CA1095833A - Controlled release pharmaceutical composition containing mono-sulfuric acid esters of higher fatty alcohols - Google Patents
Controlled release pharmaceutical composition containing mono-sulfuric acid esters of higher fatty alcoholsInfo
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- CA1095833A CA1095833A CA283,403A CA283403A CA1095833A CA 1095833 A CA1095833 A CA 1095833A CA 283403 A CA283403 A CA 283403A CA 1095833 A CA1095833 A CA 1095833A
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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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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Abstract
Abstract of the Disclosure:
The present invention provides a pharmaceutical composition for controlled release of an active agent in the intestinal tract comprising i) a pharmacologically active agent selected from the group of arylalkanolamines and aryloxyalkanolamines, and ii) a physiologically tolerable anionic surfactant selected from the group of mono-sulphuric acid esters of higher fatty alcohols.
The present invention provides a pharmaceutical composition for controlled release of an active agent in the intestinal tract comprising i) a pharmacologically active agent selected from the group of arylalkanolamines and aryloxyalkanolamines, and ii) a physiologically tolerable anionic surfactant selected from the group of mono-sulphuric acid esters of higher fatty alcohols.
Description
`` 1(~95~33 Case 100-4630 CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION
CONTAINING MONO-SULFURIC ACID ESTERS OF HIGHER
FATTY ALCOHOLS
The present invention provides a pharmaceutical composition comprising a mixture of i) a pharmacologicallyactive agent selected from the group of aryloxyalkanolamines, and ii~ a physiologically tolerable anionic surfactant selected from the group of mono-sulphuric acid esters of higher fatty alcohols.
Thus, we have found that the use of component ii) advantageously increases the enteral absorption of component i) in the intestines.
The compositions of the invention may suitably be in final form for the controlled release of the active agent in the intestinal tract.
The pharmaceutical compositions according to the invention are particularly suitable for the administration of cardiac and circulatory agents, e.g. B-adrenoceptor blocking agents and anti-arrhythmic agents.
Such agents are well-known in the art. Aryl may be, for example, of up to 10 carbon atoms, e.g. phenyl or naphthyl, and may contain one or two heteroatoms, e.g.
nitroger. as in indolyl or nitrogen and sulphur as in thiazolyl. The aryl moiety may also have one or two ring . ~
~ 1~9S833 100-4630 substituents, e.g. acetyl, allyl, allyloxy, aminocarbonyl-methyl, cyano, methyl, chloro, methoxy, methoxyethyl, amido, hydroxy, nitro, propinyloxy, (Cl 4)alkanoylamino, methylsulfamoyl, morpholino, methylthio, and tetrahydro-furylmethyloxy substituents.
The aryl moiety may also have an alkyl chain - between two adjacent carbon atoms thereby forming a saturated ring. For example, the aryl moiety nucleus may be tetralone or tetrahydronaphthalene.
The amlno moiety conveniently has a branched chain alkyl substituent of 3 to 8 carbon atoms, e.g. isopropyl - or tert.-butyl.
The alkanolamine moiety is conveniently a
CONTAINING MONO-SULFURIC ACID ESTERS OF HIGHER
FATTY ALCOHOLS
The present invention provides a pharmaceutical composition comprising a mixture of i) a pharmacologicallyactive agent selected from the group of aryloxyalkanolamines, and ii~ a physiologically tolerable anionic surfactant selected from the group of mono-sulphuric acid esters of higher fatty alcohols.
Thus, we have found that the use of component ii) advantageously increases the enteral absorption of component i) in the intestines.
The compositions of the invention may suitably be in final form for the controlled release of the active agent in the intestinal tract.
The pharmaceutical compositions according to the invention are particularly suitable for the administration of cardiac and circulatory agents, e.g. B-adrenoceptor blocking agents and anti-arrhythmic agents.
Such agents are well-known in the art. Aryl may be, for example, of up to 10 carbon atoms, e.g. phenyl or naphthyl, and may contain one or two heteroatoms, e.g.
nitroger. as in indolyl or nitrogen and sulphur as in thiazolyl. The aryl moiety may also have one or two ring . ~
~ 1~9S833 100-4630 substituents, e.g. acetyl, allyl, allyloxy, aminocarbonyl-methyl, cyano, methyl, chloro, methoxy, methoxyethyl, amido, hydroxy, nitro, propinyloxy, (Cl 4)alkanoylamino, methylsulfamoyl, morpholino, methylthio, and tetrahydro-furylmethyloxy substituents.
The aryl moiety may also have an alkyl chain - between two adjacent carbon atoms thereby forming a saturated ring. For example, the aryl moiety nucleus may be tetralone or tetrahydronaphthalene.
The amlno moiety conveniently has a branched chain alkyl substituent of 3 to 8 carbon atoms, e.g. isopropyl - or tert.-butyl.
The alkanolamine moiety is conveniently a
2-hydroxy-3-alkylaminopropyl moiety.
- Examples of aryloxyalkanola~.ines are:-Acebutolol Alprenolol Atenolol lO9S833 100-4630 Bufetolol Bunitrolol Bunolol Bupranolol Metoprolol Nadoxolol Oxprenolol Pargolol Practolol Procinolol Propranolol Talinolol Timolol Tiprenolol Tolamolol Toliprolol Trimepranol Especially interesting compounds are:-4-(2-hydroxy-3-isopropylaminopropoxy~indole (Pindolol) 4-(2-hydroxy-3-isopropylaminopropoxy )-2-methylindole, and other compounds which have a poor solubility in juices of the intestinal tract.
The active agent may be in pharmaceutically acceptable acid addition salt form. Conveniently, however, the active agent is in free base form.
The surfactant preferably has a hydrophilic-lipo-philic balance value (HLB group number) of from about 35 to about 45 [HLB group numbers are well-known in the art, see for example Pharm. Act. Helv. 44, 9`(1969) and H.P. Fiedler, Lexikon der Hilfstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, page 263, Editio Cantor KG., 1971].
Additionally, the surfactant preferably has a critical micelle concentration (CMC) of from about 10 to about 10 3.
Preferred surfactants have a high dissociation constant and may produce stable complexes with the active agent in strongly acidic media. These complexes should preferably be capable of dissolving very slowly at a pH
value of below three, e.g. in gastric juices, but dissolving quickly as the pH value changes from 3 to 7.5, particularly above 5, e.g. in the intestinal juices.
The exact choice of surfactant will naturally depend on inter alia its compatibility with the active agent used, e.g. on molecular size and shape, and basicity and other pharmaceutical diluents and carriers that may be present. For example, surfactants should ~e avoided that form sta~le, insoluble precipitation products with the active agent at pH values of 5 or more.
l~9S833 100-4630 The higher fatty alcohols may have a straight or branched chain and may contain alicyclic and/or aromatic moieties. Preferably the alcohol is a primary alcohol and has from 8 to 18 carbon atoms, especially from 12 to 14 carbon atoms.
If desired, the alcohol may be an ethoxylated fatty alcohol containing, per mole, about one to about 5 moles, and preferable 1 to 3 ~.oles, of ethylene oxide moieties. A preferred embodiment has 2.5 moles of ethylene oxide moieties per mole of surfactant.
It is preferred to use the surfactant in the form of a salt. Preferred salt forms are those which are soluble in water including those which are readilY
finely dispersible in water, especially alkaline earth metal salts, e.g. a magnesium salt, organic amine salts, e.g. a triethanolamine salt, or an ammonium salt.
Especially preferred, however, are the alkali metal salts,-e.g. a sodium salt.
The preferred surfactant, at least for use with the indole derivatives mentioned above, is sodium lauryl monosulphate.
Naturally, if desired, more than one surfactant may be ùsed.
The weight ratio of surfactant to active agent used, and total amount of surfactant used, will naturally l~9S833 depend on inter alia the chemical and physical properties of the surfactant, the type and amount of the active agent and other pharmaceutical diluents and carriers present, and the desired duration of release of active agent in the intestinal tract.
In particular, the upper limit of the weight ratio of surfactant to active agent and of the total amount of surfactant used will, of course, depend on the physiological acceptability and compatibility of the surfactant (or surfactants if more than one is present) and also the planned duration of administration and frequency of administration.
The weight ratio of surfactant to active agent in the mixture may be from about 0.2:1 to about 2:1, preferably from about 0.3:1 to about 1:1.
In particular, when the surfactant is a salt form of a monosulphuric acid ester of an alkanol, e.g. sodium lauryl sulphate, and the active agent a preferred indolyl derivative mentioned above, the preferred weight ratio of surfactant to active agent is from about 0.25:1 to about 1:1, especially from about 0.4:1 to about 0.7:1.
Further physiologically acceptable material besides the surfactant may be present. Thus, solid pharmaceutical binders and diluents may be chosen so as to afford an evenly distributed release of active material 1~9S8`33 100-46~0 over a long period of time. Preferred binders and diluents contribute towards the formation of a matrix in the digestive tract, and are substantially resistant to, or only slowly attacked by, the intestinal juices. Examples of such binders and diluents include those insoluble in intestinal juices, e.g. physiologically acceptable calcium salts, such as calcium sulphate or calcium hydrogen phosphate dihydrate; cellulose derivatives, such as ethyl cellulose; synthetic polymers, such as polyvinyl acetate, polyvinyl chloride; and copolymers of vinyl pyrrolidone and vinyl acetate; or natural, synthetic and semi-synthetic fats, e.g. mono-, di- or tri-glycerides of palmitic and stearic acids; hydrogenated castor oil and wax; and higher fatty alcohols, e.g. cetyl stearyl alcohol DAB 7.
Alternatively, the binders and diluents may be soluble in intestinal juices, e.g. physiologically acceptable:- `
lactose, mannitol and other sugars;
polyvinylpyrrolidone; and polyethylene glycols.
"Soluble" herein also covers physiologically acceptable material which is easily dispersible in the intestinal juices.
1(J95833 Further physiologically acceptable material may be present, e.g. flow agents such as talc and magnesium stearate.
Conveniently, the physiologically acceptable material comprises a mixture of, on the one hand, material insoluble in intestinal juices and, on the other hand, material soluble in intestinal juices. The weight ratio of insoluble material to soluble material will naturally very depending on, inter alia, the amount and physical and chemical properties of the active agent and surfactant used and, additionally, on the extent of delay desired in the release of the active agent.
If the mixture is administered in a finished form such that it is delivered to the intestines substantially intact and then becomes rapidly exposed to the intestinal juices, and release of active agent is desired to be between 40 and 80%, e.g. 50%, throughout the intestines distributed evenly over 1 to 7 hours, in general a suitable weight ratio of insoluble material (e.g. insoluble binders, diluents and flow agents) to soluble material te.g. soluble binders, diluents and surfactants including component ii)] may be from about 1:5 to about 1:0.3.
In particular, when the active agent is an indolyl derivative mentioned above, and the surfactant is sodium ~auryl sulphate, a ratio of insoluble material to soluble 1~95833 100-4630 material of from about 1:3 to about 1:1.5 is suitable in order to attain about a 40% release of active agent in the intestines distributed evenly over 1 to 4 hours.
In an especially preferred embodiment of the invention, the mixture of active agent i) and surfactant ii) is a medicament core coated with a physiologically acceptable film which is resistant to gastric juices but breaks down in intestinal juices.
'~he choice of film-forming material and its thickness will, of course, depend on, inter alia, the active agent, the surfactant and the solubility of any active agent-surfactant complex. In general, it is suitably a polymer. Such polymer may be selected such that the film dissolves at a pH value of from 5 to 8, preferably from 5 to 7, in the digestive tract in about 1/4 to 2 hours, preferably in 1/2 to 1 hour. Preferably the fllm does not dissol~e for at least 3 hours in artificial (U.S.P.) gastric juices at a pH value of less than 5.
Such films may be selected from known macro-molecular polymers used for the production of unit dosage forms resistant to gastric juices but soluble in the small intestine. Suitable polymers are listed in e.g. Hagers Handbuch der pharmazeutischen Praxis, 4th edition, Vol. 7a, pages 739 to 742 and 776 to 778 (Springer Verlag, 1971) and Remington's Pharmaceutical Sciences, 13th edition, pages 1689 to 1691 (Mack Publ.
Co., 1970), e.g. cellulose ester derivatives, acrylic resins, such as methylacrylate copolymers and copolymers of maleic acid and phthalic acid derivatives.
The preferred films are made from cellulose acetate phthalate; copolymers derived from methylacrylic acid and esters thereof, containing at least 40% methyl-acrylic acid; and especially hydroxypropyl methylcellulose phthalate.
The thickness of the film may depend on the degree of permeability of the film to water and acids.
Preferably the thickness of the film layer is from about 5 to about lOO ,um and, especially from about 20 to about 80 ,um. In general, hGwever, the weight of the film should not exceed 15% of the medicament core coated, and preferably is from 3 to 10~ of the medicament core coated.
The film may surroùnd a plurality of discrete pellets or granules each containing active agent i) and surfactant ii) all embedded in at least one pharmaceutical carrier or diluent. Alternatively, the film may surround a core having active agent i) and surfactant ii) dispersed homogenously throughout.
It is preferred to formulate a unit dosage form which, additionally, releases active agent i) in the acid gastric juices from an outer medicament layer containing such active agent and pharmaceutical carriers or diluents soluble in gastric juices. The active agent may be rapidly absorbed through the stomach walls so that an initial high concentration of active agent in the blood is quickly reached. The level of the active agent in the blood may then be maintained by the delayed and sustained release of active agent from the core in the more alkaline juices of the intestines.
Thus, for example, the film coating may be covered by such a medicament layer.
The weight ratio of aryloxy-alkanolamine in the medicament core covered by the film to that in the medicament layer outside the film may be, 1~ for example, from about 0.75:1 to 1.25:1, e.g. 1:1.
If desired other pharmacologically active agents ca~ be present, particularly in the outer medicament layer when used. Such agents which come into consider~tion are those influencing the heart and circulatory functions such as anti-hypertensives, diuretics, a-blockers, etc., particularly long acting diuretics. Thus, an aryloxy-alkanolamine, such as 4-(2-hydroxy-3-isopropylaminopropoxy)-indole, may be combined with a~long acting diuretic, e.g.
2-methyl-3-o-toLyl-6-sulph&myl-7-chloro-1,2,3,4-tetrahydro-4-(3H)-quinazolinone or a pharmaceutica ly acceptable 1l~95833 salt form thereof, for example both being present in an outer medicament layer and the former being present also in the r..edicament core.
The outer layer may comprise a plurality of discrete granules or pellets each containing active agent (or agents) embedded in at least one pharmaceutical carrier or diluent soluble in gastric juices. The outer layer may also surround a plurality of film-coated medicament cores. Preferably, however, the outer layer surrounds only one film coated medicament core.
Conveniently, the weight of surfactant present is from about 1 to about 30%, preferably from 1 to 10~, of the pharmaceutical composition or the medicament core, if one is present.
When the pharmaceutical composition is in unit dosage form, in general the amount of surfactant in total is less than 50 mg.
The compositions of the invention can be prepared in conventional manner. Thus, for example, component i) can be admixed with component ii), e.g. by pelleting or granulating the mixture using conventional wet or dry granulating techniques and compressing the resultant pellets or granules together to form a tablet core, or alternatively compressing directly without granulating or pelleting, and formulating into a suitable galenical 1~95833 100-4630 form.
As already indicated, a preferred embodiment is where the mixture is surrounded by a film which is resistant to gastric juices but breaks down in intestinal juices. Such film may be applied to the mixture of components i) and ii) in conventional manner, e.g. from a solution thereof at from 10 to 60C.
The following Examples illustrate the invention.
The materials used in the Examples are all conventional materials used in the galenic art.
In particular:-Hydroxypropyl methylcellulose phthalate is e.g. HPMCP HP50 (Registered Trade Mark) obtainable from Shinetsu Chem. Co., Tokyo;
Ethylcellulose is e.g.~Ethocel N~ egistered Trade Mark) 7 cps obtainable from Dow Chemical Co., Midland, Michigan, U.S.A.;
Polyvinylpyrrolidone/polyvinyl acetate is a macrocopolymer of vinylpyrrolidone and vinyl acetate (mole ratio 6:4), known as~Luviskol VA 64~, obtainable from BASF, Ludwigshafen, W. Germany;
Microcrystalline cellulose is e.g.~~Avicel~(Registered Trade Mark3 obtainable from FMC Corp., Marcus Hook, Palo Alto, U.S.A.;
* Trademark ~ 1~95833 100-4630 Polyvinylpyrrolidone is e.g. Kollidon 90 (Registered Trade Mark) obtainable from BASF, Ludwigshafen.
The palmate/stearic acid triglyceride mlxture is e.g. Precirol (Registered Trade Mark) obtainable from Establissements Gattefosse, St. Priest, France;
Hydrogenated castor oil is e.g. Cutina HR (Registered Trade Mark) obtainable from Henkel, DUsseldorf, W. Germany.
., , . , . ..... . ,, .,, ., . , ~
EX~LE 1: Retard Mantle Tablet ____________________ Core Com~onent Com~osition_(m~tablet) Active aqent _ _ __ _ __ _ _ __ 4-(2-E~ydroxy-3-isopropylamino-propoxy)-indole 5.0 Surfactant _ _ _ _ _ _ _ _ _ _ Sodium lauryl sulphate2~ 2.5 Pharmaceutical binders and diluents Ethylcellulose ) 4.5 Microcrystalline cellulose ) 7.0 Mannitol2) 27.5 Polyvinylpyrrolidone-polyvinyl-l) 2.5 acetate E~low aqents T lcl) 0.5 Magnesium stearate ) 0.5 .~ ` 50.0 mg 1) = insoluble material 2) = soluble material 109~33 100-4630 Film Hydroxypropyl methylcellulose 3.0 Medicament layer Active a~ent __ __ __ _ _ _ _ _ 4-(2-hydroxy-3-isopropylamino-propoxy)indole 5.0 Pharmaceutical binders and diluents and flow a~ents Talc 7-9 Microcrystalline cellulose 27.5 Magnesium stearate 1.3 Mannitol 110.1 Polyvinylpyrrolidone 5.2 157.0 Total tablet weight 210 mg.
Production _ The components of the core are mixed, granulated and pressed into tablet cores using a 5 mm diameter domed tablet die.
The tablet cores are then coated by spraying with a 10% (w/v) solution of hydroxypropyl methylcellulose in ethanol/acetone (1:1 v/v). The outer medicament layer is then applied in conventional manner, by mixing the active agent for the outer layer with the other components of the outer layer except for the lubricants (talc and ` 1~95833 100-4630 ma~nesium stearate) granulating the moist components, adding the lubricants and finally pressing the granulates together with the film coated medicament cores into tablets.
In analogous manner to that described in Example 1 mantle tablets with the core compositions (50.mg) given below in the table may be obtained.
The cores are then coated with hydroxypropyl methyl-cellulose phthalate ~ilm (3 mg/tablet) and a medicament layer (157 mg/tablet) as described in Example 1.
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i~' z ~ ~i h P~
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O O a) I ~ l ~ l O h O ~ ~
- Examples of aryloxyalkanola~.ines are:-Acebutolol Alprenolol Atenolol lO9S833 100-4630 Bufetolol Bunitrolol Bunolol Bupranolol Metoprolol Nadoxolol Oxprenolol Pargolol Practolol Procinolol Propranolol Talinolol Timolol Tiprenolol Tolamolol Toliprolol Trimepranol Especially interesting compounds are:-4-(2-hydroxy-3-isopropylaminopropoxy~indole (Pindolol) 4-(2-hydroxy-3-isopropylaminopropoxy )-2-methylindole, and other compounds which have a poor solubility in juices of the intestinal tract.
The active agent may be in pharmaceutically acceptable acid addition salt form. Conveniently, however, the active agent is in free base form.
The surfactant preferably has a hydrophilic-lipo-philic balance value (HLB group number) of from about 35 to about 45 [HLB group numbers are well-known in the art, see for example Pharm. Act. Helv. 44, 9`(1969) and H.P. Fiedler, Lexikon der Hilfstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, page 263, Editio Cantor KG., 1971].
Additionally, the surfactant preferably has a critical micelle concentration (CMC) of from about 10 to about 10 3.
Preferred surfactants have a high dissociation constant and may produce stable complexes with the active agent in strongly acidic media. These complexes should preferably be capable of dissolving very slowly at a pH
value of below three, e.g. in gastric juices, but dissolving quickly as the pH value changes from 3 to 7.5, particularly above 5, e.g. in the intestinal juices.
The exact choice of surfactant will naturally depend on inter alia its compatibility with the active agent used, e.g. on molecular size and shape, and basicity and other pharmaceutical diluents and carriers that may be present. For example, surfactants should ~e avoided that form sta~le, insoluble precipitation products with the active agent at pH values of 5 or more.
l~9S833 100-4630 The higher fatty alcohols may have a straight or branched chain and may contain alicyclic and/or aromatic moieties. Preferably the alcohol is a primary alcohol and has from 8 to 18 carbon atoms, especially from 12 to 14 carbon atoms.
If desired, the alcohol may be an ethoxylated fatty alcohol containing, per mole, about one to about 5 moles, and preferable 1 to 3 ~.oles, of ethylene oxide moieties. A preferred embodiment has 2.5 moles of ethylene oxide moieties per mole of surfactant.
It is preferred to use the surfactant in the form of a salt. Preferred salt forms are those which are soluble in water including those which are readilY
finely dispersible in water, especially alkaline earth metal salts, e.g. a magnesium salt, organic amine salts, e.g. a triethanolamine salt, or an ammonium salt.
Especially preferred, however, are the alkali metal salts,-e.g. a sodium salt.
The preferred surfactant, at least for use with the indole derivatives mentioned above, is sodium lauryl monosulphate.
Naturally, if desired, more than one surfactant may be ùsed.
The weight ratio of surfactant to active agent used, and total amount of surfactant used, will naturally l~9S833 depend on inter alia the chemical and physical properties of the surfactant, the type and amount of the active agent and other pharmaceutical diluents and carriers present, and the desired duration of release of active agent in the intestinal tract.
In particular, the upper limit of the weight ratio of surfactant to active agent and of the total amount of surfactant used will, of course, depend on the physiological acceptability and compatibility of the surfactant (or surfactants if more than one is present) and also the planned duration of administration and frequency of administration.
The weight ratio of surfactant to active agent in the mixture may be from about 0.2:1 to about 2:1, preferably from about 0.3:1 to about 1:1.
In particular, when the surfactant is a salt form of a monosulphuric acid ester of an alkanol, e.g. sodium lauryl sulphate, and the active agent a preferred indolyl derivative mentioned above, the preferred weight ratio of surfactant to active agent is from about 0.25:1 to about 1:1, especially from about 0.4:1 to about 0.7:1.
Further physiologically acceptable material besides the surfactant may be present. Thus, solid pharmaceutical binders and diluents may be chosen so as to afford an evenly distributed release of active material 1~9S8`33 100-46~0 over a long period of time. Preferred binders and diluents contribute towards the formation of a matrix in the digestive tract, and are substantially resistant to, or only slowly attacked by, the intestinal juices. Examples of such binders and diluents include those insoluble in intestinal juices, e.g. physiologically acceptable calcium salts, such as calcium sulphate or calcium hydrogen phosphate dihydrate; cellulose derivatives, such as ethyl cellulose; synthetic polymers, such as polyvinyl acetate, polyvinyl chloride; and copolymers of vinyl pyrrolidone and vinyl acetate; or natural, synthetic and semi-synthetic fats, e.g. mono-, di- or tri-glycerides of palmitic and stearic acids; hydrogenated castor oil and wax; and higher fatty alcohols, e.g. cetyl stearyl alcohol DAB 7.
Alternatively, the binders and diluents may be soluble in intestinal juices, e.g. physiologically acceptable:- `
lactose, mannitol and other sugars;
polyvinylpyrrolidone; and polyethylene glycols.
"Soluble" herein also covers physiologically acceptable material which is easily dispersible in the intestinal juices.
1(J95833 Further physiologically acceptable material may be present, e.g. flow agents such as talc and magnesium stearate.
Conveniently, the physiologically acceptable material comprises a mixture of, on the one hand, material insoluble in intestinal juices and, on the other hand, material soluble in intestinal juices. The weight ratio of insoluble material to soluble material will naturally very depending on, inter alia, the amount and physical and chemical properties of the active agent and surfactant used and, additionally, on the extent of delay desired in the release of the active agent.
If the mixture is administered in a finished form such that it is delivered to the intestines substantially intact and then becomes rapidly exposed to the intestinal juices, and release of active agent is desired to be between 40 and 80%, e.g. 50%, throughout the intestines distributed evenly over 1 to 7 hours, in general a suitable weight ratio of insoluble material (e.g. insoluble binders, diluents and flow agents) to soluble material te.g. soluble binders, diluents and surfactants including component ii)] may be from about 1:5 to about 1:0.3.
In particular, when the active agent is an indolyl derivative mentioned above, and the surfactant is sodium ~auryl sulphate, a ratio of insoluble material to soluble 1~95833 100-4630 material of from about 1:3 to about 1:1.5 is suitable in order to attain about a 40% release of active agent in the intestines distributed evenly over 1 to 4 hours.
In an especially preferred embodiment of the invention, the mixture of active agent i) and surfactant ii) is a medicament core coated with a physiologically acceptable film which is resistant to gastric juices but breaks down in intestinal juices.
'~he choice of film-forming material and its thickness will, of course, depend on, inter alia, the active agent, the surfactant and the solubility of any active agent-surfactant complex. In general, it is suitably a polymer. Such polymer may be selected such that the film dissolves at a pH value of from 5 to 8, preferably from 5 to 7, in the digestive tract in about 1/4 to 2 hours, preferably in 1/2 to 1 hour. Preferably the fllm does not dissol~e for at least 3 hours in artificial (U.S.P.) gastric juices at a pH value of less than 5.
Such films may be selected from known macro-molecular polymers used for the production of unit dosage forms resistant to gastric juices but soluble in the small intestine. Suitable polymers are listed in e.g. Hagers Handbuch der pharmazeutischen Praxis, 4th edition, Vol. 7a, pages 739 to 742 and 776 to 778 (Springer Verlag, 1971) and Remington's Pharmaceutical Sciences, 13th edition, pages 1689 to 1691 (Mack Publ.
Co., 1970), e.g. cellulose ester derivatives, acrylic resins, such as methylacrylate copolymers and copolymers of maleic acid and phthalic acid derivatives.
The preferred films are made from cellulose acetate phthalate; copolymers derived from methylacrylic acid and esters thereof, containing at least 40% methyl-acrylic acid; and especially hydroxypropyl methylcellulose phthalate.
The thickness of the film may depend on the degree of permeability of the film to water and acids.
Preferably the thickness of the film layer is from about 5 to about lOO ,um and, especially from about 20 to about 80 ,um. In general, hGwever, the weight of the film should not exceed 15% of the medicament core coated, and preferably is from 3 to 10~ of the medicament core coated.
The film may surroùnd a plurality of discrete pellets or granules each containing active agent i) and surfactant ii) all embedded in at least one pharmaceutical carrier or diluent. Alternatively, the film may surround a core having active agent i) and surfactant ii) dispersed homogenously throughout.
It is preferred to formulate a unit dosage form which, additionally, releases active agent i) in the acid gastric juices from an outer medicament layer containing such active agent and pharmaceutical carriers or diluents soluble in gastric juices. The active agent may be rapidly absorbed through the stomach walls so that an initial high concentration of active agent in the blood is quickly reached. The level of the active agent in the blood may then be maintained by the delayed and sustained release of active agent from the core in the more alkaline juices of the intestines.
Thus, for example, the film coating may be covered by such a medicament layer.
The weight ratio of aryloxy-alkanolamine in the medicament core covered by the film to that in the medicament layer outside the film may be, 1~ for example, from about 0.75:1 to 1.25:1, e.g. 1:1.
If desired other pharmacologically active agents ca~ be present, particularly in the outer medicament layer when used. Such agents which come into consider~tion are those influencing the heart and circulatory functions such as anti-hypertensives, diuretics, a-blockers, etc., particularly long acting diuretics. Thus, an aryloxy-alkanolamine, such as 4-(2-hydroxy-3-isopropylaminopropoxy)-indole, may be combined with a~long acting diuretic, e.g.
2-methyl-3-o-toLyl-6-sulph&myl-7-chloro-1,2,3,4-tetrahydro-4-(3H)-quinazolinone or a pharmaceutica ly acceptable 1l~95833 salt form thereof, for example both being present in an outer medicament layer and the former being present also in the r..edicament core.
The outer layer may comprise a plurality of discrete granules or pellets each containing active agent (or agents) embedded in at least one pharmaceutical carrier or diluent soluble in gastric juices. The outer layer may also surround a plurality of film-coated medicament cores. Preferably, however, the outer layer surrounds only one film coated medicament core.
Conveniently, the weight of surfactant present is from about 1 to about 30%, preferably from 1 to 10~, of the pharmaceutical composition or the medicament core, if one is present.
When the pharmaceutical composition is in unit dosage form, in general the amount of surfactant in total is less than 50 mg.
The compositions of the invention can be prepared in conventional manner. Thus, for example, component i) can be admixed with component ii), e.g. by pelleting or granulating the mixture using conventional wet or dry granulating techniques and compressing the resultant pellets or granules together to form a tablet core, or alternatively compressing directly without granulating or pelleting, and formulating into a suitable galenical 1~95833 100-4630 form.
As already indicated, a preferred embodiment is where the mixture is surrounded by a film which is resistant to gastric juices but breaks down in intestinal juices. Such film may be applied to the mixture of components i) and ii) in conventional manner, e.g. from a solution thereof at from 10 to 60C.
The following Examples illustrate the invention.
The materials used in the Examples are all conventional materials used in the galenic art.
In particular:-Hydroxypropyl methylcellulose phthalate is e.g. HPMCP HP50 (Registered Trade Mark) obtainable from Shinetsu Chem. Co., Tokyo;
Ethylcellulose is e.g.~Ethocel N~ egistered Trade Mark) 7 cps obtainable from Dow Chemical Co., Midland, Michigan, U.S.A.;
Polyvinylpyrrolidone/polyvinyl acetate is a macrocopolymer of vinylpyrrolidone and vinyl acetate (mole ratio 6:4), known as~Luviskol VA 64~, obtainable from BASF, Ludwigshafen, W. Germany;
Microcrystalline cellulose is e.g.~~Avicel~(Registered Trade Mark3 obtainable from FMC Corp., Marcus Hook, Palo Alto, U.S.A.;
* Trademark ~ 1~95833 100-4630 Polyvinylpyrrolidone is e.g. Kollidon 90 (Registered Trade Mark) obtainable from BASF, Ludwigshafen.
The palmate/stearic acid triglyceride mlxture is e.g. Precirol (Registered Trade Mark) obtainable from Establissements Gattefosse, St. Priest, France;
Hydrogenated castor oil is e.g. Cutina HR (Registered Trade Mark) obtainable from Henkel, DUsseldorf, W. Germany.
., , . , . ..... . ,, .,, ., . , ~
EX~LE 1: Retard Mantle Tablet ____________________ Core Com~onent Com~osition_(m~tablet) Active aqent _ _ __ _ __ _ _ __ 4-(2-E~ydroxy-3-isopropylamino-propoxy)-indole 5.0 Surfactant _ _ _ _ _ _ _ _ _ _ Sodium lauryl sulphate2~ 2.5 Pharmaceutical binders and diluents Ethylcellulose ) 4.5 Microcrystalline cellulose ) 7.0 Mannitol2) 27.5 Polyvinylpyrrolidone-polyvinyl-l) 2.5 acetate E~low aqents T lcl) 0.5 Magnesium stearate ) 0.5 .~ ` 50.0 mg 1) = insoluble material 2) = soluble material 109~33 100-4630 Film Hydroxypropyl methylcellulose 3.0 Medicament layer Active a~ent __ __ __ _ _ _ _ _ 4-(2-hydroxy-3-isopropylamino-propoxy)indole 5.0 Pharmaceutical binders and diluents and flow a~ents Talc 7-9 Microcrystalline cellulose 27.5 Magnesium stearate 1.3 Mannitol 110.1 Polyvinylpyrrolidone 5.2 157.0 Total tablet weight 210 mg.
Production _ The components of the core are mixed, granulated and pressed into tablet cores using a 5 mm diameter domed tablet die.
The tablet cores are then coated by spraying with a 10% (w/v) solution of hydroxypropyl methylcellulose in ethanol/acetone (1:1 v/v). The outer medicament layer is then applied in conventional manner, by mixing the active agent for the outer layer with the other components of the outer layer except for the lubricants (talc and ` 1~95833 100-4630 ma~nesium stearate) granulating the moist components, adding the lubricants and finally pressing the granulates together with the film coated medicament cores into tablets.
In analogous manner to that described in Example 1 mantle tablets with the core compositions (50.mg) given below in the table may be obtained.
The cores are then coated with hydroxypropyl methyl-cellulose phthalate ~ilm (3 mg/tablet) and a medicament layer (157 mg/tablet) as described in Example 1.
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O O a) I ~ l ~ l O h O ~ ~
3 ~ ~: a)l .C Q, Ul F: hl ~:l U U ~ ' h ~ tJ' P~ O >1 1 0 ~1]1 ~ a)l aJI ,~ o ~ I a) ~ u~ O
~ ~ R~ ~l ~ C. Wl ,~ . h ~ O U ~ ~ h U u7 R ~ ~ 1~ h I ~ C~ l ~11 ,{: U ~ ~ l O
x o u ~ I ~ 5 1 o ~ o ~ a u -~ (lS .C
dP W ~ I ~ m~ u __ 11 ~ ~ ~
_l ~
~ ~ l O O ~ 1 Z
~ .. .. _ _~ U~
~ _ _~
~ ~ D`
_ ~ a U~ l ~ ~
:C ~, R
U~
~ _. . .
_~ U~ l ~ _ . . __ _1 ,1 n u ~ u _~
_ _ ~ ~
~ ~ O, ~ _~ O U
.. _ O o a ~ ,~ ~ _, _~ u~ ~ O
. ~ U~
V U~ U~ ~ ~
_, ~ ~.
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~:
~ --~ 8 8 __ o o z ~ ,., q) ~ ~1~0 o :~_1 ~ ~ 3 R ~ ~ ~ ~m ~m o~
d~ W m~
_ . __ ~r ~ 95833 100-4630 Following the procedure used in Examples 1 and L~ to lR, the active agent, 4-(2-hydroxy-3-isopropyl-aminopropoxy)indole may be replaced by an equivalent amount of an aryloxyalkanolamine S speci~ically mentioned above.
~ ~ R~ ~l ~ C. Wl ,~ . h ~ O U ~ ~ h U u7 R ~ ~ 1~ h I ~ C~ l ~11 ,{: U ~ ~ l O
x o u ~ I ~ 5 1 o ~ o ~ a u -~ (lS .C
dP W ~ I ~ m~ u __ 11 ~ ~ ~
_l ~
~ ~ l O O ~ 1 Z
~ .. .. _ _~ U~
~ _ _~
~ ~ D`
_ ~ a U~ l ~ ~
:C ~, R
U~
~ _. . .
_~ U~ l ~ _ . . __ _1 ,1 n u ~ u _~
_ _ ~ ~
~ ~ O, ~ _~ O U
.. _ O o a ~ ,~ ~ _, _~ u~ ~ O
. ~ U~
V U~ U~ ~ ~
_, ~ ~.
~ ~ ~ C) .. ~ - , ~
~:
~ --~ 8 8 __ o o z ~ ,., q) ~ ~1~0 o :~_1 ~ ~ 3 R ~ ~ ~ ~m ~m o~
d~ W m~
_ . __ ~r ~ 95833 100-4630 Following the procedure used in Examples 1 and L~ to lR, the active agent, 4-(2-hydroxy-3-isopropyl-aminopropoxy)indole may be replaced by an equivalent amount of an aryloxyalkanolamine S speci~ically mentioned above.
Claims (25)
The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A pharmaceutical composition comprising a mixture of i) a pharmacologically active agent selected from the group of aryloxyalkanolamines, and ii) a physiologically tolerable anionic surfactant selected from the group of mono-sulphuric acid esters of higher fatty alcohols.
2. A composition according to claim 1 in final form adapted for controlled release of the active agent in the intestinal tract.
3. A composition according to claim 1, wherein the active agent is 4-(2-hydroxy-3-isopropylaminopropoxy)-indole.
4. A composition according to claim 1, wherein the active agent is 4-(2-hydroxy-3-isopropylaminopropoxy)-2-methylindole.
5. A composition according to claim 1, wherein the surfactant has a hydrophilic-lipophilic balance value of from 35 to 45.
6. A composition according to claim 1, wherein the surfactant has a critical micelle concentration of from 10-2 to 10-3.
CANADA
CANADA
7. A composition according to claim 1, wherein the higher fatty alcohol of the surfactant is a primary alcohol of from 12 to 14 carbon atoms.
8. A composition according to claim 7, wherein the fatty alcohol is ethoxylated with, per mole, from 1 to 5 ethylene oxide moieties.
9. A composition according to claim 1, wherein the surfactant is in the form of a salt.
10. A composition according to claim 1, wherein the surfactant is a sodium salt.
11. A composition according to claim 1, wherein the surfactant is sodium lauryl sulphate.
12. A composition according to claim 1, having a medicament core comprising the mixture of active agent and surfactant coated with a physiologically acceptable film which is resistant to gastric juices and breaks down at a pH of 5 or more.
13. A composition according to claim 12, wherein the film is made from hydroxypropyl methylcellulose phthalate.
14. A composition according to claim 12 or 13, wherein the film thickness is from 5 to 100 µm.
CANADA
CANADA
15. A composition according to claim 12, wherein the film is covered by a medicament layer.
16. A composition according to claim 15, wherein the medicament layer contains an aryloxy-alkanolamine which is also present in the medicament core covered by the film.
17. A composition according to claim 16, wherein the weight ratio of aryloxyalkanolamine in the medicament core covered by the film to that in the medicament layer outside the film is from 0.75:1 to 1.25:1.
18. A composition according to claim 2, in unit dosage form and containing less than 50 mg of surfactant.
19. A composition according to claim 1, wherein the weight ratio of surfactant to active agent in the mixture of components i) and ii) is from 0.2:1 to 2:1.
20. A composition according to claim 19, wherein the weight ratio is from 0.3:1 to 1:1.
21. A composition according to claim 1, wherein the mixture of components i) and ii) also comprises solid physiologically acceptable material which is insoluble in intestinal juices and solid physiologically acceptable material which is soluble in intestinal juices and the weight ratio of solid insoluble material and solid soluble material [including component ii)] is from 1:5 to 1:0.3.
22. A process for the production of a pharmaceutical composition as defined in claim 1 which comprises the step of admixing (a) a pharmacologically active agent selected from the group of aryloxyalkanolamines, and (b) a physiologically tolerable anionic surfactant selected from the group of mono-sulphuric acid esters of higher fatty alcohols.
23. A process as claimed in claim 22 which comprises the further step of coating the resultant mixture with a film which is resistant to gastric juices and breaks down at a pH of over 5.
24. A process as claimed in claim 23 which comprises the additional step of covering the film with a medicament layer containing an aryloxyalkanolamine.
25. A pharmaceutical composition for internal use comprising a medicament core comprising 4-(2-hydroxy-3-isopropylaminopropoxy) indole and sodium lauryl sulphate dispersed throughout compressed particulate pharmaceutical excipients insoluble in intestinal juices, the medicament core being coated with a coating which is insoluble in gastric juices but breaks down in intestinal juices.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH9588/76 | 1976-07-27 | ||
| CH958876 | 1976-07-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1095833A true CA1095833A (en) | 1981-02-17 |
Family
ID=4353539
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA283,403A Expired CA1095833A (en) | 1976-07-27 | 1977-07-25 | Controlled release pharmaceutical composition containing mono-sulfuric acid esters of higher fatty alcohols |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS5315411A (en) |
| AR (1) | AR216479A1 (en) |
| AT (1) | AT369987B (en) |
| AU (1) | AU515738B2 (en) |
| BE (1) | BE857122A (en) |
| CA (1) | CA1095833A (en) |
| CY (1) | CY1261A (en) |
| DE (1) | DE2732335C2 (en) |
| DK (1) | DK325677A (en) |
| ES (1) | ES461020A1 (en) |
| FI (1) | FI772217A (en) |
| FR (1) | FR2359607A1 (en) |
| GB (1) | GB1589982A (en) |
| GR (1) | GR65014B (en) |
| HK (1) | HK81884A (en) |
| HU (1) | HU178340B (en) |
| IE (1) | IE45534B1 (en) |
| IL (1) | IL52587A (en) |
| KE (1) | KE3441A (en) |
| MY (1) | MY8400057A (en) |
| NL (1) | NL176227C (en) |
| NO (1) | NO149874C (en) |
| NZ (1) | NZ184722A (en) |
| PT (1) | PT66850B (en) |
| SE (1) | SE437469B (en) |
| SG (1) | SG53884G (en) |
| ZA (1) | ZA774536B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH649216A5 (en) * | 1979-08-16 | 1985-05-15 | Sandoz Ag | METHOD FOR APPLYING AN ACID-RESISTANT FILM TO A MEDICINAL CORE AND SOLID UNIT DOSAGE FORM WITH ACID-ACID RESISTANT FILM. |
| FR2471186A1 (en) * | 1979-12-10 | 1981-06-19 | Roussel Uclaf | NEW COLIC DELITESCENCE TABLETS AND THEIR PREPARATION PROCESS |
| JPS6056122B2 (en) * | 1980-05-21 | 1985-12-09 | 塩野義製薬株式会社 | sustained release formulation |
| JPS5748908A (en) * | 1980-09-08 | 1982-03-20 | Kyorin Pharmaceut Co Ltd | Prolonged release type nicomol pharmaceutical |
| US4795327A (en) * | 1984-03-26 | 1989-01-03 | Forest Laboratories, Inc. | Controlled release solid drug dosage forms based on mixtures of water soluble nonionic cellulose ethers and anionic surfactants |
| US4540566A (en) * | 1984-04-02 | 1985-09-10 | Forest Laboratories, Inc. | Prolonged release drug dosage forms based on modified low viscosity grade hydroxypropylmethylcellulose |
| JPS61254522A (en) * | 1985-05-02 | 1986-11-12 | Takada Seiyaku Kk | Tablet composition |
| JPS62246512A (en) * | 1986-04-18 | 1987-10-27 | Fujisawa Pharmaceut Co Ltd | Drug preparation having repeating action |
| GB9714675D0 (en) * | 1997-07-11 | 1997-09-17 | Smithkline Beecham Plc | Novel composition |
| DE19959419A1 (en) | 1999-12-09 | 2001-06-21 | Ratiopharm Gmbh | Stable pharmaceutical preparations comprising a benzimidazole and process for their preparation |
| US20030113366A1 (en) * | 2001-12-14 | 2003-06-19 | Macgregor Alexander | Reverse-micellar delivery system for controlled transportation and enhanced absorption of agents |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3148124A (en) * | 1962-06-12 | 1964-09-08 | William E Gaunt | Method of preparing sustained release pharmaceutical tablets |
| CA927282A (en) * | 1968-09-03 | 1973-05-29 | S. Banker Gilbert | Entrapment compositions and processes |
| GB1301849A (en) * | 1969-12-15 | 1973-01-04 | ||
| US3558768A (en) * | 1969-12-19 | 1971-01-26 | Sterling Drug Inc | Sustained release pharmaceutical compositions |
-
1977
- 1977-07-16 DE DE2732335A patent/DE2732335C2/en not_active Expired
- 1977-07-18 DK DK325677A patent/DK325677A/en not_active Application Discontinuation
- 1977-07-18 SE SE7708265A patent/SE437469B/en unknown
- 1977-07-18 FI FI772217A patent/FI772217A/fi not_active Application Discontinuation
- 1977-07-19 NO NO772575A patent/NO149874C/en unknown
- 1977-07-22 CY CY1261A patent/CY1261A/en unknown
- 1977-07-22 NL NLAANVRAGE7708162,A patent/NL176227C/en not_active IP Right Cessation
- 1977-07-22 GB GB30856/77A patent/GB1589982A/en not_active Expired
- 1977-07-25 CA CA283,403A patent/CA1095833A/en not_active Expired
- 1977-07-25 IL IL52587A patent/IL52587A/en not_active IP Right Cessation
- 1977-07-25 AU AU27301/77A patent/AU515738B2/en not_active Expired
- 1977-07-25 GR GR54032A patent/GR65014B/en unknown
- 1977-07-25 IE IE1541/77A patent/IE45534B1/en not_active IP Right Cessation
- 1977-07-25 NZ NZ184722A patent/NZ184722A/en unknown
- 1977-07-25 HU HU77SA3050A patent/HU178340B/en unknown
- 1977-07-25 BE BE179609A patent/BE857122A/en not_active IP Right Cessation
- 1977-07-26 PT PT66850A patent/PT66850B/en unknown
- 1977-07-26 JP JP8887677A patent/JPS5315411A/en active Granted
- 1977-07-26 ES ES461020A patent/ES461020A1/en not_active Expired
- 1977-07-26 AT AT0541377A patent/AT369987B/en not_active IP Right Cessation
- 1977-07-27 AR AR268575A patent/AR216479A1/en active
- 1977-07-27 FR FR7723022A patent/FR2359607A1/en active Granted
- 1977-07-27 ZA ZA00774536A patent/ZA774536B/en unknown
-
1984
- 1984-08-03 SG SG538/84A patent/SG53884G/en unknown
- 1984-08-22 KE KE3441A patent/KE3441A/en unknown
- 1984-11-25 HK HK818/84A patent/HK81884A/en unknown
- 1984-12-30 MY MY57/84A patent/MY8400057A/en unknown
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