AU682223B2 - Creation of Inventions and Patents with Artificial Intelligence

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
Authority
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
Other versions

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
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

MUNDIPHARMA MEDICAL GmbH

Original Assignee
Euro Celtique SA
Priority date (The priority date 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 date listed.)
1993-11-23
Filing date
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
Critical
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
Application granted
granted
Critical

2014-11-23
Anticipated expiration
legal-status
Critical

Status
Expired
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

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

A61K9/1605—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

A61K9/2077—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 invention preferably all drug is added in step together with major portion hydrophobic or hydrophilic fusible carrier diluent used. Preferably amount between e.g. I 6 <99% w>Download PDF in English

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