreated Methocel K4M had an average weight of 150 mg and a thickness of 0.135-0.145 inches.
The tablets from the treated Methocel K4M had an average weight of 148 mg and a thickness of 0.130-0.140 inches.
The hardness and friabili-ty of the 6.5 mg nitroglycerin tablets were determined in theusual manner. The release rates were determined using solutions having the same pH as used with the isosorbide dinitrate tablets in Example 13. The results were as follows:
Example No. 20 21 Methocel K4M Untreated Treated .
Hardness, kg 3.0-4.5 3.0-3.5 Friability, % 0.3 0.3 Release rate Cumulative Cumulative Hour % % % %
1 26.6 26.6 23.7 23.7 2 17.5 44.1 1 13.8 37.5 (continued) '~
(contlmled) 3l4.2 58 3 13.350.8 411.6 69.9 18.269.0 510.0 79.9 16.785.7 67.7 87.6 12.~98.1 75.4 93.0 3.8 96.8 -Controlled release 5.5 mg nitroglycerin buccal tablets containing 11.1% Methocel K4M were prepared from untreated Methocel K4M having a moisture content of 1.6%.
The 5.5 mg nitroglycerin buccal tablets were prepared from the following ingredients:
-Ingredients grams mg/tablet 1 Nitroglycerin (10% in lactose) 275 5.5 2 Lactose, anhydrous237.5 47.5 3 MethoceI K4M 35 7 4 Stearic acid 5 Syloid 244 5 20 6 Cab-0-Sil M-5 5 Ingredient 1 was passed through a 20 mesh sieve.
Ingredient 2 was added and mixed, followed by ingredient 3.
A mixture of ingredients 4, 5 and 6 was added ancl mi~ed.
The mixture was compressed using a 1/4 inch concave -tool to prepare 5000 white, round buccal tablets.
The average weight of the tablets was 120 mg, the thickness was 0.130-0.140 inches.
This example describes the preparation of 5.5 mg controlled release phenylpropanolamine base buccal tablets containing 25.8% MethsceI K4M wherein the latter was subjected to humidification in an 85% relative humidity chamber for 24 hours and then dried at 120F to reduce the moisture content to 4.5%.
The 5.5 mg phenylpropanolamine tablets were prepared from the following ingredients:
Ingredients grams mg/tablet 1 Phenylpropanolamine base11 5.5 2 Lactose, anhydrous 100 50 3 MethoceI K4M 40 20 4 Spearmint flavor 1 0.5 20 5 Peppermint flavor 1 0.5 6 Stearic acid 2 Ingredients 1, 2, 4 and 5 were mixed. Ingredient 3 was then added and mixed for 10 minutes. Ingredient 6 was added and the mixture was blended for 20 minutes. The mixture was tableted under S000 psi pressure using a 1/4 inch concave punch to produce 2000 white round buccal tablets.
The average weight of the tablets was 78 mg and the thickness was 0.105-0.110 inches. The hardness, friability and release rates of the buccal -tablets were determined as described in Example 22 and gave the following results:
10 Hardness, kg 4.5-6.0 Friability, % 0.8 Release rate MinutesCumulative %
27.6 39~0 50.0 60.2 73.0 120 83.2 _ This example describes the preparation of controlled release 600 mg potassium chloride lozenges containing 24.8%
untreated Methocel K15M.
The 600 mg lozenges were prepared from the following ingredients:
-4~--Ingredients grams mg/tablet 1Potassium chloride 600 600 2Methocel Kl5M 200 200 3Stearic acid 8 8 .
Ingredient 1 was passed through a 40 mesh sieve.
Ingredient 2 was added and mixed with ingredient 1.
Ingredient 3 was passed through a 40 mesh sieve and then mixed with ingredients 1 and 2 for 20 minutes.
The mixture was compressed under 5000 psi using a 7/16 inch deep concave punch to preparelO00 round mottled white lozenges.
The average weight of the lozenges was 810 mg and the thickness was 0.255-0.265 inches.
The hardness, friability and release rates of the lozenges were determined as described in Example 22 and gave the following results:
Hardness, kg 6.0-8.5 Friability, ~/O 0.13 Release rate Hour Cumulative %
1 71.2 2 87.4 3 99.3 ~r~
Examples 25 to 27 disclose compositions containing anti inflammatory drugs such as ibuprofen, flurbiprofen, diclofenac, indomethacin and naproxen Controlled release 700 mg ibuprofen tablets contain-ing 9.5% Methocel K4M and 9.0% Methocel K15M were prepared from the untreated hydroxypropylmethylcelluloses having moisture contents in the range of 2.0-3.0%.
A tablet having the following composition was pre-pared in the usual manner:
Ingredients mg/tablet 1 Ibuprofen 700 3 MethoceI K4M 85 4 Methocel K15M 80 Syloid 5 6 Stearic Acid The tablets were compressed using 0.750" x 0.300"
capsule-shaped bisected punches at a comprssional force of about 4000 lbs/sq. in. to obtain a tablet of average weight of 893 mg and a hardness of 8 to 10 kg.
Controlled release 200 mg flurbiprofen tablets containing 12.4% Methocel K4M and 10.2% Methocel KlSM were prepared from the untreated hydroxypropylmethylcelluloses having moisture contents in tl~e range of 2~0-3~0~Y
A tablet having the following composition was prepared in the usual manner:
Ingredients mg/tablet 5 1 Fl.urbiprofen 200 2 Methocel K4M 33 3 Methocel K15M 27 4 Stearic Acid 5 Cab-0-Sil M-5 Tablets were compressed using 0.281" x 0.62511 capsule-shaped bisected punches at a compressional pressure of 4000 to 6000 lbs/sq.in. to obtain a tablet of average weight of 270 mg and a hardness of 6 to 8 kg.
15 Controlled release 100 mg diclofenac tablets con-taining 8.5~/o MethoceI K4M and 12.8% Methocel K15M were prepared from the untreated hydroxypropylmethylcelluloses having moisture contents in the range of 2.0-3.0%.
A tablet having the following composition was prepared in the usual manner:
-Ingredients mg/tablet 1Diclofenac sodium 100 2P.V.P. 5 3Methocel K4M 12 25 4 Methocel K15M 18 5Stearic Acid 5 6Cab-O-Sil M-5 Tablets were compressed using 9/32" standard concave round punches at a compressional pressure of 4000 to 6000 lbs/sq.in. to give a tablet weight of 144 mg and a hardness of 6 to 8 kg.
L~.~
The foregoing is exemplary and illustrative of compositions and products responding to the present invention, but it is to be understood that they are not limita-tive since many active medicaments of various types can be employed in the new long-lasting carrier so long as they are absorbable into blood or tissue Erom the general intestinal tract and other bodily surfaces and areas. The medicaments shown in our co-pending application Serial No. 332,348 filed December 18, 1981, now U.S. Patent No. 4,369,172 issued January 18, 1~83, may be used in the practice of the present inven-tion and are incorporated herein by reference. The invention is also intended to cover other dosage forms or forms for application of sustained release ingredients such as vaginal and rectal suppositiories. The lozenges and tablets particularly act on oral, oropharyngeal, pharyngeal and intestinal regions.
The total dosage is governed by usual medical considerations or physicians' directions and when sufficiently large doses of active medicament are incorporated in the unit dosage form, systemic as well as local action is obtained to over-come or control the pathological condition or disorder being treated.
Hardness, ~g 6.5-8.5 Friability, % 0. 2 20 Release rate Cumulative Hour % %
1 40~7 40.7 2 11.2 51.9 (continued) `` ~ ~ 34 ~
(continued) 3 7.2 59.1 ~ 7.3 66.4 6.7 73.1 6 5.7 78.8 7 7.9 86.7 8 3.5 90.2 9 6.0 96.2 Examples 16-19 descrlbe the preparation of controlled reIease 300 mg lithium carbonate tablets.
Controlled release 300 mg lithium carbonate tablets containing 24.8% Methocel K15M were prepared Erom Methocel Kl5M
which had been exposed to 85% humidity for 24 hours and then dried in a forced air oven at 120F until the moisture content w~s 5.0%.
The 300 mg lithium carbonate tablets were prepared from ~he following ingredients:
-Ingredients grams mg/tablet 1 Lithium carbonate 300 300 2 Methocel K15M 100 100 3 Cherry flavor 1.2 1.2 4 Magnesium stearate 1.6 1.6 Ingredients 1 and 2 were mi.xed, ingredient 3 was added and mixed in, followed by the addition of ingredient 4.
After mixing for 20 minutes:, the mixture was tableted under 5000 psi compression pressure using a 13/32 inch tool to pre-pare 1000 round, flat faced beveled tablets bisected on oneside.
The average weight of the tablets was 395 mg and the thickness was 0.120-0.140 inches.
The hardness and friability of the 300 mg lithium carbonate tablets were determined as described earlier. The release rates were determined using solutions having the pH
indicated in the following table:
-Hardness, kg 6.0-9.0 Friability, % 0.29 _ 15 Release rate Cumulative Cumulative Hour pH % % Hour pH % %
1 1.2 14.2 14.2 13 7.5 3.6 72.5 2 2.5 11.3 25.5 14 7.5 3.9 76.4 3 ~.5 5.6 31.1 15 7.5 3.5 79.9 ~ 7.0 5.4 36.5 16 7.5 3.3 83.2 7.0 5.3 41.8 17 7.5 4.1 87.3 6 7.5 3.9 45.7 18 7.5 2.7 90.0 7 7.5 4.0 49.7 19 7.5 2.5 92.5 8 7.5 3.3 53.0 20 7.5 2.2 94.7 9 7.5 4.2 57.2 21 7.5 2.1 96.8 (continued) (con~inued) 7.5 4.0 61.2 22 7.5 1.7 98.5 11 7.5 3.7 64.9 23 7.5 1.6 lO0.1 12 7.5 ~i.0 68.9 2~ 7.5 1.2 101.3 EX~PLE 17 Controlled release 300 mg lithium carbonate tablets containing 14.2% Methocel K15M were prepared using Methocel K15M
which had been humidified in an 85% humidity chamber and then dried at 120F to a moisture content of 5.0%.
The 300 mg lithium carbonate tablets were prepared from the ~ollowing ingredients:
Ingredients grams mg/tablet 1 Lithium carbonate 300 300 2 MethoceI ~lSM S0 50 3 Cherry flavor 1O2 1.2 4 Magnesium stearate 1.6 1.6 .
The ingredients were mixed as described in Example 16 and the mixture was tableted under a pressure of S000 psi using an 11/32 inch tool to prepare 1000 round, flat beveled tablets.
The average weight of the tablets was 354 mg and the thic~ne,ss was O.lSS-0.165 inches.
The hardness, friability and release rates of the 300 mg lithium carbonate tablets were determined as described in .
Example 16 and gave the following results:
Hardness, kg 3.8-4.0 Friability, V/~ 0.25 Release rate Cumula-tive Hour % %
1 23.3 23.3 2 11.0 34.3 3 10.5 44.8 4 8.5 53.3 8.3 61.6 6 6.8 68.4 7 7.6 76~0 8 5.4 81.4 9 5.3 86.7 4.3 91.0 11 3.2 94.2 12 4.7 98.9 Controlled release 300 mg lithium carbonate tablets containing 19.9% Methocel K15M were prepared using untreated Methocel K15M having a moisture con-tnet of 1.5%
~'J7~
Tlle 300 mg llthium carbonate -tablets were prepared from the ~ollowing ingredients:
-Ingredients grams mg/tablet .
1 Lithium carbonate 300 300 2 Methocel K15M 75 75 3 Magnesium stearate 0.8 0.8 4 Cab-O-Sil M-5 1.0 1.0 The ingredients were mixed as described in Example 16.
An 11/32 inch flat faced bevel tool was used to prepare 1000 white round tablets under 5000 psi pressure. The average weight of the tablets was 380 mg, the thickness was 0.170-0.180 inches and the hardness was 6.0-6.5 kg.
EXA~IPLE 19 Controlled release 300 mg lithium carbonate tablets containing 19.9% Methocel K4M were prepared using untreated Methocel K4M having a moisture content of 2.0%.
The tablets were prepared from the following ingredients:
-Ingredients grams mg/tablet 20 1 Lithium carbonate 300 300 2Methocel K4M 75 75 3Magnesium stearate 0.8 0.8 4 Cab-0-Sil M-5 1.0 1.0 The ingredients were mi~ed as described in Example 16 and the mixture was compressed using an 11/32 inch flat faced bevel tool to prepare 1000 white round table-~s. The average weight of the 300 mg lithium carbona-te tablets was 376 mg, the thickness was 0.165-0.170 inches and the hardness was 6.0 kg.
Examples 20-22 describe the preparation of controlled re]ease nitroglycerin tablets.
Controlled reIease 6.5 mg nitroglycerin tablets con-taining 24% Methocel K4M were prepared from untreated Methocel K4M having a moisture content of 2.5% as well as from Methocel K4M which had been humidiEied and then dried at 120F to a moisture content of 5.0% as described earlier.
Tl~e 6.5 mg nitroglycerin tablets were prepared from the :Eollowing ingredients:
Untreated Treated Methocel K4M Methocel K4M
Ingredients grams grams mg/tablet _ 1 Nitroglycerin (10% in lactose) 350 195 65 2 Lactose, anhydrous 80 120 40 3 Methocel K4M 70 105 35 4 FDC Red No. 3 0.6 0.9 0.3 Stearic acid 6 9 3 6 Syloid 244 2 3 25 7 Cab-0-Sil M-5 2 Ingredients 1, 2, 3 and 4 were mi~ed together and passed through a 20 mesh sieve. Ingredients 5 and 6, and 7 when used, were mixed, passed through a 20 mesh sieve and then mixed with the mixture of the other ingredients. After 20 minutes of blending, the mixture was compressed using a 9/32 inch tool to prepare 2000 pink, round and concave tablets bisected on one side from the untreated Methocel K4M and 3000 similar tablets from the treated Methocel K4M.
The tablets from the untreated Methocel K4M had an average weight of 150 mg and a thickness of 0.135-0.145 inches.
The tablets from the treated Methocel K4M had an average weight of 148 mg and a thickness of 0.130-0.140 inches.
The hardness and friabili-ty of the 6.5 mg nitroglycerin tablets were determined in theusual manner. The release rates were determined using solutions having the same pH as used with the isosorbide dinitrate tablets in Example 13. The results were as follows:
Example No. 20 21 Methocel K4M Untreated Treated .
Hardness, kg 3.0-4.5 3.0-3.5 Friability, % 0.3 0.3 Release rate Cumulative Cumulative Hour % % % %
1 26.6 26.6 23.7 23.7 2 17.5 44.1 1 13.8 37.5 (continued) '~
(contlmled) 3l4.2 58 3 13.350.8 411.6 69.9 18.269.0 510.0 79.9 16.785.7 67.7 87.6 12.~98.1 75.4 93.0 3.8 96.8 -Controlled release 5.5 mg nitroglycerin buccal tablets containing 11.1% Methocel K4M were prepared from untreated Methocel K4M having a moisture content of 1.6%.
The 5.5 mg nitroglycerin buccal tablets were prepared from the following ingredients:
-Ingredients grams mg/tablet 1 Nitroglycerin (10% in lactose) 275 5.5 2 Lactose, anhydrous237.5 47.5 3 MethoceI K4M 35 7 4 Stearic acid 5 Syloid 244 5 20 6 Cab-0-Sil M-5 5 Ingredient 1 was passed through a 20 mesh sieve.
Ingredient 2 was added and mixed, followed by ingredient 3.
A mixture of ingredients 4, 5 and 6 was added ancl mi~ed.
The mixture was compressed using a 1/4 inch concave -tool to prepare 5000 white, round buccal tablets.
The average weight of the tablets was 120 mg, the thickness was 0.130-0.140 inches.
This example describes the preparation of 5.5 mg controlled release phenylpropanolamine base buccal tablets containing 25.8% MethsceI K4M wherein the latter was subjected to humidification in an 85% relative humidity chamber for 24 hours and then dried at 120F to reduce the moisture content to 4.5%.
The 5.5 mg phenylpropanolamine tablets were prepared from the following ingredients:
Ingredients grams mg/tablet 1 Phenylpropanolamine base11 5.5 2 Lactose, anhydrous 100 50 3 MethoceI K4M 40 20 4 Spearmint flavor 1 0.5 20 5 Peppermint flavor 1 0.5 6 Stearic acid 2 Ingredients 1, 2, 4 and 5 were mixed. Ingredient 3 was then added and mixed for 10 minutes. Ingredient 6 was added and the mixture was blended for 20 minutes. The mixture was tableted under S000 psi pressure using a 1/4 inch concave punch to produce 2000 white round buccal tablets.
The average weight of the tablets was 78 mg and the thickness was 0.105-0.110 inches. The hardness, friability and release rates of the buccal -tablets were determined as described in Example 22 and gave the following results:
10 Hardness, kg 4.5-6.0 Friability, % 0.8 Release rate MinutesCumulative %
27.6 39~0 50.0 60.2 73.0 120 83.2 _ This example describes the preparation of controlled release 600 mg potassium chloride lozenges containing 24.8%
untreated Methocel K15M.
The 600 mg lozenges were prepared from the following ingredients:
-4~--Ingredients grams mg/tablet 1Potassium chloride 600 600 2Methocel Kl5M 200 200 3Stearic acid 8 8 .
Ingredient 1 was passed through a 40 mesh sieve.
Ingredient 2 was added and mixed with ingredient 1.
Ingredient 3 was passed through a 40 mesh sieve and then mixed with ingredients 1 and 2 for 20 minutes.
The mixture was compressed under 5000 psi using a 7/16 inch deep concave punch to preparelO00 round mottled white lozenges.
The average weight of the lozenges was 810 mg and the thickness was 0.255-0.265 inches.
The hardness, friability and release rates of the lozenges were determined as described in Example 22 and gave the following results:
Hardness, kg 6.0-8.5 Friability, ~/O 0.13 Release rate Hour Cumulative %
1 71.2 2 87.4 3 99.3 ~r~
Examples 25 to 27 disclose compositions containing anti inflammatory drugs such as ibuprofen, flurbiprofen, diclofenac, indomethacin and naproxen Controlled release 700 mg ibuprofen tablets contain-ing 9.5% Methocel K4M and 9.0% Methocel K15M were prepared from the untreated hydroxypropylmethylcelluloses having moisture contents in the range of 2.0-3.0%.
A tablet having the following composition was pre-pared in the usual manner:
Ingredients mg/tablet 1 Ibuprofen 700 3 MethoceI K4M 85 4 Methocel K15M 80 Syloid 5 6 Stearic Acid The tablets were compressed using 0.750" x 0.300"
capsule-shaped bisected punches at a comprssional force of about 4000 lbs/sq. in. to obtain a tablet of average weight of 893 mg and a hardness of 8 to 10 kg.
Controlled release 200 mg flurbiprofen tablets containing 12.4% Methocel K4M and 10.2% Methocel KlSM were prepared from the untreated hydroxypropylmethylcelluloses having moisture contents in tl~e range of 2~0-3~0~Y
A tablet having the following composition was prepared in the usual manner:
Ingredients mg/tablet 5 1 Fl.urbiprofen 200 2 Methocel K4M 33 3 Methocel K15M 27 4 Stearic Acid 5 Cab-0-Sil M-5 Tablets were compressed using 0.281" x 0.62511 capsule-shaped bisected punches at a compressional pressure of 4000 to 6000 lbs/sq.in. to obtain a tablet of average weight of 270 mg and a hardness of 6 to 8 kg.
15 Controlled release 100 mg diclofenac tablets con-taining 8.5~/o MethoceI K4M and 12.8% Methocel K15M were prepared from the untreated hydroxypropylmethylcelluloses having moisture contents in the range of 2.0-3.0%.
A tablet having the following composition was prepared in the usual manner:
-Ingredients mg/tablet 1Diclofenac sodium 100 2P.V.P. 5 3Methocel K4M 12 25 4 Methocel K15M 18 5Stearic Acid 5 6Cab-O-Sil M-5 Tablets were compressed using 9/32" standard concave round punches at a compressional pressure of 4000 to 6000 lbs/sq.in. to give a tablet weight of 144 mg and a hardness of 6 to 8 kg.
L~.~
The foregoing is exemplary and illustrative of compositions and products responding to the present invention, but it is to be understood that they are not limita-tive since many active medicaments of various types can be employed in the new long-lasting carrier so long as they are absorbable into blood or tissue Erom the general intestinal tract and other bodily surfaces and areas. The medicaments shown in our co-pending application Serial No. 332,348 filed December 18, 1981, now U.S. Patent No. 4,369,172 issued January 18, 1~83, may be used in the practice of the present inven-tion and are incorporated herein by reference. The invention is also intended to cover other dosage forms or forms for application of sustained release ingredients such as vaginal and rectal suppositiories. The lozenges and tablets particularly act on oral, oropharyngeal, pharyngeal and intestinal regions.
The total dosage is governed by usual medical considerations or physicians' directions and when sufficiently large doses of active medicament are incorporated in the unit dosage form, systemic as well as local action is obtained to over-come or control the pathological condition or disorder being treated.
Claims (10)
1. A carrier base material combined with a therapeutically active medicament and shaped and compressed to a solid unit dosage form having a regular and prolonged release pattern upon administration, the carrier base material being one or more hydroxypropylmethylcelluloses or a mixture of one or more hydroxypropylmethylcelluloses and up to 30% by weight of the mixture of methyl cellulose, sodium carboxymethylcellulose and/or other cellulose ether, and wherein at least one of the hydroxypropylmethylcelluloses has a methoxy content of 16-24 weight-%, a hydroxypropoxyl content of 4-32 weight-% and a number average molecular weight of at least 50,000 and wherein the carrier base material constitutes less than about one third of the weight of the solid unit dosage form.
2. A composition according to claim 1 in which the carrier base material consists of a mixture of one or more hydroxypropylmethylcelluloses and 0-30% sodium carboxy-methylcellulose.
3. A composition according to claim 1 in which the carrier base material consists of a mixture of one or more hydroxypropylmethylcelluloses and 0-30% of methyl-cellulose or other cellulose ether.
4. A composition according to claim 1 in which the active medicament is a moisture sensitive material.
5. A composition according to claim 4 in which the moisture sensitive medicament is selected from but not limited to aspirin, theophylline, phenacetin, procainamide, nikethamide, polymixin, barbiturates, idoxuridine, hydantoins, angiotensinamide, nitroglycerin, isosorbide dinitrate, benzocaine, scopolamine, meperidine, codeine, morphine, streptomycin, ascorbic acid, sulfonamide drugs, tolbutamide, chlorpheniramine, brompheniramine, phenylephrine, diphen-hydramine, penicillins, tropine alkaloids, diethylcarbamizine, dihydroergotamine, caffeine, dexamethasone, and pharmaceutically acceptable salts of any of the above, alkaloid salts and adrenocortical steroid esters.
6. A composition according to claim 1 in which the active medicament is lithium carbonate.
7. A composition according to claim 1 in which the active medicament is phenylpropanolamine.
3. A composition according to claim 1 in which the active medicament is potassium chloride.
9. A composition according to claim 1 in which the active medicament is an anti-inflammatory drug selected from and not limited to ibuprofen, flurbiprofen, diclofenac, indomethacin and naproxen.
10. A method for the preparation of a therapeutically active solid unit dosage form having a regular and prolonged release pattern upon administration, consisting of compressing and shaping a mixture of a therapeutically active medicament and a carrier base material consisting of one or more hydroxy-propylmethylcelluloses or a mixture of one or more hydroxy-propylmethylcelluloses and up to 30% by weight of the mixture of methylcellulose, sodium carboxymethylcellulose or other cellulose ether, and wherein at least one of the hydroxy-propylmethylcelluloses has a methoxyl content of 16-24 weight-%, a hydroxypropoxyl content of 4-32 weight-% and a number average molecular weight of at least 50,000, and wherein the carrier base material constitutes less than about one third of the weight of the solid unit dosage form.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/362,104 US4389393A (en) | 1982-03-26 | 1982-03-26 | Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose |
US362,104 | 1982-03-26 | ||
BR8300260A BR8300260A (en) | 1982-03-26 | 1983-01-19 | PROCESS FOR THE PREPARATION OF HYDROXYPROPYLMETHYL CELLULOSE |
AU56761/86A AU583616B2 (en) | 1982-03-26 | 1986-04-28 | Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose |
Publications (1)
Publication Number | Publication Date |
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CA1188614A true CA1188614A (en) | 1985-06-11 |
Family
ID=36910975
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000423322A Expired CA1188614A (en) | 1982-03-26 | 1983-03-10 | Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose |
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US (1) | US4389393A (en) |
JP (2) | JPS58174311A (en) |
AR (1) | AR230569A1 (en) |
AU (1) | AU583616B2 (en) |
BE (1) | BE896136A (en) |
BR (1) | BR8300260A (en) |
CA (1) | CA1188614A (en) |
CH (1) | CH655241A5 (en) |
DE (1) | DE3309516A1 (en) |
DK (1) | DK161014C (en) |
ES (1) | ES520994A0 (en) |
FR (1) | FR2523845B1 (en) |
GB (1) | GB2117239B (en) |
IL (1) | IL68233A (en) |
IT (1) | IT1171119B (en) |
MX (1) | MX155695A (en) |
NL (1) | NL8301042A (en) |
SE (1) | SE453797B (en) |
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-
1982
- 1982-03-26 US US06/362,104 patent/US4389393A/en not_active Expired - Lifetime
-
1983
- 1983-01-19 BR BR8300260A patent/BR8300260A/en unknown
- 1983-03-10 CA CA000423322A patent/CA1188614A/en not_active Expired
- 1983-03-10 BE BE0/210301A patent/BE896136A/en not_active IP Right Cessation
- 1983-03-16 ZA ZA831817A patent/ZA831817B/en unknown
- 1983-03-17 DE DE3309516A patent/DE3309516A1/en active Granted
- 1983-03-21 AR AR292456A patent/AR230569A1/en active
- 1983-03-23 GB GB08307960A patent/GB2117239B/en not_active Expired
- 1983-03-23 CH CH1599/83A patent/CH655241A5/en not_active IP Right Cessation
- 1983-03-23 NL NL8301042A patent/NL8301042A/en not_active Application Discontinuation
- 1983-03-23 SE SE8301579A patent/SE453797B/en not_active IP Right Cessation
- 1983-03-23 FR FR8304751A patent/FR2523845B1/en not_active Expired
- 1983-03-24 JP JP58049671A patent/JPS58174311A/en active Granted
- 1983-03-24 IL IL68233A patent/IL68233A/en unknown
- 1983-03-25 DK DK137983A patent/DK161014C/en not_active IP Right Cessation
- 1983-03-25 ES ES520994A patent/ES520994A0/en active Granted
- 1983-03-25 IT IT12471/83A patent/IT1171119B/en active
- 1983-03-25 MX MX196733A patent/MX155695A/en unknown
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1985
- 1985-11-08 JP JP60250570A patent/JPS61178916A/en active Pending
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1986
- 1986-04-28 AU AU56761/86A patent/AU583616B2/en not_active Ceased
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DE3309516C2 (en) | 1988-03-24 |
IL68233A (en) | 1986-10-31 |
IT1171119B (en) | 1987-06-10 |
GB2117239B (en) | 1987-03-11 |
IL68233A0 (en) | 1983-06-15 |
DK161014C (en) | 1991-10-28 |
GB2117239A (en) | 1983-10-12 |
JPH0415208B2 (en) | 1992-03-17 |
JPS58174311A (en) | 1983-10-13 |
AR230569A1 (en) | 1984-05-31 |
US4389393A (en) | 1983-06-21 |
MX155695A (en) | 1988-04-13 |
DE3309516A1 (en) | 1983-12-01 |
ES8500740A1 (en) | 1984-11-01 |
GB8307960D0 (en) | 1983-04-27 |
FR2523845A1 (en) | 1983-09-30 |
IT8312471A0 (en) | 1983-03-25 |
JPS61178916A (en) | 1986-08-11 |
AU5676186A (en) | 1987-10-29 |
DK137983D0 (en) | 1983-03-25 |
FR2523845B1 (en) | 1986-02-21 |
US4389393B1 (en) | 1985-10-22 |
CH655241A5 (en) | 1986-04-15 |
AU583616B2 (en) | 1989-05-04 |
SE453797B (en) | 1988-03-07 |
BR8300260A (en) | 1984-08-28 |
SE8301579L (en) | 1983-09-27 |
ZA831817B (en) | 1983-12-28 |
BE896136A (en) | 1983-07-01 |
DK161014B (en) | 1991-05-21 |
DK137983A (en) | 1983-09-27 |
NL8301042A (en) | 1983-10-17 |
SE8301579D0 (en) | 1983-03-23 |
ES520994A0 (en) | 1984-11-01 |
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