U.S. patent application number 09/740732 was filed with the patent office on 2001-09-06 for sustained release compositions and a method of preparing pharmaceutical compositions.
Invention is credited to Challis, Deborah, Heafield, Joanne, Knott, Trevor John, Leslie, Stewart Thomas, Malkowska, Sandra Therese Antoinette, Miller, Ronald Brown, Prater, Derek Allan.
Application Number | 20010019725 09/740732 |
Document ID | / |
Family ID | 46251812 |
Filed Date | 2001-09-06 |
United States Patent
Application |
20010019725 |
Kind Code |
A1 |
Miller, Ronald Brown ; et
al. |
September 6, 2001 |
Sustained release compositions and a method of preparing
pharmaceutical compositions
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.
Inventors: |
Miller, Ronald Brown;
(Basle, CH) ; Leslie, Stewart Thomas; (Cambridge,
GB) ; Malkowska, Sandra Therese Antoinette;
(Cambridge, GB) ; Prater, Derek Allan; (Cambridge,
GB) ; Knott, Trevor John; (Essex, GB) ;
Heafield, Joanne; (Cambridge, GB) ; Challis,
Deborah; (Kent, GB) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Family ID: |
46251812 |
Appl. No.: |
09/740732 |
Filed: |
December 19, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09740732 |
Dec 19, 2000 |
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09370270 |
Aug 9, 1999 |
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6162467 |
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09370270 |
Aug 9, 1999 |
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08944106 |
Sep 30, 1997 |
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5965163 |
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08944106 |
Sep 30, 1997 |
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08343360 |
Nov 22, 1994 |
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6129977 |
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Current U.S.
Class: |
424/489 ;
514/253.04; 514/282 |
Current CPC
Class: |
A61K 9/1617 20130101;
A61K 9/2095 20130101; A61K 31/485 20130101; A61K 9/2054 20130101;
A61K 9/2072 20130101; A61K 31/135 20130101; A61K 9/2077 20130101;
A61K 9/2013 20130101; A61K 9/1641 20130101; A61K 9/2866
20130101 |
Class at
Publication: |
424/489 ;
514/282; 514/253.04 |
International
Class: |
A61K 009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 23, 1993 |
GB |
9324045.5 |
Mar 1, 1994 |
GB |
9403922.9 |
Mar 9, 1994 |
GB |
9404544.0 |
Mar 14, 1994 |
GB |
9404928.5 |
Jun 14, 1994 |
GB |
9411842.9 |
Jun 9, 1994 |
EP |
94304144.2 |
Apr 29, 1994 |
EP |
94303128.6 |
Claims
What is claimed is:
1. A process for the manufacture of controlled 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.degree. 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, step (c), 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.
4. A process according to claim 1, wherein said drug is morphine,
tramadol, hydromorphone, oxycodone, diamorphine or a
pharmaceutically acceptable salt of any one of these.
5. A process according to claim 1, wherein said hydrophobic fusible
carrier or diluent is a wax selected from the group consisting of
hydrogenated vegetable oil, hydrogenated castor oil, Beeswax,
Carnauba wax, microcrystalline wax and glycerol monostearate.
6. A process according to claim 1, wherein said water-soluble
fusible material optionally included in the mixture in step (a) is
PEG having a molecular weight of from about 1,000 to about
20,000.
7. A process according to claim 6, wherein said PEG has a molecular
weight of from about 1,000 to about 6,000.
8. A process according to claim 6, wherein said water-soluble
fusible material is a poloxamer.
9. A process according to claim 1, wherein the fusible carrier or
diluent is added stepwise during mechanical working.
10. A solid dosage form obtained 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.degree. C., the solid dosage form
optionally containing conventional tabletting excipients.
11. 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.degree. C. and optionally containing
conventional capsuling excipients.
12. A solid dosage form according to claim 11 wherein said
particles are obtained 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 150.degree. C. at a speed
and energy input which allows the carrier or diluent to melt or
soften and form particles of a desired size.
13. A capsule according to claim 11 wherein said particles are
obtained 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 150.degree. C. at a speed and energy input
which allows the carrier or diluent to melt or soften and form
particles of a desired size.
14. A solid dosage form according to claim 10, wherein said
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.
15. A capsule according to claim 10, wherein said 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.
16. A solid dosage form according to claim 10, wherein said
particles contain a release modifier which is a hydrophilic release
modifier, or a water soluble or insoluble particulate organic or
inorganic material.
17. A capsule according to claim 11, wherein said particles contain
a release modifier which is a hydrophilic release modifier, or a
water soluble or insoluble particulate organic or inorganic
material.
18. A solid dosage form according to claim 11, wherein the active
ingredient is unstable in water.
19. A capsule according to claim 11, wherein the active ingredient
is unstable in water.
20. A solid dosage form according to claim 10, wherein said
particles are obtained by the steps comprising: (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.degree. 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.
21. A capsule according to claim 11, wherein said particles are
obtained by the steps comprising: (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.degree. 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.
22. Pharmaceutical particles produced by a process comprising the
steps of: (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.degree. 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.
Description
BACKGROUND OF THE INVENTION
[0001] 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 3.0 mm. 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.
[0002] Patent application PCT/SE93/06225 published under No. WO
93/18753 describes a process for the preparation of sustained
release pellets which comprises pelletizing a mixture containing
the drug in finely divided form and a binder; the process is
characterized in that:
[0003] (a) 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 40.degree. C. and
[0004] (b) the pelletization 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
pelletization to take place. Patent application PCT/SE92/06679
describes a similar process.
[0005] Processes of this kind are sometimes referred to as
"melt-pelletization" 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.
[0006] 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.
[0007] The present invention thus includes in one aspect a process
for the manufacture of particles, preferably sustained release
particles, which comprises
[0008] (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.degree. 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;
[0009] (b) breaking down the larger agglomerates to give controlled
release particles; optionally
[0010] (c) continuing mechanically working optionally with a
further addition of low percentage of the carrier or diluent;
and
[0011] (d) optionally repeating step (c) and possibly (b) one or
more, e.g. up to five, times.
[0012] 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.
[0013] 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 molding into suppositories,
pessaries or forming into other suitable dosage forms.
[0014] 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.
[0015] Among the active ingredients which can be used in the
process of the invention are the following;
[0016] ANALGESICS
[0017] Dihydrocodeine, Hydromorphone, Morphine, Diamorphine,
Fentanyl, Alfentanil, 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.
[0018] ANTIALLERGICS
[0019] Pheniramine, Dimethindene, Terfenadine, Astemizole,
Tritoqualine, Loratadine, Doxylamine, Mequitazine,
Dexchlorpheniramine, Triprolidine, Oxatomide.
[0020] ANTIHYPERTENSIVE
[0021] 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, Nicardipine,
Verapamil, Diltiazem, Felodipine, Nimodipine, Flunarizine,
Quinapril, Lisinopril, Captopril, Ramipril, Fosinopril, Cilazapril,
Enalapril.
[0022] ANTIBIOTICS
[0023] Democlocycline, Doxycycline, Lymecycline, Minocycline,
Oxytetracycline, Tetracycline, Sulfametopyrazine, Ofloxacin,
Ciproflaxacin, Aerosoxacin, Amoxycillin, Ampicillin, Becampicillin,
Piperacillin, Pivampicillin, Cloxacillin, Penicillin V,
Flucloxacillin, Erythromycin, Metronidazole, Clindamycin,
Trimethoprim, Neomycin, Cefaclor, Cefadroxil, Cefixime,
Cefpodoxime, Cefuroxine, Cephalexin, Cefradine.
[0024] BRONCHODILATOR/ANTI-ASTHMATIC
[0025] Pirbuterol, Orciprenaline, Terbutaline, Fenoterol,
Clenbuterol, Salbutamol, Procaterol, Theophylline,
Cholintheophyllinate, Theophylline-ethylenediamine, Ketofen.
[0026] ANTIARRHYTHMICS
[0027] Viquidil, Procainamide, Mexiletine, Tocainide, Propafenone,
Ipratropium.
[0028] CENTRALLY ACTING SUBSTANCES
[0029] Amantadine, Levodopa, Biperiden, Benzotropine,
Bromocriptine, Procyclidine, Moclobemide, Tranylcypromine,
Tranylcypromide, Clomipramine, Maprotiline, Doxepin, Opipramol,
Amitriptyline, Desipramine, Imipramine, Fluroxamin, Fluoxetin,
Paroxetine, Trazodone, Viloxazine, Fluphenazine, Perphenazine,
Promethazine, Thioridazine, Triflupromazine, Prothipendyl,
Thiothixene, Chlorprothixene, Haloperidol, Pipamperone, Pimozide,
Sulpiride, Fenethylline, Methylphenildate, Trifluoperazine,
Thioridazine, Oxazepam, Lorazepam, Bromoazepam, Alprazolam,
Diazepam, Clobazam, Clonazepam, Buspirone, Piracetam.
[0030] CYTOSTATICS AND METASTASIS INHIBITORS
[0031] Melfalan, Cyclophosphamide, Trofosfamide, Chlorambucil,
Lomustine, Busulfan, Prednimustine, Fluorouracil, Methotrexate,
Mercaptopurine, Thioguanin, Hydroxycarbamide, Altretamine,
Procarbazine.
[0032] ANTI-MIGRAINE
[0033] Lisuride, Methysergide, Dihydroergotamine, Ergotamine,
Pizotifen.
[0034] GASTROINTESTINAL
[0035] Cimetidine, Famotidine, Ranitidine, Roxatidine, Pirenzipine,
Omeprazole, Misoprostol, Proglumide, Cisapride, Bromopride,
Metoclopramide.
[0036] ORAL ANTIDIABETICS
[0037] Tolbutamide, 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.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] 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 carrier or diluent used. Preferably the
amount of fusible carrier or diluent 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.
[0042] The fusible carrier or diluent may be added stepwise during
mechanical working, in step a) or step c).
[0043] In step (c) the amount of additional fusible carrier or
diluent added is preferably between 5% and 75% w/w of the total
amount of ingredients added.
[0044] 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.degree. 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.degree. C. have structural integrity
and resistance to crushing between the fingers. At this stage the
agglomerates are of an irregular size, shape and appearance.
[0045] 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.degree. C. may be conveniently
used.
[0046] The agglomerates are broken down by any suitable means,
which will comminute oversize agglomerates and produce a mixture of
powder and small particles preferably with a diameter under 2 mm.
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.
[0047] 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.
[0048] 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 (b) 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.
[0049] 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.
[0050] Energy may also be delivered through other means such as by
a heating jacket or via the mixer impeller and chopper blades.
[0051] After the particles have been formed they are sieved to
remove any oversized or undersized material and then cooled or
allowed to cool.
[0052] The resulting particles may be used to prepare dosage units,
e.g., tablets or capsules in manners known per se.
[0053] 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 minimize adhesion of the
material to the walls of the bowl. To minimize 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 optimized to avoid the problems mentioned above.
For example in the processes described below in the Examples a bowl
temperature of approximately 50-60.degree. C. has been found to be
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.
[0054] 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 Apr.
29, 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.
[0055] 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.
[0056] 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, Carnauba wax, microcrystalline wax and glycerol
monostearate, and suitably have melting points of from 35 to
150.degree. C., preferably 45 to 90.degree. C.
[0057] Suitable substances for use as hydrophilic carrier or
diluent materials are natural or synthetic waxes or oils, for
example polyethylene glycols (PEGs) having molecular weights of
1000 to 20,000 e.g. 1,000 to 6,000 or 10,000 suitably having
melting points of from 35 to 150.degree. C., preferably 45 to
90.degree. C.
[0058] 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, hydroxypropylcellulose, and
hydroxypropylmethylcellulose.
[0059] We have also found that particles produced by the melt
pelletization processes described in application PCT/SE93/00225 and
the process described herein are particularly useful for processing
into the form of tablets.
[0060] To produce tablets in accordance with the invention,
particles produced as described above 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.
[0061] 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.
[0062] 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/SE93/00225 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 been found to work satisfactorily with other binders
and using conventional mixers with stainless steel linings.
[0063] 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 20 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 60 .mu.m and that electrostatic 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
particles size distribution with 50% of particles larger than 24 to
50 .mu.m and 10% larger than 100-140 .mu.m.
[0064] In order that the invention may be well understood the
following examples are given by way of illustration only.
EXAMPLES
Examples 1 to 4
[0065] Particles, having the formulations given in Table I below,
were prepared by the steps of:
[0066] i) Placing the ingredients (a) to (c) (total batch weight 20
kg) in the bowl of a 75 liter capacity Collette Vactron Mixer (or
equivalent) equipped with variable speed mixing and granulating
blades;
[0067] ii) Mixing the ingredients at about 150-350 rpm while
applying heat until the contents of the bowl are agglomerated.
[0068] iii) Classifying the agglomerated material by passage
through a Comil and/or Jackson Crockatt to obtain controlled
release particles.
[0069] iv) Adding the classified material to the heated bowl of a
75 liter 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 yields of greater than 80%.
[0070] v) Discharging the particles from the mixer and sieving them
to separate out the particles collected between 0.5 and 2 mm
aperture sieves and then allowing them to cool.
1 TABLE I EXAMPLE 1 2 3 a) Morphine Sulphate 55.0 52.19 53.48 (wt
%) B.P. b) Hydrogenated Vegetable 34.95 33.17 33.98 Oil USNF (wt %)
c) Polyethylene Glycol 0.05 0.047 0.049 6000 USNF (wt %) d)
Hydrogenated Vegetable 10.0 14.60 12.49 Oil USNF (wt %) YIELD %
90.5 83.4 90.1
[0071] The in-vitro release rates of Examples 1, 2 and 3 were
assessed by modified Ph. Eur. Basket method at 100 rpm in 900 ml
aqueous buffer (pH 6.5) containing 0.05% w/v polysorbate 80 at
37.degree. 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 of 60 mg of morphine
sulphate were tested. The results set out in Table II below give
the mean values for each of the six samples tested.
2TABLE II PRODUCT OF EXAMPLES HOURS AFTER 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 30 83 85 89
[0072] 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, 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.
3TABLE IIa PRODUCT OF EXAMPLE 4 HOURS AFTER % MORPHINE START OF
TEST RELEASED 2 15 4 24 6 30 8 36 12 46 18 57 24 65 30 71
[0073] 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 60 mg of
morphine sulphate. The capsules produced were used in open,
randomized crossover pharmacokinetic studies. As part of these
studies patients received after overnight fasting either one
capsule according to the invention or one MST CONTINUS.RTM. tablet
30 mg (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.
[0074] 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.
[0075] The capsules containing particles produced according to
Examples 2 and 4 in particular gave a mean C.sub.max of 11.9 ng/ml
at median t.sub.max 4 hours and mean C.sub.max of 9.2 ng/ml at
median t.sub.max 2.5 hours respectively (these values represent the
mean of the individual C.sub.max and t.sub.max values). In contrast
the C.sub.max and t.sub.max for the patients who received MST
CONTINUS.RTM. 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
[0076] Particles were produced analogously to Examples 1 to 4 but
having the following ingredients
4 wt % Morphine sulphate 55.0 Hydrogenated vegetable oil 44.7
Polyethylene glycol 6000 0.3
[0077] 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 7.1 mm diameter normal concave tooling on a single punch F3
Manesty tabletting machine. The ingredients per dosage unit
amounted to the following:
5 TABLE III Mg/Tablet 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
[0078] The dissolution of the samples of non-compressed particles
(each sample containing 60 mg 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:
6TABLE IV HOURS AFTER START OF TEST PARTICLES TABLET 1 TABLET 2 %
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 30 94 70 NR 36 95 74 NR NR =
Not recorded
[0079] The above results show that the tabletting procedure results
in a considerable reduction in the release rate of the active
ingredient.
Example 6
[0080] The procedure of Example 5 was repeated but with the
following variations.
[0081] The particles were made with the following ingredients.
7 wt % Morphine Sulphate 55.0 Hydrogenated Vegetable Oil 44.4
Polyethylene Glycol 6000 0.6
[0082] Two lots of tablets (3 and 4 ) were produced from the
particles using a 7.1 mm diameter concave tooling. The ingredients
per dosage unit were as follows:
8 TABLE V Mg/Tablet 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
[0083] The dissolution of the tablets and samples of non-compressed
particles (each sample containing 60 mg of morphine sulphate) were
assessed by the methods described above.
[0084] The results are shown in Table VII below:
9TABLE 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 60 16 NR NR 67 24 NR NR 77 NR = Not recorded
[0085] 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 188.RTM.) 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
[0086] 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:
10 wt % Tramadol Hydrochloride 50 Hydrogenated Vegetable Oil 50
[0087] Three lots of tablets (5, 6 and 7) were produced from
particles using respectively (a) 14 mm.times.6 mm, (b) 16
mm.times.7 mm and (c) 18.6 mm.times.7.5 mm capsule shaped tooling.
The ingredients per dosage unit were as follows:
11 TABLE VII Mg/Tablet 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
[0088] The tablets were assessed by dissolution in 0.1 N HCl Ph.
Eur. Paddle at 100 rpm. For the non-compressed particles the Ph.
Eur. Paddle was replaced by the modified Ph. Eur. Basket, each
sample of particles containing 400 mg of tramadol hydrochloride.
The results are shown in Table VIII below:
12TABLE VIII HOURS AFTER START TABLET TABLET TABLET OF PARTICLES 5
6 7 TEST % TRAMADOL HCl RELEASED 1 54 16 15 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 10 96 50 45 45
12 98 55 49 49 16 100 63 57 56 20 NR 70 63 NR NR = Not recorded
[0089] These results confirm the effectiveness of the tabletting in
reducing the release rate of tramadol, a highly water soluble
drug.
Example 8
[0090] 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;
13 wt % Tramadol Hydrochloride 75 Hydrogenated Vegetable Oil 25
[0091] Three lots of tablets (8, 9 and 10) were produced from the
particles using respectively tooling (a), (b) and (c) described in
Example 7. The ingredients per unit dosage were as follows:
14 TABLE IX Mg/Tablet Tablet Ingredient 8 9 10 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
[0092] The tablets and samples of non-compressed particles (each
sample containing 400 mg of tramadol hydrochloride) were assessed
by the methods described in Example 7. The results are shown in
Table X below:
15TABLE X HOURS AFTER START PARTICLES TABLET 8 TABLET 9 TABLET 10
OF TEST % TRAMADOL HCl 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 10 102 NR 96 97
NR = Not recorded
[0093] These results show that by increasing the loading of the
highly water soluble tramadol 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.
Example 9
[0094] 0.35 kg 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.degree. 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.degree.
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 0.5-2.0 mm sieve fraction.
[0095] The procedure described in the preceding paragraph was
repeated but the collected sieve fraction is blended in a
conventional blender with 0.006 kg talc for 5 minutes; 0.004 kg
magnesium stearate is then added and the blending continued for 3
minutes. The blend is then discharged and compressed using a 4
mm.times.8 mm capsule shaped tooling on a F3 tablet machine. The
resulting tablet had a hardness of 1.7 kp, a thickness of 2.8-3.0
mm and a friability of <1.0% and the following conditions:
16 TABLE XI 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
[0096] The dissolution rates of the resulting multiparticulates and
tablets, measured respectively by the Ph. Eur. Basket or Paddle
method at 100 rpm in either phosphate or acetate buffer, were as
follows:
17 TABLE XII % DIAMORPHINE HCL RELEASED Tablets Tablets
Multiparticulates Paddle/ Paddle/ TIME Basket/Phosphate Phosphate
Acetate (HRS) Buffer Buffer Buffer 1 30 -- 24 2 44 35 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
[0097] The examples provided above are not meant to be exclusive.
Many other variations of the present invention would be obvious to
those skilled in the art, and are contemplated to be within the
scope of the appended claims.
* * * * *