U.S. patent number 3,728,445 [Application Number 05/082,548] was granted by the patent office on 1973-04-17 for controlled release medicament.
This patent grant is currently assigned to Controlled Medications Limited. Invention is credited to Frank M. Bardani.
United States Patent |
3,728,445 |
Bardani |
April 17, 1973 |
CONTROLLED RELEASE MEDICAMENT
Abstract
The invention relates to novel extended-release medicament
preparations, particularly in tablet form, and to a method of
preparing same. The preparations of the invention are based on the
desired medicament, an excipient such as a sugar, a defined class
of binder and a "barrier" salt such as magnesium stearate.
Inventors: |
Bardani; Frank M. (Rye,
NY) |
Assignee: |
Controlled Medications Limited
(Calgary, Alberta, CA)
|
Family
ID: |
10439802 |
Appl.
No.: |
05/082,548 |
Filed: |
October 19, 1970 |
Foreign Application Priority Data
|
|
|
|
|
Sep 28, 1970 [GB] |
|
|
46086/70 |
|
Current U.S.
Class: |
424/465;
424/469 |
Current CPC
Class: |
A61K
9/2004 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); A61k 027/12 () |
Field of
Search: |
;424/22 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Rose; Shep K.
Claims
What I claim as my invention is:
1. A method for preparing a shaped, orally administrable medicinal
preparation having extended-release characteristics in the
gastrointestinal tract which comprises preparing a mixture of a
medicament with a solid sugar excipient, said mixture having a
particle size of -100 mesh, granulating said mixture by moistening
same with a 5 to 30 percnet w/v solution of cellulose acetate
phthalate in an amount that provides from 5 to 15 percent by weight
of said celulose acetate phthalate based on the weight of the
mixture of medicament and excipient, evaporating solvent and
recovering granules having a size between about 1/2 and 3 mm in
diameter, and compressing the dried granules under high pressure to
form an essentially void-free shaped preparation, said preparation
including also a calcium or magnesium salt of a higher fatty acid
in an amount of between 1/2 to 10 percent by weight based on the
weight of the medicament and excipient to provide same with a 1 to
12 hour release pattern, said preparation having a hardness of at
least 5 kilograms as measured on a hardness tester of U. S.
Pharmacopeia specification.
2. A method as claimed in claim 1 wherein the calcium or magnesium
salt is a stearate.
3. A method as claimed in claim 1 wherein the excipient is lactose
and the calcium or magnesium salt is magnesium stearate.
4. A method as claimed in claim 1 wherein the excipient is sucrose
and the calcium or magnesium salt is magnesium stearate.
5. A method as claimed in claim 1 wherein the mixture of medicament
and sugar is granulated with a 10 to 20 percent by weight solution
of the callulose acetate phthalate in acetone, and the granules are
admixed with from about 1/2 to 5 percent by weight magnesium
stearate and said mixture is then pressed into substantially
void-free tablets.
6. A method as claimed in claim 5 wherein the sugar is lactose.
7. A method as clained in claim 5 wherein the sugar is sucrose.
8. A shaped orally administrable preparation having
extended-release characteristics in the gastrointestinal tract
comprising a solidly-compacted, substantially void-free body having
a hardness of at least 5 kilograms as measured on a hardness tester
of U. S. Pharmacopeia specifications, said body being formed in
accordance with the process of claim 1 of compressed granules
having a size between about 1/2 and 3 mm in diameter and consisting
essentially of a medicant, a sugar excipient and 5 to 15 percent by
weight of cellulose acetate phthalate, based on the weight of the
mixture of medicament and excepient, said body including also
between about 1/2 to 10 percent by weight of a calcium or magnesium
salt of a higher fatty acid to provide same with a 1 to 12 hour
release pattern.
9. The preparation of claim 8 in the form of a tablet.
10. The preparation of claim 9 wherein the calcium or magnesium
salt is a stearate.
11. The preparation of claim 10 wherein the medicament is a
steroid.
12. The preparation of claim 11 wherein the steroid is ethisterone.
Description
BACKGROUND OF THE INVENTION
It is often desirable and sometimes even necessary that a
particular medicament be released in the gastrointestinal tract
over a prolonged period of time. Ordinary tablets and capsules
release the contained medicament substantially completely upon
disintegration and at one time the usual method of providing an
approximation of extended-release of the medicament was to
administer to the patient a number of tablets or capsules at
invervals of perhaps 3 or 4 hours.
Recently a large number of different types of delayed-release or
extended release tablets or capsules have been developed but these
mostly suffer from various disadvantages including complexity of
manufacture and/or inadequate performance. In particular one
commonly available type of capsule contains a number of different
type of granules, each type containing the medicament but designed
to dissolve after different periods of time in the gastrointestinal
tract. These granules are typically coated with an enteric coating
but do not achieve anything like a linear release of the
medicamanet but rather release dosages of the medicament at timed
intervals. Apart from the difficulty of manufacture of such
capsules, there is the additional difficulty of making sure that
each capsule contains the same proportions of each type of
timed-release granule. Moreover for certain purposes, even that
type of medicament gives an inadequate performance owing to the
impossibility of achieving a continuous and preferably
substantially linear release of medicament.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide shaped,
orally-administrable medicinal preparations, particularly tablets,
with extended-release characteristics.
It is a further object to provide tablets which upon oral
administration release their medicament over a period up to about
12 hours after administration.
Yet another object of the invention is to provide tablets which
release their medicament continuously over a period of some
hours.
A still further object of the invention is to provide tablets which
release their medicament approximately linearly with time during
their passage through the gastrointestinal tract.
According to the present invention there is provided a shaped,
orally administrable medicinal preparation having extended-release
characteristics in the gastrointestinal tract, which comprises a
solidly-compacted, substantially void-free body of medicament-solid
excipient-binder granules, said binder being a phramaceutically
acceptable celulose derivative dicarboxylic-acid ester, said body
including also a calcium or magnesium salt of a higher fatty acid
in an amount sufficient to provide same with a 1 to 12 hour release
pattern.
The present invention also provides a method for preparing a
shaped, orally administrable medicinal preparation having
extended-release character-istics in the gastrointestinal tract
which comprises preparing a mixture of a medicament with a solid
excipient, said mixture having a particle size of -100 mesh,
granulating said mixture with a pharmaceutically acceptable
cellulose derivative dicarboxylic acid ester binder, and
compressing the dried granules under high pressure to form an
essentially void-free shaped preparation, said preparation
including also a calcium or magnesium salt of a higher fatty acid
in an amount sufficient to provide same with a 1 to 12 hour release
pattern.
DESCRIPTION OF PREFERRED EMBODIMENTS
The medicament which may be included in the medicinal preparations
of this invention may be any medicament which can be administered
in tablets, capsules, or the like. Thus, for example, the
medicament may be a tranquilizer, a diuretic, a sedative, an
antibiotic, a vitamin, an analgesic, or the like. However, the
invention is of particular value for the administration of various
steroid drugs, which commonly, if administered by means of an
ordinary tablet or capsule, give rise to what is known as "steroid
shock." This undesirable effect of the normal mode of
administration of steroids can be largely or completely overcome by
administering the steroid by means of an extended-release tablet
which enables the steroid to be released in the gastrointestinal
tract over a period of some hours. This extended release of
medicaments, and particularly of steroids, has the additional
advantage that the peak blood levels of the medicament are
maintained lower, and consequently less of the medicament is
metabolized to non-effective derivatives. This in turn enables
considerably lower overall dosages of the medicament to be
employed.
The excipient to be used in the medicinal preparations of the
invention may be any suitable solid excipient normally employed in
medicinal tablets provided of course that it can be obtained as a
very fine powder or milled to produce such a fine powder. Typical
excipients are lactose, surcose, dextrose, dextrose monohydrate,
starch, and the like, the sugars being particularly suitable
because of their solubility in water. The particle size of the
excipient should be below 100 mesh and preferably below 200 mesh
(the mesh size in question refer to either U.S. standard or British
standard mesh since they are practically identical, corresponding
to a particle size of less than about 150 microns for 100 mesh and
less than about 75 microns for 200 mesh; there is a slightly
greater difference between the U.S. and British meshes in the lower
sieve sizes i.e., larger particle sizes). Conveniently the
excipient is mixed with the active medicament and thereafter milled
to the required particle size e.g., by the use of a pharmaceutical
hammer mill or other pulverizer fitted with a screen of the
required mesh size.
The binder employed in the preparations of this invention is, as
stated above, a pharmaceutically acceptable cellulose derivative
dicarboxylic acid ester. Such esters have free carboxylic acid
groups, and hence are pH sensitive. Cellulose esters derived from
both a fatty acid, particularly a lower fatty acid, and a
dicarboxylic acid, are particularly suitable and of these materials
the ester which is currently considered the most suitable and which
moreover is a recognized pharmaceutical ingredient in most
countries, is cellulose acetate phthalate. Although a solvent may
not be necessary if the ingredients are sufficiently fine and the
tabletting pressures are sufficiently high, in the presently
preferred embodiment of the process of the invention the ester is
employed dissolved in a suitable volatile organic solvent such as
acetone, alcohols or chlorinated hydrocarbon, and this solution is
used for the granulation process. Such a granulation procedure is
known in the art as wet-gransulation or moist-granulation. The
finely powdered mixture of medicament and excipient is moistened
with the binder solution in a mixer, and the moistened material
usually in the form of a dough is pressed through one or more
screens to produce grandules having a size between about one-half
to 3 millimeters in diameter. The prepared granules are thereafter
dried by evaporation of the solvent. Where the nature of the
materials permits, evaporation of the solvents may be hastened by
the application of moderate heat in a draft or under reduced
pressure. The dried granules may then be screened again to a
particle size suitable for the size of tablet or shaped preparation
to be made, (hereinafter for the sake of convenience, jointly
referred to as tablets). The granulation procedure is carried out
according to well known known procedures, while care is taken to
avoid introducing too much of the binder which would tend to
produce coated granules. Normally, satisfactory granulation can be
achieved by using a 5 to 30 percent concentration of the binder in
the organic solvent and in the case of cellulose acetate phthalate
a 10 to 20 percent and particularly a 15 percent solution in
acetone is particularly preferred. However, the mixing operation at
the start of the granulation procedure may be accompanied by some
evaporation of the solvent and accordingly there is some degree of
latitude in both the amount of solution employed for the
granulation and the concentration of binder therein. When
dry-mixing is used, i.e., without solvent, it may be advisable for
some medications to carry out the process step-wise by high
pressure slugging of a part of the mixture, after which these slugs
are broken and screened in a suitable comminuting mill before they
are returned to the mixer for incorporation with the remainder of
the mixture. Usually the amount of binder required is from about 5
to 15 percent based on the weight of the active ingredient and
excipient. The amount of binder employed has some effect on the
properties of the final preparation and greater amounts of binder
will generally result in preparations having a longer release
period.
In a modification of the invention the above described class of
binder is partially replaced e.g., up to the extent of about 10
percent by weight with a pH insensitive pharmaceutically acceptable
binder such as ethyl cellulose. The preparations prepared according
to this embodiment of the invention show a slower release and
moreover a tendency for a slower rate of release initially in the
intestinal fluids.
The last of the essential ingredients of the preparations of the
invention is a calcium or magnesium salt of a higher fatty acid
such as for instance calcium or magnesium palmitate, stearate or
oleate. Of these materials, magnesium stearate is at present
preferred. Such materials have been employed as mold lubricants for
tabletting operations but primarily serve a different purpose in
the preparations of this invention. These materials are metallic
soaps of an essentially water insoluble character, and in
accordance with the invention they appear to act as a barrier to
delay penetration of fluids into the center of the tablet. The
amount of calcium or magnesium soap employed in accordance with the
invention may be greater than is normally used for mold release
purposes e.g., up to about 10 percent by weight of the medicament
plus excipient, although commonly less than 5 percent and typically
1/2 to 2 percent will be sufficient. The use of the calcium or
magnesium soap as a barrier to the penetration of fluids to the
center of the tablet delays disintegration of the tablet and
ensures that release of the medicament occur essentially only at
the exposed surface of the tablet.
The calcium or magnesium soaps may be added to the other
ingredients either prior to or subsequent to granulation, or some
of the metallic soap may be added prior to the granulating
procedure and the remainder mixed with dried granules prior to
compression.
The dried granules of medicament plus excipient plus binder, either
containing or admixed with the calcium or magnesium soap are then
formed into a substantially void-free tablet under high pressure.
Normal tabletting procedures employ pressures considerably lower
than those utilized in accordance with the process of this
invention, and are typically around one-half the pressures needed
in accordance with this invention in order to achieve a void-free
tablet. Tabletting pressure depends primarily on the thickness of
tablet it is desired to produce and for instance for a 13/64 inch
thick tablet, a tabletting pressure which will give a hardness of
at least about 5 to 6 kilograms on a hardness tester of U.S.P.
specification must be employed to produce the necessary
consolidation of the ingredients and achieve a substantially
void-free tablet. Failure to use a sufficiently high pressure would
result in either premature disintegration of the tablet or
penetration of fluids into interstices with resulting deleterious
effects on the release pattern of the medicament. Typical die loads
for tablets of the above size are 15 to 20 tons.
It is an advantage of the present invention that tabelts may be
made in a straight-forward manner while achieving extended-release
characteristics of a predetermined period. In the preferred
embodiments of the invention the release pattern approaches
linearity, with release of the medicament starting in the gastric
fluids when the active ingredient is appreciably water-soluble and
continuing as the tablet passes into the intestinal fluids. The
structure of the tablet provides a relatively larger surface for
the release of medicament in the acidic gastric fluid, under which
conditions the pH sensitive binder is less soluble, and as the
tablet proceeds through a gastrointestinal tract into a more
alkaline environment with a concomitant increase in the solubility
of the binder, disintegration proceeds at the surface of the tablet
so reducing the total surface area of the tablet exposed to the
fluids.
When the active ingredient is practically water-insoluble very
little is released in the stomach fluid whereas release occurs in
the intestinal fluid. Otherwise the dissolution behaviour is the
same.
The invention is illutrated by the following examples. In these
examples the screen sizes mentioned are U.S. standard mesh and the
abbreviation CAP stands for cellulose acetate phthalate.
Example 1
To prepare 1,000 extended-release tablets each containing 15 mg. of
ethisterone (17.beta.-hydroxypregn-4-en-20-yn-3-one):
100 g. of lactose USP is admixed with 15 g. of ethisterone and the
mixture pulverized by the use of a pharmaceutical hammer mill
fitted with a 100 mesh screen. The finely powdered mixture of
medicament and excipient is placed in a mixer and granulated by the
addition of a solution of 15 g. of CAP in 50 cc. of acetone USP.
The granules are dried at 100.degree. F for a period of about 8
hours and finally screened through a number 16 mesh screen. The
granules so produced are throughly admixed with 1 g. of magnesium
stearate and formed into tablets weighing 131 mg. by the use of a
9/32 inch punch at 20 ton load to form tablets of 13/64 inch in
thickness.
When gently agitated first for one hour in simulated gastric fluid
and thereafter for one hour in simulated intestinal fluid, these
tablets showed a release of 45 percent of the medicament at the end
of the first hour and a release of all the remaining medicament at
the end of the second hour.
EXAMPLE 2
To prepare 1,000 extended-release tablets each containing 98.9 mg.
of sodium amobarbital (sodium 5-ethyl-5-(3-methylbutyl)barbituric
acid):
300 g. sucrose is admixed with 98.9 g. sodium amobarbital and
powdered to pass a 100 mesh screen as described in Example 1. The
finely powdered mixture is granulated with a solution of 50 g. CAP
in 250 cc. acetone, and the granules dried as described previously.
The dried granules are screened through number 15 mesh screen and
thoroughly mixed with 2 g. magnesium stearate and 2 g. talc. This
admixture is then formed into tablets of 453 mg. by the use of a
13/32 inch punch at 20 ton load to form tablets of 7/32 inch in
thickness.
When gently agitated for 1 1/2 hours in simulated gastric fluid
followed by 6 1/2 hours in simulated intestinal fluid, these
tablets showed the following release pattern;
25 percent after one-half hour
42 percent after 2 hours
55 percent after 4 1/2 hours
87 percent after 6 hours
98 percent after 7 hours
100 percent after 8 hours.
Example 3
To prepare 1,000 extended-release tablets each containing 15 mg.
Dextro amphetamine sulfate:
Following the procedure of Example 1, 15 g. of Dextro amphetamine
sulfate and 400 g. sucrose were powdered to pass a 100 mesh sieve
and were granulated with a solution of 40 g. CAP and 5 g. ethyl
cellulose in 150 cc. acetone. The granules were dried at
100.degree. F to pass through a number 16 screen and thereafter
admixed thoroughly with 1 to 2 percent of magnesium stearate. 460
mg. tablets were parepared with a 11/32 punch at 20 ton load, the
tablets having a thickness of 13/64 inch.
These tablets, tested by the procedure outlined in Example 2,
showed the following release pattern:
29 percent after one-half hour
55 percent after 2 hours
73 percent after 4 1/2 hours
100 percent after 7 hours.
* * * * *