Note: Descriptions are shown in the official language in which they were submitted.
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METHOD FOR PREPARING IOW DOSE PHARMACEUTICAL PRODUCTS
This invention relates to a new method for preparing
solid pharmaceutical compositions for oral administration of
low-dose medications whose active ingredients have steroidal
or steroid-like structures.
BACKGROUND OF THE INVENTION
The pharmaceutical art recognizes that, when highly
active medicaments are prepared in pharmaceutical form for
administration to subjects in need of therapy, the even
distribution of active ingredient throughout the carrier is
important for insuring a proper dosage and no toxic effects
due to hot spots of drug. The problem is especially
applicable to low dose steroidal compounds; for example,
estrogens, progestins, digitalis, spironolactone. These are
known to migrate through the carrier upon drying.
The prior art of low dose pharmaceutical formulation
is illustrated in the literature for estrogen (e. g.,
estradiol). Much of the prior art comprises broad
disclosures of standard preparative methods; for example,
Pasquale, U.S. Patent No. 4,544,554, etc., or Lerner, U.S.
Patent No. 3,568,828, with no mention of the problem of non-
uniform distribution. The latter reference describes the
preparation of low dose drugs using conventional wet
granulating methods with organic solvents such as chloroform.
DeEaan (Akzo), European Patent Application
No. 0503521 , discusses the problem of uneven distribution
of low dose medicaments in solid pharmaceutical dose units.
This, as stated above, may be due in part to migration of the
medicament. DeHaan further states that liquid granulation
methods for preparing solid dosage units of low dose
medicaments are also not acceptable because of the cost and
environmental handicaps of the organic solvents which are
unacceptable for this use.
DeHaan suggests an alternative method of manufacture
which uses the compression of a dry solid mix containing an
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excipient having a prescribed binding-demixing ratio of the
medicament to excipient.
There remains a need in the art for other methods of
preparing solid dosage forms, mainly tablets of low-dosage
medicaments, which can be adapted by manufacturing
pharmaceutical companies to available equipment.
SUGARY OF THE INVENTION
This invention relates to a method for preparing
solid pharmaceutical dosage units containing low dose active
ingredients using a wet. granulation technique which employs
aqueous solvents and applicable surfactants.
DETAILED DESCRIPTION OF THE INVENTION
This method utilizes an aqueous medium Which contains
the active ingredient or ingredients, a quantity of one or
more surfactants sufficient to dissolve or suspend said
active ingredients uniformly throughout the medium and other
manufacturing additives as known to the art. The latter
include granulating-binding agents such as gelatin; natural
gums, such as acacia, tragacanth; starches, sodium alginate,
sugars, polyvinylpyrrolidone; cellulose derivatives such as
hydroxypropylmethylcellulose, polyvinyloxoazolidones;
pharmaceutical fillers such as lactose, microcrystalline
cellulose, dicalcium phosphate, tricalcium phosphate, calcium
sulfate, dextrose, mannitol, sucrose; tabletting lubricants
if needed such as calcium and magnesium stearate, stearic
acid, talc, steroteX (alkaline stearate).
The components are granulated, the resulting granules
are dried, sieved and compressed into tablets or filled into
capsules. Other oral product forms may be similarly prepared
by art methods such as chewable tablets, lozenges, troches,
sustained or delayed release products or suspensions.
The active ingredients comprise any medicament which
has a low effective dose such as those below 10 mg per dosage
unit. Most useful are those medicaments having a steroidal
nucleus, the cyclopentanoperhydrophenanthrene ring system, in
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their chemical structures such as the estrogens or
progestins.
Examples of the former are ethinylestradiol, estrone,
mestranol, 17-alpha-ethinyl estradiol-3-methylether
esterified estrogens, and, especially estradiol, methyl
testosterone. The dosage amounts and indications of these
and other active ingredients are those described in the
literature such as the Physician's Desk Reference (PDR 56
EDITION 2002).
The progestins are 3-ketodesogestrel, desogestrel,
levo-desogestrel, norgestrel, gestodene, mestranol,
norethindrone, norethindrone acetate.
Other medications known to the art which are used in
low doses are spironolactone, digoxin, glipizide, estazolam,
clorazepate dipotassium, albuterol sulfate, clonidine HCZ,
alprazolam.
The term "aqueous medium" for the second ingredient
of this invention is used within the custom of the
pharmaceutical art. Primarily, it connotes a water medium,
with added water-miscible solvents such as isopropanol or
ethanol when needed, to support the active ingredient or
pharmaceutical aids.
The third ingredient of the critical step of this
invention is a surfactant acceptable in pharmaceutical
manufacturing practice and selected from the three categories
of surfactants: cationic, anionic and non-ionic compounds.
Exemplary of useful surfactants are sodium lauryl sulfate,
sorbitan monolaurate, sorbitan monostearate,'polysorbate 80,
polysorbate 60, poloxamer 407, poloxamer 188 (polyoxethylene,
polyoxypropylene block polymers), polyoxyl 20 cetostearyl
ether, dioctyl sodium sulfosuccinate, dioctyl calcium
sulfosuccinate, nonoxynol, benzalkonium chloride, sorbitan
monooleate.
The quantity of surfactant in the granulating mixture
is enough to be non-toxic and to support the steroidal active
ingredient in solution or suspension. Usually, this means
very small, almost catalytic, quantities, such as less than
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0.01% by weight. Applicant has devised a simple test
procedure for determining the applicability of a selected
surfactant for this process. Details are presented below.
Other pharmaceutically acceptable additives are used
in the first step granulation but are not considered critical
to this invention. These include binding-granulating agents
such as polyacrylamides, polyvinyloxoazolidones, sucrose, and
sodium carboxymethylcellulose; fillers such as lactose, talc,
cellulosics, dibasic calcium phosphate, starches;
disintegrants if a tablet or capsule is formed, such as
croscarmellose sodium, starch, sodium carboxymethyl starch;
veegum, ion exchange resins (amberlite), sodium bicarbonate;
or lubricants for tablet compression such as polyethylene
glycol 4000 and 5000, hydrogenated vegetable oils, light
mineral oil.
The practice of this invention depends on the novelty
and practical benefits of using a low dose medicament, a
pharmaceutically acceptable quantity of surfactant and an
aqueous medium. The preferred ingredients are estradiol,
sodium lauryl sulfate and water from a povidone solution.
The final product form is a tablet containing 2.00 mg of
medicament per tablet. The therapeutic utility is
demonstrated by oral administration of such a dosage unit
from 1-5 times daily to a subject in need of treatment, for
example for menopausal abnormalities.
In practice, the estradiol is suspended in a 1%
povidone solution containing a trace (0.005%) of surfactant.
The aqueous suspension is blended with fillers and granulated
in a granulating vessel. The granulation is dried, screened
and blended with fillers, disintegrants and lubricants. The
granulation is then compressed into tablets.
Alternatively, the dried granules may be filled into
a capsule. Where extended or delayed release of the low dose
medicament is desired the granules or capsule may be coated
as known to the art.
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The following examples are designed to teach the
operation of this invention.
Example 1
ESTRADIOL 2 mg TABLETS
Formula
Materials Percent MgjTablet
Microcrystalline Cellulose 20.00 32.80
(Avicel''-PH102), NF
Lactose 316 (Fast Flo), NF 51.94 85.18
Dibasic Calcium Phosphate 23.70 38.87
Cal-Star ) ; ' USP
Colloidal Silicone Dioxide 1.00 1.64
(Cab-o-sil); NF
Croscarmellose Sodium 1.00 1.64
( Ac-Di-Sol ) ; ! NF
Magnesium Stearate 1.00 1.64
Povidone K92-32, NF 0.14 0.23
Sodium Lauryl Sulfate, NF 0.0003 Trace
(Trace)
Estradiol, USP 1.22 2.00
Procedure
1. Suspend the estradiol in a 1% povidone solution in which
0.005% sodium lauryl sulfate has been dispersed.
2. Blend the Cal-Star and lactose until homogeneous.
3. Granulate the blend from Step 2 with the suspension of
estradiol in povidone solution from Step 1.
4. Dry the above granulation.
5. Screen and blend the dried granulation from Step 4 with
the other ingredients.
6. Compress the blend from Step 5 into 164 mg tablets.
Each tablet containing 2 mg of estradiol.
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Example 2
PROTOCOL FOR SCREENING SURFACTANT FOR
LOW DOSE DRUG SUSPENSIONS
I. Prepare a 1% povidone stock solution in water.
II. Prepare reference solution of 1% povidone - 0.005%
sodium lauryl sulfate (SLS).
A. Prepare a 14.3% w/w solution with the SLS solution
and estradiol.~
B. Prepare a 14.3% w/w solution with the SLS solution
and spironolactone.
C. Compare the estradiol solution and the
spironolactone solution. If they have the same
appearance, spironolactone can be used as the model
drug and estradiol can be used for a check.
III. Use the stock povidone solution to prepare solutions
with the other surfactants to be investigated, such as,
but not limited to, dioctyl sodium sulfosuccinate,
dioctyl calcium sulfosuccinate, nonoxynol, benzalkonium
chloride, sorbitan monooleate.
A. Prepare 1% povidone - 1% surfactant solutions.
1. Prepare 14.3% w/w solution with the surfactant
and the steroidally derived drug.
2. Compare to reference solution.
3. If the surfactant/steroidal solution conforms
to the reference solution:
a. Dilute surfactant solution with 1%
povidone solution in 0.5% increments.
b. Determine the lowest concentration of
surfactant that a flocculated suspension
can be formed.
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