GB2287880A - Production of sustained release compositions - Google Patents

Production of sustained release compositions Download PDF

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Publication number
GB2287880A
GB2287880A GB9404928A GB9404928A GB2287880A GB 2287880 A GB2287880 A GB 2287880A GB 9404928 A GB9404928 A GB 9404928A GB 9404928 A GB9404928 A GB 9404928A GB 2287880 A GB2287880 A GB 2287880A
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United Kingdom
Prior art keywords
particles
diluent
carrier
optionally
hydrophobic
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.)
Withdrawn
Application number
GB9404928A
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GB9404928D0 (en
GB2287880A8 (en
Inventor
Ronald Brown Miller
Stewart Thomas Leslie
Kevin John Smith
Sandra Therese Antoinette Malkowska
Derek Allan Prater
Trevor John Knott
Joanne Heafield
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Euro Celtique SA
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Euro Celtique SA
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Priority to GB9404928A priority Critical patent/GB2287880A/en
Priority to NZ260408A priority patent/NZ260408A/en
Priority to IL109460A priority patent/IL109460A/en
Priority to IL11966094A priority patent/IL119660A/en
Publication of GB9404928D0 publication Critical patent/GB9404928D0/en
Priority to PT04030658T priority patent/PT1527775E/en
Priority to ES04014719T priority patent/ES2247574T3/en
Priority to AT04014719T priority patent/ATE303140T1/en
Priority to AT94303128T priority patent/ATE138566T1/en
Priority to AT04030658T priority patent/ATE468850T1/en
Priority to DE0729751T priority patent/DE729751T1/en
Priority to PT95114527T priority patent/PT699436E/en
Priority to EP09004973.5A priority patent/EP2103303B1/en
Priority to SG1996008705A priority patent/SG67347A1/en
Priority to AT95114527T priority patent/ATE201989T1/en
Priority to DE9422335U priority patent/DE9422335U1/en
Priority to DE0699436T priority patent/DE699436T1/en
Priority to DE69427472T priority patent/DE69427472T3/en
Priority to DE09004973T priority patent/DE09004973T8/en
Priority to PT04014719T priority patent/PT1468679E/en
Priority to ES04030658T priority patent/ES2346651T3/en
Priority to DE69435295T priority patent/DE69435295D1/en
Priority to ES09004973T priority patent/ES2331046T1/en
Priority to DK94303128.6T priority patent/DK0624366T3/en
Priority to EP94303128A priority patent/EP0624366B1/en
Priority to EP95114527A priority patent/EP0699436B2/en
Priority to DK95114527.5T priority patent/DK0699436T4/en
Priority to DK04030658.1T priority patent/DK1527775T3/en
Priority to EP96101147A priority patent/EP0729751A1/en
Priority to EP04014719A priority patent/EP1468679B1/en
Priority to DE69400215T priority patent/DE69400215T2/en
Priority to EP04030658A priority patent/EP1527775B1/en
Priority to ES94303128T priority patent/ES2088312T3/en
Priority to DK04014719T priority patent/DK1468679T3/en
Priority to ES95114527T priority patent/ES2159591T5/en
Priority to DE69434479T priority patent/DE69434479T2/en
Priority to CZ19941093A priority patent/CZ288517B6/en
Priority to HU9401478A priority patent/HU228177B1/en
Priority to FI942092A priority patent/FI942092A/en
Priority to NO941719A priority patent/NO306446B1/en
Priority to CA002123160A priority patent/CA2123160C/en
Priority to AU61963/94A priority patent/AU6196394A/en
Priority to IDP991104D priority patent/ID25988A/en
Priority to US08/241,129 priority patent/US5591452A/en
Priority to SK1437-98A priority patent/SK283143B6/en
Priority to JP6096671A priority patent/JP3045924B2/en
Priority to CN94105356A priority patent/CN1094755C/en
Priority to SK541-94A priority patent/SK279971B6/en
Priority to TW085103273A priority patent/TW496736B/en
Priority to IL10994494A priority patent/IL109944A/en
Priority to AT94304144T priority patent/ATE172376T1/en
Priority to SG1996009186A priority patent/SG50706A1/en
Priority to DE69414046T priority patent/DE69414046T3/en
Priority to ES94304144T priority patent/ES2124372T5/en
Priority to EP94304144A priority patent/EP0636370B2/en
Priority to DK94304144T priority patent/DK0636370T4/en
Priority to CZ19941550A priority patent/CZ287918B6/en
Priority to SK763-94A priority patent/SK280534B6/en
Priority to NZ260883A priority patent/NZ260883A/en
Priority to PL94304062A priority patent/PL179282B1/en
Priority to NO942470A priority patent/NO306449B1/en
Priority to FI943141A priority patent/FI114285B/en
Priority to CA002127166A priority patent/CA2127166C/en
Priority to AU66105/94A priority patent/AU6610594A/en
Priority to HU9402007A priority patent/HU220075B/en
Priority to CN 94106701 priority patent/CN1230154C/en
Priority to JP15121994A priority patent/JP3647897B2/en
Priority to KR1019940015740A priority patent/KR100365572B1/en
Priority to BG99077A priority patent/BG62316B1/en
Priority to BG99078A priority patent/BG62473B1/en
Priority to PT94308493T priority patent/PT654263E/en
Priority to DK94308493T priority patent/DK0654263T3/en
Priority to EP94308493A priority patent/EP0654263B1/en
Priority to AT94308493T priority patent/ATE212224T1/en
Priority to DE69429710T priority patent/DE69429710T2/en
Priority to ES94308493T priority patent/ES2168290T3/en
Priority to NZ264953A priority patent/NZ264953A/en
Priority to CZ19942866A priority patent/CZ289650B6/en
Priority to IL11170994A priority patent/IL111709A/en
Priority to BG99198A priority patent/BG62429B1/en
Priority to NO19944473A priority patent/NO314124B1/en
Priority to HU9403353A priority patent/HU217205B/en
Priority to SK1406-94A priority patent/SK280496B6/en
Priority to PL94305939A priority patent/PL178883B1/en
Priority to FI945476A priority patent/FI113335B/en
Priority to AU79015/94A priority patent/AU682223C/en
Priority to CN94118503A priority patent/CN1121213C/en
Priority to KR1019940031398A priority patent/KR100354702B1/en
Priority to JP28993694A priority patent/JP3411114B2/en
Priority to EP95301337A priority patent/EP0672416A1/en
Priority to ZA952103A priority patent/ZA952013B/en
Priority to JP7052498A priority patent/JPH0840905A/en
Priority to CA002144500A priority patent/CA2144500A1/en
Priority to AU14755/95A priority patent/AU694475B2/en
Priority to FI951155A priority patent/FI951155A/en
Priority to NO950950A priority patent/NO950950L/en
Priority to US08/449,772 priority patent/US6326027B1/en
Publication of GB2287880A publication Critical patent/GB2287880A/en
Publication of GB2287880A8 publication Critical patent/GB2287880A8/en
Priority to US08/607,851 priority patent/US5891471A/en
Priority to US08/607,852 priority patent/US5849240A/en
Priority to GR960401422T priority patent/GR3020084T3/en
Priority to US08/677,798 priority patent/US6254887B1/en
Priority to IL11966096A priority patent/IL119660A0/en
Priority to US08/774,229 priority patent/US5843480A/en
Priority to US08/843,571 priority patent/US5879705A/en
Priority to US08/944,106 priority patent/US5965163A/en
Priority to AU39957/97A priority patent/AU3995797A/en
Priority to AU52995/98A priority patent/AU722358B2/en
Priority to JP22971898A priority patent/JP3267561B2/en
Priority to US09/264,399 priority patent/US6143328A/en
Priority to CNB991066421A priority patent/CN1146410C/en
Priority to NO19993484A priority patent/NO313124B1/en
Priority to US09/370,270 priority patent/US6162467A/en
Priority to AT0081699U priority patent/AT3413U3/en
Priority to US09/740,732 priority patent/US20010019725A1/en
Priority to US09/800,204 priority patent/US7074430B2/en
Priority to NO20013566A priority patent/NO331650B1/en
Priority to GR20010401419T priority patent/GR3036565T3/en
Priority to JP2001297270A priority patent/JP3443574B2/en
Priority to JP2002271157A priority patent/JP2003113075A/en
Priority to FI20030560A priority patent/FI121565B/en
Priority to US11/435,015 priority patent/US20060269603A1/en
Priority to US12/152,474 priority patent/US20090117191A1/en
Priority to FI20105856A priority patent/FI122717B/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • 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
    • 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
    • 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

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

2287880 PHARMACEUTICAL COMPOSITIONS AND METHOD OF PRODUCING THE SAMEE 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. Omm. 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:
(a) the binder is in particle form consisting of one or more waterinsoluble or water-soluble, wax-like binder substance(s) with a melting point above 4TC and (b) 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 the binder to melt and pelletisation to take place.
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 1 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.
2 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 a product with reproducible controlled release characteristics.
The present invention thus includes in one aspect a process for the manufacture of particles, preferably sustained release particles, which comprises (a) 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 energy input which allows the carrier or diluent to melt or soften, whereby it forms agglomerates; (b) breaking down the larger agglomerates to give controlled release particles; optionally (c) continuing mechanically working optionally with a further addition of low percentage of the carrier or diluent; and (d) optionally repeating step (c) and possibly (b) one or more, e.g. up to five, times.
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 over 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 1 - into sachets or moulding into suppositories, pessaries or forming into other suitable dosaRe forms.
S 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, ibuprofen, indomethacin and nifedipine.
Among the active ingredient 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 4 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 ANTIALLERGICS Pheniramine Dimethindene Terfenadine Astemizole Tritoqualine Loratadine Doxylamine Mequitazine 1 -b.
Dexchlorpheniramine Triprolidine Oxatomide ANTIHYPERTENSIVE Clonidine Moxonidine Methyidopa Doxazosin Prazosin Urapidil Terazosin Minoxidil Dihydralazin Deserpidine Acebutalol Alprenolol Atenolol Metoprolol Bupranolol Penbutolol Propranolol Esmolol Bisoprolol Ciliprolol Sotalol Metipranolol Nadolol Oxprenolol Nifedipine Nicadipine Verapamil 6 Diltiazem Felodipine Nimodipine Flunarizine Quinapril Lisinopril Captopril Ramipril Fosinopril Cilazapril Enalapril BRONCHODILATOR/ANTI-ASTHMATIC Pirbuterol Orciprenaline Terbutaline Fenoterol Clenbuterol Salbutamol Procaterol Theophylline Cholintheophyllinate Theophylline-ethylenediamine Ketofen ANTIARRHYTHMICS Viquidil Procainamide Mexiletine Tocainide Propafenone Ipratropium 7 CENTRALLY ACTING SUBSTANCES Amantadine Levodopa Biperiden Benzotropine Bromocriptine Procyclidine Moclobemide Tranylcypromide Clomipramine Maprotiline Doxepin Opipramol Amitriptyline Desipramine Imipramine Fluroxamin Fluoxetin Paroxetine Trazodone Viloxazine Fluphenazine Perphenazine Promethazine Thioridazine Triflupromazine Prothipendyl Tiotixene Chlorprothixene Haloperidol Pipamperone Pimozide 8 Sulpiride Fenethylline Methylphenildat Trifluoperazine Thioridazine Oxazepam Lorazepam Bromoazepam Alprazolam Diazepam Clobazam Buspirone Piracetam CYTOSTATICS AND METASTASIS INHIBITORS Melfalan Cyclophosphamide Trofosfamide Chlorambucil Lomustine Busulfan Prednimustine Fluorouracil Methotrexate Mercaptopurine Thioguanin Hydroxycarbamide Altretamine Procarbazine ANTI-MIGRALNE Lisuride 9 Methysergide Dihydroergotamine Ergotamine Pizotifen GASTROWTESTINAL 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 process of the invention may advantageously be used for preparing dosage forms containing active substances 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 (a) together with a major portion of the hydrophobic or hydrophilic fusible release control material used. Preferably the amount of fusible release control material added in step (a) is between e.g. 10% and <99% w/w of the total amount of ingredients added in the entire manufacturing operation.
In step (c) the amount of additional fusible release control material added is preferably between 5% and 75% w/w of the total amount of ingredients added.
Stage (a) of the process may be carried out in conventional high speed mixers with a standard stainless steel interior, e.g. a Collette Vactron 75 or equivalent mixer. The mixture is processed until a bed temperature above 40'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 non-aggregated original material. Such material, in the case of the embodiments described below, has the appearance of agglomerates which upon cooling below 40'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'C may be conveniently used.
The agglomerates are broken down by any suitable means, which will comminute oversize agglomerates and produce a mixture of powder and small particles preferably 11 with a diameter under 2min. 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.
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 ftisible materials used begin to soften/melt and additional hydrophobic and/or hydrophilic fusible material is then added. 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 speed mixer it is preferred to supply at least part of the energy by means of microwave energy.
Energy 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 over 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 13er se.
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 United Kingdom Patent Application No. 9315467.2 filed on 12 27 July 1993, 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 also found that particles produced by the melt pelletisation processes described in application PCT/SE93/00225 and the process described and claimed in our prior unpublished UK application No. 9324045. 5 filed on 23 November 1993 as well as the process described herein are particularly useful for processing into the form of tablets.
We have found that by suitable selection of the materials used in forming the particles 0 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.
To produce tablets in accordance with the invention, particles produced in accordance with the invention may be mixed or blended with the desired excipient(s), 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 druas a higher loadin- of the dru- 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 t 13 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 order that the invention may be well understood the following examples are given by way of illustration only.
EXAMPLES 1 to 4 Particles, having the formulations given in Table I below, were prepared by the steps of:
Placing the ingredients (a) to (c) (total batch weight 20kg) in the bowl of a 75 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.
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 (d), and continuing the mechanical working until uniform particles of the desired predetermined size range are formed in yield of greater than 80%.
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.
14 TABLE I
EXAMPLE 1 2 3 a) MORPHINE SULPHATE (WT%) 55.0 52.19 53.48 B.P.
b) HYDROGENATED VEGETABLE OIL
USNF (WT%) 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%) % 90.5 83.4 90.1 The in vitro release rates of Examples 1, 2, 3 and 4 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 371C (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 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.
is TABLEII
PRODUCT OF EXAMPLES HOURS AFTER 1 1 2 3 START OF TEST % MORPHINE RELEASED 2 21 15 20 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 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 (d) and mixing, heating by jacket heating and microwave being applied during mixing. The in vitro release rate is given in Table IIa and demonstrates that although the composition of the proaucts in Exampl es 3 and 4 are the same the different processing results in modified release rates.
TABLE Ha
PRODUCT OF EXAMPLE 4 HOURS AFTER % OF MORPHINE START OF TEST RELEASED 2 15 4 24 6 30 8 3 6 12 46 18 57 24 65 71 16 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, randornised 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 30ing (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 nglml of morphine at median thnes between 2 and 6 hours following administration and blood sampling according to the above protocol.
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 CONTINUS' 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 5
Particles were produced analogously to Examples 1 to 4 but having the following I'D ingredients ,Vt% Morphine sulphate 55.0 Hydrogenated vegetable oil 44.7 17 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. lmm diameter normal concave tooling on a single punch F3 Manesty tabletting machine. The ingredients per dosage unit amounted to the following:
TABLE III
Tablet Mg/Tablet Ingredient 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 2.0 Purified Talc 2.18 3.0 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:
18 TABLE IV
HOURS AFTER PARTICLES [TABLET 1 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 following ingredients.
Morphine Sulphate Wt% 55.0 19 Hydrogenated Vegetable Oil 44.4 Polyethylene Glycol 6000 0.6 Two lots of tablets (3 and 4) were produced from the particles using a 7. l mm diameter concave tooling. The ingredients per dosage unit were as follows; TABLE V
TABLET Me/Tablet INGREDIENT 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 5.0 Magnesium Stearate 2.0 2.0 Purified Talc 3.0 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; TABLE VI
HOURS AFTER PARTICLES 1 TABLETA 1 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 60 16 NR NR 67 2,1 NR NR 77 These results demonstrate again a dramatic reduction in the release rate 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 18811) as a tabletting excipient, the release rate for tablet 4 which contains the surface active agents being greater that 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 in-redients; Wt% Tramadol Hydrochloride 50 Hydrogenated Vegetable Oil 50 21 Three lots of tablets (5, 6 and 7) were produced from particles using respectively (a) 14mm x 6min, (b) 16mm x 7mm and (c) 18.6 x 7.5mirt capsule shaped tooling. The ingredients per dosage unit were as follows; TABLE VII
TABLET MG/TABLET INGREDIENT 5 6 7 Tramadol HCl 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 HCl 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; 22 HOURS AFTER Particles 1 Tablet 5 1 Tablet 6 1 Tablet 7 START OF TEST % TRAMADOL H0 RELEASED 1 54 16 is 15 2 68 23 20 21 3 76 28 25 25 4 82 32 28 28 6 89 40 35 35 8 93 46 41 40 96 50 45 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 75 Hydrogenated Vegetable Oil 25 Three lots of tablets (8, 9 and 10) were produced from the particles using respectiveh 23 tooling (a), (b) and (c) described in Example 7. The ingredients per unit dosage were as follows:
TABLE X
TABLET MG/TABLET INGREDIENT 8 9 10 Tramadol HQ 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 10 START OF TEST % TRAMADOL 11C1 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 24 These results show that by increasing the loading of the highly water soluble trarnadol hydrochloride (75 % w/w in this example compared with 50 % w/w in Example 7) a significantly faster release rate of the active ingredient can be achieved.
1 z I

Claims (14)

1. A process for the manufacture of particles, preferably sustained release particles, which comprises (a) 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 energy input which allows the carrier or diluent to melt or soften whereby it forms agglomerates; (b) breaking down the agglomerates to give controlled release particles; and optionally (c) continuing mechanically working optionally with the addition of a low percentage of the carrier or diluent; and optionally (d) repeating steps (c) and possibly (b) one or more times.
2. A process according to claim 1, wherein during the mechanical working, heat is supplied thereto by microwave radiation.
3.
A process according to claim 2, wherein only part of the heating is supplied by microwave radiation.
A process according to any one of claims 1 to 3, wherein the drug is morphine 26 tramadol, hydromorphone, oxycodone or a pharmaceutically acceptable salt of any one of these.
5. A process according to any one of claims 1 to 4, wherein the 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 watersoluble fusible material or diluent optionally included in the mixture in step (a) is PEG having a molecular weight of from 1000 to 6000, or a poloxamer.
7. A process according to any one of claims 1 to 6 wherein the fusible carrier or diluent is added stepwise during mechanical working.
8. A solid dosage form obtainable by compressing particles comprising a pharmaceutically active substance in a matrix of a hydrophobic and/or hydrophilic fusible material having a melting point of from 35 to 1500C, the solid dosage form optionally containing conventional tabletting excipients.
9. A capsule for oral dosing containing particles comprising a pharmaceutically active substance in a matrix of a hydrophobic and/or hydrophilic fusible material having a melting point of from 35 to 150'C and optionally containing 4 conventional capsuling excipients.
10. A solid dosage form according to Claim 8 or 9 wherein the particles are those obtainable by a process 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 1501C at a speed and energy input which allows the carrier or diluent to melt or soften and particles of a desired size to form.
11 1 27 11. A solid dosage form as set forth in any one of Claims 8 to 10 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 energy input sufficient to cause the fusible material to melt or soften whereby it forms particles with the active ingredient and thereafter separating particles having a desired size range.
12. A solid dosage form as set forth in any one of claims 8 to 11, whereas the particles contain a release modifier which is a hydrophilic release modifier, or a water soluble or insoluble particulate organic or inorganic material.
13. A solid dosage form as set forth in any one of claims 8 to 12, wherein the active ingredient is unstable in water.
14. A solid dosage form as set forth in claim 8 or 9, wherein the particles are obtainable by a process as defiped in any one of claims 1 to 6.
GB9404928A 1991-12-24 1994-03-14 Production of sustained release compositions Withdrawn GB2287880A (en)

Priority Applications (122)

Application Number Priority Date Filing Date Title
GB9404928A GB2287880A (en) 1994-03-14 1994-03-14 Production of sustained release compositions
NZ260408A NZ260408A (en) 1993-05-10 1994-04-27 Controlled release preparation comprising tramadol
IL109460A IL109460A (en) 1993-05-10 1994-04-27 Controlled release formulation comprising tramadol
IL11966094A IL119660A (en) 1993-05-10 1994-04-27 Controlled release formulation comprising tramadol
PT04030658T PT1527775E (en) 1993-05-10 1994-04-29 Controlled release formulation containing tramadol
ES04014719T ES2247574T3 (en) 1993-05-10 1994-04-29 FORMULATION OF CONTROLLED RELEASE THAT INCLUDES TRAMADOL.
AT04014719T ATE303140T1 (en) 1993-05-10 1994-04-29 MEDICINAL PRODUCT CONTAINING TRAMADOL WITH CONTROLLED RELEASE OF ACTIVE INGREDIENTS
AT94303128T ATE138566T1 (en) 1993-05-10 1994-04-29 DELAYED RELEASE MEDICINAL PRODUCT CONTAINING TRAMADOL
AT04030658T ATE468850T1 (en) 1993-05-10 1994-04-29 MEDICINAL PRODUCT CONTAINING TRAMADOL WITH CONTROLLED RELEASE OF ACTIVE INGREDIENTS
DE0729751T DE729751T1 (en) 1993-05-10 1994-04-29 Tramadol-containing drug with delayed drug delivery
PT95114527T PT699436E (en) 1993-05-10 1994-04-29 CONTROLLED LIBERATION FORMULA
EP09004973.5A EP2103303B1 (en) 1993-05-10 1994-04-29 Controlled release formulation containing tramadol
SG1996008705A SG67347A1 (en) 1993-05-10 1994-04-29 Controlled release formulation
AT95114527T ATE201989T1 (en) 1993-05-10 1994-04-29 MEDICINAL PRODUCTS WITH CONTROLLED DELIVERY OF ACTIVE INGREDIENTS
DE9422335U DE9422335U1 (en) 1993-05-10 1994-04-29 Controlled release formulation
DE0699436T DE699436T1 (en) 1993-05-10 1994-04-29 Controlled drug delivery drugs
DE69427472T DE69427472T3 (en) 1993-05-10 1994-04-29 Drugs with controlled release of active ingredient
DE09004973T DE09004973T8 (en) 1993-05-10 1994-04-29 Controlled release formulation
PT04014719T PT1468679E (en) 1993-05-10 1994-04-29 CONTROLLED FREQUENCY FORMULA CONTAINING TRAMADOL
ES04030658T ES2346651T3 (en) 1993-05-10 1994-04-29 FORMULATION OF CONTROLLED LIBERATION THAT TRAMADOL FORMULATION OF CONTROLLED LIBERATION CONTAINING TRAMADOL.
DE69435295T DE69435295D1 (en) 1993-05-10 1994-04-29 Tramadol-containing drug with controlled release of active ingredient
ES09004973T ES2331046T1 (en) 1993-05-10 1994-04-29 CONTROLLED RELEASE FORMULATION.
DK94303128.6T DK0624366T3 (en) 1993-05-10 1994-04-29 Composition containing controlled release tramadol
EP94303128A EP0624366B1 (en) 1993-05-10 1994-04-29 Controlled release formulation containing tramadol
EP95114527A EP0699436B2 (en) 1993-05-10 1994-04-29 Controlled release formulation
DK95114527.5T DK0699436T4 (en) 1993-05-10 1994-04-29 Controlled release preparation
DK04030658.1T DK1527775T3 (en) 1993-05-10 1994-04-29 Controlled release tramadol-containing composition
EP96101147A EP0729751A1 (en) 1993-05-10 1994-04-29 Controlled release formulation containing tramadol
EP04014719A EP1468679B1 (en) 1993-05-10 1994-04-29 Controlled release formulation containing tramadol
DE69400215T DE69400215T2 (en) 1993-05-10 1994-04-29 Tramadol-containing medicine with delayed release of active ingredient
EP04030658A EP1527775B1 (en) 1993-05-10 1994-04-29 Controlled release formulation containing tramadol
ES94303128T ES2088312T3 (en) 1993-05-10 1994-04-29 CONTROLLED RELEASE FORMULATION CONTAINING TRAMADOL.
DK04014719T DK1468679T3 (en) 1993-05-10 1994-04-29 Controlled release tramadol-containing formulation
ES95114527T ES2159591T5 (en) 1993-05-10 1994-04-29 Controlled Release Formulation
DE69434479T DE69434479T2 (en) 1993-05-10 1994-04-29 Tramadol-containing drug with controlled release of active ingredient
CZ19941093A CZ288517B6 (en) 1993-05-10 1994-05-04 Pharmaceutical preparation in unit dosage form and process of its preparation
HU9401478A HU228177B1 (en) 1993-05-10 1994-05-06 Controlled release formulation containing tramadol
FI942092A FI942092A (en) 1993-05-10 1994-05-06 Restrained released composition
NO941719A NO306446B1 (en) 1993-05-10 1994-05-09 Oral pharmaceutical preparation comprising tramadol with controlled release effect
CA002123160A CA2123160C (en) 1993-05-10 1994-05-09 Controlled release formulation
AU61963/94A AU6196394A (en) 1993-05-10 1994-05-09 Controlled release formulation
IDP991104D ID25988A (en) 1993-05-10 1994-05-10 DRUG FORMULATION WHICH SOLVED CAN BE ARRANGED (Fraction of P-940726)
US08/241,129 US5591452A (en) 1993-05-10 1994-05-10 Controlled release formulation
SK1437-98A SK283143B6 (en) 1993-05-10 1994-05-10 Pharmaceutical preparation for controlled release
JP6096671A JP3045924B2 (en) 1993-05-10 1994-05-10 Controlled release oral drug formulations
CN94105356A CN1094755C (en) 1993-05-10 1994-05-10 Controlled release formulation
SK541-94A SK279971B6 (en) 1993-05-10 1994-05-10 Controlled release pharmaceutical composition and process for its preparation
TW085103273A TW496736B (en) 1993-05-10 1994-05-12 Controlled release formulation
IL10994494A IL109944A (en) 1993-07-01 1994-06-08 Sustained release dosage unit forms containing morphine and a method of preparing these sustained release dosage unit forms
AT94304144T ATE172376T1 (en) 1993-07-01 1994-06-09 MORPHINE-CONTAINING MEDICINAL COMPOSITIONS WITH DELAYED RELEASE
SG1996009186A SG50706A1 (en) 1993-07-01 1994-06-09 Sustained release compositions and a method of preparing pharmaceutical compositions
DE69414046T DE69414046T3 (en) 1993-07-01 1994-06-09 Morphine-containing medicinal compositions with delayed drug delivery
ES94304144T ES2124372T5 (en) 1993-07-01 1994-06-09 SUSTAINED RELEASE COMPOSITIONS CONTAINING MORPHINE.
EP94304144A EP0636370B2 (en) 1993-07-01 1994-06-09 Sustained release compositions containing morphine
DK94304144T DK0636370T4 (en) 1993-07-01 1994-06-09 Deposits containing morphine
CZ19941550A CZ287918B6 (en) 1993-07-01 1994-06-23 Orally administered unit dosage form with controlled release and process for preparing thereof
SK763-94A SK280534B6 (en) 1993-07-01 1994-06-23 Sustained release preparations of morphine and a method of preparing the same
NZ260883A NZ260883A (en) 1993-07-01 1994-06-29 Oral sustained-release medicaments containing morphine
PL94304062A PL179282B1 (en) 1993-07-01 1994-06-30 Retarded release compositions and method of obtaining such compositions
NO942470A NO306449B1 (en) 1993-07-01 1994-06-30 Orally administered morphine preparation for sustained release as well as preparation of multiparticulates for use in the preparation
FI943141A FI114285B (en) 1993-07-01 1994-06-30 Process for preparing sustained release pharmaceutical dosage unit form
CA002127166A CA2127166C (en) 1993-07-01 1994-06-30 Sustained release morphine compositions and a method of preparation
AU66105/94A AU6610594A (en) 1991-12-24 1994-06-30 Sustained release compositions and a method of preparing pharmaceutical compositions
HU9402007A HU220075B (en) 1993-07-01 1994-07-01 Retarde pharmaceutical compositions containing morphine and process for producing them
CN 94106701 CN1230154C (en) 1993-07-01 1994-07-01 Sustained release compositions and a method of preparing pharmaceutical compositions
JP15121994A JP3647897B2 (en) 1993-07-01 1994-07-01 Sustained release unit dosage form
KR1019940015740A KR100365572B1 (en) 1993-07-01 1994-07-01 Sustained-release and pharmaceutical compositions
BG99077A BG62316B1 (en) 1993-10-07 1994-09-29 Pharmaceutical forms with continuous release and method for their preparation
BG99078A BG62473B1 (en) 1993-11-23 1994-09-29 Pharmaceutical preparation with monitored release
PT94308493T PT654263E (en) 1993-11-23 1994-11-17 METHOD FOR THE PREPARATION OF A PROLONGED LIBERTYACAO COMPOSITION
DK94308493T DK0654263T3 (en) 1993-11-23 1994-11-17 Process for the preparation of a sustained release preparation
EP94308493A EP0654263B1 (en) 1993-11-23 1994-11-17 Method for preparing a sustained release composition
AT94308493T ATE212224T1 (en) 1993-11-23 1994-11-17 METHOD FOR PRODUCING A MEDICINAL COMPOSITION WITH DELAYED RELEASE
DE69429710T DE69429710T2 (en) 1993-11-23 1994-11-17 Process for the preparation of a drug composition with delayed drug delivery
ES94308493T ES2168290T3 (en) 1993-11-23 1994-11-17 METHOD FOR PREPARING A SUSTAINED RELEASE COMPOSITION.
NZ264953A NZ264953A (en) 1993-11-23 1994-11-18 Manufacture of drug-containing particles from a mixture of particulate drug and a particulate hydrophobic and/or hydrophilic fusible carrier or diluent in a high speed mixer such that the carrier/diluent melts and breaking up the agglomerates thus formed; sustained release forms
CZ19942866A CZ289650B6 (en) 1993-11-23 1994-11-21 Process for preparing a medicament controllably releasing active substance thereof
IL11170994A IL111709A (en) 1993-11-23 1994-11-21 Process for the manufacture of sustained release particles and dosage forms comprising particles obtained by the process
BG99198A BG62429B1 (en) 1993-11-23 1994-11-21 Method for the preparation of pharmaceutical compositions
NO19944473A NO314124B1 (en) 1993-11-23 1994-11-22 Process for the preparation of particles
HU9403353A HU217205B (en) 1993-11-23 1994-11-22 Sustained release compositions and a method of preparing pharmaceutical compositions
SK1406-94A SK280496B6 (en) 1993-11-23 1994-11-22 Process for preparing particles with permanent release of active substance
PL94305939A PL178883B1 (en) 1993-11-23 1994-11-22 Prolonged release compositions and method of obtaining them
FI945476A FI113335B (en) 1993-11-23 1994-11-22 Process for the preparation of particles useful in pharmaceutical compositions
AU79015/94A AU682223C (en) 1993-11-23 1994-11-23 Sustained release compositions and a method of preparing pharmaceutical compositions
CN94118503A CN1121213C (en) 1993-11-23 1994-11-23 Sustained release compositions and a method of preparing pharmaceutical compositions
KR1019940031398A KR100354702B1 (en) 1993-11-23 1994-11-23 Manufacturing method and sustained release composition of pharmaceutical composition
JP28993694A JP3411114B2 (en) 1993-11-23 1994-11-24 Method for producing long-acting composition and pharmaceutical composition
EP95301337A EP0672416A1 (en) 1994-03-14 1995-03-02 Pharmaceutical composition comprising diamorphine
ZA952103A ZA952013B (en) 1994-03-14 1995-03-10 Pharmaceutical preparation
JP7052498A JPH0840905A (en) 1994-03-14 1995-03-13 Pharmaceutical preparation
CA002144500A CA2144500A1 (en) 1994-03-14 1995-03-13 Pharmaceutical preparation
AU14755/95A AU694475B2 (en) 1994-03-14 1995-03-13 Pharmaceutical preparation
FI951155A FI951155A (en) 1994-03-14 1995-03-13 Pharmaceutical preparation
NO950950A NO950950L (en) 1994-03-14 1995-03-13 Pharmaceutical preparation
US08/449,772 US6326027B1 (en) 1993-05-10 1995-05-24 Controlled release formulation
US08/607,851 US5891471A (en) 1993-11-23 1996-02-27 Pharmaceutical multiparticulates
US08/607,852 US5849240A (en) 1993-11-23 1996-02-27 Method of preparing sustained release pharmaceutical compositions
GR960401422T GR3020084T3 (en) 1993-05-10 1996-05-30 Controlled release formulation containing tramadol.
US08/677,798 US6254887B1 (en) 1993-05-10 1996-07-10 Controlled release tramadol
IL11966096A IL119660A0 (en) 1993-05-10 1996-11-20 Controlled release formulation
US08/774,229 US5843480A (en) 1994-03-14 1996-12-27 Controlled release diamorphine formulation
US08/843,571 US5879705A (en) 1993-07-27 1997-04-18 Sustained release compositions of morphine and a method of preparing pharmaceutical compositions
US08/944,106 US5965163A (en) 1993-11-23 1997-09-30 Substained release compositions and a method of preparing pharmaceutical compositions
AU39957/97A AU3995797A (en) 1993-05-10 1997-10-07 Controlled release formulation
AU52995/98A AU722358B2 (en) 1991-12-24 1998-02-06 Sustained release compositions and a method of preparing pharmaceutical compositions
JP22971898A JP3267561B2 (en) 1993-05-10 1998-08-14 Use of tramadol or a pharmaceutically acceptable salt thereof and analgesic
US09/264,399 US6143328A (en) 1993-07-27 1999-03-08 Sustained release compositions and a method of preparing pharmaceutical compositions
CNB991066421A CN1146410C (en) 1993-05-10 1999-05-17 Controlled release formulation
NO19993484A NO313124B1 (en) 1993-05-10 1999-07-15 Use of tramadol in the manufacture of a medicament for the treatment of pain
US09/370,270 US6162467A (en) 1993-11-23 1999-08-09 Sustained release compositions and a method of preparing pharmaceutical compositions
AT0081699U AT3413U3 (en) 1993-05-10 1999-11-25 MEDICINAL PRODUCT WITH CONTROLLED RELEASE OF TRAMADOL
US09/740,732 US20010019725A1 (en) 1993-11-23 2000-12-19 Sustained release compositions and a method of preparing pharmaceutical compositions
US09/800,204 US7074430B2 (en) 1993-05-10 2001-03-06 Controlled release tramadol tramadol formulation
NO20013566A NO331650B1 (en) 1993-05-10 2001-07-19 Oral preparation of tramadol or a pharmaceutically acceptable salt thereof with controlled release effect
GR20010401419T GR3036565T3 (en) 1993-05-10 2001-09-06 Controlled release formulation
JP2001297270A JP3443574B2 (en) 1993-05-10 2001-09-27 Analgesic containing tramadol or a salt thereof
JP2002271157A JP2003113075A (en) 1993-11-23 2002-09-18 Sustained release composition
FI20030560A FI121565B (en) 1993-05-10 2003-04-14 A process for the preparation of a controlled release formulation of tramadol
US11/435,015 US20060269603A1 (en) 1993-05-10 2006-05-16 Controlled release tramadol formulations
US12/152,474 US20090117191A1 (en) 1993-05-10 2008-05-14 Controlled release tramadol formulations
FI20105856A FI122717B (en) 1993-05-10 2010-08-17 The method produces a controlled release preparation of tramadol hydrochloride

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EP0582380B1 (en) * 1992-06-26 1996-09-04 McNEIL-PPC, INC. Dry granulation using a fluidized bed

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ZA952013B (en) 1995-12-11
GB2287880A8 (en) 1995-12-04

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