CA1268051A - Controlled release powder and process for its preparation - Google Patents
Controlled release powder and process for its preparationInfo
- Publication number
- CA1268051A CA1268051A CA000494130A CA494130A CA1268051A CA 1268051 A CA1268051 A CA 1268051A CA 000494130 A CA000494130 A CA 000494130A CA 494130 A CA494130 A CA 494130A CA 1268051 A CA1268051 A CA 1268051A
- Authority
- CA
- Canada
- Prior art keywords
- active ingredient
- controlled release
- particles
- release powder
- polymer
- 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.)
- Expired - Lifetime
Links
Classifications
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
- A23G4/00—Chewing gum
- A23G4/18—Chewing gum characterised by shape, structure or physical form, e.g. aerated products
- A23G4/20—Composite products, e.g. centre-filled, multi-layer, laminated
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2989—Microcapsule with solid core [includes liposome]
Abstract
A B S T R A C
CONTROLLED RELEASE POWDER AND PROCESS FOR ITS PREPARATION
A controlled release powder containing discrete microparticles for use in edible, pharmaceutical and other controlled release compositions. The microparticles have an average size in the range 0.1 to 125 µ m, each of the microparticles being in the form of a micromatrix of an active ingredient uniformly distributed in at least one non-toxic polymer. The microparticles have a predetermined release of active ingredient when the dissolution rate thereof is measured according to the Paddle method of U.S.
Pharmacopoeia XX at 37°C and 75 r.p.m.
CONTROLLED RELEASE POWDER AND PROCESS FOR ITS PREPARATION
A controlled release powder containing discrete microparticles for use in edible, pharmaceutical and other controlled release compositions. The microparticles have an average size in the range 0.1 to 125 µ m, each of the microparticles being in the form of a micromatrix of an active ingredient uniformly distributed in at least one non-toxic polymer. The microparticles have a predetermined release of active ingredient when the dissolution rate thereof is measured according to the Paddle method of U.S.
Pharmacopoeia XX at 37°C and 75 r.p.m.
Description
This invention relates to controlled release formulations and, in particular, to sustained release powders consisting of discrete micro-particles.
Many types of controlled or sustained release pellets are known which are loaded into capsules for oral administration. These pellets can be described as macro-particles and invariably have an average size greater than 400 ~m. Such pellets are the subject, for example, of the Applicants' EP-A- 0 122 077, EP-A- 0 123 470, ~P-A- 0 156 077 and EP-A- 0 149 920.
Sustained release pellets cannot be readily formulated as liquids. Sustained release liquids are desirable for use as geriatric and paediatric formulations.
Various processes are known for the production of micro-spheres using solvent evaporation emulsion techniques.
Known micro-encapsulation techniques are generally employed for phase transformation, such as for the conversion of liquids to solids. Alternatively, such techniques may be used for protecting an active material, such as coating aspirin to mask its stomach irritant properties.
Sustained release liquids are known which contain ion exchange resins. In such sustained release liquids the active ingredient is bound to an ion exchange resin in the form of a reversible complex and is displaced therefrom in vivo. Such sustained release liquids are described, for example, in French Patent Publication No. 2 278 325.
It is an object of the present invention to provide a controlled release powder of discrete micro-particles which can be readily formulated in liqu~d form but which can also be formuIated in other sustained release forms such as tablets`which have improved properties relative to the known forms.
......
, 12~
Accordingly, the invention provides a controlled release powder containing discrete micro-particles for use in controlled release compositions, said powder comprising particles containing an active ingredient and optionally an excipient in intimiate admixture with at least one non-toxic polymer, each of said particles being in the form of a micromatrix with active ingredient and the excipient, if present, uni~ormly distributed throughout the matrix, said particles having an average size o~
between 0.1 and 125 ~m and having a predetermined release of active ingredient when the dissolution rate thereof is measured according to the Paddle Method of U.S.
Pharmacopoeia XX at 37C and 75 r.p.m., said dissolution rate being substantially proportional to the square root of time.
Pre~erably~ the particles have a~ ave~age size o~
between 5 and 100 ~m.
The Applicants have coined the term "pharmasomes" ~or the micro-particles of the powder according to the invention and which term is used hereinafter in the Specification.
The controlled release powders according to the invention can permit a sustained release of active ingredient as hereinafter demonstrated.
Further preferably, the active ingredient is a drug, a nutrient, a colouring agent, a fragrance, a herbic.ide, a pesticide, a flavouring agent or a sweetening agent.
The powder can be dispersed or suspended in a liquid vehicle and will maintain its sustained release characteristics for a useful period of time. Such dispersions or suspensions have both chemical stability and stability in terms of dissolution rate.
The polymer may be soluble, insoluble, permeable, impermeable or biodegradable. The polymers may be polymers or co-polymers. The polymer may be a natural or synthetic polymer. Natural polymers include polypeptides, polysaccharides and alginic acid. A suitable polypeptide is zein and a suitable polysaccharide is cellulose.
Representative synthetic polymers include alkyl celluloses, hydroxyalkyl celluloses r cellulose ethers, `! ,`;
' ~
5~
cellulose esters, nitro cellulose~, ~olymer~ of acrylic and methacrylic acids and esters thereof, polyamides, poly-carbonates, polyalkylenes, polyalkylene glycols, poly-alkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes and polyurethanes and co-polymers thereo~.
Particularly suitable polymers include: methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxy~utyl methyl cellulose, cellulose acetate, cellulose propionate ~lower, medium or higher molecular weight), cellulose ace~ate propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulphate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate~, polytisQbutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate~, poly(lauryl methacryla~e), poly(phenyl methacrylate~, poly(methyl acrylate), poly(isopropyl acrylate), poly(iso~utyl acrylate), poly(octadecyl acrylate), poly(ethylene~, poly(ethylene) low density, poly(ethylene) high density, poly~propylene~, poly(ethylene glycol), poly(ethylené oxide), polylethylene terephthalate), poly(vinyl alcohol3, poly(vinyl i80~utyl ether), poly(vinyl acetate), poly~vinyl chloride) and polyvinylpyrrolidone.
Especially suitable co-polymers include: butyl methacrylate/isobutyl methacrylate co-polymer, high molecular weight, methylvinyl ether/m~leic acid co-polymer, methylvinyl ether/m~leic acid, monoethyl ester co-polymer, methylvinyl ether/maleic anhydride co-polymer and vinyl alcohol/vinyl acetate co-polymer.
Representative biodegradable pol~mers include, poly glycolides, ~oly(ethylene terephthalate) and polyurethane.
Representative acrylates and methacrylate~ are polymers sold under the Trade ~ark Eudragit.
When t~e active ingredient is a drug there is essentially no limitation on the type o drug which may be used.
: ~,:, : ~. :
0~1 Representative active ingredients include antacids, anti-inflammatory substances, coronary dilator6, cerebral dilators, peripheral vasodilators, anti-infectives, psychotropics, anti-manics, stimulants, anti-hi~tamines, laxatives, decongestants, vitamins, gastro-intestina-sedatives, anti-diarrheal preparations, anti-anginal drugs, vasodilators, anti-arrhythmics, anti-hypertensive drugs, vasoconstrictors and mi~raine treatments, anti-coagulants and anti-thrombotic drugs, analgesics, anti-pyretics, hypno~ics, sedatives, anti emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypo~lycaemic agents, thyroid and anti-thyroid preparati.ons, diuretics, anti-spasmodics, uterine rela~ants, mineral and nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs, anti-asthmatics, bronchodilators, expectorants, cough suppressants, mucolytics and anti-uricemic dru~s.
~ ypical active ingredients include gastro-intestinal sedatives such as meto~lopramide and propantheline bromide, antacids such as aluminium trisilicate, aluminium hydroxide and cimetidine, anti-inflammatory drugs such as phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, prednisone and prednisolone, coronary vasodilator drugs such as slyceryl trinitrate, isosorbide dinitrate and penta~rythritol tetranitrate, peripheral and cere~ral vasodilators ~uch as soloctidilum, vincamine, naftidrofuryl oxalate, co-dergocrine mesylate, cyclandelate, papaverine and nicotinic acid, anti-infective substances such as erythromycin s~earate, cephalexin, nalidixic acid, tetracycline hydrochlorid~, ampicillin, flucloxacillin sodium, hexamine mandela~e and hexamine hippurate, neuroleptic drugs such as 1urazepam, diazepam, temazepam, amitryptyline, doxepin, lithium carbonate, lithium sulfate, chlorpromazine, th oridazine, trifluperazine, fluphenazine/ piperothiazine, haloperidol, maprotiline hydrochloride, imipramine and desmethylimipramine, central nervous stimulants such a~
methylphenida~e, ephedrine, epinephrine, isoproterenol, '.:
..
S~
amphetamine sulfate and amphetamine hydr~chloride, anti-histamic drugs such as diphenhydramine, diphenylpyraline, chlorpheniramine and brompheniramine, anti-diarrheal drugs such as bisacodyl and magnesium hydroxide, the laxative 5 drug, dioctyl ~odium sulfosuccinate, nutritional supplements such as ascorbic acid, alpha tocopherol, thiamine an~
pyridoxine, anti-spasmodic drugs such as dicyclomine and diphenoxylate, drugs affecting the rhythm of the heart such as verapamil, ni.edipine, diltiazem, procainamide, disopyramide, bretylium tosylate, quinidine sulfate and quinidine gluconate, drugs used in the treatment o~
hypertension such as propranolol hydrochloride, guanethidine monosulpha~e, methyldopa, oxprenolol hydrochloride, captopril and hydralazine, drugs used in the trea~ment of migraine such as ergotamine, drugs affecting coagulability of blood such as epsilon aminocaproic acid and protamine sulfate, analgesic drugs such as acetylsalicylic acid, acetaminophen, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxycodeinone, morphine, heroin, nal~uphine, butorphanol tartrate, penta~ocine hydrochloride, cyclazacine, pethidine, buprenorphine, scopolamine and mefenamic acid, anti-epileptic drugs such as phenytoin sodium and sodium valproate, neuromuscular drugs such as dantrolene sodium, substances used in the treatment of diabetes such as tolbutamide, disbenase glucagon and insu~in, dru~s used in the trea~ment of thyroid gland disfunction such as triiodothyronine, thyroxine and propylthiouracil, diuretic drugs such as furosemide, chlorthalidone, hydrochlorthiaæide, spironolactone and triamterene, the uterine relaxant drug ritodrine, appetite suppressants such as fenfluramine hydrochloride, phentermine and diethylproprion hydrochloride, anti-asthmatic and bronchodilator drugs such as aminophylline, theop~lylline, salbutamol, orciprenaline sulphate and terbutaline ~ulphate, expectorant drugs such as guaiphenesin, cough suppressants such as dextromethorphan and noscapine, mucolytic drugs such as carbocisteine, anti-septics such as cetylpyridinium .
805~
chloride, tyrothricin and chlorhexidine, decongestant drugs such as phenylpropanolamine and p~eudoephedrine, hypnotic drugs such as dichloralphenazone and nitrazepam, anti-nauseant dru~s such as promethazine theoclate, haemopoietic drugs such as ~errous sulphate, folic acid and calcium gluconate, uricosuric drugs such as sulphinpyra~one, allopurinol and probenecid.
Particularly preferred active ingredients are:
ibuprofen, paracetamol, 5-amino-salicylic acid, dextromethorphan, propranolol, theophylline, dil~ia7em, methyldopa, pseudoephedrine, cimetidine, cephalexin, cephaclor, cephradine, naproxen, piroxicam, diazepam, diclofenac, indomethacin, amoxycillin, pivampicillin, bacampicillin, dicioxacillin, erythromycin, erythromycin stearate, lincomycin, co-dergocrine mesylate, d~xycycline, dipyridamole, frusemide, triamterene, sulindac, nifedipine, atenolol, lora7.epam, glibenclamide, sal~utamol, trimethoprimtsulphamethoxazole, spironolactone, carbinoxamine maleate, guaiphenesin, potassium chloride and metoprolol tartrate.
Especially preferred active ingredients include theophylline, paracetamol an~ potassium chloride.
The active ingredient may also be a saccharin for use in edible compositions wherein it is desired to obtained a controlled release of saccharin, such as, for e~ample in chewing gums. The active ingredient may also be other sweetening agents, such asl for example, aspartame which is especially suitable for use in chewing gums.
The invention alsv provides a process for preparing the controlled release powder according to the invention which comprises:
a) orming a solution of the polym~r or polymers in a solvent;
b) dissolving or dispersing the active ingredient in said polymer solution so as to form a uniform mixture; and c) r~moving the solvent from the mi~ture so as to `- obtain micro-particles having an average si~e in the range 0 1 to 125~ m.
~. . ;,; .
: : ' ' .
~. , : ', 12~ 5~L
The solvent is selected from water, alcohols, Xetones, halogenated aliphatic compounds, halogenated aromatic hydrocarbon compounds, aromatic hydrocarbon compounds and cyclic ethers or a mixture thereof.
Especially preferred solvents inc~ude, water, hexane, heptane, methanol, ethanol, acetone, methylethyl ketone, methylisobutyl ketone, methylene chloride, chloroform, carbon tetrachloride, toluene, ~ylene and ~etrahydro~uran.
The choice of solvent or solvents will be dictated by the particular polymer or polymers selected. For example, suitable solvents for use with the celluloses are acetone or a mixture of methanol and methylene chloride.
The concentration of the polymer in the solvent will normally be less than 75% by weight. Normally the concentration will be in the range of 10-30% by weight.
If the active ingredient is not soluble in the polymer solution the particle size of the active ingredient is reduced to less than lQ ~ m. The reduction of particle size may be achieved ~y milling, for example, by ball milling or jet milling.
The active ingredient may, of cour~e, be a liquid.
~ he ratio of drug to polymer will vary within w~de limits, such as within the range 0.1:10 to 10:1.
The uniform mixture of the active ingredient in the polymer solution may be achieved by rapid and continuous mixing.
The removal of the solvent and the formation of particles of the desired si~e may be achieved in a number of ways.
1. SPRAY ~RYI~G.
The mixture of active ingredient and polymer in the solvent i~ sprayed into a stream of hot air in conventionat manner. This causes the solvent ~o evaporate and the powder is collected in the spray drying vessel.
The size of the particles may be controlled in a number of ways, for example, by pre-~electing the inle~ and outlet - temperature of the ~pray drying vessel; the rate of .;, : . , - :
~2~i~305:~
introduction of the spray, the size of the spray tip or the ratio of the concentration of active ingredient to polymer.
Many types of controlled or sustained release pellets are known which are loaded into capsules for oral administration. These pellets can be described as macro-particles and invariably have an average size greater than 400 ~m. Such pellets are the subject, for example, of the Applicants' EP-A- 0 122 077, EP-A- 0 123 470, ~P-A- 0 156 077 and EP-A- 0 149 920.
Sustained release pellets cannot be readily formulated as liquids. Sustained release liquids are desirable for use as geriatric and paediatric formulations.
Various processes are known for the production of micro-spheres using solvent evaporation emulsion techniques.
Known micro-encapsulation techniques are generally employed for phase transformation, such as for the conversion of liquids to solids. Alternatively, such techniques may be used for protecting an active material, such as coating aspirin to mask its stomach irritant properties.
Sustained release liquids are known which contain ion exchange resins. In such sustained release liquids the active ingredient is bound to an ion exchange resin in the form of a reversible complex and is displaced therefrom in vivo. Such sustained release liquids are described, for example, in French Patent Publication No. 2 278 325.
It is an object of the present invention to provide a controlled release powder of discrete micro-particles which can be readily formulated in liqu~d form but which can also be formuIated in other sustained release forms such as tablets`which have improved properties relative to the known forms.
......
, 12~
Accordingly, the invention provides a controlled release powder containing discrete micro-particles for use in controlled release compositions, said powder comprising particles containing an active ingredient and optionally an excipient in intimiate admixture with at least one non-toxic polymer, each of said particles being in the form of a micromatrix with active ingredient and the excipient, if present, uni~ormly distributed throughout the matrix, said particles having an average size o~
between 0.1 and 125 ~m and having a predetermined release of active ingredient when the dissolution rate thereof is measured according to the Paddle Method of U.S.
Pharmacopoeia XX at 37C and 75 r.p.m., said dissolution rate being substantially proportional to the square root of time.
Pre~erably~ the particles have a~ ave~age size o~
between 5 and 100 ~m.
The Applicants have coined the term "pharmasomes" ~or the micro-particles of the powder according to the invention and which term is used hereinafter in the Specification.
The controlled release powders according to the invention can permit a sustained release of active ingredient as hereinafter demonstrated.
Further preferably, the active ingredient is a drug, a nutrient, a colouring agent, a fragrance, a herbic.ide, a pesticide, a flavouring agent or a sweetening agent.
The powder can be dispersed or suspended in a liquid vehicle and will maintain its sustained release characteristics for a useful period of time. Such dispersions or suspensions have both chemical stability and stability in terms of dissolution rate.
The polymer may be soluble, insoluble, permeable, impermeable or biodegradable. The polymers may be polymers or co-polymers. The polymer may be a natural or synthetic polymer. Natural polymers include polypeptides, polysaccharides and alginic acid. A suitable polypeptide is zein and a suitable polysaccharide is cellulose.
Representative synthetic polymers include alkyl celluloses, hydroxyalkyl celluloses r cellulose ethers, `! ,`;
' ~
5~
cellulose esters, nitro cellulose~, ~olymer~ of acrylic and methacrylic acids and esters thereof, polyamides, poly-carbonates, polyalkylenes, polyalkylene glycols, poly-alkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes and polyurethanes and co-polymers thereo~.
Particularly suitable polymers include: methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxy~utyl methyl cellulose, cellulose acetate, cellulose propionate ~lower, medium or higher molecular weight), cellulose ace~ate propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulphate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate~, polytisQbutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate~, poly(lauryl methacryla~e), poly(phenyl methacrylate~, poly(methyl acrylate), poly(isopropyl acrylate), poly(iso~utyl acrylate), poly(octadecyl acrylate), poly(ethylene~, poly(ethylene) low density, poly(ethylene) high density, poly~propylene~, poly(ethylene glycol), poly(ethylené oxide), polylethylene terephthalate), poly(vinyl alcohol3, poly(vinyl i80~utyl ether), poly(vinyl acetate), poly~vinyl chloride) and polyvinylpyrrolidone.
Especially suitable co-polymers include: butyl methacrylate/isobutyl methacrylate co-polymer, high molecular weight, methylvinyl ether/m~leic acid co-polymer, methylvinyl ether/m~leic acid, monoethyl ester co-polymer, methylvinyl ether/maleic anhydride co-polymer and vinyl alcohol/vinyl acetate co-polymer.
Representative biodegradable pol~mers include, poly glycolides, ~oly(ethylene terephthalate) and polyurethane.
Representative acrylates and methacrylate~ are polymers sold under the Trade ~ark Eudragit.
When t~e active ingredient is a drug there is essentially no limitation on the type o drug which may be used.
: ~,:, : ~. :
0~1 Representative active ingredients include antacids, anti-inflammatory substances, coronary dilator6, cerebral dilators, peripheral vasodilators, anti-infectives, psychotropics, anti-manics, stimulants, anti-hi~tamines, laxatives, decongestants, vitamins, gastro-intestina-sedatives, anti-diarrheal preparations, anti-anginal drugs, vasodilators, anti-arrhythmics, anti-hypertensive drugs, vasoconstrictors and mi~raine treatments, anti-coagulants and anti-thrombotic drugs, analgesics, anti-pyretics, hypno~ics, sedatives, anti emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypo~lycaemic agents, thyroid and anti-thyroid preparati.ons, diuretics, anti-spasmodics, uterine rela~ants, mineral and nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs, anti-asthmatics, bronchodilators, expectorants, cough suppressants, mucolytics and anti-uricemic dru~s.
~ ypical active ingredients include gastro-intestinal sedatives such as meto~lopramide and propantheline bromide, antacids such as aluminium trisilicate, aluminium hydroxide and cimetidine, anti-inflammatory drugs such as phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, prednisone and prednisolone, coronary vasodilator drugs such as slyceryl trinitrate, isosorbide dinitrate and penta~rythritol tetranitrate, peripheral and cere~ral vasodilators ~uch as soloctidilum, vincamine, naftidrofuryl oxalate, co-dergocrine mesylate, cyclandelate, papaverine and nicotinic acid, anti-infective substances such as erythromycin s~earate, cephalexin, nalidixic acid, tetracycline hydrochlorid~, ampicillin, flucloxacillin sodium, hexamine mandela~e and hexamine hippurate, neuroleptic drugs such as 1urazepam, diazepam, temazepam, amitryptyline, doxepin, lithium carbonate, lithium sulfate, chlorpromazine, th oridazine, trifluperazine, fluphenazine/ piperothiazine, haloperidol, maprotiline hydrochloride, imipramine and desmethylimipramine, central nervous stimulants such a~
methylphenida~e, ephedrine, epinephrine, isoproterenol, '.:
..
S~
amphetamine sulfate and amphetamine hydr~chloride, anti-histamic drugs such as diphenhydramine, diphenylpyraline, chlorpheniramine and brompheniramine, anti-diarrheal drugs such as bisacodyl and magnesium hydroxide, the laxative 5 drug, dioctyl ~odium sulfosuccinate, nutritional supplements such as ascorbic acid, alpha tocopherol, thiamine an~
pyridoxine, anti-spasmodic drugs such as dicyclomine and diphenoxylate, drugs affecting the rhythm of the heart such as verapamil, ni.edipine, diltiazem, procainamide, disopyramide, bretylium tosylate, quinidine sulfate and quinidine gluconate, drugs used in the treatment o~
hypertension such as propranolol hydrochloride, guanethidine monosulpha~e, methyldopa, oxprenolol hydrochloride, captopril and hydralazine, drugs used in the trea~ment of migraine such as ergotamine, drugs affecting coagulability of blood such as epsilon aminocaproic acid and protamine sulfate, analgesic drugs such as acetylsalicylic acid, acetaminophen, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxycodeinone, morphine, heroin, nal~uphine, butorphanol tartrate, penta~ocine hydrochloride, cyclazacine, pethidine, buprenorphine, scopolamine and mefenamic acid, anti-epileptic drugs such as phenytoin sodium and sodium valproate, neuromuscular drugs such as dantrolene sodium, substances used in the treatment of diabetes such as tolbutamide, disbenase glucagon and insu~in, dru~s used in the trea~ment of thyroid gland disfunction such as triiodothyronine, thyroxine and propylthiouracil, diuretic drugs such as furosemide, chlorthalidone, hydrochlorthiaæide, spironolactone and triamterene, the uterine relaxant drug ritodrine, appetite suppressants such as fenfluramine hydrochloride, phentermine and diethylproprion hydrochloride, anti-asthmatic and bronchodilator drugs such as aminophylline, theop~lylline, salbutamol, orciprenaline sulphate and terbutaline ~ulphate, expectorant drugs such as guaiphenesin, cough suppressants such as dextromethorphan and noscapine, mucolytic drugs such as carbocisteine, anti-septics such as cetylpyridinium .
805~
chloride, tyrothricin and chlorhexidine, decongestant drugs such as phenylpropanolamine and p~eudoephedrine, hypnotic drugs such as dichloralphenazone and nitrazepam, anti-nauseant dru~s such as promethazine theoclate, haemopoietic drugs such as ~errous sulphate, folic acid and calcium gluconate, uricosuric drugs such as sulphinpyra~one, allopurinol and probenecid.
Particularly preferred active ingredients are:
ibuprofen, paracetamol, 5-amino-salicylic acid, dextromethorphan, propranolol, theophylline, dil~ia7em, methyldopa, pseudoephedrine, cimetidine, cephalexin, cephaclor, cephradine, naproxen, piroxicam, diazepam, diclofenac, indomethacin, amoxycillin, pivampicillin, bacampicillin, dicioxacillin, erythromycin, erythromycin stearate, lincomycin, co-dergocrine mesylate, d~xycycline, dipyridamole, frusemide, triamterene, sulindac, nifedipine, atenolol, lora7.epam, glibenclamide, sal~utamol, trimethoprimtsulphamethoxazole, spironolactone, carbinoxamine maleate, guaiphenesin, potassium chloride and metoprolol tartrate.
Especially preferred active ingredients include theophylline, paracetamol an~ potassium chloride.
The active ingredient may also be a saccharin for use in edible compositions wherein it is desired to obtained a controlled release of saccharin, such as, for e~ample in chewing gums. The active ingredient may also be other sweetening agents, such asl for example, aspartame which is especially suitable for use in chewing gums.
The invention alsv provides a process for preparing the controlled release powder according to the invention which comprises:
a) orming a solution of the polym~r or polymers in a solvent;
b) dissolving or dispersing the active ingredient in said polymer solution so as to form a uniform mixture; and c) r~moving the solvent from the mi~ture so as to `- obtain micro-particles having an average si~e in the range 0 1 to 125~ m.
~. . ;,; .
: : ' ' .
~. , : ', 12~ 5~L
The solvent is selected from water, alcohols, Xetones, halogenated aliphatic compounds, halogenated aromatic hydrocarbon compounds, aromatic hydrocarbon compounds and cyclic ethers or a mixture thereof.
Especially preferred solvents inc~ude, water, hexane, heptane, methanol, ethanol, acetone, methylethyl ketone, methylisobutyl ketone, methylene chloride, chloroform, carbon tetrachloride, toluene, ~ylene and ~etrahydro~uran.
The choice of solvent or solvents will be dictated by the particular polymer or polymers selected. For example, suitable solvents for use with the celluloses are acetone or a mixture of methanol and methylene chloride.
The concentration of the polymer in the solvent will normally be less than 75% by weight. Normally the concentration will be in the range of 10-30% by weight.
If the active ingredient is not soluble in the polymer solution the particle size of the active ingredient is reduced to less than lQ ~ m. The reduction of particle size may be achieved ~y milling, for example, by ball milling or jet milling.
The active ingredient may, of cour~e, be a liquid.
~ he ratio of drug to polymer will vary within w~de limits, such as within the range 0.1:10 to 10:1.
The uniform mixture of the active ingredient in the polymer solution may be achieved by rapid and continuous mixing.
The removal of the solvent and the formation of particles of the desired si~e may be achieved in a number of ways.
1. SPRAY ~RYI~G.
The mixture of active ingredient and polymer in the solvent i~ sprayed into a stream of hot air in conventionat manner. This causes the solvent ~o evaporate and the powder is collected in the spray drying vessel.
The size of the particles may be controlled in a number of ways, for example, by pre-~electing the inle~ and outlet - temperature of the ~pray drying vessel; the rate of .;, : . , - :
~2~i~305:~
introduction of the spray, the size of the spray tip or the ratio of the concentration of active ingredient to polymer.
2. USE OF ~N EXTERMAL LIQUID PHASE.
The mi~ture of active ingredient and polymer, which is in the form of a solution or ~uspension, is p~ured into a liquid external phase. The liquid external phase comprises a solvent which is immiscible or partially immuscible with the active ingredient/polymer mixture.
The choice of external liquid phase will be determined by the particular combination of active ingredient and polymer selected. Suitable liquids for the external li~uid phase include water, aqueous solutions, for example, sugar solutions, organic solvents, mineral oil, vegeta~le oils, fixed oils, syrups or silicones. The aqueous s~lution may include a thickening agent, such as xanthan gum, to increase the viscosity thereof. Oils may be made more viscous ~y ~he addition ~f substances such as magnesium stearate. The external liquid pha~e may also c~mprise a solution of a different pH, for example, a buffer.
The ratio of external liquid phase to poly~Pr mixture will be at least 2:1.
Following addition of the active ingredient~polymer mixture to the external liquid phase, the two phase mixture obtained is emulsified, for e~ample, by rapid ~i~ing. The emulsion formed may be either stable or unstable. Globules of the active ingredient/polymer are thereby formed in the emulsion.
The solvent may be removea in a number of ways. If the solvent is volatile it can ~e removed passively. For example, if the solvent is aoetone it would normally be removed by evaporation duri~g the mixing step. The particles form~d are ~hen harvested by filtration or centrifugation.
The solvent can also be removed ~y heàting while mixing the two phase mi~ture. For egample, the solvent may ~e removed on a rotary film evaporator. The solvent may also be removed under vacuum wi~h or without heating. Microwave .
:, . .
:- ..
. ~ . ,~-, ,. .:
~2~i8~5~
drying may al60 be employed with or without the application of a vacuum. Ano~her mode of ~ol~ent removal is free~e drying.
After harvesting of the micro-particles, they will 5 normally be given successive washings with a suitable solvent, follGwed by drying.
For e~ample, when the solvent used is acetone and the external liquid phase is mineral oil, then the m1cro-particles will be given successive washings with hexane and dried at 45C.
On a commercial scale emulsification of the mixture may be achieved by emulsification with an in-line mixer or mixers.
The particle size may be controlled in a number of ways For example, the particle size may be controlled b~
the rate of mixing, the viscosity of the external liquid phase, the ViSGosity of the internal phase, the active ingredient particle si~e or the volatility of the solvent.
The mi~ture of active ingredient and polymer, which is in the form of a solution or ~uspension, is p~ured into a liquid external phase. The liquid external phase comprises a solvent which is immiscible or partially immuscible with the active ingredient/polymer mixture.
The choice of external liquid phase will be determined by the particular combination of active ingredient and polymer selected. Suitable liquids for the external li~uid phase include water, aqueous solutions, for example, sugar solutions, organic solvents, mineral oil, vegeta~le oils, fixed oils, syrups or silicones. The aqueous s~lution may include a thickening agent, such as xanthan gum, to increase the viscosity thereof. Oils may be made more viscous ~y ~he addition ~f substances such as magnesium stearate. The external liquid pha~e may also c~mprise a solution of a different pH, for example, a buffer.
The ratio of external liquid phase to poly~Pr mixture will be at least 2:1.
Following addition of the active ingredient~polymer mixture to the external liquid phase, the two phase mixture obtained is emulsified, for e~ample, by rapid ~i~ing. The emulsion formed may be either stable or unstable. Globules of the active ingredient/polymer are thereby formed in the emulsion.
The solvent may be removea in a number of ways. If the solvent is volatile it can ~e removed passively. For example, if the solvent is aoetone it would normally be removed by evaporation duri~g the mixing step. The particles form~d are ~hen harvested by filtration or centrifugation.
The solvent can also be removed ~y heàting while mixing the two phase mi~ture. For egample, the solvent may ~e removed on a rotary film evaporator. The solvent may also be removed under vacuum wi~h or without heating. Microwave .
:, . .
:- ..
. ~ . ,~-, ,. .:
~2~i8~5~
drying may al60 be employed with or without the application of a vacuum. Ano~her mode of ~ol~ent removal is free~e drying.
After harvesting of the micro-particles, they will 5 normally be given successive washings with a suitable solvent, follGwed by drying.
For e~ample, when the solvent used is acetone and the external liquid phase is mineral oil, then the m1cro-particles will be given successive washings with hexane and dried at 45C.
On a commercial scale emulsification of the mixture may be achieved by emulsification with an in-line mixer or mixers.
The particle size may be controlled in a number of ways For example, the particle size may be controlled b~
the rate of mixing, the viscosity of the external liquid phase, the ViSGosity of the internal phase, the active ingredient particle si~e or the volatility of the solvent.
3. Other methods for the removal of the solvent include phase separation, interfacial polymer deposition and coacervation.
The optional excipient u~ed in association with the or each active ingredient will frequently have an active role to play following administration. For example, the excipien~ may be a surface-active agent which facilitates the transport of water into the particles, for example, sodium lauryl sulphate or a surface-active agent sold under the Trade MarX Tween. The e~cipient may also be an active transport agent such as, for example, glucose or one or more 3Q amino acids.
The e~cipient may comprise one or more organic acids which facilitate the dissolution of drugs which are poorly soluble in alkaline media. Such acids include, for example, ascorbic acid, citric acid, fumaric acid, malic acid, 35 succinic acid and tartaric acid. Bimilarly, the excipient may compris~ one or more basic materials which facilitate the aissolution of drugs which are poorly solu~le in acid media. Such basic material~ include sodium carbonate, ,:
~ ,',~ - ' ~ , .: :, . ::: : ~ .
o~
sodium citrate and sodium bicarbonate.
When the active ingredient is a drug, ~he micro-particle~ according to the invention may be formulated in a wide variety of forms. Pharmaceutical formulations according to the invention include pill6 and ta~lets, or example, coated tablets, effervescent tablets, chewable tablets, moulded tablets and melt tablets. The particles according to the invention may be compressed into tablets and optionally coated without any substantial change occurring in the particles. Furthermore, because of the micro-particulate nature of the particles they are unlikely to be significantly degraded or ground by any che~ing action.
Powder formulations according to the invention include dusting powders and douche powders.
The particles according to the invention may also be loaded into capsules which may be either soft gelatin capsules or hard gelatin capsules.
Other solid dosage forms include pessaries, rectal suppositories, vaginal tablets and vaginal inserts.
The particles according to the invention may also be used in implants and ocular inserts.
The powders can also be formulated in form~s ~uitable for topical application, such as, for example, as creams or ointments and for ,ransdermal delivery, for e2~mp1e, in the form of transdermal patches.
The micro-particlate powders according to the invention may also be used in the form of foams, gels, pastes, gums, mucilages and jellies~
Other suitable formulations incorporating the micro-particles according to the invention include inhalants, magmas, intrauterine devices, patches, biodegradable wound dressings and other topical dressings.
~he micro-particulate powders according to the invention are Pspecially ~uitable ~or formulation as liquids for oral, local or parenteral admini6tration. Thus, they can be formulated in liqu~d form for use as eye drops, nasal drops, ear drop~, suspensions, syrups, infusion ana ,"; . ~; , , .. ,, ,,, .. ,.~ ~ " .
' :~,' ,.' :.' ' , or ~
injectable ~olutions. The powders can also be formulated as nasal sprays. The injectable solutions i~clude intravenous, subcutaneous and intramuscular injectable solutions.
The oral suspensions and syrups according to the 5 invention are particularly suitable for use in geriatric and paediatric ~edicine. The liquids formed hav~ good mouth feel. Furthermore, because the polymer substantially coats the active ingredient, the coating masks any unpleasant taste.
A characteristic of good mouth feel also applies to chewable and effervescent tablets. Because of the micro-particulate nature of the powder one does not e~perience a granular sensation.
Preferred paediatric liquids according to the invention are suspensions or syrups of bronchial rela~ants, analgesics, anti-pyretics, anti-tussives~ anti-spa~modics, anti-nauseants, anti-histamines, anti-epileptics and antibiotics.
Other especially suitable liquid formulations according to th~ invention are non-aqueous suspensions ~f highly water soluble or water insoluble active ingredients. Suitable drugs for formulating in this way include de~tro~e~horphan, guaiphenesin and pseudoephedrine or a salt thereof or potassium chloride.
The liquid formulations have good shelf life and demonstrate stability both in chemical t~rms and in terms of dissolution rates up to thirty days~ It i~ e~t~mated that the shelf life can be as long as five year~.
In the liquid formulations according to the iQvention one can achieve a concentration of active ingredient of up to 1 g per 5 ml.
Heretofore many drugs have not been sta~le in liquid form, for example, analgesic~, necessita~ing a dosa~e regimen of every 4-6 hours. The liquids accoxding to the invention offer versatility and the possibili~y of twice daily administra~ion for a medicament such as, for example, analgesics, anti-histamine~ and bronc~ial relasant~
The taste masking ~ea~ure of ~he powders according to the invention is of significant importance in the area of : .,: ~.
- . :
S~L
paediatric medicine. However, this feature is of e~ual importance in veterinary medicine. For example, in the case of antibiotics such as erythromycin which have an extremely unpleasant bitter taste it is virtually impossible to administer such antibiotics orally to animals because it is not possible to successfully mask the bitter taste.
Accordingly, such known oral formulations are re]ected by anlmals .
The present invention therefore in one important aspect provides controlled release antibiotic formulations substantially free from the taste of said antibiotic for pharmaceutical or veterinary use which:
a) are in the form of powders according to the invention;
b) are in the form of non-aqueous suspensions of the powders according to the invention; or c) are in the form of reconstitutable aqueous suspensions of the powders according to the invention.
The powders according to the invention can be used in pre-mixes for animal feedstuffs and other feed additives.
In addition to drugs, nutritional supplements such as vitamins can be administered orally to animals using the powders according to the invention.
Suitable veterinary preparations according to the invention include veterinary feeds, boluses, drenches and washes.
In the agricultural field the powders according to the invention can also be used for preparation of controlled release herbicides and pesticides.
In the cosmetics field one use of the controlled release powders according to the invention is as sustained release fragrance particles for use in talcum powders, creams, lotions and other cosmetic preparations.
:, . -~i8~
- 13a -BRIEF DESCRIPTION OF THE FIGURES
-In the accompanying Figures:
Fig. 1 is an electron micrograph of microparticles according to the invention;
Fig. 2 is an electron micrograph of microparticles of the type depicted in Fig. 1 but from which the active ingredient has been leached by dissolution in water for 24 hours;
Fig. 3 is a graph of plasma levels t~g/ml) versus time after administration (hours) for a syrup according to the invention;
Fig. 4 is a graph representing percentage dissolution of a suspension according to the invention versus time over a fifteen week period;
Fig. 5 is a graph comparing plasma levels (~g/ml) versus time after administration (hours) of a syrup according to the invention (curve a) with a conventional syrup (curve b);
Fig. 6 is a graph comparing plasma levels (~g/ml) versus time after administration (hours) of two suspensions according to the invention (curves a and b) with a conventional syrup (curve c);
Fig. 7 is a graph comparing three suspensions according to the invention in terms of percentage dissolution versus time (hours~;
Fig. 8 is a graph representing percentage dissolution of a suspension according to the invention versus time over a tbirty ~eek period;
Fig. 9 is a graph comparing plasma levels (~g/ml) versus time after administration (hours) of a suspension according to the invention (curve a) with a conventional syrup (curve b);
Fig. 10 is a graph comparing plasma levels (~g~ml) versus time after administration (hours) of a :" '' " ,:
:- , ::: , ~2~5~
- 13b -suspension according to the invention (curve a) with a conventional syrup (curve b);
Fig. 11 is a graph comparing plasma levels (~g/ml~
versus time after administration (hours) of a suspension according to the invention (curve a~ with a conventional syrup (curve b);
Fig. 12 is a graph of percentage dissolution versus time (hours) for three suspensions according to the invention;
Fig. 13 is a graphic representation of observed sweetness for a chewing gum containing aspartame~
containing microparticles according to the invention with a conventional aspartame-containing chewing gum;
Fig. 14 is a graphic representation of percentage dissolution versus time (hours) of microparticles according to the invention ~curve a) relative to chewable tablets prepared therefrom ~curve b);
Fig. 15 is a graphic representation of percentage dissolution versus time ~hours) of microparticles according to the invention ~curve a) relative to melt tablets prepared therefrom (curve b); and Fig. 16 is a graphic representation of percentage dissolution versus time (hours) of microparticles according to the invention (curve a) relative to capsules prepared therefrom ~curve b).
Each of the particles of the controlled release powder accord7ng to the invention represents a true micromatrix with the active ingredient and optionally one or more excipients uniformly distributed therethrough as depicted in ' ~ . .- : ': ' ': : .
i8~
Fig. 1 of ~e accompanying drawings which is a half-tone drawing prepared from an electron micrograph of "pharmasomes"
containing theophylline and prepared as described in Example 1 below. The theophylline can be observed to form veins or a labyrinth throughout the polymeric material of the "pharmasome". Fig. 2 is a half-tone drawing prepared from an electron micrograph of the "pharmasomes" after the theophylline has been leached out by dissolution in water for 24 hours. One is left with a matrix structure of polymeric material.
The micromatrix nature of the particles can also be demonstrated by their dissolution profile. Referring, for example, to Examples 1 and 2 hereinbelow, it is found that the dissolution rate (D) is directly proportional to the square root of time (t) according to the following equation:
D a ~ t after an initial burst of release of active ingredient which is considered to be active ingredient lying close to the surface of the particles. The dissolution rate is dependent on the amount of active ingredient remaining in the particle matrix at any given time. Theoretically the last molecule of ac.ive ingredient never leaches out. The dissolution rate is assumed to reach 100~ at infinity.
The particles according to the invention also have a degree of p~rosity which can be calculated from the absolute density of the particles measured on a pycnometer. ~le dissolution rate of the particles according to the invention is also found to relate to the degree of porosity of said particles.
The microparticles according to the invention are to be distinguished from microcapsules in that in the la~ter the active ingredient is encapsulated by a polymer coating, , ~ ,, i8~353 whereas in the former the active ingredient i~ uniformly distributed throug~out the polymeric material as described above and as indicated in Figs. 1 and 2 of the accompanying drawings.
The invention will be further illustrated by the 5/ following e~amples. In the e~amples the dissolution rate o~
the various pharmaceutical formulations is measured by the Paddle Method of U.S. Pharmacopoeia XX at 37~C and 75 r.p.m., using 200 mg of sample per 900 ml of simulated intestinal fluid excluding enzymes~
Preparation of micro-particles containing theop~ylline Theophylline was ground in a motorised ball mill and then sieYed through a 38 ~m mesh sieve.
Cellulose acetate butyrate (CAB) was dissolved in acetone so as to give a concentration of CAB in acetone o~
15~ w/v.
Hexane (20 ml) was added to an aliquot of the CAB
solution (100 g) with constant stirring.
A portion of the sieved theophylline ~10 9~ was then ~0 added to the polymer solution under constant agitation to ensure an even dispersion of the theophylline. ~his product constituted an internal phase for the su~sequent emulsification step.
Magnesium stearate was dissolved in heavy mineral oil U.S. Pharmacopoeia so as to achieve a concentration of 1.5% w/v. This solution was used as an e~ternal liquid phase. 150 ml of the external liquid phase was decanted into a tall 600 ml beaker and the internal phase prepared above was added thereto. Emulsification was achieved using a Silverson mixer (Silverson is a Trade Mar~ a~ full speed for 2 minutes and thsn dropping the speed as re~uired to achieve the desired particle size.
The suspension of particles in the e~t~rnal phase was then introduced into a rotary evaporatvr and the acetone 35 removed under vacu~m. The suspension now consisted solely , ~
of polymer coated theophylline or "pharmasomes" suspended in the external liquid phase. On microscopic examination particle size was found to range from 10 to 180 ~m.
The particles were centrifuged down and the external phase decanted. The particles were then washed repeatedly with heptane to remove the external liquid phase. The final product was then filtered and dried at 45C for two hours.
The particles were then sieved with mesh sizes of 50, 90, 125 and 180 ~m. The major proportion of particles were retained by the 90 ~m sieve.
The dissolution rate of the 90-125 ~m fraction of the particles was estimated using the Paddle Method of U.S.
Pharmacopoeia XX as indicated above. The results were as follows:
15 Time (h) ~ Release 0.5 42
The optional excipient u~ed in association with the or each active ingredient will frequently have an active role to play following administration. For example, the excipien~ may be a surface-active agent which facilitates the transport of water into the particles, for example, sodium lauryl sulphate or a surface-active agent sold under the Trade MarX Tween. The e~cipient may also be an active transport agent such as, for example, glucose or one or more 3Q amino acids.
The e~cipient may comprise one or more organic acids which facilitate the dissolution of drugs which are poorly soluble in alkaline media. Such acids include, for example, ascorbic acid, citric acid, fumaric acid, malic acid, 35 succinic acid and tartaric acid. Bimilarly, the excipient may compris~ one or more basic materials which facilitate the aissolution of drugs which are poorly solu~le in acid media. Such basic material~ include sodium carbonate, ,:
~ ,',~ - ' ~ , .: :, . ::: : ~ .
o~
sodium citrate and sodium bicarbonate.
When the active ingredient is a drug, ~he micro-particle~ according to the invention may be formulated in a wide variety of forms. Pharmaceutical formulations according to the invention include pill6 and ta~lets, or example, coated tablets, effervescent tablets, chewable tablets, moulded tablets and melt tablets. The particles according to the invention may be compressed into tablets and optionally coated without any substantial change occurring in the particles. Furthermore, because of the micro-particulate nature of the particles they are unlikely to be significantly degraded or ground by any che~ing action.
Powder formulations according to the invention include dusting powders and douche powders.
The particles according to the invention may also be loaded into capsules which may be either soft gelatin capsules or hard gelatin capsules.
Other solid dosage forms include pessaries, rectal suppositories, vaginal tablets and vaginal inserts.
The particles according to the invention may also be used in implants and ocular inserts.
The powders can also be formulated in form~s ~uitable for topical application, such as, for example, as creams or ointments and for ,ransdermal delivery, for e2~mp1e, in the form of transdermal patches.
The micro-particlate powders according to the invention may also be used in the form of foams, gels, pastes, gums, mucilages and jellies~
Other suitable formulations incorporating the micro-particles according to the invention include inhalants, magmas, intrauterine devices, patches, biodegradable wound dressings and other topical dressings.
~he micro-particulate powders according to the invention are Pspecially ~uitable ~or formulation as liquids for oral, local or parenteral admini6tration. Thus, they can be formulated in liqu~d form for use as eye drops, nasal drops, ear drop~, suspensions, syrups, infusion ana ,"; . ~; , , .. ,, ,,, .. ,.~ ~ " .
' :~,' ,.' :.' ' , or ~
injectable ~olutions. The powders can also be formulated as nasal sprays. The injectable solutions i~clude intravenous, subcutaneous and intramuscular injectable solutions.
The oral suspensions and syrups according to the 5 invention are particularly suitable for use in geriatric and paediatric ~edicine. The liquids formed hav~ good mouth feel. Furthermore, because the polymer substantially coats the active ingredient, the coating masks any unpleasant taste.
A characteristic of good mouth feel also applies to chewable and effervescent tablets. Because of the micro-particulate nature of the powder one does not e~perience a granular sensation.
Preferred paediatric liquids according to the invention are suspensions or syrups of bronchial rela~ants, analgesics, anti-pyretics, anti-tussives~ anti-spa~modics, anti-nauseants, anti-histamines, anti-epileptics and antibiotics.
Other especially suitable liquid formulations according to th~ invention are non-aqueous suspensions ~f highly water soluble or water insoluble active ingredients. Suitable drugs for formulating in this way include de~tro~e~horphan, guaiphenesin and pseudoephedrine or a salt thereof or potassium chloride.
The liquid formulations have good shelf life and demonstrate stability both in chemical t~rms and in terms of dissolution rates up to thirty days~ It i~ e~t~mated that the shelf life can be as long as five year~.
In the liquid formulations according to the iQvention one can achieve a concentration of active ingredient of up to 1 g per 5 ml.
Heretofore many drugs have not been sta~le in liquid form, for example, analgesic~, necessita~ing a dosa~e regimen of every 4-6 hours. The liquids accoxding to the invention offer versatility and the possibili~y of twice daily administra~ion for a medicament such as, for example, analgesics, anti-histamine~ and bronc~ial relasant~
The taste masking ~ea~ure of ~he powders according to the invention is of significant importance in the area of : .,: ~.
- . :
S~L
paediatric medicine. However, this feature is of e~ual importance in veterinary medicine. For example, in the case of antibiotics such as erythromycin which have an extremely unpleasant bitter taste it is virtually impossible to administer such antibiotics orally to animals because it is not possible to successfully mask the bitter taste.
Accordingly, such known oral formulations are re]ected by anlmals .
The present invention therefore in one important aspect provides controlled release antibiotic formulations substantially free from the taste of said antibiotic for pharmaceutical or veterinary use which:
a) are in the form of powders according to the invention;
b) are in the form of non-aqueous suspensions of the powders according to the invention; or c) are in the form of reconstitutable aqueous suspensions of the powders according to the invention.
The powders according to the invention can be used in pre-mixes for animal feedstuffs and other feed additives.
In addition to drugs, nutritional supplements such as vitamins can be administered orally to animals using the powders according to the invention.
Suitable veterinary preparations according to the invention include veterinary feeds, boluses, drenches and washes.
In the agricultural field the powders according to the invention can also be used for preparation of controlled release herbicides and pesticides.
In the cosmetics field one use of the controlled release powders according to the invention is as sustained release fragrance particles for use in talcum powders, creams, lotions and other cosmetic preparations.
:, . -~i8~
- 13a -BRIEF DESCRIPTION OF THE FIGURES
-In the accompanying Figures:
Fig. 1 is an electron micrograph of microparticles according to the invention;
Fig. 2 is an electron micrograph of microparticles of the type depicted in Fig. 1 but from which the active ingredient has been leached by dissolution in water for 24 hours;
Fig. 3 is a graph of plasma levels t~g/ml) versus time after administration (hours) for a syrup according to the invention;
Fig. 4 is a graph representing percentage dissolution of a suspension according to the invention versus time over a fifteen week period;
Fig. 5 is a graph comparing plasma levels (~g/ml) versus time after administration (hours) of a syrup according to the invention (curve a) with a conventional syrup (curve b);
Fig. 6 is a graph comparing plasma levels (~g/ml) versus time after administration (hours) of two suspensions according to the invention (curves a and b) with a conventional syrup (curve c);
Fig. 7 is a graph comparing three suspensions according to the invention in terms of percentage dissolution versus time (hours~;
Fig. 8 is a graph representing percentage dissolution of a suspension according to the invention versus time over a tbirty ~eek period;
Fig. 9 is a graph comparing plasma levels (~g/ml) versus time after administration (hours) of a suspension according to the invention (curve a) with a conventional syrup (curve b);
Fig. 10 is a graph comparing plasma levels (~g~ml) versus time after administration (hours) of a :" '' " ,:
:- , ::: , ~2~5~
- 13b -suspension according to the invention (curve a) with a conventional syrup (curve b);
Fig. 11 is a graph comparing plasma levels (~g/ml~
versus time after administration (hours) of a suspension according to the invention (curve a~ with a conventional syrup (curve b);
Fig. 12 is a graph of percentage dissolution versus time (hours) for three suspensions according to the invention;
Fig. 13 is a graphic representation of observed sweetness for a chewing gum containing aspartame~
containing microparticles according to the invention with a conventional aspartame-containing chewing gum;
Fig. 14 is a graphic representation of percentage dissolution versus time (hours) of microparticles according to the invention ~curve a) relative to chewable tablets prepared therefrom ~curve b);
Fig. 15 is a graphic representation of percentage dissolution versus time ~hours) of microparticles according to the invention ~curve a) relative to melt tablets prepared therefrom (curve b); and Fig. 16 is a graphic representation of percentage dissolution versus time (hours) of microparticles according to the invention (curve a) relative to capsules prepared therefrom ~curve b).
Each of the particles of the controlled release powder accord7ng to the invention represents a true micromatrix with the active ingredient and optionally one or more excipients uniformly distributed therethrough as depicted in ' ~ . .- : ': ' ': : .
i8~
Fig. 1 of ~e accompanying drawings which is a half-tone drawing prepared from an electron micrograph of "pharmasomes"
containing theophylline and prepared as described in Example 1 below. The theophylline can be observed to form veins or a labyrinth throughout the polymeric material of the "pharmasome". Fig. 2 is a half-tone drawing prepared from an electron micrograph of the "pharmasomes" after the theophylline has been leached out by dissolution in water for 24 hours. One is left with a matrix structure of polymeric material.
The micromatrix nature of the particles can also be demonstrated by their dissolution profile. Referring, for example, to Examples 1 and 2 hereinbelow, it is found that the dissolution rate (D) is directly proportional to the square root of time (t) according to the following equation:
D a ~ t after an initial burst of release of active ingredient which is considered to be active ingredient lying close to the surface of the particles. The dissolution rate is dependent on the amount of active ingredient remaining in the particle matrix at any given time. Theoretically the last molecule of ac.ive ingredient never leaches out. The dissolution rate is assumed to reach 100~ at infinity.
The particles according to the invention also have a degree of p~rosity which can be calculated from the absolute density of the particles measured on a pycnometer. ~le dissolution rate of the particles according to the invention is also found to relate to the degree of porosity of said particles.
The microparticles according to the invention are to be distinguished from microcapsules in that in the la~ter the active ingredient is encapsulated by a polymer coating, , ~ ,, i8~353 whereas in the former the active ingredient i~ uniformly distributed throug~out the polymeric material as described above and as indicated in Figs. 1 and 2 of the accompanying drawings.
The invention will be further illustrated by the 5/ following e~amples. In the e~amples the dissolution rate o~
the various pharmaceutical formulations is measured by the Paddle Method of U.S. Pharmacopoeia XX at 37~C and 75 r.p.m., using 200 mg of sample per 900 ml of simulated intestinal fluid excluding enzymes~
Preparation of micro-particles containing theop~ylline Theophylline was ground in a motorised ball mill and then sieYed through a 38 ~m mesh sieve.
Cellulose acetate butyrate (CAB) was dissolved in acetone so as to give a concentration of CAB in acetone o~
15~ w/v.
Hexane (20 ml) was added to an aliquot of the CAB
solution (100 g) with constant stirring.
A portion of the sieved theophylline ~10 9~ was then ~0 added to the polymer solution under constant agitation to ensure an even dispersion of the theophylline. ~his product constituted an internal phase for the su~sequent emulsification step.
Magnesium stearate was dissolved in heavy mineral oil U.S. Pharmacopoeia so as to achieve a concentration of 1.5% w/v. This solution was used as an e~ternal liquid phase. 150 ml of the external liquid phase was decanted into a tall 600 ml beaker and the internal phase prepared above was added thereto. Emulsification was achieved using a Silverson mixer (Silverson is a Trade Mar~ a~ full speed for 2 minutes and thsn dropping the speed as re~uired to achieve the desired particle size.
The suspension of particles in the e~t~rnal phase was then introduced into a rotary evaporatvr and the acetone 35 removed under vacu~m. The suspension now consisted solely , ~
of polymer coated theophylline or "pharmasomes" suspended in the external liquid phase. On microscopic examination particle size was found to range from 10 to 180 ~m.
The particles were centrifuged down and the external phase decanted. The particles were then washed repeatedly with heptane to remove the external liquid phase. The final product was then filtered and dried at 45C for two hours.
The particles were then sieved with mesh sizes of 50, 90, 125 and 180 ~m. The major proportion of particles were retained by the 90 ~m sieve.
The dissolution rate of the 90-125 ~m fraction of the particles was estimated using the Paddle Method of U.S.
Pharmacopoeia XX as indicated above. The results were as follows:
15 Time (h) ~ Release 0.5 42
4 69 The particles were found to be tasteless with complete masking of the normally bitter taste of theophylline.
Preparation of Micro-particles containing paracetamol Example 1 was repeated except that 20 g of paracetamol was used in place of 10 g of theophylline. In the external liquid phase heavy mineral oil was replaced by light mineral oil. A major proportion of the particles had an average size of 90 ~m.
1~8~35~
The dissolution rate of the particles was determined and waS found to be as foll~s:
Time (h)% Release O O
0.5 43 ~9 The particles were found to be tasteless.
EXA~IPLF. 3 Preparation of micro-particles containing nifedipine.
Example 1 was repeated except that 16 g of nifedipine was used in place of theophylline. The inter~al phase consisted of Eudra~it RS 100 (Eudragit RS 100 is a Trade Mark~ in me~hanol at a concentration of 33% w/v. The external phase consisted o magnesium stearate in light mineral oil at a concentr~tion of 2.5 ~ w/v.
The dissolution rate of the particles formed was determined and was found to be as follows:
Time ~h) ~ Release 0.5 25 --~ 30 4 70 The particles were found to be ta6teless~
:. , -, :~. .
~ ' ',' ,"'',1,.,'~,' ' `'"' .. " ' ~L2 f~
EXAMPL~ 4 Preparation of micro-particles containing dextromethorphan hydrobromide.
Example 1 was repeated except that 10 g of theophylline was replaced by 10 g of dextromethorphan hydrobromide.
The dissolution rate of the particles was determined and was found to be as follows:
Time (h ) ~ Release 0.5 4S
6 9o Preparation of micro-particles containing 6acchari~ 60dium.
Example 1 was repeated except that theophylline was replaced by 6~5 g o saccharin sodium. The internal phase consisted of Ethocel (e~hyl cellulose~ ~Ethocel is a Trade Mark) 45 cps dissolved in ethanol so as to give a concentration vf 15% w/v. Saccharin sodium was added to 50 g of the polymer solution. The external liquid phase consisted of heavy mineral oil ~.S. Pharmacopoeia.
The dissolution rate of the particles was determlned and was found to be as follGws:
Time (sec.) ~ Release 3~ 15 8~
' " ~' - . :
'', ., ~ ' :
~' ': `
Preparation of micro-particles containing pseudephedrine hydrochloride.
The procedure of Example 1 was repeated except that the theophylline was replaced by 10 g of pseudoephedrine hydrochloride. 50 g of CAB was used which was dissolved in 20 ml of hexane so as to form the polymer solution.
The dissolution rate of the particles was determined and found to be as follows:
Time (h) % Release 0.5 35 ~ EXAMPLE 7 Preparation of micro-particles containing carbinoxamine maleate Example 1 was repeated llsing carbinoxamine maleate in place of theophylline. The dissolution rate of the particles was determined and found to be as follows:
Time (h) ; % Release 0.5 20 2 30 :-~!`
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Preparation of micro-particles containing guaiphenesin Example 1 was repeated except that theophylline was replaced by guaiphenesin (12.5 g). The polymer solution S consisted of Ethocel (Ethocel is a Trade Mark) (ethyl cellulose) 4 cps dissolved in ether so as to give a concentration of 25% w/v.
The external phase consisted of an aqueous solution of sorbitol 7Q% w/w (sorbitol solution B.P.) Upon removal of the solvent of the internal phase the particles or "pharmasomes" remained suspended in the sorbitol solution. The particles were harvested ~y decanting the sorbitol solution. The dissolution rate of the particles was determined and was found to be as follows:
Time ~h) % Release 0.5 50 ~ 61 ~ 76 Example 8 was rep~ated without decanting the ~orbitol solution. The suspension thereby obtained was flavoured and made up to the required strength for use as an oral suspension.
. . . : .
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Preparation of micro-particles containing erythromycin base Example 1 was repeated except that theophylline was replaced by erythromycin base. .The polymer used was a mixture of cellulose acetate butyrate and cellulose acetate phthalate in a ratio of 2:1. The dissolution rate of the particles was determlned and was found to be as follows:
Time (h) % Release 0.5 20 l 30 Other mixed polymers were used in the internal phase and proved successful in achieving a 100% release o~ the active inyredient from the particles ~ormed. ~xamples of mi~ed polymers used were as foll~ws:
Polymer Ratio Cellulose acetate butyrate/
polyvinylpyrrolidone 9:1 Cellulose acetate butyrate/
polyvinylpyrrolidone 4Ol Cellulose acetate butyrate/
Poly~methyl methacrylic acid) l:l ; Cellulose acetate butyrate/
Poly(methyl methacrylic acid) 3:1 .. :................... .
.. .. ... . .
., ~'..~ ' ~ ' '. ;.
.: , ". "' ' ' Polymer Ratio Eudragit RS/Eudragit RL 9:1 Ethocel/polyvinylpyrrolidone 9:1 -Preparation of theophylline syrup.
Particles prepared according to Example 1 were suspended in a sugar solution in water (65%) so as to obtain a theophyl}ine syrup containing 200 mg of theophylline per 5 ml of syrup. When administered orally the normally bitter taste of theophylline was completely masked.
P~ARMACOLOGICAL DATA
The plasma level profile of theophylline was obtained from the mean values obtained for tWQ subjects according to the data listed in Tables 1 and 2. Fig. 3 is a graph of plasma levels (mcg~ml) versus time after administration (hours~ for the 6yrup prepared according to Example 11 ba~ed on the values indicated ir Tables ~ and 2.
It will be ob6erved from the accompanying Fig. 3 and Tables 1 and 2 that the plasma level~ after 10 hour~ are'not significan~ly different from the plasma levels after one hour. Accordingly, the graph shows a prolonged absorption phase with the minimum of fluctuation of plasma levels over 10 hours. Normally, theophylline (rapid or i~mediate release) peaks at 2 hours. The apparent biolo~ical half-life of theophylline has been found to range from 4-9 hours.
One would normally expect half the peak pla~ma levels by 7 hours and appro~imately one third of the peak plasma levels by 10 hours.
These results suggest that the syrup prepared according ~o Example 11 could potentially be dosed quite safely at intervals of 12 hours i.e. twice daily. This is half the ~, dosage frequency of conventional non-sus~ained or immediat~
release theophylline.
~: - . ~ . - - .
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TABL~: 1 BLOOD LEVEL STUDY RESUL - SUM~Y OF P~ RMACOKI~ETIC DATA
THEOP~YLLI~E - S00 mg S . D.
PL~SMA L~TELS mcg/ml HOURS AFTER ADMINISTRATIO~
SUBJ 0.00 1.00 2.00 4.00 6.00 8.00 10.00 0.00 3.15 4.~5 4.70 3.45 3.00 2~85 2 0.00 2.90 4.85 5.05 5.00 4.30 4.~5 MEAN 0.00 3.03 4.55 4.88 4.23 3.65 3.55 ST DEV 0.00 0.18 0.42 0.25 1.10 0.92 0.99 * CV (96) 0.00 5.84 9.32 5.08 25.94 2s.la 27.89 ~X 0.00 3.15 4.85 5.05 5.00 4.30 4.25 MI~ 0.00 2.90 4.25 4~70 3.45 3.00 2.85 * Coefficient of varia ion :. , ~2~i80S~
- 2~ -THEOPHYLLINE - 600 mg S.D.
PHARMACOKINETIC PARAMETERS
AUC* PEAKING PEAK C(max)/C(min~ ELIMINATIO~ HALF-LIFE
(0.00- TIME HEIGHTAT 10.00 HOURSRATE ~ 1/2 10.00 H) T(ma~) C(max) K EL
134.67 4.00 4.70 1.65 0.Q5 14.51 243.13 4.00 5.05 1.19 0.03 ~0.74 ~EAN38.90 4.00 4.88 1.42 0.04 17.o2 ST DEV 5.98 0.00 0.25 0.33 0~01 4.41 CV (%) 15.3~ 0.00 5.08 22.~1 ~5.00 25.00 ~ASED ON MEA~ BLOOD LEVEL CURVE
MEA~ 4.00 4.88 1.37 * Area under curve 1~;80~jl Theophylline Suspension Theophylline microparticles "Pharmasomes" (prepared as per Example 1) were suspended in a liquid vehicle consisting of:
70~ Sorbitol Solution89.9~ by weight Glycerin 10.0~ by weight Polysorbate-800.1% by weight (Trade Mark) 0 60 as to give a suspension containing 200 mg th~ophylline per 5 ml.
Samples of the suspension were stored at room temperature and tested at intervals to determine the stability of the "pharmasomes" in suspension.
At the time of preparation the assayed content of theophylline was 18B.4 m~/5 ml and after 15 weeks it was 190.5 mg/5 ml indicating that there had ~een no chemical breakdown of th~ drug.
The dissolution rate was also tested over a 15 week period and the results are ~ummarised in Table 3 and Fig. 4.
In summary the data shows that the suspension retains its potency and dissolution characteristics for at least 15 weeks after preparation.
PHARMACOLCGICAL DA~A
The suspension prepared as per Example 1~ was tested in a 6iX subject bioava.ilability study at a dose o 720 mg ~18 ml~ versus a conventional ~yrup (Somop~ylline) given as ~wo doses of 360 mg at 0 and 6 hours. The results are summ~rised in Table 4 and Fig. 5~ In ~ig. 5 the curve (a~
represents the suspension of E~ample 12 and curve (b) ~he Somophylline syrup used as reference.
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. ~ : :: -: ,. ,,, ,., :
TABL~ 3 THEOPHYLLI~ SUSPE~SIO~ OF EXAMPLE 12 (200 mg/5ml ) STABILITY OF DISSOLUTIO~
Percentage Disolution TIME ( HOURS ) 0.00 1.00 2.00 3.00 4.00 5 ~ 00 6.00 24.00 O Wks 0.00 43.30 59.~0 7S.~0 80.00 84.30 87.70 100.0Q3 WXs 0~00 39.50 S9.10 70.70 77.~0 84.~0 87.70 99.50
Preparation of Micro-particles containing paracetamol Example 1 was repeated except that 20 g of paracetamol was used in place of 10 g of theophylline. In the external liquid phase heavy mineral oil was replaced by light mineral oil. A major proportion of the particles had an average size of 90 ~m.
1~8~35~
The dissolution rate of the particles was determined and waS found to be as foll~s:
Time (h)% Release O O
0.5 43 ~9 The particles were found to be tasteless.
EXA~IPLF. 3 Preparation of micro-particles containing nifedipine.
Example 1 was repeated except that 16 g of nifedipine was used in place of theophylline. The inter~al phase consisted of Eudra~it RS 100 (Eudragit RS 100 is a Trade Mark~ in me~hanol at a concentration of 33% w/v. The external phase consisted o magnesium stearate in light mineral oil at a concentr~tion of 2.5 ~ w/v.
The dissolution rate of the particles formed was determined and was found to be as follows:
Time ~h) ~ Release 0.5 25 --~ 30 4 70 The particles were found to be ta6teless~
:. , -, :~. .
~ ' ',' ,"'',1,.,'~,' ' `'"' .. " ' ~L2 f~
EXAMPL~ 4 Preparation of micro-particles containing dextromethorphan hydrobromide.
Example 1 was repeated except that 10 g of theophylline was replaced by 10 g of dextromethorphan hydrobromide.
The dissolution rate of the particles was determined and was found to be as follows:
Time (h ) ~ Release 0.5 4S
6 9o Preparation of micro-particles containing 6acchari~ 60dium.
Example 1 was repeated except that theophylline was replaced by 6~5 g o saccharin sodium. The internal phase consisted of Ethocel (e~hyl cellulose~ ~Ethocel is a Trade Mark) 45 cps dissolved in ethanol so as to give a concentration vf 15% w/v. Saccharin sodium was added to 50 g of the polymer solution. The external liquid phase consisted of heavy mineral oil ~.S. Pharmacopoeia.
The dissolution rate of the particles was determlned and was found to be as follGws:
Time (sec.) ~ Release 3~ 15 8~
' " ~' - . :
'', ., ~ ' :
~' ': `
Preparation of micro-particles containing pseudephedrine hydrochloride.
The procedure of Example 1 was repeated except that the theophylline was replaced by 10 g of pseudoephedrine hydrochloride. 50 g of CAB was used which was dissolved in 20 ml of hexane so as to form the polymer solution.
The dissolution rate of the particles was determined and found to be as follows:
Time (h) % Release 0.5 35 ~ EXAMPLE 7 Preparation of micro-particles containing carbinoxamine maleate Example 1 was repeated llsing carbinoxamine maleate in place of theophylline. The dissolution rate of the particles was determined and found to be as follows:
Time (h) ; % Release 0.5 20 2 30 :-~!`
... .
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. :-.
.,.,. . .: ,.
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Preparation of micro-particles containing guaiphenesin Example 1 was repeated except that theophylline was replaced by guaiphenesin (12.5 g). The polymer solution S consisted of Ethocel (Ethocel is a Trade Mark) (ethyl cellulose) 4 cps dissolved in ether so as to give a concentration of 25% w/v.
The external phase consisted of an aqueous solution of sorbitol 7Q% w/w (sorbitol solution B.P.) Upon removal of the solvent of the internal phase the particles or "pharmasomes" remained suspended in the sorbitol solution. The particles were harvested ~y decanting the sorbitol solution. The dissolution rate of the particles was determined and was found to be as follows:
Time ~h) % Release 0.5 50 ~ 61 ~ 76 Example 8 was rep~ated without decanting the ~orbitol solution. The suspension thereby obtained was flavoured and made up to the required strength for use as an oral suspension.
. . . : .
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Preparation of micro-particles containing erythromycin base Example 1 was repeated except that theophylline was replaced by erythromycin base. .The polymer used was a mixture of cellulose acetate butyrate and cellulose acetate phthalate in a ratio of 2:1. The dissolution rate of the particles was determlned and was found to be as follows:
Time (h) % Release 0.5 20 l 30 Other mixed polymers were used in the internal phase and proved successful in achieving a 100% release o~ the active inyredient from the particles ~ormed. ~xamples of mi~ed polymers used were as foll~ws:
Polymer Ratio Cellulose acetate butyrate/
polyvinylpyrrolidone 9:1 Cellulose acetate butyrate/
polyvinylpyrrolidone 4Ol Cellulose acetate butyrate/
Poly~methyl methacrylic acid) l:l ; Cellulose acetate butyrate/
Poly(methyl methacrylic acid) 3:1 .. :................... .
.. .. ... . .
., ~'..~ ' ~ ' '. ;.
.: , ". "' ' ' Polymer Ratio Eudragit RS/Eudragit RL 9:1 Ethocel/polyvinylpyrrolidone 9:1 -Preparation of theophylline syrup.
Particles prepared according to Example 1 were suspended in a sugar solution in water (65%) so as to obtain a theophyl}ine syrup containing 200 mg of theophylline per 5 ml of syrup. When administered orally the normally bitter taste of theophylline was completely masked.
P~ARMACOLOGICAL DATA
The plasma level profile of theophylline was obtained from the mean values obtained for tWQ subjects according to the data listed in Tables 1 and 2. Fig. 3 is a graph of plasma levels (mcg~ml) versus time after administration (hours~ for the 6yrup prepared according to Example 11 ba~ed on the values indicated ir Tables ~ and 2.
It will be ob6erved from the accompanying Fig. 3 and Tables 1 and 2 that the plasma level~ after 10 hour~ are'not significan~ly different from the plasma levels after one hour. Accordingly, the graph shows a prolonged absorption phase with the minimum of fluctuation of plasma levels over 10 hours. Normally, theophylline (rapid or i~mediate release) peaks at 2 hours. The apparent biolo~ical half-life of theophylline has been found to range from 4-9 hours.
One would normally expect half the peak pla~ma levels by 7 hours and appro~imately one third of the peak plasma levels by 10 hours.
These results suggest that the syrup prepared according ~o Example 11 could potentially be dosed quite safely at intervals of 12 hours i.e. twice daily. This is half the ~, dosage frequency of conventional non-sus~ained or immediat~
release theophylline.
~: - . ~ . - - .
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TABL~: 1 BLOOD LEVEL STUDY RESUL - SUM~Y OF P~ RMACOKI~ETIC DATA
THEOP~YLLI~E - S00 mg S . D.
PL~SMA L~TELS mcg/ml HOURS AFTER ADMINISTRATIO~
SUBJ 0.00 1.00 2.00 4.00 6.00 8.00 10.00 0.00 3.15 4.~5 4.70 3.45 3.00 2~85 2 0.00 2.90 4.85 5.05 5.00 4.30 4.~5 MEAN 0.00 3.03 4.55 4.88 4.23 3.65 3.55 ST DEV 0.00 0.18 0.42 0.25 1.10 0.92 0.99 * CV (96) 0.00 5.84 9.32 5.08 25.94 2s.la 27.89 ~X 0.00 3.15 4.85 5.05 5.00 4.30 4.25 MI~ 0.00 2.90 4.25 4~70 3.45 3.00 2.85 * Coefficient of varia ion :. , ~2~i80S~
- 2~ -THEOPHYLLINE - 600 mg S.D.
PHARMACOKINETIC PARAMETERS
AUC* PEAKING PEAK C(max)/C(min~ ELIMINATIO~ HALF-LIFE
(0.00- TIME HEIGHTAT 10.00 HOURSRATE ~ 1/2 10.00 H) T(ma~) C(max) K EL
134.67 4.00 4.70 1.65 0.Q5 14.51 243.13 4.00 5.05 1.19 0.03 ~0.74 ~EAN38.90 4.00 4.88 1.42 0.04 17.o2 ST DEV 5.98 0.00 0.25 0.33 0~01 4.41 CV (%) 15.3~ 0.00 5.08 22.~1 ~5.00 25.00 ~ASED ON MEA~ BLOOD LEVEL CURVE
MEA~ 4.00 4.88 1.37 * Area under curve 1~;80~jl Theophylline Suspension Theophylline microparticles "Pharmasomes" (prepared as per Example 1) were suspended in a liquid vehicle consisting of:
70~ Sorbitol Solution89.9~ by weight Glycerin 10.0~ by weight Polysorbate-800.1% by weight (Trade Mark) 0 60 as to give a suspension containing 200 mg th~ophylline per 5 ml.
Samples of the suspension were stored at room temperature and tested at intervals to determine the stability of the "pharmasomes" in suspension.
At the time of preparation the assayed content of theophylline was 18B.4 m~/5 ml and after 15 weeks it was 190.5 mg/5 ml indicating that there had ~een no chemical breakdown of th~ drug.
The dissolution rate was also tested over a 15 week period and the results are ~ummarised in Table 3 and Fig. 4.
In summary the data shows that the suspension retains its potency and dissolution characteristics for at least 15 weeks after preparation.
PHARMACOLCGICAL DA~A
The suspension prepared as per Example 1~ was tested in a 6iX subject bioava.ilability study at a dose o 720 mg ~18 ml~ versus a conventional ~yrup (Somop~ylline) given as ~wo doses of 360 mg at 0 and 6 hours. The results are summ~rised in Table 4 and Fig. 5~ In ~ig. 5 the curve (a~
represents the suspension of E~ample 12 and curve (b) ~he Somophylline syrup used as reference.
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. ~ : :: -: ,. ,,, ,., :
TABL~ 3 THEOPHYLLI~ SUSPE~SIO~ OF EXAMPLE 12 (200 mg/5ml ) STABILITY OF DISSOLUTIO~
Percentage Disolution TIME ( HOURS ) 0.00 1.00 2.00 3.00 4.00 5 ~ 00 6.00 24.00 O Wks 0.00 43.30 59.~0 7S.~0 80.00 84.30 87.70 100.0Q3 WXs 0~00 39.50 S9.10 70.70 77.~0 84.~0 87.70 99.50
5 Wks 0.00 40.00 ~0.10 69.80 78.20 85.10 ~5.90 g9.00 7 Wks 0.00 42.00 63.00 79.20 8~.20 90.00 90.60 100.0 15 Wks 0.00 45.80 60.90 72.5~ 80.70 8~.90 88.00 99~90 . , , ,. ~ : ~ :
~: . . : :
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MEAN THEOPHYLLI~E PLASMA CONCENTRATIO~ (mcg/ml) T~EOPHYLLI~E
TIME ~h) SOMOPHYLLI~E SUSPE~SION
0.0 0.0 0.0 0-5 7.9~ 1.38 1.0 10.24 3.57 1.5 8.68 6.09 2.0 8.17 7.31 10 3.0 7.68 8.81 4.0 5.93 9.75
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~. :
MEAN THEOPHYLLI~E PLASMA CONCENTRATIO~ (mcg/ml) T~EOPHYLLI~E
TIME ~h) SOMOPHYLLI~E SUSPE~SION
0.0 0.0 0.0 0-5 7.9~ 1.38 1.0 10.24 3.57 1.5 8.68 6.09 2.0 8.17 7.31 10 3.0 7.68 8.81 4.0 5.93 9.75
6.0 5.25 g.l7 6.5 10.94 9.75
7.0 11.20 9.~8 15 7.5 11.75 ~.84
8.0 12.37 9.14
9.0 11.98 8.37
10.0 10.7~ 7.52 12.0 8.~9 6.26 _ The data clearly sh~ws that although the theophylline suspension of ~xample 12 is slightly less bioavailable (~7%) than the refer~nce, the time to peak and the duration of significant blood levels is indicative of a twice dail~
dosage regimen. the usual dosage regimen for theophylline is four times per aay.
.; , :
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. . ,: ~ , - , , ~XAMPLES 13 and 14 Theophylline microparticles "phaxmasomes" were prepared according to Example 1 and screened into two fractions:
Example 13 - microparticles having an average particle size of less than 30 microns Example 14 - microparticles havin~ an average particle siæe of greater than 90 microns.
The "pharmasomes" were suspended in a vehi~le made up o:
~ b~ welght 70~ Sorbitol Solution 85.3 Avicel RC 591 (Trade Mark~ 0.7 Potassium Sorbate 0.3 Titanium Dioxide 25% 2.7 (in 70% Sorbitol) Simethicone (Trade Mark) 10~ Emulsion 0.01 Glycerin 10.8 Citric Acid 0.3 Soaium Lauryl Sulphate 0.04 so as to produce a suspension containing 300 mg Theophylline per 5 ml.
PHARMACOLOGI~AL DATA
The suspensions of Examples 13 and 14 were tested for bioavailability in four subjects at a dose of 690 mg ~11.5 ml) for the syrups of Example~ 13 and 14 ver~us a conventional syrup (Somophylline) given as two do~e~ of 320 mg ~t 0 and 6 hours. The results are ~ummarised in Tahle 5 and Fig. ~. The Fig. 6, the curve (a) represents the suspension of Example 13, the curve ~b) the suspen~ion ~f Example 14 and the curve (c) the Somophylline ~yrup used as reference.
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~2~(35~
MEAN THEOPHYLLINE PLASMA CO~CENTRATIONS - mcg/ml Suspension Suspension - o~ of Time (h) Somophylline Example 13 Example 14 0.5 ~.53 2.65 l.g8 1 10.14 5.08 ~.07 1.5 9.~1 6.94 6.~5 2 8.64 7.16 ~.81 3 7.74 6.93 7~67 4 ~.82 7.7~ 7.~g 6 5.21 6.4~ 7.08 6.5 8.79 7 1~.00 6.74 ~.g3 7.5 1~.01 - -8 12.11 6.03 6~47 9 11.61 - ~
10.17 5~5 5.82 12 8.07 4.06 5.02 -2.77 4.04 18 -2.22 ~.67 21 2.44 1.79 1.95 2~ 1.55 1.2~ 1.59 The results confirm the finding~ for Example 12 as ~5 indicated in Fig. 7, wherein cu~ve (a) represents the suspension of Example 12, curve ~b) the ~uspension of Example 13 and curve ~c~ the suspension of Example 14.
.f ~2~
.
PARACETAMO~ SUSPE~SIO~
Paracetamol "pharmasomes" prepared as per E~ample 2 were suspended in a liquid vehicle prepared a6 per Example 12 to give a suspension containing 300 mg of Paracetamol per 5 ml.
The suspension was stored at room temperature and tested at intervals for 30 weeks.
At the time of preparation the assayed content was 299.8 mg (paracetamol) per 5 ml and after 30 weeks was 2~7.9 mg/5 ml indicating that there was no significant loss of activity.
During the above time period the dissolution was also tested and the results are ~iven in Table 6.
PERCENTAGE DISSOLUTIO~
TIME (h) 0.00 1.00 2.00 3.00 4.00 5.00 6000 O Wks O.O0 56.50 70.60 7~.O0 81.30 83.80 86 D 3 0 202 Wks 0.00 58.40 71.80 80~40 ~31.70 B5.40 87.90 5 WXs 0.00 5~.90 72.50 77.20 80.40 ~3.~0 ~4.40 0.00 5~.30 69.10 7~.~0 ~0.30 82.90 84.7~
15Wks 0.00 58.90 69.30 76.78 80.60 8~.80 84.30 30W~s 0.00 58.10 71.50 76.90 81.90 84.70 87.30 .
A graphic representation of these results is shown in Fig. 8.
,..,~
.. -- - . - - ,.:- ::
:-~-.
35~L
The ~u pen~ion was tested or bioavailability i~ 6 subject~ a~ a do~e o 1000 mg versus a reference solution (Do~ol-Eli~ir (Dozol is a Trade Mark)) which wa~ given as two divided do~es of 500 mg. The results are given in Table 7.
MEAN PARACETAMOL PLASMA CONCENTRATIONS (mcg/ml) Reference Suspension of Time (h) (DOZOL) Example 15 0.0 -0.5 7~74 3.44 1.0 6.49 6~05 2.0 4.14 7.36 3.0 3.04 5.80 4.0 2.04 4.60 6.~ 1.08 3.15 6.5 5.33 2.~5 7.0 5.88 2.26 8.0 ~.79 1.~
9.0 4.C0 1.63 10.0 3.05 1.44 1~.0 1.81 1.06 14.0 1.10 0.72 16.0 0.69 0.49 24.0 0.18 0.14 A graphic representation is given in Fig. 9, wherein curve (a~ represents the suspension of ~xample 15 and curve (b). the conv~ntional Ellxir.
The data shows ~hat although the suspension of ~xample 15 is slightly less bioavailable (90~) than the reference, the blood level is maintained for almost twice a~ long equating ~o halving of the dosage frequency.
, , ' : ,, :
., '' . ~ : ' :
~2~
EX~MPLE 16 "Pharmasomes" were prepared a~ per Example 2 and suspended in liquid as per Example 1~ sc a~ to give a suspension cont.aining 320 mg per 5 ml. This suspension was tested fGr bioavailability in 6 su~jects using a conventional (Tylenol (Trade Mark)) Elixir as reference. A single dose of paracetamol "pharmasomes" 2000 mg (31.25 ml) was administered and two doses of Tylenol (1000 mg) at 0 and 6 hours. The results are given in Table 8.
TABhE 8 MEA~ PARACETAMOL PLASMA CONCE~TRATIO~S (mcg/ml) Reference Suspension of TIME (~) ~Tylenol Elixir) Example 16 -0.0 0.0 0.0 0.5 14.~3 ~.27 1.0 14.05 15.09 2.0 6.69 14.34 3.0 6.95 13.~4 4.0 ~.43 11.53 4.5 15.53 9.52 5.0 14.67 8.08 6.0 12.72 6.10 7.~ 8.92 4.43 8.0 6.61 3.54 ~5 10.0 3.64 2.~3 12.0 2.17 1.10 14.0 1.31 1.10 16.0 0.77 0.68 24~0 0.02 ~.17 os~ ~
The results are presented graphically in Figure 10 wherein curve (a) corresponds to the suspen~ion of Example 16 and curve (b) corresponds to the reference Eli~ir. The prolonged absorption profile again can be seen with no significant loss in bioavailability, indicating a reduced dosage frequency.
"Pharmasomes" were prepared as per Example 2 with cellulose acetate being substituted for the cellulose acetate butyrate. The suspension was prepared as per Example 16. The suspension was tested in a 6 subject bioavailability study at a single dose of 2000 mg against a reference solution (Tylen~l Elixir) giv~n as two 1000 mg doses. The results are given in Table 9.
MEA~ PARACETAMOL PLAS~A CO~CENTRATIO~S (mcg/ml~
Tylenol Eli~ir Suspension of TIME ~h)1 g x 2 Example 17 2 9 x 1 r 0.0 0.00 0.0 0.5 12.30 5.11 0.75 12.88 7.07 1.0 12.~9 9.1 1.5 10.17 12.01 2.0 8.19 12.47 3.0 6.00 11~1 4.0 ~.35 4,5 13.S4 ~.37 4.75 1~.00 8.
5.0 13.02 7.55 5.5 13.09 6.57 ~L268051 TABLE 9 (contd) Tylenol Eli2ir ~uspension of TIME (h) 1 9 ~ 2 Example 17 2 g ~ 1 6.0 11.20 ~.71 7.0 ~.17 4.54 8.0 5.98 3.76 10.0 3.4~ 6 12.0 1.98 1.6 14.0 1.~4 l.Q3 16.0 0.82 0.83 2~.0 0.~6 0.39 The figures given in Table ~ and accompanying Figs. 11 and 12 again demonstrate the prolonged absorption nature of the product. In Fig. 11 curve (a) corresp~nds to the ~uspension of Example 19 and curve (b) the reference Tylenol Elixir. In Fig. 12 curve (a) corresponds to the suspension of Example 15, curve (h) to the suspension of Example 16 and curve (c) to the suspension of Example 17.
EX~MPLE 18 Chewing gum containing microparticles of Aspartame were prepared in the following manner.
An internal phase was prepared by dissolving ethylcellulose (45 cps~ in sufficient ethanol to produce ~00 g of ~olution. 100 9 o~ Aspartame (Particle si~e less than 60 microns) was di~persed in 300 9 of acetone. The two liquids were t~en mi~ed by mechanical a~itation. The external phase was prepared according to E~ample 1, 2 litres ~, being required. The internal a~d external phase were mixed , ., ~
: .
~268~91 by mechanical agitation and then passed through an emulsifier. The emulsion was placed in a vacuum and the solvents tacetone and ethanol) evaporated. The Aspartame/
ethylcellulose microparticles were harvested by centrifugation.
To evaluate the Aspartame-containing "pharmasomes", unsweetened chewing gum was used. Pure Aspartame powder and the prepared "pharmasomes" were folded into the gum so as to give a 0.2~ concentration of Aspartame. Both types of gum were chewed by a panel of 24 volunteers in a blind, crossover manner. The volunteers were asked to report their perception of the intensity (on a scale of 0 to 10) and duration of sweetness. On average the duration of sweetness for the pure Aspartame-containing gum was 10 minute~. The gum containing the "pharmasomes" was perceived as being less intensely sweet but observably sweet for 30 minutes on average. The results are indicated in Fig. 13 which is a graphic representation of the Aspartame sweetnes~ test giving mean values for the testing panel of 24 volunieers.
CHEWABLE TABLET CO~TAI~I~G PARACETAMOL
The following materials were mixad together:
1000 g Paracetamol "pharmasomes" - as per Example 2 (equivalent to 500 g of Paracetamol) 250 g Dipac (Trade Mark) (Sucrose 97~, Dextrins 3%) 250 g Mannitol S g Colloidal Silicon Dioxide 25 g Maize Starch 20 g Magneqiu~l Stearate 15 g Orange Flavour 35 g Orange Colour , ': :. ,, : :
~X~i8~35~
The blend was compressed at a weight of 960 ~9 into tablets each containing 300 mg of Paracetamol. The tablets were pleasant to chew and the dissolution characteristics of the "pharma~omes" were unchanged as shcwn in Table 10 and Fig. 14.
DISSOLUTI0~ RATE
TIME (h) "PHARMASOMES" TABLE~S
1 58.7% 59.
3 79.~ 80.7 6 9~.6% 95.
-In Fig. 14 curve ~a) corresponds to the dissolution pattern of the "pharmasomes" of B~ample 19 and curve (b) to the chewable tablets prepared therefrom.
EXAMPL~ 20 "MELT" TABLETS CO~TAI~l~G PA~ACETAMOL
Melt tablets are similar to chewable table~s except that they disintegrate rapidly in the mouth and do not need to be chewed. Such tablets were prepared as foll~ws:
' ~
,.
' " ' ' -~26l~
- 3~ -1000 g Paracetamol "pharmasomes" ~a~ per E~ample 2) (equivalent to 500 g Paracetamol) 50 g Mannitol 250 g Microcrystalline Cellulose 30 9 Strawberry Flavour 15 g Red Colour 60 g Cross-Povidone 5 g Sodium Lauryl Sulphate 30 g Carboxymethyl starch 15 g Magnesium Stearate 15 9 Talc The blend was compressed at a weight of 8~2 mg to give tablets each containing 300 mg o Paracetamol. ~he disintegration time of the tablets was less than 30 saconds and the dissolution rate of the "pharmasomes" was unchanged as indicated in Table 11 and Fig. 15.
-DISSOLUTIO~ RATE
TIME ~h) ~P~ARMhSOMES" TABLETS
1 58.7% ~0.1 3 79.8~ 81.2 6 95.6~ 95.5~
In Fig. 15 curve (a) corresponds to the dissolution pattern for the "pharmasomes" of Example 20 and curve (b) to the melt tablets prepared therefrom.
~2~i8~5~
EY~MPLE 21 CAPSULES CONTAINI~G NIFEDIPI~E
"Pharmasomes" were prepared as per Example 3. By nature they were free flowing and only 0.5% magnesium stearate needed to be added to prevent sticking during capsule filling. The equivalent of 20 mg of ~ifedipine was encapsulated into si~e ~o. 4, two piece hard gelatin capsules. The dissolution rate xemained unchan~ed as shown in Table 12 and Fiy. 16. In Figure 16 curve (a) corresporlds to the dissolution pattern for the "pharmasomes" of E~ample 21 and curve (b) to the capsules prepared thereÇrom.
TAB~E 1~
DISSOLUTIO~ ~TE
-15 TIM~ (h) ~'PHA~MASO~ES" _ CAPS~LES
0.5 42.6% 41.7%
1 56.1% 54~3%
3 7~.6% 73.6 85.9% ~ %
8 . ~8.7% 97.~%
Although not wishing to be bound by any theoretical explanation of the invention, it i8 believed tha~ the polymer ~ubstantially but not entirely coats the active ingredient, because a 100% release of active in~redient can 25 be achieved even when an insoluble polymer is used.
.
: .
- . ~
~6805~
NO~-AQ~EOUS SUSPE~5ION OF POTASSIUM CHLORIDE
A non aqueous suspension of potassium chloride -containing "pharmasomes" was prepared, having a 5 concentration of potassium chloride of 300 mg/~ ml and which in addition to the "pharmasomes" contained the following ingredients:
Oil ~SP (Soy, cotton seed) 425.00 ml Sorbitol Powder USP 100.00 g 10 Aerosil R 972 (Trade Mark) 12.50 g Tenox GT 1 (Trade Mark) 0.20 g Citric acid 0.025 g Chocolate flavour # 3~6676 0.52 ml Chocolate mint flavour ~ 395496 0.37 ml 15 Flavour enhancer l.G0 g Br~wn Lake dye 0.05 Titanium dioxide 0.10 g The total volume of the suspension without the "pharmasomes" was 500 ml.
The Sorbitol powder USP and Aerosil R 972 (Trade Mark~
were dry blended and t~em ball milled with t~e oil mi~ ~o produce an even dispersion. The Tenox GT 1 (Trade Mark) which is an anti-oxidant and the citric acid were dry blended and th~n di~persed with constant agitatior. into the - 25 oil mixture~ The chocolate and chocolate mint flavour~ and the flavour enhancer were then dlspersed into the oil mixture. ~inally, the Brown La~e dye and ~he titanium dioxide were adaed to the oil mixture and the resultant mixture was agitated for one hour to ensure even dispersion of the various ingredients. An amount of potassium chloride - con~aining "pharmasomes", prepared according to the procedure described in Example 1 but substi~uti~g potassium chloride for theophylline, and e~uivalent to 300 mg potassium chloride per 5 ml was blended tog~ther with the 3`5 oil mixture re~ulting in an evenly mixed su~pension.
"" . .
dosage regimen. the usual dosage regimen for theophylline is four times per aay.
.; , :
, :: ~. " ~ :;
. . ,: ~ , - , , ~XAMPLES 13 and 14 Theophylline microparticles "phaxmasomes" were prepared according to Example 1 and screened into two fractions:
Example 13 - microparticles having an average particle size of less than 30 microns Example 14 - microparticles havin~ an average particle siæe of greater than 90 microns.
The "pharmasomes" were suspended in a vehi~le made up o:
~ b~ welght 70~ Sorbitol Solution 85.3 Avicel RC 591 (Trade Mark~ 0.7 Potassium Sorbate 0.3 Titanium Dioxide 25% 2.7 (in 70% Sorbitol) Simethicone (Trade Mark) 10~ Emulsion 0.01 Glycerin 10.8 Citric Acid 0.3 Soaium Lauryl Sulphate 0.04 so as to produce a suspension containing 300 mg Theophylline per 5 ml.
PHARMACOLOGI~AL DATA
The suspensions of Examples 13 and 14 were tested for bioavailability in four subjects at a dose of 690 mg ~11.5 ml) for the syrups of Example~ 13 and 14 ver~us a conventional syrup (Somophylline) given as two do~e~ of 320 mg ~t 0 and 6 hours. The results are ~ummarised in Tahle 5 and Fig. ~. The Fig. 6, the curve (a) represents the suspension of Example 13, the curve ~b) the suspen~ion ~f Example 14 and the curve (c) the Somophylline ~yrup used as reference.
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~2~(35~
MEAN THEOPHYLLINE PLASMA CO~CENTRATIONS - mcg/ml Suspension Suspension - o~ of Time (h) Somophylline Example 13 Example 14 0.5 ~.53 2.65 l.g8 1 10.14 5.08 ~.07 1.5 9.~1 6.94 6.~5 2 8.64 7.16 ~.81 3 7.74 6.93 7~67 4 ~.82 7.7~ 7.~g 6 5.21 6.4~ 7.08 6.5 8.79 7 1~.00 6.74 ~.g3 7.5 1~.01 - -8 12.11 6.03 6~47 9 11.61 - ~
10.17 5~5 5.82 12 8.07 4.06 5.02 -2.77 4.04 18 -2.22 ~.67 21 2.44 1.79 1.95 2~ 1.55 1.2~ 1.59 The results confirm the finding~ for Example 12 as ~5 indicated in Fig. 7, wherein cu~ve (a) represents the suspension of Example 12, curve ~b) the ~uspension of Example 13 and curve ~c~ the suspension of Example 14.
.f ~2~
.
PARACETAMO~ SUSPE~SIO~
Paracetamol "pharmasomes" prepared as per E~ample 2 were suspended in a liquid vehicle prepared a6 per Example 12 to give a suspension containing 300 mg of Paracetamol per 5 ml.
The suspension was stored at room temperature and tested at intervals for 30 weeks.
At the time of preparation the assayed content was 299.8 mg (paracetamol) per 5 ml and after 30 weeks was 2~7.9 mg/5 ml indicating that there was no significant loss of activity.
During the above time period the dissolution was also tested and the results are ~iven in Table 6.
PERCENTAGE DISSOLUTIO~
TIME (h) 0.00 1.00 2.00 3.00 4.00 5.00 6000 O Wks O.O0 56.50 70.60 7~.O0 81.30 83.80 86 D 3 0 202 Wks 0.00 58.40 71.80 80~40 ~31.70 B5.40 87.90 5 WXs 0.00 5~.90 72.50 77.20 80.40 ~3.~0 ~4.40 0.00 5~.30 69.10 7~.~0 ~0.30 82.90 84.7~
15Wks 0.00 58.90 69.30 76.78 80.60 8~.80 84.30 30W~s 0.00 58.10 71.50 76.90 81.90 84.70 87.30 .
A graphic representation of these results is shown in Fig. 8.
,..,~
.. -- - . - - ,.:- ::
:-~-.
35~L
The ~u pen~ion was tested or bioavailability i~ 6 subject~ a~ a do~e o 1000 mg versus a reference solution (Do~ol-Eli~ir (Dozol is a Trade Mark)) which wa~ given as two divided do~es of 500 mg. The results are given in Table 7.
MEAN PARACETAMOL PLASMA CONCENTRATIONS (mcg/ml) Reference Suspension of Time (h) (DOZOL) Example 15 0.0 -0.5 7~74 3.44 1.0 6.49 6~05 2.0 4.14 7.36 3.0 3.04 5.80 4.0 2.04 4.60 6.~ 1.08 3.15 6.5 5.33 2.~5 7.0 5.88 2.26 8.0 ~.79 1.~
9.0 4.C0 1.63 10.0 3.05 1.44 1~.0 1.81 1.06 14.0 1.10 0.72 16.0 0.69 0.49 24.0 0.18 0.14 A graphic representation is given in Fig. 9, wherein curve (a~ represents the suspension of ~xample 15 and curve (b). the conv~ntional Ellxir.
The data shows ~hat although the suspension of ~xample 15 is slightly less bioavailable (90~) than the reference, the blood level is maintained for almost twice a~ long equating ~o halving of the dosage frequency.
, , ' : ,, :
., '' . ~ : ' :
~2~
EX~MPLE 16 "Pharmasomes" were prepared a~ per Example 2 and suspended in liquid as per Example 1~ sc a~ to give a suspension cont.aining 320 mg per 5 ml. This suspension was tested fGr bioavailability in 6 su~jects using a conventional (Tylenol (Trade Mark)) Elixir as reference. A single dose of paracetamol "pharmasomes" 2000 mg (31.25 ml) was administered and two doses of Tylenol (1000 mg) at 0 and 6 hours. The results are given in Table 8.
TABhE 8 MEA~ PARACETAMOL PLASMA CONCE~TRATIO~S (mcg/ml) Reference Suspension of TIME (~) ~Tylenol Elixir) Example 16 -0.0 0.0 0.0 0.5 14.~3 ~.27 1.0 14.05 15.09 2.0 6.69 14.34 3.0 6.95 13.~4 4.0 ~.43 11.53 4.5 15.53 9.52 5.0 14.67 8.08 6.0 12.72 6.10 7.~ 8.92 4.43 8.0 6.61 3.54 ~5 10.0 3.64 2.~3 12.0 2.17 1.10 14.0 1.31 1.10 16.0 0.77 0.68 24~0 0.02 ~.17 os~ ~
The results are presented graphically in Figure 10 wherein curve (a) corresponds to the suspen~ion of Example 16 and curve (b) corresponds to the reference Eli~ir. The prolonged absorption profile again can be seen with no significant loss in bioavailability, indicating a reduced dosage frequency.
"Pharmasomes" were prepared as per Example 2 with cellulose acetate being substituted for the cellulose acetate butyrate. The suspension was prepared as per Example 16. The suspension was tested in a 6 subject bioavailability study at a single dose of 2000 mg against a reference solution (Tylen~l Elixir) giv~n as two 1000 mg doses. The results are given in Table 9.
MEA~ PARACETAMOL PLAS~A CO~CENTRATIO~S (mcg/ml~
Tylenol Eli~ir Suspension of TIME ~h)1 g x 2 Example 17 2 9 x 1 r 0.0 0.00 0.0 0.5 12.30 5.11 0.75 12.88 7.07 1.0 12.~9 9.1 1.5 10.17 12.01 2.0 8.19 12.47 3.0 6.00 11~1 4.0 ~.35 4,5 13.S4 ~.37 4.75 1~.00 8.
5.0 13.02 7.55 5.5 13.09 6.57 ~L268051 TABLE 9 (contd) Tylenol Eli2ir ~uspension of TIME (h) 1 9 ~ 2 Example 17 2 g ~ 1 6.0 11.20 ~.71 7.0 ~.17 4.54 8.0 5.98 3.76 10.0 3.4~ 6 12.0 1.98 1.6 14.0 1.~4 l.Q3 16.0 0.82 0.83 2~.0 0.~6 0.39 The figures given in Table ~ and accompanying Figs. 11 and 12 again demonstrate the prolonged absorption nature of the product. In Fig. 11 curve (a) corresp~nds to the ~uspension of Example 19 and curve (b) the reference Tylenol Elixir. In Fig. 12 curve (a) corresponds to the suspension of Example 15, curve (h) to the suspension of Example 16 and curve (c) to the suspension of Example 17.
EX~MPLE 18 Chewing gum containing microparticles of Aspartame were prepared in the following manner.
An internal phase was prepared by dissolving ethylcellulose (45 cps~ in sufficient ethanol to produce ~00 g of ~olution. 100 9 o~ Aspartame (Particle si~e less than 60 microns) was di~persed in 300 9 of acetone. The two liquids were t~en mi~ed by mechanical a~itation. The external phase was prepared according to E~ample 1, 2 litres ~, being required. The internal a~d external phase were mixed , ., ~
: .
~268~91 by mechanical agitation and then passed through an emulsifier. The emulsion was placed in a vacuum and the solvents tacetone and ethanol) evaporated. The Aspartame/
ethylcellulose microparticles were harvested by centrifugation.
To evaluate the Aspartame-containing "pharmasomes", unsweetened chewing gum was used. Pure Aspartame powder and the prepared "pharmasomes" were folded into the gum so as to give a 0.2~ concentration of Aspartame. Both types of gum were chewed by a panel of 24 volunteers in a blind, crossover manner. The volunteers were asked to report their perception of the intensity (on a scale of 0 to 10) and duration of sweetness. On average the duration of sweetness for the pure Aspartame-containing gum was 10 minute~. The gum containing the "pharmasomes" was perceived as being less intensely sweet but observably sweet for 30 minutes on average. The results are indicated in Fig. 13 which is a graphic representation of the Aspartame sweetnes~ test giving mean values for the testing panel of 24 volunieers.
CHEWABLE TABLET CO~TAI~I~G PARACETAMOL
The following materials were mixad together:
1000 g Paracetamol "pharmasomes" - as per Example 2 (equivalent to 500 g of Paracetamol) 250 g Dipac (Trade Mark) (Sucrose 97~, Dextrins 3%) 250 g Mannitol S g Colloidal Silicon Dioxide 25 g Maize Starch 20 g Magneqiu~l Stearate 15 g Orange Flavour 35 g Orange Colour , ': :. ,, : :
~X~i8~35~
The blend was compressed at a weight of 960 ~9 into tablets each containing 300 mg of Paracetamol. The tablets were pleasant to chew and the dissolution characteristics of the "pharma~omes" were unchanged as shcwn in Table 10 and Fig. 14.
DISSOLUTI0~ RATE
TIME (h) "PHARMASOMES" TABLE~S
1 58.7% 59.
3 79.~ 80.7 6 9~.6% 95.
-In Fig. 14 curve ~a) corresponds to the dissolution pattern of the "pharmasomes" of B~ample 19 and curve (b) to the chewable tablets prepared therefrom.
EXAMPL~ 20 "MELT" TABLETS CO~TAI~l~G PA~ACETAMOL
Melt tablets are similar to chewable table~s except that they disintegrate rapidly in the mouth and do not need to be chewed. Such tablets were prepared as foll~ws:
' ~
,.
' " ' ' -~26l~
- 3~ -1000 g Paracetamol "pharmasomes" ~a~ per E~ample 2) (equivalent to 500 g Paracetamol) 50 g Mannitol 250 g Microcrystalline Cellulose 30 9 Strawberry Flavour 15 g Red Colour 60 g Cross-Povidone 5 g Sodium Lauryl Sulphate 30 g Carboxymethyl starch 15 g Magnesium Stearate 15 9 Talc The blend was compressed at a weight of 8~2 mg to give tablets each containing 300 mg o Paracetamol. ~he disintegration time of the tablets was less than 30 saconds and the dissolution rate of the "pharmasomes" was unchanged as indicated in Table 11 and Fig. 15.
-DISSOLUTIO~ RATE
TIME ~h) ~P~ARMhSOMES" TABLETS
1 58.7% ~0.1 3 79.8~ 81.2 6 95.6~ 95.5~
In Fig. 15 curve (a) corresponds to the dissolution pattern for the "pharmasomes" of Example 20 and curve (b) to the melt tablets prepared therefrom.
~2~i8~5~
EY~MPLE 21 CAPSULES CONTAINI~G NIFEDIPI~E
"Pharmasomes" were prepared as per Example 3. By nature they were free flowing and only 0.5% magnesium stearate needed to be added to prevent sticking during capsule filling. The equivalent of 20 mg of ~ifedipine was encapsulated into si~e ~o. 4, two piece hard gelatin capsules. The dissolution rate xemained unchan~ed as shown in Table 12 and Fiy. 16. In Figure 16 curve (a) corresporlds to the dissolution pattern for the "pharmasomes" of E~ample 21 and curve (b) to the capsules prepared thereÇrom.
TAB~E 1~
DISSOLUTIO~ ~TE
-15 TIM~ (h) ~'PHA~MASO~ES" _ CAPS~LES
0.5 42.6% 41.7%
1 56.1% 54~3%
3 7~.6% 73.6 85.9% ~ %
8 . ~8.7% 97.~%
Although not wishing to be bound by any theoretical explanation of the invention, it i8 believed tha~ the polymer ~ubstantially but not entirely coats the active ingredient, because a 100% release of active in~redient can 25 be achieved even when an insoluble polymer is used.
.
: .
- . ~
~6805~
NO~-AQ~EOUS SUSPE~5ION OF POTASSIUM CHLORIDE
A non aqueous suspension of potassium chloride -containing "pharmasomes" was prepared, having a 5 concentration of potassium chloride of 300 mg/~ ml and which in addition to the "pharmasomes" contained the following ingredients:
Oil ~SP (Soy, cotton seed) 425.00 ml Sorbitol Powder USP 100.00 g 10 Aerosil R 972 (Trade Mark) 12.50 g Tenox GT 1 (Trade Mark) 0.20 g Citric acid 0.025 g Chocolate flavour # 3~6676 0.52 ml Chocolate mint flavour ~ 395496 0.37 ml 15 Flavour enhancer l.G0 g Br~wn Lake dye 0.05 Titanium dioxide 0.10 g The total volume of the suspension without the "pharmasomes" was 500 ml.
The Sorbitol powder USP and Aerosil R 972 (Trade Mark~
were dry blended and t~em ball milled with t~e oil mi~ ~o produce an even dispersion. The Tenox GT 1 (Trade Mark) which is an anti-oxidant and the citric acid were dry blended and th~n di~persed with constant agitatior. into the - 25 oil mixture~ The chocolate and chocolate mint flavour~ and the flavour enhancer were then dlspersed into the oil mixture. ~inally, the Brown La~e dye and ~he titanium dioxide were adaed to the oil mixture and the resultant mixture was agitated for one hour to ensure even dispersion of the various ingredients. An amount of potassium chloride - con~aining "pharmasomes", prepared according to the procedure described in Example 1 but substi~uti~g potassium chloride for theophylline, and e~uivalent to 300 mg potassium chloride per 5 ml was blended tog~ther with the 3`5 oil mixture re~ulting in an evenly mixed su~pension.
"" . .
Claims (30)
1. A controlled release powder containing discrete micro-particles for use in controlled release compositions, said powder comprising particles containing an active ingredient in intimate admixture with at least one non-toxic polymer, each of said particles being in the form of a micromatrix with the active ingredient uniformly distributed throughout the polymer, said particles having an average size in the range 0.1 to 125 µm, and having a predetermined release of active ingredient when the dissolution rate thereof is measured according to the Paddle Method of U.S. Pharmacopoeia XX at 37°C and 75 r.p.m., said dissolution rate being substantially proportional to the square root of time.
2. A controlled release powder according to Claim 1, wherein the particles include an excipient in addition to the active ingredient and the polymer.
3. A controlled release powder according to claim 1, wherein the particles have an average size in the range 5 to 100 µm.
4. A controlled release powder according to any one of claims 1 to 3, wherein the active ingredient is a drug, a nutrient, a flavouring agent or a sweetening agent.
5. A controlled release powder according to any one of claims 1 to 3, wherein the active ingredient is a colouring agent, a fragrance, a herbicide or a pesticide.
6. A controlled release powder according to any one of claims 1 to 3, wherein the polymer is selected from:
alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic acids and esters therof, polya-mides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes and polyurethanes and co-polymers therof.
alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic acids and esters therof, polya-mides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes and polyurethanes and co-polymers therof.
7. A process for preparing a controlled release powder according to claim 1, which comprises the steps of:
a) forming a solution of the polymer or polymers in solvent;
b) dissolving or dispersing the active ingredient in said polymer solution so as to form a uniform mixture; and c) removing the solvent from the mixture so as to obtain micro-particles having an average size in the range 0.1 to 125 µm.
a) forming a solution of the polymer or polymers in solvent;
b) dissolving or dispersing the active ingredient in said polymer solution so as to form a uniform mixture; and c) removing the solvent from the mixture so as to obtain micro-particles having an average size in the range 0.1 to 125 µm.
8. A process according to claim 7, wherein the particles obtained have an average size in the range 5 to 100 µm.
9. A process according to claim 7 or 8 wherein the solvent is selected from the group consisting of: water, alcohols, ketones, halogenated aliphatic compounds, halogenated aromatic hydrocarbon compounds, aromatic hydrocarbon compounds and cyclic ethers or a mixture thereof, and the solvent is removed in step (c) by spray drying, use of an external liquid phase, phase separation, interfacial polymer deposition or coacervation.
10. A pharmaceutical composition comprising a therapeutically effective amount of a controlled release powder according to claim 1 in admixture with a pharmaceutically acceptable carrier or diluent.
11. A pharmaceutical composition containing a controlled release powder according to claim 1, and which is in the form of tablets, capsules, suppositories, implants or ocular inserts.
12. A pharmaceutical composition according to claim 10, which is in the form of chewable tablets or melt tablets.
13. A pharmaceutical composition containing a controlled release powder according to claim l, and which is in the form of a cream, an ointment or a formulation suitable for transdermal delivery.
14. A pharmaceutical composition containing a controlled release powder according to claim l, and which is in the form of a liquid for oral, local or parenteral administration.
15. A pharmaceutical composition according to claim 13 , which is in the form of eye drops, nasal drops, ear drops, a suspension, a syrup, or an infusion or injectable solution.
16. A pharmaceutical composition according to claim wherein the active ingredient is selected from:
ibuprofen, paracetamol, 5-amino-salicylic acid, dextro-methorpha, propranolol, theophylline, diltiazem, methyldopar pseudoephedrine, cimetidine, cephalexin, cephaclor, cephradine, naproxen, piroxican, diazepam, diclofenacr indomethacin, amoxycillin, pivampicillin, bacampicillin, dicloxacillin, erythromycin, lincomycin, codergocrine mesylate, doxycycline, dipyridamole, frusemide, triamterene, sulindac, nifedipine, atenolol, erythromycin stearate, lorazepam, glibenclamide, salbutamol, trimethoprim/sulpha-methoxazole, spironolactone, carbinoxamine maleate, guaiphenesin and metoprolol tartrate.
ibuprofen, paracetamol, 5-amino-salicylic acid, dextro-methorpha, propranolol, theophylline, diltiazem, methyldopar pseudoephedrine, cimetidine, cephalexin, cephaclor, cephradine, naproxen, piroxican, diazepam, diclofenacr indomethacin, amoxycillin, pivampicillin, bacampicillin, dicloxacillin, erythromycin, lincomycin, codergocrine mesylate, doxycycline, dipyridamole, frusemide, triamterene, sulindac, nifedipine, atenolol, erythromycin stearate, lorazepam, glibenclamide, salbutamol, trimethoprim/sulpha-methoxazole, spironolactone, carbinoxamine maleate, guaiphenesin and metoprolol tartrate.
17. A pharmaceutical composition according to claim 10 for oral administration, wherein the active ingredient is theophylline.
18. A pharmaceutical composition according to claim 10for oral administration, wherein the active ingredient is paracetamol.
19. A pharmaceutical composition according to claim 10for oral administration, wherein the active ingredient is potassium chloride.
20. An oral formulation for administration to human and non-human animals which is substantially free of the taste of the active ingredient comprising an effective amount of a controlled release powder according to claim 1 in admixture with a carrier or diluent.
21. An oral formulation according to claim 20 which is in the form of a liquid, chewable tablet, melt tablet, foam, gel or gum.
22. A chewable gum which comprises microparticles according to claim 1, which microparticles contain an effective sweetening amount of aspartame as active ingredient.
23. A non-aqueous suspension of a highly water-soluble or water-insoluble active ingredient, wherein the active ingredient is in the form of microparticles of a controlled release powder according to claim 1.
24. A non-aqueous suspension according to claim 23, wherein the highly water-soluble active ingredient is selected from: dextromethorphan, guaiphenesin and pseudoephedrine and salts therof and potassium chloride.
25. A controlled release antibiotic formulation substantially free from the taste of said antibiotic for pharmaceutical or veterinary use which comprises a controlled release powder according to claim 1 containing a therapeutically effective amount of said antibiotic as active ingredient in admixture with a carrier or diluent.
26. An antibiotic formulation according to claim 25, wherein the powder is in the form of a non-aqueous suspension.
27. An antibiotic formulation according to claim 25, which is in the form of a reconstitutable aqueous suspension.
28. A controlled release powder containing discrete micro-particles for use in controlled release compositions, said powder comprising particles containing an active ingredient in intimate admixture with at least one non-toxic polymer, each of said particles being in the form of a micromatrix with the active ingredient uniformly distributed throughout the matrix, said particles having an average size from 0.1 to 125 µm, said micromatrix remaining substantially intact following release of the active ingredient.
29. An oral formulation containing a controlled release powder according to claim 28 and which is in the form of chewable tablets or gum wherein said micromatrix has sufficient mechanical and chemical stability to resist degradation by any chewing action.
30. A topical formulation containing a controlled release powder according to claim 28 and which is in the form of a cream, ointment, foam, gel, paste, gum, mucilage, jelly, lotion, talcum powder or a formulation suitable for transdermal delivery.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE278884A IE58110B1 (en) | 1984-10-30 | 1984-10-30 | Controlled release powder and process for its preparation |
IE2788/84 | 1984-10-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1268051A true CA1268051A (en) | 1990-04-24 |
Family
ID=11036490
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000494130A Expired - Lifetime CA1268051A (en) | 1984-10-30 | 1985-10-29 | Controlled release powder and process for its preparation |
Country Status (16)
Country | Link |
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US (3) | US4940588A (en) |
JP (1) | JP2820239B2 (en) |
AU (1) | AU579415B2 (en) |
BE (2) | BE903541Q (en) |
CA (1) | CA1268051A (en) |
CH (1) | CH669728A5 (en) |
DE (1) | DE3538429C2 (en) |
DK (1) | DK175329B1 (en) |
FR (1) | FR2572282B1 (en) |
GB (1) | GB2166651B (en) |
HK (1) | HK44091A (en) |
IE (1) | IE58110B1 (en) |
IT (1) | IT1185831B (en) |
NL (1) | NL193582C (en) |
SE (1) | SE8505099L (en) |
ZA (1) | ZA858300B (en) |
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-
1984
- 1984-10-30 IE IE278884A patent/IE58110B1/en not_active IP Right Cessation
-
1985
- 1985-10-24 CH CH4590/85A patent/CH669728A5/fr not_active IP Right Cessation
- 1985-10-29 ZA ZA858300A patent/ZA858300B/en unknown
- 1985-10-29 CA CA000494130A patent/CA1268051A/en not_active Expired - Lifetime
- 1985-10-29 NL NL8502951A patent/NL193582C/en not_active IP Right Cessation
- 1985-10-29 DE DE3538429A patent/DE3538429C2/en not_active Expired - Lifetime
- 1985-10-29 AU AU49161/85A patent/AU579415B2/en not_active Ceased
- 1985-10-29 BE BE0/215789A patent/BE903541Q/en not_active IP Right Cessation
- 1985-10-29 JP JP60242585A patent/JP2820239B2/en not_active Expired - Lifetime
- 1985-10-29 FR FR858516065A patent/FR2572282B1/en not_active Expired
- 1985-10-29 DK DK198504955A patent/DK175329B1/en not_active IP Right Cessation
- 1985-10-29 GB GB08526591A patent/GB2166651B/en not_active Expired
- 1985-10-29 BE BE0/215788A patent/BE903540A/en not_active IP Right Cessation
- 1985-10-29 SE SE8505099A patent/SE8505099L/en not_active Application Discontinuation
- 1985-10-29 IT IT67913/85A patent/IT1185831B/en active
-
1988
- 1988-03-17 US US07/171,131 patent/US4940588A/en not_active Expired - Lifetime
- 1988-03-17 US US07/169,447 patent/US4952402A/en not_active Expired - Lifetime
-
1990
- 1990-07-09 US US07/537,065 patent/US5354556A/en not_active Expired - Lifetime
-
1991
- 1991-06-06 HK HK440/91A patent/HK44091A/en not_active IP Right Cessation
Also Published As
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DE3538429A1 (en) | 1986-04-30 |
GB2166651A (en) | 1986-05-14 |
DE3538429C2 (en) | 1996-10-24 |
SE8505099L (en) | 1986-05-01 |
GB8526591D0 (en) | 1985-12-04 |
NL8502951A (en) | 1986-05-16 |
IT1185831B (en) | 1987-11-18 |
CH669728A5 (en) | 1989-04-14 |
GB2166651B (en) | 1988-11-16 |
US4940588A (en) | 1990-07-10 |
BE903540A (en) | 1986-02-17 |
AU4916185A (en) | 1986-05-08 |
FR2572282A1 (en) | 1986-05-02 |
DK495585D0 (en) | 1985-10-29 |
JP2820239B2 (en) | 1998-11-05 |
DK495585A (en) | 1986-05-01 |
DK175329B1 (en) | 2004-08-23 |
ZA858300B (en) | 1986-07-30 |
FR2572282B1 (en) | 1989-03-31 |
IT8567913A0 (en) | 1985-10-29 |
NL193582B (en) | 1999-11-01 |
JPS61109711A (en) | 1986-05-28 |
IE58110B1 (en) | 1993-07-14 |
SE8505099D0 (en) | 1985-10-29 |
NL193582C (en) | 2000-03-02 |
HK44091A (en) | 1991-06-14 |
US5354556A (en) | 1994-10-11 |
US4952402A (en) | 1990-08-28 |
AU579415B2 (en) | 1988-11-24 |
BE903541Q (en) | 1986-02-17 |
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