AU682223B2 – Sustained release compositions and a method of preparing pharmaceutical compositions
– Google Patents
AU682223B2 – Sustained release compositions and a method of preparing pharmaceutical compositions
– Google Patents
Sustained release compositions and a method of preparing pharmaceutical compositions
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Publication number
AU682223B2
AU682223B2
AU79015/94A
AU7901594A
AU682223B2
AU 682223 B2
AU682223 B2
AU 682223B2
AU 79015/94 A
AU79015/94 A
AU 79015/94A
AU 7901594 A
AU7901594 A
AU 7901594A
AU 682223 B2
AU682223 B2
AU 682223B2
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AU
Australia
Prior art keywords
particles
diluent
carrier
hydrophobic
fusible
Prior art date
1993-11-23
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
Application number
AU79015/94A
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AU7901594A
(en
AU682223C
(en
Inventor
Deborah Challis
Joanne Heafield
Trevor John Knott
Stewart Thomas Leslie
Sandra Therese Antoinette Malkowska
Ronald Brown Miller
Derek Allan Prater
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MUNDIPHARMA MEDICAL GmbH
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Euro Celtique SA
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1993-11-23
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1994-11-23
Publication date
1997-09-25
1993-11-23
Priority claimed from GB9324045A
external-priority
patent/GB2284760B/en
1994-03-01
Priority claimed from GB9403922A
external-priority
patent/GB2288117A/en
1994-03-09
Priority claimed from GB9404544A
external-priority
patent/GB9404544D0/en
1994-03-14
Priority claimed from GB9404928A
external-priority
patent/GB2287880A/en
1994-04-29
Priority claimed from EP94303128A
external-priority
patent/EP0624366B1/en
1994-06-09
Priority claimed from EP94304144A
external-priority
patent/EP0636370B2/en
1994-06-14
Priority claimed from GB9411842A
external-priority
patent/GB9411842D0/en
1994-11-23
Application filed by Euro Celtique SA
filed
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Euro Celtique SA
1995-06-01
Publication of AU7901594A
publication
Critical
patent/AU7901594A/en
1997-09-25
Publication of AU682223B2
publication
Critical
patent/AU682223B2/en
2000-03-16
Assigned to MUNDIPHARMA MEDICAL GMBH
reassignment
MUNDIPHARMA MEDICAL GMBH
Alteration of Name(s) in Register under S187
Assignors: EURO-CELTIQUE S.A.
2005-03-24
Publication of AU682223C
publication
Critical
patent/AU682223C/en
2005-03-24
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2014-11-23
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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
A61K9/14—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
A61K9/1617—Organic compounds, e.g. phospholipids, fats
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K31/00—Medicinal preparations containing organic active ingredients
A61K31/13—Amines
A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K31/00—Medicinal preparations containing organic active ingredients
A61K31/13—Amines
A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K31/00—Medicinal preparations containing organic active ingredients
A61K31/33—Heterocyclic compounds
A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
A61K31/47—Quinolines; Isoquinolines
A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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
A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K9/00—Medicinal preparations characterised by special physical form
A61K9/20—Pills, tablets, discs, rods
A61K9/2004—Excipients; Inactive ingredients
A61K9/2013—Organic compounds, e.g. phospholipids, fats
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K9/00—Medicinal preparations characterised by special physical form
A61K9/20—Pills, tablets, discs, rods
A61K9/2004—Excipients; Inactive ingredients
A61K9/2022—Organic macromolecular compounds
A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K9/00—Medicinal preparations characterised by special physical form
A61K9/20—Pills, tablets, discs, rods
A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K9/00—Medicinal preparations characterised by special physical form
A61K9/20—Pills, tablets, discs, rods
A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K9/00—Medicinal preparations characterised by special physical form
A61K9/20—Pills, tablets, discs, rods
A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K9/00—Medicinal preparations characterised by special physical form
A61K9/20—Pills, tablets, discs, rods
A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
A61K9/2806—Coating materials
A61K9/2833—Organic macromolecular compounds
A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P25/00—Drugs for disorders of the nervous system
A61P25/04—Centrally acting analgesics, e.g. opioids
Abstract
A process for the manufacture of particles comprises mechanically working a mixture of a drug and a hydrophobic and/or hydrophilic fusible carrier in a high speed mixture so as to form agglomerates, breaking the agglomerates to give controlled release particles and optionally continuing the mechanical working with the optional addition of a low percentage of the carrier or diluent.
Description
SUSTAINED RELEASE COMPOSITIONS AND A METHOD OF PREPARING PHARMACEUTICAL COMPOSITIONS The present invention relates generally to a method of manufacturing pharmaceutical dosage forms, for human or veterinary use, preferably sustained release particles, such particles having diameters ranging from 0.1 to 3.0mm. Such particles may contain analgesics, such as morphine, or other active ingredients. The present invention also relates to dosage forms obtained by processing of the aforesaid particles, such as tablets, suppositories or pessaries.
Patent Application PCT/SE93/00225 published under No. WO 93/18753 describes a process for the preparation of sustained release pellets which comprises pelletising a mixture containing the drug in finely divided form and a binder; the process is characterised in that: the binder is in particle form consisting of one or more water-insoluble or water-soluble, wax-like binder substance(s) with a melting point above and the pelletisation step is performed by mechanically working the mixture, in a so-called high-shear mixer, under the input of a sufficient amount of energy for *Gs the binder to melt and pelletisation to take place.
The so-called high-shear mixer is described in US 5,030,400 is incorporated by 20 reference in PCT/WO/93 18753 and which refers to the mixers as high speed mixers.
Patent Application PCT/SE92/06679 describes a similar process.
Processes of this kind are sometimes referred to as «melt-pelletisation» processes. We have found that operating according to these processes using commercial manufacturing equipment with a standard stainless steel interior, which is also the method described in Schaefer et al. (Drug Development and Industrial Pharmacy, 16(8), 1249-1277 (1990) and Taggart et al. (International Journal of Pharmaceutics 19 (1984) 139-148), results in yields of pellets in the preferred size range of only about 30 to 60% compared with the theoretical. Use of a wider particle size range to improve the yield results in an erratic in vitro release rate and irreproducible performance.
There is, therefore, a need for a commercial process for producing satisfactory controlled release particles which has a much higher yield. One object of the invention is, therefore, to provide a process which has an improved yield and preferably produces La product with reproducible controlled release characteristics.
[N:\LIBAA]00837:TCW 2 The present invention thus discloses a process for the manufacture of sustained release particles, which comprises: mechanically working in a high-speed mixer, a mixture of a particulate drug and a particulate, hydrophobic and/or hydrophilic fusible carrier or diluent having a melting point from 35 to 150’C and optionally a release control component comprising a water-soluble fusible material or a particulate, soluble or insoluble organic or inorganic material, at a speed and external energy input which allows the carrier or diluent to melt or soften whereby it forms agglomerates; and comminuting the agglomerates to give controlled release particles.
This process is capable of giving a high yield (over 80 of particles in a desired size range with a desired in vitro release rate and, uniformity of release rate.
The resulting particles may be sieved to eliminate any oversized or undersized material then formed into the desired dosage units by for example, encapsulation into hard gelatin capsules containing the required dose of the active substance or by tabletting, filling into sachets or moulding into suppositories, pessaries or forming into other suitable dosage forms.
The present invention also discloses a solid dosage form obtainable by compressing particles comprising a pharmaceutically active substance in a matrix of a hydrophobic and/or hydrophilic fusible diluent or carrier having a melting point of from 35 to 1500 C, the solid dosage form optionally containing conventional tabletting excipients.
The present invention further discloses a capsule for oral dosing containing particles comprising a pharmnaceutically active substance in a matrix of a hydrophobic and/or hydrophilic fusible carrier or diluent having a melting point of from 35 to 150*C and optionally containing conventional capsuling excipients.
0A 4***BA]087:C ‘p S 9’ 3 The drug may be water soluble or water insoluble. Water soluble drugs will usually be used in amounts giving for example a loading of up to about 90% w/w in the resulting particles; water insoluble drugs may be used in higher amounts eg. up to 99% w/w of the resulting particles; Examples of water soluble drugs which can be used in the method of the invention are morphine, hydromorphone, diltiazem, diamorphine and tramadol and pharmaceutically acceptable salts thereof; examples of water insoluble drugs which can be used in the process of the invention are naproxen, ibuiprofen, indomethacin and nifedipine.
Among the active ingredients which can be used in the process of the invention are the following;
ANALGESICS
Dihydrocodeine, Hydromorphone, Morphine, Diamorphine, Fentanyl, Alflentanil, Sufentanyl, Pentazocine, Buprenorphine, Nefopam, Dextropropoxyphene, Flupirtine, Tramadol, Oxycodone, Metamizol, Propyphenazone, Phenazone, Nifenazone, Paracetamol, Phenylbutazone, Oxyphenbutazone, Mofebutazone, Acetyl salicylic acid, Diflunisal, Flurbiprofen, Ibuprofen, Diclofenac, Ketoprofen, Indomethacin, Naproxen, Meptazinol, Methadone, Pethidine, Hydrocodone, Meloxicam, Fenbufen, Mefenamic acid, Piroxicam, Tenoxicam, Azapropazone, Codeine, :i ANTIALLERGICS Pheniramine, Dimethindene, Terfenadine, Astemizole, Tritoqualine, Loratadine, Doxylamine, Mequitazine, Dexchlorpheniramine, Triprolidine, Oxatomide,
ANTIHYPERTENSIVE
i: Clonidine, Moxonidine, Methyldopa, Doxazosin, Prazosin, Urapidil, Terazosin, Minoxidil, Dihydralazin, Deserpidine, Acebutalol, Alprenolol, Atenolol, Metoprolol, Bupranolol, Penbutolol, Propranolol, Esmolol, Bisoprolol, Ciliprolol, Sotalol, Metipranolol, Nadolol, Oxprenolol, Nifedipine, Nicadipine, Verapamil, Diltiazem, Felodipine, Nimodipine, Flunarizine, Quinapril, Lisinopril, Captopril, Ramipril, Fosinopril, Cilazapril, Enalapril.
-sr 4 4. Z. ,4U *4.4.44. 44E.IOTIC ‘4’ Deoloylie Doyycie Lyeycie Mioycie Oxt’A.ylie p ANIBOIS OINI-SE AI bTeryln, Suipelfam etoyraine facn, Cirolaacne, Asacinamo, Ainoxcirl~, Flucoxacllin, Erylithoyin e trondaolelindamtycin, Time ethoim,Noyc,
ANTIARRHYTHMICS
Viquidil, Procainam-ide, Mexiletine, Tocainide, Propafenone, Ipratropium, CENTRALLY ACTING SUBSTANCES Amantadine, Lpevodopa, Biperiden, Benzotropine, Bromocriptine, Procyc lidine, Moclobemide, Trartylcypromide, Clomipramine, Maprotiline, Doxepin, Opipramol, Amitriptyline, Desipramine, Imipramine, Fluroxamin, Fluoxetin, Paroxetine, Trazodone, Viloxazine, Fiuphenazine, Perphenazine, Promethazine, Thioridazine, Triflupromazine, Prothipendyl, Tiotixene, Chlorprothixene, Haloperidol, Pipamnperone, Pimozide, Sulpiride, Fenethylline, Methyiphenildat, Trifluoperazine, Thioridazine, Oxazepamn, Lorazepamn, Bromoazepam, Aiprazolamn, Diazepam, Clobazam, Buspirone, Piracetamn, CYTOSTATICS AND METASTASIS INHIBITORS Melfalan, Cyclophospharnide, Trofosfamide, Chiorambucil, Lomnustine, Busulfan, Prednimustine, Fluorouracil, Methotrexate, Mercaptopurine, Thioguanin, Hydroxycarbainide, Altretamine, Proc arbazine,.
ANTI-MIGRAINE
Lisuride, Methysergide, Dihydroergotamnine, Ergotamine, Pizotifen,
GASTROINTESTINAL
Cimetidine, Famotidine, Ranitidine, Roxatidine, Pirenzipine, Omeprazole, Misoprostol, Proglumide, Cisapride, Bromopride, Metoclopramide, ORAL ANTIDIABETICS Tobutamide, Glibenclamide, Glipizide, Gliquidone, Gliboruride, Tolazamide, Acarbose and the pharmaceutically active salts or esters of the above and combinations of two or more of the above or salts or esters thereof.
The hydrolysis of drugs constitutes the most frequent, and perhaps therefore the most important, route of drug decomposition. Analysis of a collection of stability data in Connors KA, Amidon GL, Stella VJ, Chemical stability of pharmaceuticals. A handbook for pharmacists, 2nd ed. New York: John Wiley Sons, 1986, a standard text, shows that over 70% of the drugs studied undergo hydrolytic degradation reactions. Of these, 61.4% can be classed as reactions of carboxylic acid derivatives (esters, amides, thiol esters, lactams, imides), 20% of carbonyl derivatives (imines, oximes) 14.3% of nucleophilic displacements, and 4.3% of phosphoric acid derivatives.
Cephalosporins, penicillins and barbituates are particularly susceptible drug classes.
The process of the invention may advantageously be used for preparing dosage forms containing active substances as mentioned above which are unstable in the presence of water, e.g. diamorphine. Thus stable formulations of such drugs having normal or controlled release characteristics can be obtained in accordance with the invention.
In a preferred method according to the invention morphine sulphate, or other water soluble drug, e.g. tramadol, is used in an amount which results in particles containing e.g. between 1% and 90 especially between about 45 and about 75 w/w active ingredient for a high dose product and e.g. <1 and 45% for a low dose product.
In the method of the invention preferably all the drug is added in step together with a major portion of the hydrophobic or hydrophilic fusible carrier or diluent used.
Preferably the amount of fusible carrier or diluent added in step is between e.g.
I
6 and <99% w/w of the total amount of ingredients added in the entire manufacturing operation.
The fusible carrier or diluent may be added stepwise during mechanical working, in step a) or step c).
In step the amount of additional fusible carrier or diluent added is preferably between 5% and 75% w/w of the total amount of ingredients added.
Stage of the process may be carried out in conventional high speed mixers widi a standard stainless steel interior, e.g. a Collette Vactron 75 or equivalent mixer. The mixture is processed until a bed temperature above 40 0 C is achieved and the resulting mixture acquires a cohesive granular texture, with particle sizes ranging from about 1-3 mm to fine powder in the case of .aon-aggregated original material. Such material, in the case of the embodiments described below, has the appearance of agglomerates which upon cooling below 40 0 C have structural integrity and resistance to crushing between the fingers. At this stage the agglomerates are of an irregular size, shape and appearance.
The agglomerates are preferably allowed to cool. The temperature to which it cools is not critical and a temperature in the range room temperature to 41 0 C may be conveniently ust~ s The agglomerates are broken down by any suitable means, which will comminute S• oversize agglomerates and produce a mixture of powder and small particles preferably with a diameter under 2mm. It is currently preferred to carry out the classification using a Jackson Crockatt granulator using a suitable sized mesh, or a Comil with an appropriate sized screen. We have found that if too small a mesh size is used in the aforementioned apparatus the agglomerates melting under the action of the beater or impeller will clog the mesh and prevent further throughput of mixture, thus reducing yield.
U f. '4^ 7 The classified material is preferably returned to the high speed mixer and processing continued. It is believed that this leads to cementation of the finer particles into particles of uniform size range.
In one preferred form of the process of the invention processing of the classified materials is continued, until the hydrophobic and/or hydrophilic fusible carrier or diluent materials used begin to soften/melt and additional hydrophobic and/or hydrophilic fusible carrier or diluent material is then added; most preferably the additional hydrophobic and/or hydrophilic fusible carrier or diluent material is added after any fines generated in stage have been taken up by the larger sized particles.
Mixing is continued until the mixture has been transformed into particles of the desired predetermined size range.
In order to ensure uniform energy input into the ingredients in the high spcad ,ii, er it is preferred to supply at least part of the energy by means of microwave energy.
StEnergy may also be delivered through other means such as by a heating jacket or via the mixer impeller and chopper blades.
After the particles have been formed they are sieved to remove any oversized or undersized material and then cooled or allowed to cool.
'The resulting particles may be used to prepare dosage units e.g. tablets or capsules in manners known per se.
In this process of the invention the temperature of the mixing bowl throughout the mechanical working is chosen so as to avoid excessive adhesion, suitably to minimise adhesion of the material to the walls of the bowl. To minimise adhesion we have generally found that the temperature should be neither too high nor too' low with respect to the melting temperature of the material and it can be readily optimised to avoid the problems mentioned above. For example in the processes described below in the Examples a bowl temperature of approximately 50 60°C has been found to be 8 satisfactory and avoids adhesion to the bowl. It is not possible to generalize as to the appropriate temperature for any particular mixture to be processed. However, in practice, it is a matter of simple experimentation and observation to establish a suitable temperature and processing time for a particular mixture under consideration.
The process of the invention described above is capable, in a preferred form, of providing particles which function as sustained release dosage forms. In particular, as described in co-pending European Patent Application No. 94303128.6 filed on 29th April 1994, an orally administrable sustained release dosage unit form containing morphine, or a pharmaceutically acceptable salt thereof, as active ingredient which formulation has a peak plasma level of morphine from 1 to 6 hours after administration.
We have found that by suitable selection of the materials used in forming the particles and in the tabletting and the proportions in which they are used, enables a significant degree of control in the ultimate dissolution and release rates of the active ingredients from the compressed tablets.
Suitable substances for use as hydrophobic carrier or diluent materials are natural or synthetic waxes or oils, for example hydrogenated vegetable oil, hydrogenated castor oil, Beeswax, Carauba wax, microcrystalline wax and glycerol monostearate, and suitably have melting points of from 35 to 150°C, preferably 45 to 0 Suitable substances for use as hydrophillic carrier or diluent materials are natural or synthetic waxes or oils, for example PEGs having molecular weights of 1000 to 20,000 e.g. 1000 to 6000 or 10000 suitably having melting points of from 35 to 150°C, "preferably 45 to 90 0
C.
The optionally added release control component when a water soluble, fusible material may be a PEG of appropriate molecular weight; suitable particulate inorganic and organic materials are, for example dicalcium phosphate, calcium sulphate, talc, colloidal anhydrous silica, and lactose, poloxamers, microcrystalline cellulose, starch, i 9 hydroxypropylcellulose, and hydroxypropylmethylcellulose.
We have also found that particles produced by the melt pelletisation processes described in application PCT/SE93/00225 and the process described herein are particularly useful for processing into the form of tablets.
To produce tablets in accordance with the invention, part: ';ty ed as described above may be mixed or blended with the desired excipte. if any, using conventional procedures e.g. using a Y-Cone or bin-blender and the resulting mixture compressed according to conventional tabletting procedure using a suitably sized tabletting tooling. Tablets can be produced using conventional tabletting machines, and in the embodiments described below were produced on standards single punch F3 Manesty machine or Kilian RLE15 rotary tablet machine.
Generally speaking we find that even with highly water soluble active agents such as morphine or tramadol tablets formed by compression according to standard methods give very low in vitro release rates of the active ingredient e.g. corresponding to release over a period of greater than 24 hours, say more than 36. We have found that the in vitro release profile can be adjusted in a number of ways. For instance in the case of water soluble drugs a higher loading of the drug will be associated with increased release rates; the use of larger proportions of the water soluble fusible material in the particles or surface active agent in the tabletting formulation will also be associated with a higher release rate of the active ingredient: Thus, by controlling the relative amounts of these ingredients it is possible to adjust the release profile of the active ingredient, whether this be water soluble or water insoluble.
In Drug Development and Industrial Pharmacy, 20(7), 1179-1197 (1994) by L J Thomsen et al, which was published after the priority date of this application, a process similar to that described in PCT/SE93!/0225 is discussed in detail. In the results and discussion on page 1186 it is states that glyceryl monostearate was the only substance which showed pronounced potential as a meltable binder, and then only with mixers lined with polytetrafluoroethylene. By contrast the process of the present invention has I I, been found to work satisfactorily with other binders and using conventional mixers with stainless steel linings.
In Pharmaceutical Technology Europe October 1994 pp 19-24 L J Thomsen describes the same process as mentioned in the above article. In the passage bridging pages and 21 it is stated higher drug loads with larger drug crystals did not pelletize and that his results suggest manufacturers using melt pelletization should avoid starting materials containing amounts of crystals larger than 60pm and that electostatic charging of mass and adhesion to the walls of the mixer bowl made it impossible to make acceptable quality pellets with a binder of pure microcrystalline wax so that substantial amounts of glycerol monostearate was essential. In the process of the invention described herein drug crystal size has not been found to be a critical parameter; in the Examples described below the morphine sulphate typically has a particle size distribution with of particles larger than 24 to 50pm and 10% larger than 100-140pm.
In order that the invention may be well understood the following examples are given **4 by way of illustration only.
EXAMPLES 1 to 4 Particles, having the formulations given in Table I below, were prepared by the steps "fft of: 0t e i) Placing the ingredients to (total batch weight 20kg) in the bowl of a litre capacity Collette Vactron Mixer (or equivalent) equipped with variable speed mixing and granulating blades; ii) Mixing the ingredients at about 150-350rpm whilst applying heat until the contents of the bowl are agglomerated.
iii) Classifying the agglomerated material by passage through a Comil and/or Jackson Crockatt to obtain controlled release particles.
11 iv) Adding the classified material to the heated bowl of a 75 litre Collette Vactron, allowing the particles to heat up under mixing, then adding ingredient and continuing the mechanical working until uniform particles of the desired predetermined size range are formed in yields of greater than v) Discharging the particles from the mixer and sieving them to separate out the particles collected between 0.5 and 2mm aperture sieves and then allowing them to cool.
oo 9 s r o~, eo r s rr r TABLE I EXAMPLE 1 2 3 a) MORPHINE SULPHATE 55.0 52.19 53.48
B.P.
b) HYDROGENATED VEGETABLE OIL USNF 34.95 33.17 33.98 c) POLYETHYLENE GLYCOL 6000 0.05 0.047 0.049 USNF (WT%) d) HYDROGENATED VEGETABLE OIL 10.0 14.60 12.49 USNF (WT%) YIELD 90.5 83.4 90.1 *r The in vitro release rates of Examples 1, 2 and 3 were assessed by modified Ph. Eur.
Basket method at 100 rpm in 900ml aqueous buffer (pH 6.5) containing 0.05%w/v polysorbate 80 at 37 0 C (corresponding to the Ph. Eur. Basket method but using a basket with a finer mesh, with the same open area and with a slightly concave top).
For each of the products, six samples of the particles, each sample containing a total mr~ 12 of 60mg of morphine sulphate were tested. The results set out in Table II below give the mean values for each of the six samples tested.
TABLE II PRODUCT OF EXAMPLES HOURS AFTER 1 2 3 START OF TEST MORPHINE
RELEASED
2 21 15 4 33 25 36 6 43 35 49 8 52 43 59 12 62 57 72 18 74 71 82 24 82 81 86 83 85 89 9 9 9. 9 999* 99 9 The procedure of Example 3 was repeated but the operation varied by adding the classified particles to a cold bowl of the Collette Vactron, followed by adding ingredient and mixing, heating by jacket heating and microwave being applied during mixing. The in vitro release rate, obtained using the same procedure as for Examples 1 to 3, is given in Table IIa and demonstrates that although the composition of the products in Examples 3 and 4 are the same the different processing results in modified release rates.
-i ~po~au_-r 13 TABLE Ha PRODUCT OF EXAMPLE 4 HOURS AFTER OF MORPHINE START OF TEST RELEASED 2 4 24 6 8 36 12 46 18 57 24 71 Particles produced according to Examples 1 to 4 were each blended with purified talc and magnesium stearate and used to fill hard gelatin capsules such that each capsule contains 60mg of morphine sulphate. The capsules produced were used in open, randomised crossover pharmacokinetic studies. As part of these studies patients received after overnight fasting either one capsule according to the invention or one MST CONTINUSR tablet 30mg (a twice a day preparation). Fluid intake was unrestricted from 4 hours after dosing. A low-fat lunch was provided four hours after dosing, a dinner at 10 hours post dose and a snack at 13.5 hours post-dose. No other food was allowed until a 24 hour post-dose blood sample had been withdrawn. Blood samples were taken at the following times 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours post-dose.
The pharmacokinetic studies using these capsules gave peak plasma levels of from 3.2 to 29.2 ng/ml of morphine at median times between 2 and 6 hours following administration and blood sampling according to the above protocol.
-r I- I i B~n~sl~ 14 The capsules containing particles produced according to Examples 2 and 4 in particular gave a mean Cmax of 11.9 ng/ml at median tmax 4 hours and mean Cmax of 9.2 ng/ml at median tmax 2.5 hours respectively (these values represent the mean of the individual Cmax and tmax values). In contrast the Cmax and tmax for the patients who received MST CONTINUSR tablets were 10.6 -11.4 ng/ml and 2.0 -2.5 hours respectively. It was found, however, that the plasma concentrations of morphine in the blood of patients given capsules according to the invention at 24 hours were greater than the concentrations at 12 hours in those patients given MST CONTINUS tablets.
Example Particles were produced analogously to Examples 1 to 4 but having the following ingredients wt% Morphine sulphate 55.0 Hydrogenated vegetable oil 44.7 :Polyethylene glycol 6000 0.3 Samples of the particles were then blended with magnesium stearate and purified talc in two lots (1 and 2) using a Y-Cone or bin-blender machine. The blended mixtures were then each compressed on a 7.1mm diameter normal concave tooling on a single punch F3 Manesty tabletting machine. The ingredients per dosage unit amounted to the following: ~s a I-I TABLE III Tablet Mg/Tablet Ingredient 1 2 1 2 Morphine Sulphate 60.00 60.00 Hydrogenated Vegetable Oil 48.77 48.77 Polyethylene Glycol 0.33 0.33 Sub Total 109.1 109.1 Magnesium Stearate 1.42 Purified Talc 2.18 e a a a a a s a a a o a o a sc a a u a a r The dissolution of the samples of non-compressed particles (each sample containing 60mg of morphine sulphate) was assessed by the modified Ph. Eur. Basket method described above. For the dissolution of the tablets the Ph. Eur. Basket was replaced by the Ph. Eur. Paddle Method. The results are shown in Table IV below: Ics a sllaa I o oo TABLE IV HOURS AFTER PARTICLES TABLET 1 TABLET 2 START OF TEST MORPHINE SULPHATE
RELEASED
1 27 13 11 2 43 20 17 4 63 29 26 8 82 42 37 12 88 50 44 16 91 57 NR 24 93 65 NR 94 70 NR 36 95 74 NR NR Not recorded The above results show that the tabletting procedure results in a considerable reduction in the release rate of the active ingredient.
Example 6 The procedure of Example 5 was repeated but with the following variations.
The particles were made with the fcilowing ingredients.
wt% Morphine Sulphate 55.0 Hydrogenated Vegetable Oil 44.4
B(LII
Polyethylene Glycol 6000 Two lots of tablets (3 and 4) were produced from the particles using a 7.1mm diameter concave tooling. The ingredients per dosage unit were as follows; TABLE V TABLET Mg/Tablet SIGREDIENT 3 4 Morphine Sulphate 60.0 60.0 Hydrogenated Vegetable Oil 48.44 48.44 Polyethylene Glycol 6000 0.655 0.655 Sub Total 109.1 109.1 Poloxamer 188 Magnesium Stearate 2.0 Purified Talc 3.0 The dissolution of the tablets and samples of non-compressed particles (each sample containing 60mg of morphine sulphate) were assessed by the methods described above.
The results are shown in Table VII below; Le a *o **a I -s 9 TABLE VI HOURS AFTER PARTICLES TABLET 3 TABLET 4 START OF TEST MORPHINE SULPHATE
RELEASED
1 56 16 19 2 75 24 28 4 90 34 38 8 95 46 52 12 97 54 16 NR NR 67 24 NR NR 77 These results demonstrate again a dramatic reduction in the re we of the morphine sulphate resulting from compression tabletting of the particles; comparison of the release rates for Tablets 3 and 4 also show that the release rate can be adjusted by use of a surface active agent (in this case Poloxamer 188®) as a tabletting excipient, the release rate for tablet 4 which contains the surface active agent being greater than that for tablet 3 without the surface active agent.
Example 7 A procedure analogous to Example 5 was carried out using tramadol hydrochloride as active ingredient in place of morphine sulphate. The particles were made with the following ingredients; wt% o o a r c e o ~r a r r Tramadol Hydrochloride Hydrogenated Vegetable Oil I 19 Three lots of tablets 6 and 7) were produced from particles using respectively (a) 14mm x 6mm, 16mm x 7mm and 18.6 x 7.5mm capsule shaped tooling. The ingredients per dosage unit were as follows; TABLE VII TABLET MG/TABLET 6 7 Tramadol HCI 200 300 400 Hydrogenated Vegetable Oil 200 300 400 Sub Total 400 600 800 Purified Talc 12.63 18.95 25.26 Magnesium Stearate 8.42 12.63 16.84 The tablets were assessed by dissolution in 0.1N HC1 Ph. Eur. Paddle at 100rpm. For the non-compressed particles the Ph. Eur. Paddle was replaced by the modified Ph.
Eur. Basket, each sample of particles containing 400mg of tramadol hydrochloride.
The results are shown in Table VIII below;
S
S. S So S 5 I i rr ~pra~ HOURS AFTER Particles Tablet 5 Tablet 6 Tablet 7 START OF TEST TRAMADOL HCI RELEASED 1 54 16 15 2 68 23 20 21 3 76 28 25 4 82 32 28 28 6 89 40 35 8 93 46 41 96 50 45 12 98 55 49 49 16 100 63 57 56 NR 70 63 NR These results confirm the effectiveness of the tabletting in reducing the release rate of tramadol, a highly water soluble drug.
Example 8 The procedure of Example 7 was repeated but with a higher loading of tramadol hydrochloride in the particles. Thus particles were made with the following ingredients; wt% Tramadol Hydrochloride Hydrogenated Vegetable Oil Three lots of tablets 9 and 10) were produced from the particles using respectively tooling and described in Example 7. The ingredients per unit dosage were as follows: 0
S..
S
S.
S
G0 0 I TABLE X TABLET MG/T.-BLET
INGREDIENT
8 9 Tramadol HCl 200 300 400 Hydrogenated Vegetable Oil 66.7 100 133 Sub Total 266.7 400 533 Purified Talc 7.63 11.44 15.25 Magnesium Stearate 5.16 7.63 10.17 The tablets and samples of non-compressed particles (each sample containing 400mg of tramadol hydrochloride) were assessed by the methods described in Example 7. The results are shown in Table XI below; HOURS AFTER Particles Tablet 8 Tablet 9 Tablet START OF TEST TRAMADOL HCI RELEASED 1 77 43 40 42 2 92 64 55 56 3 98 75 65 66 4 100 83 72 73 6 102 94 83 84 8 102 100 91 91 102 NR 96 97 These results show that by increasing the loading of the highly water soluble tramadol hydrochloride (75 9 w/w in this example compared with 50% w/w in Example 7) a 0* 0 *00 0 000000 0*
I--
22 significantly faster ielease rate of the active ingredient can be achieved.
Example 9 0.35kg particulate diamorphine hydrochloride and the same weight of particulate hydrogenated vegetable oil (Lubritab) were placed in the bowl of a Collette Gral 10 or equivalent mixer, preheated to 60 0 C. Mixing was carried out at the following speeds for the Collette Gral 10 mixer 350 rpm; chopper 1500 rpm, until the contents of the bowl are slightly agglomerated. The agglomerates are then allowed to cool to approximately 40 0 C, are removed from the bowl and are milled in a Comill to obtain controlled release seeds. The seeds are then placed in the mixer bowl and processing carried out until multiparticulates of a desired size are obtained. The contents of the bowl are then discharged and sieved to collect the 0.5 2.0mm sieve fraction.
The procedure described in the preceding paragraph was repeated but the collected sieve fraction is blended in a conventional blender with 0.006kg talc for 5 minutes; 0.004kg magnesium stearate is then added and the blending continued for 3 minutes.
S The blend is then discharged and compressed using a 4mm x 8mm capsule shaped tooling on a F3 tablet machine. The resulting tablet had a hardness of 1.7kp, a thickness of 2.8 3.0mm and a friability of 1.0% and the following constitution: CONSTITUENT MG/TABLET W/W Diamorphine Hydrochloride 40.0 47.6 Hydrogenated Vegetable Oil 40.0 47.6 Talc 2.40 2.86 Magnesium Stearate 1.6 1.91 TOTAL 84 o a cc -e I The dissolution rates of the resulting multiparticulates and tablets, measured respectively by the Ph. Eur, Basket or Paddle method at 100rpm in either phosphate or acetate buffer, were as follows: TIME (HRS) DIAMORPHINE HCL RELEASED Multiparticulates Tablets Tablets Basket/Phosphate Paddle/Phosphate Par~dle/Acetate Buffer Buffer Buffer 1n3 24 2 44 35 3 54 41 43 4 62 47 49 6 70 57 59 8 78 64 67 12 87 75 78 16 92 84 86 a.
a a *0~00~ a a..
a a. a a a a.
a a a a. a a a a.
Claims (17)
1. A process for the manufacture of sustained release particles, which comprises: mechanically working in a high-speed mixer, a mixture of a particulate drug and a particulate, hydrophobic and/or hydrophilic fusible carrier or diluent having a melting point from 35 to 150°C and optionally a release control component comprising a water-soluble fusible material or a particulate, soluble or insoluble organic or inorganic material, at a speed and external energy inp t which allows the carrier or diluent to melt or soften whereby it forms agglomerates; and comminuting the agglomerates to give controlled release particles.
2. A process according to claim 1, hich further comprises: continuing mechanically working optionally with the addition of a low percentage of the carrier or diluent; and optionally repeating steps and possibly one or more times, wherein during the mechanical working, heat is supplied thereto by microwave radiation.
3. process according to claim 2, wherein only part of the heating is 20 supplied by microwave radiation.
4. A process according to any one of claims 1 to 3, wherein the drug is morphine tramadol, hydromorphone, oxycodone, diamorphine or a pharmaceutically acceptable salt of any one of these.
5. A process according to any one of claims 1 to 4, wherein the S 25 hydrophobic fusible carrier(s) or diluent(s) is a wax, e.g. chosen from hydrogenated vegetable oil, hydrogenated castor oil, Beeswax, Carnauba wax, microcrystalline wax and glycerol monostearate.
6. A process according to any one of claims 1 to 5, wherein the water- soluble fusible material optionally included in the mixture in step is PEG having a molecular weight of from 1 000 to 20,000, or a poloxamer.
7. A process according to claim 6 wherein the PEG has a molecular weight of from 1 000 to 6 000.
8. A process according to any one of claims 1 to 7 wherein the fusible carrier or diluent is added stepwise during mechanical working.
9. A solid dosage form obtainable by compressing particles comprising a pharmaceutically active substance in a matrix of a hydrophobic and/or hydrophilic fusible diluent or carrier having a melting point of from 35 to 150°C, the solid dosage form optionally containing conventional tabletting excipients. [N.\LIBAA]00837:TCW I A capsule for oral dosing containing particles comprising a pharmaceutically active substance in a matrix of a hydrophobic and/or hydrophilic fusible carrier or diluent having a melting point of from 35 to 150 0 C and optionally containing conventional capsuling excipients.
11. A solid dosage form according to claim 9 or 10 wherein the particles are those obtainable by a proces,; comprising the steps of mechanically working a mixture containing a particulate drug and a particulate, hydrophobic and/or hydrophilic fusible carrier or diluent having a melting point from 35 to 150 0 C at a speed and external energy input which allows the carrier or diluent to melt or soften and particles of a desired si', to form.
12. A solid dosage form according to any one of claims 9 to 11 wherein the particles are obtained by mechanically working a mixture comprising the active ingredient, a hydrophobic and/or hydrophilic fusible carrier or diluent and optionally a release modifier in a high speed mixer at a rate and external energy input sufficient to cause the fusible carrier or diluent to melt or soften whereby it forms particles with the active ingredient and thereafter separating particles having a desired size range.
13. A solid dosage form accr ing to any one of claims 9 to 12, wherein the particles contain a release modifier w hich is a hydrophilic release modifier, or a water soluble or insoluble particulate organic or inorganic material. 20 14. A solid dosage form according to any one of claims 9 to 13, wherein **the active ingredient is unstable in water.
15. A l Ad dosage form according to claim 9 or 10, wherein the particles are obtainable by a process as defined in any one of claims 1 to 8.
16. A process for the manufacture of sustained release particles, substantially as hereinbefore described with reference to any one of the examples.
17. A solid dosage form, substantially as hereinbefore described with reference to any one of the examples.
18. A capsule for oral dosing, substantially as hereinbefore described with reference to any one of the examples.
19. Particles produced by the process of any one of claims 1 to 8 or 16. Dated 19 June, 1997 Euro-Celtique S.A. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [N:\LIBAA]00837:TCW a qlllB LI ~rSu ABSTRACT SUSTAINED RELEASE COMPOSITIONS A process for the manufacture of particles comprises mechanically working a mixture of a drug and a hydrophobic and/or hydrophilic fusible carrier in a high speed mixture so as to form agglomerates, breaking the agglomerates to give controlled release particles and optionally continuing the mechanical working with the optional addition of a low percentage of the carrier o. diluent. S SS o PA0240.SP Our Ref: P/0359 28/10/94 28/10/94
AU79015/94A
1993-11-23
1994-11-23
Sustained release compositions and a method of preparing pharmaceutical compositions
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1993-11-23
1993-11-23
A method of preparing pharmaceutical compositions by melt pelletisation
GB9324045
1993-11-23
GB9403922A
GB2288117A
(en)
1994-03-01
1994-03-01
Sustained release morphine
GB9403922
1994-03-01
GB9404544A
GB9404544D0
(en)
1994-03-09
1994-03-09
Controlled release formulation
GB9404544
1994-03-09
GB9404928A
GB2287880A
(en)
1994-03-14
1994-03-14
Production of sustained release compositions
GB9404928
1994-03-14
EP94303128A
EP0624366B1
(en)
1993-05-10
1994-04-29
Controlled release formulation containing tramadol
EP94303128
1994-04-29
EP94304144
1994-06-09
EP94304144A
EP0636370B2
(en)
1993-07-01
1994-06-09
Sustained release compositions containing morphine
GB9411842A
GB9411842D0
(en)
1994-06-14
1994-06-14
Pharmaceutical preparation
GB9411842
1994-06-14
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Families Citing this family (57)
* Cited by examiner, † Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
GB9514842D0
(en)
*
1995-07-20
1995-09-20
Smithkline Beecham Plc
Novel formulation
US6548084B2
(en)
1995-07-20
2003-04-15
Smithkline Beecham Plc
Controlled release compositions
GB9519363D0
(en)
1995-09-22
1995-11-22
Euro Celtique Sa
Pharmaceutical formulation
GB9713549D0
(en)
*
1996-10-18
1997-09-03
Euro Celtique Sa
Pharmaceutical combination formulation
BE1010803A3
(en)
*
1996-12-16
1999-02-02
Therabel Research Sa
Tablets pharmaceutical sustained release tramadol a basic and their preparation.
DE19729487A1
(en)
*
1997-07-10
1999-01-14
Dresden Arzneimittel
Process for the preparation of active ingredient preparations with controlled release from a matrix
RS49982B
(en)
1997-09-17
2008-09-29
Euro-Celtique S.A.,
Synergistic analgesic combination of opioid analgesic and cyclooxygenase-2 inhibitor
PT1685839E
(en)
1997-12-22
2013-07-08
Euro Celtique Sa
Pharmaceutical oral dosage form comprising a combination of an opioid agonist and opioid antagonist
US6375957B1
(en)
1997-12-22
2002-04-23
Euro-Celtique, S.A.
Opioid agonist/opioid antagonist/acetaminophen combinations
DE19901687B4
(en)
*
1999-01-18
2006-06-01
Grünenthal GmbH
Opioid controlled release analgesics
DE19901683B4
(en)
*
1999-01-18
2005-07-21
Grünenthal GmbH
Controlled-release analgesic
DE19923551A1
(en)
*
1999-05-21
2000-11-30
Lohmann Therapie Syst Lts
Pharmaceutical preparation with the active ingredient diamorphine and its use in a method for treating opiate addiction
SK285128B6
(en)
1999-12-28
2006-07-07
Zentiva, A. S.
A remedy with controlled release comprising tramadol hydrochloride and method for preparation thereof
WO2002092060A1
(en)
2001-05-11
2002-11-21
Endo Pharmaceuticals, Inc.
Abuse-resistant controlled-release opioid dosage form
SI2425824T1
(en)
2002-04-05
2017-06-30
Mundipharma Medical Cee Gmbh
Pharmaceutical preparation containing oxycodone and naloxone
US7776314B2
(en)
2002-06-17
2010-08-17
Grunenthal Gmbh
Abuse-proofed dosage system
US8487002B2
(en)
2002-10-25
2013-07-16
Paladin Labs Inc.
Controlled-release compositions
TWI319713B
(en)
2002-10-25
2010-01-21
Sustained-release tramadol formulations with 24-hour efficacy
DE10300325A1
(en)
2003-01-09
2004-07-22
Hexal Ag
Granules with oily substance, manufacturing process and tablet
US8075872B2
(en)
2003-08-06
2011-12-13
Gruenenthal Gmbh
Abuse-proofed dosage form
DE102005005446A1
(en)
2005-02-04
2006-08-10
Grünenthal GmbH
Break-resistant dosage forms with sustained release
US20070048228A1
(en)
2003-08-06
2007-03-01
Elisabeth Arkenau-Maric
Abuse-proofed dosage form
DE10361596A1
(en)
2003-12-24
2005-09-29
Grünenthal GmbH
Process for producing an anti-abuse dosage form
DE102004032051A1
(en)
2004-07-01
2006-01-19
Grünenthal GmbH
Process for the preparation of a secured against misuse, solid dosage form
DE10336400A1
(en)
2003-08-06
2005-03-24
Grünenthal GmbH
Anti-abuse dosage form
EP1604666A1
(en)
2004-06-08
2005-12-14
Euro-Celtique S.A.
Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD)
DE102004032049A1
(en)
*
2004-07-01
2006-01-19
Grünenthal GmbH
Anti-abuse, oral dosage form
AR050615A1
(en)
*
2004-08-27
2006-11-08
Novartis Ag
PHARMACEUTICAL COMPOSITIONS FOR ORAL ADMINISTRATION
GB2418854B
(en)
2004-08-31
2009-12-23
Euro Celtique Sa
Multiparticulates
DE102005005449A1
(en)
2005-02-04
2006-08-10
Grünenthal GmbH
Process for producing an anti-abuse dosage form
EP1702558A1
(en)
2005-02-28
2006-09-20
Euro-Celtique S.A.
Method and device for the assessment of bowel function
US8795723B2
(en)
2005-09-09
2014-08-05
Angelini Pharma Inc.
Sustained drug release compositions
EP2001445B1
(en)
2006-03-16
2014-07-23
Euro-Celtique S.A.
Pharmaceutical spheroids
SA07280459B1
(en)
2006-08-25
2011-07-20
بيورديو فارما إل. بي.
Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic
DE102007011485A1
(en)
2007-03-07
2008-09-11
Grünenthal GmbH
Dosage form with more difficult abuse
AU2009207796B2
(en)
2008-01-25
2014-03-27
Grunenthal Gmbh
Pharmaceutical dosage form
RU2508092C2
(en)
2008-05-09
2014-02-27
Грюненталь Гмбх
Method for preparing solid dosage form, particularly tablet for pharmaceutical application and method for preparing solid dosage form precursor, particularly tablet
RS58240B1
(en)
2009-03-10
2019-03-29
Euro Celtique Sa
Immediate release pharmaceutical compositions comprising oxycodone and naloxone
DE102009019268A1
(en)
*
2009-04-28
2010-11-11
Lts Lohmann Therapie-Systeme Ag
Perorally administrable solid drug, useful for the controlled release of active agent in gastrointestinal tract, comprises a porous matrix made of a material in which an active component is dissolved, emulsified, suspended or dispersed
EP2456424B1
(en)
2009-07-22
2013-08-28
Grünenthal GmbH
Oxidation-stabilized tamper-resistant dosage form
MX2012000317A
(en)
2009-07-22
2012-02-08
Gruenenthal Gmbh
Hot-melt extruded controlled release dosage form.
ES2487244T3
(en)
2010-09-02
2014-08-20
Grünenthal GmbH
Handling resistant dosage form comprising an anionic polymer
CN103269688A
(en)
2010-09-02
2013-08-28
格吕伦塔尔有限公司
Tamper resistant dosage form comprising inorganic salt
AR087359A1
(en)
2011-07-29
2014-03-19
Gruenenthal Gmbh
TEST ALTERATION TABLET PROVIDING IMMEDIATE RELEASE OF THE PHARMACO
ES2655900T3
(en)
2011-07-29
2018-02-22
Grünenthal GmbH
Tamper-proof tablet that provides immediate release of a medication
WO2013127831A1
(en)
2012-02-28
2013-09-06
Grünenthal GmbH
Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
AU2013248351B2
(en)
2012-04-18
2018-04-26
Grunenthal Gmbh
Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10064945B2
(en)
2012-05-11
2018-09-04
Gruenenthal Gmbh
Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
MX371432B
(en)
2013-05-29
2020-01-30
Gruenenthal Gmbh
Tamper-resistant dosage form containing one or more particles.
AR096438A1
(en)
2013-05-29
2015-12-30
Gruenenthal Gmbh
DOSAGE FORM RESISTANT TO INDEBITED USE WITH BIMODAL RELEASE PROFILE, PROCESS
EP3019157A1
(en)
2013-07-12
2016-05-18
Grünenthal GmbH
Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
AU2014295042B2
(en)
2013-07-23
2017-03-30
Mundipharma Pty Limited
A combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation
AU2014356581C1
(en)
2013-11-26
2020-05-28
Grunenthal Gmbh
Preparation of a powdery pharmaceutical composition by means of cryo-milling
EP3142646A1
(en)
2014-05-12
2017-03-22
Grünenthal GmbH
Tamper resistant immediate release capsule formulation comprising tapentadol
US9872835B2
(en)
2014-05-26
2018-01-23
Grünenthal GmbH
Multiparticles safeguarded against ethanolic dose-dumping
EA035434B1
(en)
2015-04-24
2020-06-15
Грюненталь Гмбх
Tamper-resistant dosage form with immediate release and resistance against solvent extraction
EP3346991A1
(en)
2015-09-10
2018-07-18
Grünenthal GmbH
Protecting oral overdose with abuse deterrent immediate release formulations
Citations (1)
* Cited by examiner, † Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
WO1992006679A1
(en)
*
1990-10-16
1992-04-30
Kabi Pharmacia Ab
A method for drug formulation and a pharmaceutical composition
Family Cites Families (3)
* Cited by examiner, † Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
US4132753A
(en)
*
1965-02-12
1979-01-02
American Cyanamid Company
Process for preparing oral sustained release granules
SE9200858L
(en)
*
1992-03-20
1993-09-21
Kabi Pharmacia Ab
Method for producing delayed release pellets
CN1230154C
(en)
*
1993-07-01
2005-12-07
欧洲凯尔特公司
Sustained release compositions and a method of preparing pharmaceutical compositions
1994
1994-11-17
DK
DK94308493T
patent/DK0654263T3/en
active
1994-11-17
AT
AT94308493T
patent/ATE212224T1/en
active
1994-11-17
EP
EP94308493A
patent/EP0654263B1/en
not_active
Expired - Lifetime
1994-11-17
DE
DE69429710T
patent/DE69429710T2/en
not_active
Expired - Lifetime
1994-11-17
ES
ES94308493T
patent/ES2168290T3/en
not_active
Expired - Lifetime
1994-11-17
PT
PT94308493T
patent/PT654263E/en
unknown
1994-11-18
NZ
NZ264953A
patent/NZ264953A/en
not_active
IP Right Cessation
1994-11-21
IL
IL11170994A
patent/IL111709A/en
not_active
IP Right Cessation
1994-11-21
CZ
CZ19942866A
patent/CZ289650B6/en
not_active
IP Right Cessation
1994-11-21
BG
BG99198A
patent/BG62429B1/en
unknown
1994-11-22
NO
NO19944473A
patent/NO314124B1/en
not_active
IP Right Cessation
1994-11-22
SK
SK1406-94A
patent/SK280496B6/en
not_active
IP Right Cessation
1994-11-22
FI
FI945476A
patent/FI113335B/en
not_active
IP Right Cessation
1994-11-22
HU
HU9403353A
patent/HU217205B/en
unknown
1994-11-23
CN
CN94118503A
patent/CN1121213C/en
not_active
Expired - Lifetime
1994-11-23
AU
AU79015/94A
patent/AU682223C/en
not_active
Expired
1994-11-24
JP
JP28993694A
patent/JP3411114B2/en
not_active
Expired - Lifetime
2002
2002-09-18
JP
JP2002271157A
patent/JP2003113075A/en
active
Pending
Patent Citations (1)
* Cited by examiner, † Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
WO1992006679A1
(en)
*
1990-10-16
1992-04-30
Kabi Pharmacia Ab
A method for drug formulation and a pharmaceutical composition
Also Published As
Publication number
Publication date
SK140694A3
(en)
1995-07-11
DK0654263T3
(en)
2002-04-29
HU217205B
(en)
1999-12-28
IL111709A0
(en)
1995-01-24
FI945476A0
(en)
1994-11-22
CZ289650B6
(en)
2002-03-13
NO944473L
(en)
1995-05-24
CZ286694A3
(en)
1995-06-14
FI945476A
(en)
1995-05-24
NZ264953A
(en)
1996-11-26
HU9403353D0
(en)
1995-02-28
SK280496B6
(en)
2000-03-13
CN1116521A
(en)
1996-02-14
NO944473D0
(en)
1994-11-22
AU7901594A
(en)
1995-06-01
DE69429710D1
(en)
2002-03-14
EP0654263A1
(en)
1995-05-24
ATE212224T1
(en)
2002-02-15
AU682223C
(en)
2005-03-24
BG99198A
(en)
1995-08-28
HUT74910A
(en)
1997-03-28
JPH07196475A
(en)
1995-08-01
FI113335B
(en)
2004-04-15
JP2003113075A
(en)
2003-04-18
EP0654263B1
(en)
2002-01-23
BG62429B1
(en)
1999-11-30
JP3411114B2
(en)
2003-05-26
NO314124B1
(en)
2003-02-03
CN1121213C
(en)
2003-09-17
ES2168290T3
(en)
2002-06-16
PT654263E
(en)
2002-06-28
IL111709A
(en)
2002-12-01
DE69429710T2
(en)
2002-08-08
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Legal Events
Date
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Description
2000-03-16
PC
Assignment registered
Owner name:
MUNDIPHARMA MEDICAL GMBH
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FORMER OWNER WAS: EURO-CELTIQUE S.A.
2004-09-23
DA2
Applications for amendment section 104
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THE NATURE OF THE PROPOSED AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 19990726
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