Method for dry blend compression of medicaments

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 medicament(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.

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. 
BACKGROUND 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. Fonner et. 
al., Pharmaceutical Dosage Forms: Tablets, Volume 2, pp. 253.). European 
Patent Application 92103963.2, AKZO N. V. p. 6 describes the inadequate 
homogeneity encountered with compositions containing hydrous lactose DT 
(U.S. Pat. No. 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. Pat. 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 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. 
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. 
EXAMPLE I 
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ESTRADIOL 2 mg TABLETS 
Materials A (%) B (%) C (%) 
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Microcrystalline Cellulose 
45.89 23.20 
(Avicel PHI 02) 
Starch 1500 -- 20.00 20.00 
Dibasic Calcium Phosphate 
-- -- 23.20 
(Cal-Star) 
Agglomerated Mannitol 
47.39 50.08 50.08 
Croscarmellose Sodium 
5.00 5.00 5.00 
(Ac-Di-Sol) 
Magnesium Stearate 
0.50 0.50 0.50 
Estradiol 1.22 1.22 1.22 
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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. 
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.