PROCEDE DE COMPRESSION D'UN MELANGE SEC DE MEDICAMENTS

METHOD FOR DRY BLEND COMPRESSION OF MEDICAMENTS

Abrégé français

Procédé de compression d'un mélange sec de substances médicamenteuses puissantes présentant une faible solubilité, telles que des médicaments stéroïdiens, à l'aide d'excipients agglomérés pouvant être compressés directement, ces excipients n'étant pas un polyalcool ou un lactose classique ou séché par pulvérisation. Lesdits excipients agglomérés peuvent être du mannitol, de la malto-dextrine ou du sirop de maïs déshydraté, et servent à retenir le(s) médicament(s) dans les fissures des agglomérats. Cette invention décrit également les rapports critiques excipients agglomérés/agents stéroïdiens, notamment l'oestradil, qui est réparti uniformément dans le mélange sec puis compressé sous forme de comprimés.

Abrégé anglais

Disclosed is a method of dry blend compression of potent drugs with low solubility, such as steroidal medicaments using directly
compressible agglomerated excipients that are not a conventional or spray dried polyalcohol or lactose. The agglomerated excipients include
mannitol, maltodextrin or corn syrup solids which hold the medicaments (s) in the crevices of the agglomerates. Also disclosed are the critical
ratios of the agglomerated excipients to steroidal agent, specifically estradiol, that is distributed uniformly throughout the dry blend and
then compressed into tablets.

Revendications

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Claims


1. A method of making pharmaceutical tablets comprising the
steps of:

blending a unit dosage quantity of one or more low dosage
medicaments with an agglomerated excipient in a ratio of
from 1:40 to 1:100 of medicament to excipient, wherein
the medicament is selected from the group consisting of
estrogens and progestins, and the excipient is selected
from the group consisting of mannitol, maltodextrin, corn
syrup solid, and mixtures thereof;

adding optional tabletting aids selected from the group
consisting of one or more tabletting fillers,
disintegrating agents and lubricants; and

compressing the blended mixture.

2. The method of claim of 1 wherein the estrogen is
estradiol.

3. The method of claim 1 wherein the estrogen is a
conjugated estrogen.

4. The method of claim 1 wherein the progestin is selected
from the group consisting of 3-ketodesogestrel,
desogestrel, levodesogestrel, norgestrel, gestodene,
norethindrone, and norethindrone acetate.

5. The method of any of claims 1 to 4, wherein the excipient
is selected from the group consisting of mannitol,
maltodextrin and a combination thereof.

6. A pharmaceutical composition comprising one or more low
dosage medicaments and an agglomerated excipient in a
ratio from about 1:40 to about 1:100 of medicament to







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excipient, wherein the agglomerated excipient is selected
from the group consisting of mannitol, maltodextrin, corn
syrup solid, and mixtures thereof and one or more
optional excipients, disintegrating agents, or
lubricants.

7. The composition of claim 6 wherein said medicament is
selected from the group consisting of an estrogen and a
progestin.

8. The composition of claim 7 wherein said estrogen is
estradiol.

9. The composition of claim 7 wherein said estrogen is a
conjugated estrogen.

10. The composition of claim 7 wherein the progestin is
selected from the group consisting of 3-ketodesogestrel,
desogestrel, levodesogestrel, norgestrel, gestodene,
norethindrone, and norethindrone acetate.

11. The composition of claim 9 wherein said progestin is
medroxyprogesterone acetate.

12. The composition of any one of claims 6 or 7 wherein the
excipient is selected from the group consisting of
mannitol, maltodextrin, and a combination thereof.

13. The composition of any one of claims 6 or 7 wherein said
composition is in the form of a tablet.

Description

CA 02176460 2005-09-23
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Description
Method for Dry Blend Compression of Medicaments
Technical Field
This invention relates to a method of dry blend
compression of insoluble potent drug substances using a
directly compressible, agglomerated excipient that is not a
conventional spray dried polyalcohol or lactose.
Backgrround Art
Inadequate distribution of low-dose potent drugs is a
constant threat to the uniform potency of tablets and
capsules containing such drugs.
The greatest potential for drug-diluent segregation in
a tablet system occurs with powder or particulate mixtures
intended for direct compression or wet granulation in which
the drug migration occurs (Dale E. Former et. al.,
Pharmaceutical Dosage Forms: Tablets, Volume 2, pp. 253.).
European Patent No. 0503521 B1, AKZO N.V. p. 6
describes the inadequate homogeneity encountered with
compositions containing hydrous lactose DT (U. S. Patent
4,544,554 etc. issued to Samuel A. Pasquale). The migration
of a low-dose potent drug disrupts the distribution
throughout the mix, giving rise to inconsistency in the
content uniformity of the dosage form.
U.S. Patent No. 3,568,828 issued to Leonard Joseph
Lerner describes wet processes using potent drug substances
such as estrogens with organic solvents such as chloroform.
Such processes are now regarded as environmentally unsafe and
can incur considerable manufacturing expenses, in that
appropriate solvent scrubbing and/or explosion proof
equipment must be acquired at substantial capital
expenditure.
Estradiol and a number of other low-dose potent drugs
precipitate in a variety of polymorphs and/or crystal habits.
The changes in the crystal structure on drying can affect the
bioavailability of the drug. It is well known in the



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literature that the micronized form is more bioavailable than
larger drug particle size. This invention offers an
important alternative to wet granulation, thus eliminating
recrystallization and the issue of polymorphism and
bioavailability. It also offers the choice of dry mixing or
direct compression with materials other than the conventional
spray dried polyalcohols or lactoses.
Disclosure the Invention
The following describes the use of low dose medicinal
agents such as micronized steroidal medicinal agents;
estradiol, equilin, estrone, spironolactone, and
non-micronized materials; such as, estropipate, conjugated
estrogens, esterified estrogens, progestins or other
medicinal agents having the structure which includes the
cyclopentanoperhydrophenanthrene ring system which agents
are formulated by a drug pharmaceutical preparation. The
dry preparation makes use of excipients that have been
prepared by agglomeration methods other than by spray
drying. Such excipients include granular mannitol,
agglomerated maltodextrin, corn syrup solids and mixtures
of these agents with added conventional direct compression
excipients.
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 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, conjugated
estrogens, 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.
SLJ~STITUTf SHEET (RULE 2fi)



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The progestins are 3-ketodesogestrel, desogestrel,
levo-desogestrel, norgestrel, gestodene, 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 HCL, alprazolam.
The agglomerated excipients used in this method are
those listed above. These are differentiated from those
used in the AKZO method of reference in not having the AKZO
prescribed affinity-demixing range of properties of active
ingredient to dry excipient. The latter property gives the
method of this invention a commercial advantage in
manufacturing procedure.
Studies comparing the properties of the AKZO
preferred excipient (spray dried lactose) with applicant's
lead species (agglomerated mannitol) demonstrated that the
former retained 2 to 3 times the quantity of estradiol on
its surface than did the claimed ingredient. The tablet of
this invention, however, gave good drug distribution
figures despite not having the high affinity AKZO states to
be necessary.
Also, photomicrographs of the samples demonstrated
that the AKZO mix had drug uniformly attached to all the
surfaces of the excipient. In contrast, the mix of this
invention had drug located in crevices of the agglomerate.
This indicates a different mechanism of attachment.
The method of this invention, therefore, comprises
mixing one or more low-dose medicaments with the
agglomerated excipient, usually in a ratio of from about
1:40 to 1:100, medicament to excipient. Other excipients,
' disintegrating agents or lubricants are optionally added.
After dry mixing, the mix is compressed into tablets.
The following examples illustrate the method of this
invention in more detail.
~BSTITUFE S#if ET (RtkE 2f'~3

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Example I
ESTRAD10L 2 mg TABLETS
Materials A (%) B (%) C (%)
Microcrystalline Cellulose
TM
(Avicel PHI 02) 45.89 23.20
Starch 1500 - 20.00 20.00
Dibasic Calcium Phosphate
(Cal-StarTM) - - 23.20
Agglomerated Mannitol 47.39 50.08 50.08
Croscarmellose Sodium
(Ac-Di-SolTM ) 5. 00 5. 00 5.00
Magnesium Stearate 0.50 0.50 0.50
Estradiol 1.22 1.22 1.22
1. Screen estradiol and mannitol together through a #20
mesh screen into a slant-cone high speed mixer.
2. Screen Avicel PH 102 and Ac-Di-Sol through the screen
and force any remaining estradiol through as well.
3. Blend for fourteen (14) minutes with the agitator bar
off, two (2) minutes with the agitator bar on, and
blend fourteen (14) minutes with the agitator bar off
(total of thirty (30) minutes).
4. Add the magnesium stearate and blend for three (3)
minutes with the agitator bar off.
5. Compress into tablets on a high speed tablet press.
Tablet weight of 1 64 ~ 3%.
Other illustrations are:
1. Using the process of example 1 with agglomerated
maltodextrin blended with estradiol and a progestin.
2. Using the process of example 1 with a combination of
agglomerated mannitol and maltodextrin blended with
an estrogen or a progestin or a combination of
estrogen and progestin.



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3. Using the process of example 1 with a combination of
agglomerated mannitol and maltodextrin blended with
conjugated estrogens alone or in combination with a
progestin.
SUBSTITUTE SHEET (RULE 26)