Note: Descriptions are shown in the official language in which they were submitted.
lZ3~;6~
The present invention relates -to a pharmaceutica
composition contairling a liquid lubricant.
Solid, hydrophobic lubricants continue to be currently
used in the pharmaceutical art of tableting and filling of hard
gelatin capsules even though it is known that the use of hydro-
phobic lubxicants such as magnesium stearate diminish dissolu-
tiOIl rates, and consequently could possibly reduce absorption
rates, of the dosage formulation. Diminished dissolution rates
of several capsule formulations with increases of maynesium
stearate concentration were disclosed by Samyn and Jung, J.
Pharm. Sci. 59, 169 (1970). Iranloye et al., J. Pharm. Sci. 67,
535, (1978), studied the effects of concentration of hydro-
phobic lubricants (calcium stearte, glyceryl monostearate,
magnesium s-tearate, stearic acid and talc) on the dissolution
rate of salicylic acid, aspirin and equimolar mixtures thereof
and reported decreased dissolution rates with increased concen-
tration of each lubricant other than talc. The authors con-
cluded that, if hydrophobic lubricants slow dissolution, highly
water-soluble lubricants might enhance dissolution. ~lowever,
polyethylene glycol 4000 failed to affect dissolution at concen-
trations as high as 5 percent, leading -the authors to speculate
that the lubricant must simultaneously be water-soluble and
surface active to enhance dissolution. Levy et al., J. Pharm.
Sci. 52, 1139 (1963), had previously shown tha-t sodium lauryl
sulfate increased dissolution rates of salicylic acid over that
of magnesium stearate in compressed tablets.
The use of surfactants in pharmaceutical formulations
to assist in disintegration and dissolu-tion of drug material is
well ~cnown. Lachman et al., Theory and Practice of Industrlal
Pharmacy, Second Edition, pp. 108-9, disclose the use of surface
active agents or surfactahts in almost every dosage form includ-
ing liquids, semi-solids and solids. The surface active agents
c~ - 1 -
~23S66~
play an important role in the absorption and efficacy of certain
dru~s. Irhe nature of this role is quite obscure. Both enhance~
ment of ahsorption and retardation of druy absorption have been
credited to the presence of surface active agents. It cannot
always be determined whether the function of a surfactan-t is to
alter solubility, dissolution rates, and/or absorbability of the
drug based upon its action on the drug itself or on a semi-
\
- la -
- ~Z~566~'
permeable membrane wlthln the host body. Slmllarly, whether the
formatlon of mlcelle unlts and thelr polar/non-polar molecule
orlenta-tlon Is crltlcal to the functlon of the surfactants Is not
readlly ascertalnable.
Chlou et al., J. Pharm. Scl. 65, 170Z (1976), dlsclose
enhanced dlssolutlon rates for poorly watér soluble drugs by
crystalllzatlon from an aqueous surfactant solutlon. Polysorbate
80 (a trademar~) (Tween 80, a trademark) was employed In 2.5%
aqueous solutlon for the purpose of drug preclpltatlon.
Lerk et al., J. Pharm. Scl. 67, 935 (1978), dlsclose
hydrophlllc coatlng of hydrophoblc drug partlcles to enhance wet-
tlng and dlssolutlon. Hersh, U.S. 3,927,196, had shown earller
that a hydrophoblc lubrlcant could be coated wlth a hydrophlllc
materlal to enhance dlssolutlon of a therapeutlc composltlon con-
talnlng the lubrlcant.
Goodhart et al., J. Pharm. Scl. 62, 30~ (1973), dls-
close a method for testlng tablet and capsule dlssolutlon rates.The authors note that prevlous studles have demonstrated pro-
longed dlslntegratlon/dlssolutlon tImes wlth an Increase In the
level of magneslum stearate whlch Is the standard lubrlcant
employed In hard gelatln capsule formulatlons. The magneslum
stearate in effect waterproofs the contents of a hard gelatlon
capsule. The authors noted on page 308, that the addltlon of a
surfactant such as sodlum lauryl sulfate Improved dlslntegratlon
of the capsules when tested In artlflclal gastrlc fluld wlthout
enzymes.
Short et al., J. Pharm. Scl. 61, 1733 (1972), dlsclose
the dlssolutlon of hydrocortlsone In a number of systems contaln-
lng an N-alkylpolyoxyethylene surfactant.
U.S. Patent 3,862,311 granted January 21, 1975, to Lee-
son, dlscloses the use of varlous types of surfactants In con-
, ~
~35661'
Junctlon wlth polyethylene 01ycol carrlers for asslstance In dls
solutlon and absorptlon of composl~lons contalnlng progesterone.
The preferred surfactants are non-lonlcs.
Geneldl et al., J. Pharm. Scl. 67, 114 (1978), dlsclose
the theoretlcal relatlonshlp between enhancement of dlssolutlon
rate of a drug and Its Gl absorptlon rate;
26
~5
_ 2a -
1~3~6~'
Description of the Invention
In accordance with this invention, there is provided a solid pharmaceutical
- composition of matter comprising a therapeutic agent in intimate admixture with a
pharmaceutically-acceptableJ liquid, hydrophilic lubricant. The solid pharmaceutical
composition is suitable for use in hard capsule production or tableting.
The liquid, hydrophilic lubricant employed in the pharmaceutical composi-
tions of this invention functions as a classical solid, hydrophobic lubricant in as much
as it provides for proper flow characteristics of the dry composition when filling a
hard gelatin capsule body [Reier et al., J. Pharm. Sci. 57, 660 (1968) ], prevents
binding of the rotary auger in the powder filled hopper [C. Lindenwald, Pharm. Ind.
28, 614 (1965) ] employed in filling hard gelatin capsules and permits smooth
telescoping closure of the filied capsule body part into the cap, while not reducing
the friction between the capsule halves to the point where they will easily separate
upon further manipulation.
In addition, the use of a liquid as the lubricant markedly reduces the
production of dust which conventionally attends the filling of capsules and prepara-
tion of pharmaceutical powder mixes. The reduction of atmospheric dust is of great
value in the handling of tranquilizers, barbiturates, analgesics, antibiotics, antihyper-
tensives, antiinflammatory agents, steroids (hormones), etc., which may cause
contact dermatitis or induce systemic effects upon inhalation by workers. When
using a liquid lubricant, the reduction in dust is such that it is no longer necessary to
polish hard gelatin capsules after filling.
Furthermore, the liquid lubricant provides an ideal medium for inclusion,
by solution, suspension or emulsion, of surfactants, low level actives or other
adjuvants which are desireably made as homogeneous as possible in a solid pharma-
ceutical formulation. And, the liquid lubricant present in a hard gelatin capsule tends
to reduce aging (hardening of the gelatin capsule via further polymerization) which
results in lower dissolution rates.
Similar advantages attend the use of the pharmaceutical compositions of
this invention in production of tablets. The liquid lubricant provides good flow and
compression characteristics of the powder mix, minimiæes dust formation and
Z3S6~
transport, and adequately lubrlcates the dle and punch to prevent
blndlng of the tablet and metal parts.
The llquld, hydrophlllc lubrIcants whlch may be
employed In varlous pharmaceutlcal formulatlons Include polyalky-
lene glycols of molecular welght between about 200 and about 900,
such as, polyethylene glycol and polypropylene glycol; glycerln,
propylene glycol, and llquld polyhydrlde alcohol fatty acld
esters (e.g. Glycomul ~ or Glycosperse ~ ). Each of these
lubrlcants pose unlque problems whlch mlght dlctate agalnst thelr
use In a speclflc appllcatlon. For example, glycerln and propy-
lene glycol are so hydroscoplc that they may cause physlcal and
chemlcal problems wlth the pharmaceutlcal. The more vlscous Gly-
cosperse ~ tends to coat the external llp portlon of a hard cap-
sule body and provlde such a frictlonless blndlng that the cap-
sules tend to separate on handlIng. Hence, the preferred llquld
lubrlcants are the polyethylene glycols of molecular welght from
about 200 to about 900. The most preferred llquld lubrlcant Is
polyethylene glycol havlng a molecular welght range of from about
20 380 to about 420 (PEG 400). These lubrIcants exert some level of
surface actlvlty In addltlon to lubrlcatlon and otherwlse appear
to be Ideally sulted for use In productlon of pharmaceutlcal com-
posltlons for hard gelatln capsule fllllng.
26 In addltlon, thls Inventlon provldes solld pharmaceutl-
cal composltlons comprlslng a therapeutlc agent In IntImate
admlxtur0 wlth a pharmaceutlcally acceptable, llquld, hydrophlllc
lubrlcant and a surface actlve agent. The surfactant further
Improves the dlssolutlon rate by reduclng the surface tenslon at
the llquld-solld lnterface created between the pharmaceutlcal
composltlon and fluld dlssolvlng the composltlon. Thus, the
hydrophlllclty of the llquld lubrlcant alds In drawlng water Into
the matrlx of the tablet or capsule whlle the surface actlve
agent Improves the wettablllty of the solId materlal to afford,
In concert, a markedly Improved dlssolutlon rate. Typlcal sur-
factants whlch are Incorporated Into the pharmaceutlcal compo~1-
~ 3566~'
tlons Of thls Inventlon are catlonlc, anlonlc and non-lonlc sur-
face actlve agents well-known In the art, such as, the fatty
esters of polyoxyethylene sorbltan (Tween (a trademar~) serles 20
to 85, ICI, Unlted States), a polyoxyethylene condensate of a
hydrophoblc base formed by polymerlzatlon of propylene oxlde and
propylene glycol (Pluronlc (a trademark) or Poloxamer (a trade-
mark) serles, BASF Wyandotte Chemlcal Co.), sorbltan monolaurate
(Span 20 (a trademark), ICI Unlted States), octylphenoxy
polyethoxy cthanol ~Trlton X, a trademark) Rohm and Haas), cetyl-
pryldlnlum chlorlde, dloctyl sodlum sulfosucclnate, and the llke.
The quan-tlty of llquld, hydrophlllc lubrlcant and sur-
factant employed In the manufacture of the pharmaceutlcal compo-
sltlons of thls Inventlon may vary greatly dependlng upon the
characterlstlcs of the therapeutlc agent and other tablet or cap-
sule adJuvants employed. The optlmum quantlty of elther or both
Is, however, readlly determlned by emplrlcal Investlgatlon. For
example, a serles of Incremental 5 percent Increases of PEG 400
admlxed wlth the conventlonal formulatlon contalnlng oxazepam as
presented In Example 1, Infra, demonstrated a maxlmum useful con-
centratlon of lubrlcant at about 25 percent by welght, at whlch
polnt the formulatlon was clumpy and would not run In automatlc
or seml-automatlc flllers. AdJustment of the quantlty of llquld
lubrlcant and surfactant to provlde 75 percent or be-tter dlssolu-
tlon in forty-flve mlnutes Is also readlly achleved by emplrlcal
Investlgatlon of In vltro dlssolutlon rates.
The therapeutlc agent contemPlated for use In the novel
pharmaceutlcal composlt ! ons of thls Inventlon Is any known thera-
peutlc agent adaptable for admlnlstratlon vla a hard gelatln cap-
sule or a tablet. In general, the comblnatlon of a pharmaceutl-
cally acceptable llquld lubrlcant and surfactant Is employed wlth
greatest advantage for the purpose of dramatlcally Improvlng the
dlssolutlon rate of poorly soluble therapeutlc agents Includlng
tranqulllzers, barblturates, analgeslcs, antlblotlcs, antlhyper-
tenslves, antl-lnflammatorles, hormonal sterolds, and the llke,
1~35~
whlch exhlblt slow In vltro avallablllty rates. D I sso I utlon
enhancement of the composltlons of thls Inventlon contalnlng the
poorly soluble actlve pharmaceutlcal Is further optImlzed after
Incluslon of the lubr I cant~surfactant comblnatlon by achlevlng
maxlmum dlstrlbutlon of the lubrlcant-surfactant comblnatlon vla
mllllng or screenlng to reduce agglomerates of loosely adherlng
partlcles. Multlple mllllng or screenlng may enhance the dlsso-
lutlon rate, dependlng Upon the efflclency of the Inltlal agglom-
erated partlcle dlsruptlon.
Oxazepam Is employed as the therapeutlc agent In the
followlng examples of therapeutlc composltlons for fllllng hard
gelatln capsules because It Is a good example of a compound wlth
a slow dlssolutlon rate. It Is to be understood that the Inven-
tlon Is not llmlted to use wlth oxazepam or drugs whlch are rela-
tlvely Insol Ub I e. The use of a llquld, hydrophlllc lubrlcant-
surfactant, wlth or wlthout the addltlon of an addltlonal surface
actlve agent, serves to Increase the dlssolutlon rate of tableted
and hard encapsulated pharmaceutlcal composltlons whlch are cus-
tomarlly and presently formulated wlth solId hydrophoblc lubrl-
cants such as magneslum stearate, talc, or stearlc acld, even
when the drug Itself Is readlly soluble In vltro and In vlvo.
In each of the followlng formulatlons employed to
Illustrate the typlcal Improvement In dlssolutlon rates achleved
wlth thls Inventlon, the solld Ingredlents conslstlng of the
actlve materlal (oxazepam) and tablet exclplents (lactose and
croscarmellose) are fIrst mlxed In a sultable mlxer. The llquld
Ingredlents conslstlng of the lubrlcant (PEG 400) and surfactant
(supplled under the trademark Polysorbate 80) are comblned and
mlxed wlth a sultable mlxer. Thls comblnatlon Is added slowly to
the mlxed powders and mlxed to achleve adequate dlsperslon. Thls
wetted materlal Is passed through a No. 30 screen and then
remlxed to further homogeneous dlspersal. In formulatlons where
magneslum stearate Is present, thls solId hydrophoblc lubrlcant
Is added through a fIne screen to the mlxed powders whlch are
23S66~`
then thoroughly mlxed. All components of these formulatlons are
In mllllgrams.
.
26
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As may be readily seen, the dissolution rate is markedly improved in
Formula II by merely reducing the quantity of solid ~lydrophobic lubricant (magnesium
- stearate) and adding an internally cross-linked carboxymel:hylcellulose sodium salt
disintegrant (croscarmellose sodium). The resuits obtained from Formula III demon-
strate that the addition of a disintegrant alone with exclusion of a lubricant is not the
answer to the problem. ~issolution of Formula IV demonstrates a marked improve-
ment resulting from the addition of a liquid, hydrophilic, low molecular weight
polyethylene glycol (PEG 400) which acts as a lubricant and weak surfactant. Upon
addition of a minor amount of another surfactant (Polysorbate 80) the thirty minute
in vitro dissolution rate is improved to between 85 to 95 percent of the composition
dosage. This exceeds the desired in vitro dissolution rate of not less than 75 percent
in forty-five minutes currently propounded by the U.S.P. XX - N.F. XV, 1980, as
desireable.
Other surface active agents work similarly well with the liquid, hydro-
philic lubricant to afford rapid dissolution of the pharmaceutical compositions as may
be seen in the following examples:
Example No. VI VII VIII IX
PEG & Sorbitan PEG andPEG and PEG and
Monolaurate TritonCet~lpyrid. DSS *
~O Oxazepam, mg 30 30 30 30
Lactose USP 147.1 147.1 147.1 182
Croscarmellose
Sodium, USP 6.6 6.6 6.6 6.6
PEG 400, NF 1.1 1.1 1.1 1.1
Triton X-100 - 0.185
Cetylpyridinium
Chloride - - 0.185
Sorbitan monolaurate 1). l 85
Dioctyl Sodium
~0 Sulfosuccinate * - - - 0.26
Magnesium Stearate, USP
~6 dissolved in 30 91 96 86 93
1~35f~
All of the in vitr_ dissolution studies wl.ich produced
the data reported above were run by the method descri.bed .i.n the
U.S. Pharmacopeia XX, The Ma-terial Formulary ~V page 959 (1980)
using 0.1 N hydxochloric acid as dissolution medium. In actual
practice, hard gelatin capsules fi.lled wlth -the pharmaceutical
formulation of Example V, supra, provided bioavailability ln
vivo which was not statistically distinct with respect -to rate
and extent of absorption from compressed tablets now employed in
the trade, a very desireable but difficult result to achieve
~ with any given drug. Thus, a -typical pharmaceu-tical formula-
tion employing oxazepam as the active ingredient contains from
about 10 to about 30 milligrams oxazepam; 0.5 to about 25 weigh-t
percent of composition of liquid polyalkylene glycol of molecu-
lar weight from about 200 to about 900; about 0.1 to about 25
weight percent of composition of surfactant, plus a filler.
The preferred formulations for oxazepam to be employed
in filling hard gelatin capsules contain from abou-t 10 to about
30 milligrams oxazepam, about 3 to about 11 weight percent ratio
to active of polyethylene glycol lubricant of molecular weight
~ from about 380 to 420, about 0.5 to about 2.5 weight percent
ratio to active of nonionic surfactant, made up with filler
and/or adjuvant(s) to provide a unit dose of from about 165 to
205 milligrams.
Three specific examples of formulations for unit
dosage administration via hard gelatin capsules, expressed in
milligrams, are:
oxazepam, USP 10 15 30
Lactose, USP 167 162 147
Croscarmellose Sodium, NF 6.6 6.6 6.6
PEG 400, NF 1.1 1.1 1.1
Polysorbate 80, NF ~ 0.22 0.22 0.22
g
. .
