Note: Descriptions are shown in the official language in which they were submitted.
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A MULTICOMPARTMENT HARD CAPSULE
WITH CONTROL RELEASE PROPERTIES
Technical Field
The present invention relates to a hard capsule
which can deliver a desirable agent, such as a drug or an
odoriferous agent, over a prolonged period of time.
The invention provides a hard capsule made from
gelatin, starch or a hydrophilic polymer, such as
hydroxypropyl methylcellulose (HPMC) or carboxymethyl
cellulose, which by virtue of its design and composition
provides an immediate and sustained mode of release of
its ph~r~cologically active or otherwise desirable
components in an aqueous envi~ el,t.
Backqround Art
Suppositories are known to be useful in the delivery
of drugs. For example, United States Patent No.
3,814,809 to Gordon et al. discloses a vaginal
suppository composed of CARBOWAX~ and a medicament such
as prostagl ~n~ i n .
Suppositories may be multilayered. Japanese
Publication Nos. JP-150,421 and JP-150,422 disclose a
multi-layered suppository. In each layer, one or more
medical components are mixed with one or more water-
soluble base materials such as Macrogol. The suppository
disclosed in the Abstract of 150,422 _ontains two layers
and does not contain an outer coating layer.
25 Japanese Application 065289 discloses a two-layered
suppository comprising successively charged molten water-
soluble bases (Macrogol or glycerogelatin). The
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suppository includes a water-soluble base layer in the
lower half of the suppository and a fat-soluble base
layer in the upper half. The suppositories are both
rapid and long-acting. This suppository does not include
an outer coating layer which includes a drug to provide
immediate drug release.
Japanese Application 102,055 discloses a slow-
release rectal suppository which is the product of
connecting a suppository prepared with a water-soluble
base material and a suppository prepared with a water-
soluble base material and sùrface coated with a base
material which is insoluble in water and which does not
melt quickly at rectal temperatures. The water-soluble
base material may be a mixture of gelatin and glycerine
or a mixture of two or more Macrogol. The coated
suppository is a slow-releasing rectal suppository and
does not include an outer coating layer which includes a
drug to provide immediate drug release.
U~ Patent 1,431,092 discloses that certain types of
suppositories have thin protective coatings, which may
also contain medicaments or the like are, and which are
sometimes used to reduce premature melting. This outer
coating appears to teach away from the use of a fast
releasing outer coating which contains a drug.
United States Patent No. 3,197,369 to Widman et al.
discloses coated gelatin capsules. The coating of the
gelatin capsule does not contain a medicament for
immediate drug release.
United States Patent No. 3,122,475 to Schaeppi
-30 discloses a multi-layer suppository contA i ni ng
sequentially acting medicaments effecti~e for treating
heart decompensation. In this suppository, the core
represents about one-fifth to one-third of the total
weight of the suppository and the shell represents the
rPmAining four-fifth to two-thirds. The suppository core
can be composed of cocoa butter, solidified glycerin or
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paraffinic wax. The suppository shell can be composed of
the same ingredients and melts at 37 to 38 C.
United States Patent No. 3,415,249 to Sperti
discloses a suppository comprising a first and second
body. The first body consists of a suppository base and
a coating. The base may be a polyethylene glycol and the
coating may also be a polyethylene glycol. Sperti also
discloses that the base of the coating should have a
substantially lower melting point than the base of the
suppository. Sperti discloses that it is possible to
locate a thin barrier layer over the body of the
suppository prior to the application of the coating.
Such an additional layer may be of moisturized gelatin.
The coating can contain an anesthetic substance and the
body of the suppository contains a medicament such as an
agent for the stimulation of cellular respiration. The
thin barrier layer does not contain a medicament.
United States Patent No. 4,707,362 to Nuwayser
discloses a vehicle for providing both rapid release and
prolonged release of a drug. The vehicle may be a
vaginal suppository. The suppository body melts at body
temperature and includes a bioerodible film insert. The
suppository may contain a spermicide such as Nonoxynol-9.
The supposi~ory does not include three compartments for
differential drug release.
United States Patent No. 4,880,830 to Rhodes
discloses a slow release formulation for the preparation
of tablets, capsules, suppositories or implants (see
column 2, line 59) which comprises granules which are
composed of particles comprising an inactive ingredient
and a primary matrix of water-soluble slow release
material in which are dispersed particles compr~sing an
active ingredient. The formulation also c~ ains a
secondary matrix of water-soluble dispers_J ~ slow
release material in which the granules of medicament are
dispersed. At least one of the matrices may be gelatin.
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The suppository can contain secondary granules which are
of a larger size than primary granules, and if desired
tablets or capsules may be enteric film or sugar coated.
Rhodes does not disclose a fast releasing outer coating
contAin;ng a medicament.
United States Patent No. 4,828,840 to Sakamoto et
al. discloses a sustained released formulation of a
water-soluble active ingredient comprising an inert core,
a powder coating layer surrounding the core, a second
powder coating layer surrounding the first powder coating
layer, and a film coating layer surrounding the second
powder coating layer. The film coating layers include
polyvinylpyrrolidone, hydroxypropyl methylcellulose and
starches. The film coating layer does not contain a
medicament.
An example of a controlled release product which is
commercially available is the product PROCARDIA XL~
distributed by Pfizer (35 East 42nd St., New York, NY).
This is an extended release tablet which is designed to
provide the cardiovascular drug nifedipine at an
approximate constant rate over 24 hours (PDR 47th Ed.
1993, Medical Economics Data). In PROCARDIA XL~ the
tablet depends for its action on the existence of an
osmotic gradient between the contents of its bilayer core
and the fluid in the GI tract. Drug delivery is
essentially constant as long as the osmotic gradient
remains constant, and then it gradually falls to zero.
Upon swallowing, the biologically inert components of the
tablet remain intact during GI transit and are el ;mi n~ted
in the feces as an insoluble shell. The osmotic gradient
in this tablet is achieved by the introduction of a
semipPrm~Ahle membrane surrounding an osmotically active
drug core. The core is divided into two layers: an
"active~ layer contAining the drug, and a "push~ layer
contAi~;ng phAr~cologically inter (but osmotically
active) components. As water from the gastrointestinal
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tract enters the tablet, pressure increases in the
osmotic layer and ~'pushes" against the drug layer,
releasing the drug through a precision laser drilled
tablet orifice in the active layer.
There is a need in the medical and pharmaceutical
disciplines for a drug delivery system which incorporates
pharmacologically active components in three or more
differentially releasing drug compartments. This need
particularly exists in vaginal applications wherein the
release of the drug has to begin shortly after
administration such as in the case of a spermicide or an
anti-HI~ agent and in which the drug release must
continue for several hours to achieve the desired
spermicidal and anti-HIV result.
The drug delivery system of the present invention
provides a capsule of differentially releasing distinct
compartments. The outer compartment provides a rapid
release of a drug incorporated into the outer
compartment. An intermediate compartment provides an
intPrr~Aiary speed release portion of the delivery
system. And the innermost compartment provides a slow
release component of the delivery system. The drug
delivery system overcomes inadequacies of prior capsule
formulations to provide controlled immediate and
prolonged release of a desired agent in an aqueous
environment.
Disclosure of the Invention
The present invention provides a hard capsule drug
delivery system comprising at least one inner
compartment, at least one interme~iate compartment
surrounding the at least one inner compartment and at
least one outer compartment surrounding the at least one
intermPA;ate compartment, and wherein each compartment
comprises at least one drug component.
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The present invention provides a drug delivery
system of a hard capsule comprising an outer compartment,
an interm~iAte compartment and an inner compartment,
wherein the rate of release of the drug component of the
outer compartment is faster than the rate of release of
the interm~iAte compartment, and the rate of release of
the intPrm~iAte compartment is faster than the rate of
release of the inner compartment.
In a further embodiment, the invention provides a
hard capsule drug delivery system comprising at least one
inner compartment, at least one intPrm~ te compartment
surrounding the at least one inner compartment and at
least one outer compartment surrounding the at least one
intPr~iate compartment, and wherein each compartment
comprises at least one drug component, wherein the outer
compartment begins release of the drug component about 1
minute after immersion of the hard capsule into an
aqueous medium and completes release of the drug
component about 4S to 50 minutes after immersion of the
capsule into an aqueous medium.
A still further embodiment of the invention provides
a method for manufacturing a drug delivery system
comprising the steps of forming a capsule comprising at
least one inner compartment;
2S surro~ ing the inner compartment with at least one
interme~i~te compartment; and
surrounding the intermediate compartment with at
least one outer compartment, wherein each compartment
comprises at least one drug component and wherein the
outer component comprises a mixture of the drug component
and an excipient coating the int~ -~;ate compartment.
An additional embodiment of the invention provides
drug or active agent release from the outer compartment
of the capsule from 45 to 50 minutes after immersion of
the capsule into an aqueous medium; release of the drug
or active agent from the intermediate compartment occurs
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from 10 min. to 1.5 hours after immersion of the capsule
in a liquid medium and the release of the drug from the
intermediate compartment is completed from 4 to 5 hours
after immersion of the capsule in a liquid medium. The
initial release of the drug or active agent from an inner
compartment of the drug delivery system occurs from about
1 to 2 hours after immersion of the capsule in a liquid
medium and the release of the drug from an inner
compartment is completed from about 7 to 8 hours after
immersion of the capsule in a liquid medium.
The invention also provides a drug delivery system
useful in vaginal applications wherein the release of the
drug begins shortly after administration such as in the
case of a spermicide or an anti-HIV agent and in which
the drug release must continue for several hours to
achieve the desired spermicidal and anti-HIV result.
The capsule of invention provides an ideal vehicle
for colonic drug delivery of peptide drugs and an
inexpensive method for drug delivery to the
gastrointestinal tract.
The multicompartment coated capsule of the
invention, in an additional embodiment comprises a "One
a Day~ single dosage control release capsule.
Other objects, features, aspects and advantages of
the invention will be more apparent to those of s~ill in
the dispensing art from the following detailed
specification taken in conjunction with the drawing
figures and the accompanying claims.
Brief DescriPtion of Drawinqs
Figure 1 shows a perspective view of the capsule of
the present invention.
Figure 2 shows a chart indicating the rate of
release of an active component measured by the rate of
iodine release from the outer compartment of the capsule.
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Figure 3 shows a chart indicating the rate of
release from the middle compartment of a hard capsule
packed with 170 mg of PVP-I/N-9 and 170 mg of Ac-Di-Sol.
Figure 4 shows a chart indicating the rate of
release from the inner compartment of a hard capsule
packed with five PCP-I/N-9 pellets dispersed into a
powder cont~in;ng 170 mg of PVP and 170 mg of Ac-Di-Sol.
Description of the Invention
The present invention relates to a hard capsule
formulated into a delivery system which incorporates
pharmacologically active components in three or more
distinct compartments.
The capsule includes at least one inner compartment,
at least one intPrmeAiate compartment surrounding the at
least one inner compartment and at least one outer
compartment surrounding the at least one intermediate
compartment, and each compartment comprises at least one
drug co...~ol,ent or active agent.
Preferably in the hard capsule the rate of release
of the drug component of the outer compartment is faster
than the rate of release of the intprm~Ai~te compartment,
and the rate of release of the intPrmPAi~te compartment
is faster than the rate of release of the inner
compartment.
The capsule may be made from gelatin, starch,
hydro~y~lo~ylmethylcelluloseorcarboxymethyl cellulose,
for example.
When three compartments are utilized in the capsule,
the outer compartment may incorporate a drug, active
agent or odoriferous agent and excipients into a layer
which coats and thus surrounds the intPrmeAi~te component
of the capsule. This outer component represents the
rapid release portion of the delivery system. The
intermediate compartment comprises a powder formulation
which represents the intermediate rate of release portion
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of the delivery system. The innermost compartment
incorporates the active ingredient or ingredients in a
multiparticulate form, such as small pellets which may be
coated or uncoated, and represents the slow release
compartment of the delivery system.
Thus the drug delivery system of the invention
possesses the ability to deliver a desired drug or
combination of drugs from a period of time ranging from
seconds after administration to several hours.
The rate of release of the drugs from a capsule
consisting of three or more compartments may be
controlled. An alteration in its composition as well as
in the temperature will result in the changed release
profile. The optimal ratio of drug to excipient in the
outer compartment may be adjusted based on the drug
properties and the required coating extent of the outer
surface of the capsule according to methods known in the
art. The release of the drug or drugs from the outer
compartment of the capsule can begin as quickly as about
one minute after the capsule's immersion into an aqueous
medium, and a complete release of the drug in the outer
compartment can occur within a period of 45 to 50 minutes
after immersion.
The interme~i~te compartment may contain up to
300 mg of a drug powder in an 0-size capsule. Although
a 0-size capsule is preferred, any size capsule may be
used. Capsule size is directly related to the method of
administration of the capsule. Larger capsules may be
hard to swallow. If the capsule is for gastrointestinal
administration-0-size, 00-size or 000-size capsules are
preferred. Larger capsules may be used for ~aginal or
rectal administration.
Release of the drug from the interm~ te or middle
- compartment may begin at approximately one hour after
immersion of the capsule in an aqueous medium, and
release may be completed within 4 to 5 hours after
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administration an immersion in an aaueous medium. The
interme~;ate compartment comprises a powder drug
component or active agent. The release time of the drug
from this compartment could be changed by an appropriate
alteration in its formulation.
The drug component or active agent contained in an
inner compartment of the capsule is preferably a pellet
formulation. The inner compartment consists of one or
more pellets which may be coated or uncoated. The
coating solution for the pellet is adapted for sustained
release in the gastrointestinal tract and may contain
mixtures of waxes with glycerol monostearate, stearic
acid, palmitic acid, shellac and zein-polymers,
ethylcellulose acrylic resins and other materials as
outlined in Reminqton's Pharmaceutical Sciences. The
rate of release of the drug from the inner compartment is
a function of the rate of disintegration of the hard
capsule wall and that of the pellets. The size of the
pellet may be adjusted in accordance with the amount of
drug to be delivered and the desired rate of drug
release. For example, the pellets may range in size from
about 1 mm to about 3 mm in diameter. The release of the
drug from an inner compartment is completed from about 7
to 8 hours after immersion of the capsule in a liquid
medium.
The drug delivery system is particularly useful in
vaginal applications wherein the release of the drug or
odoriferous agent has to begin shortly after
~mi ni stration such as in the case of a spermicide or an
anti-HIV agent and in which the drug release must
continue for several hours to achieve the desired
spermicidal and anti-HIV result.
Applications of the drug delivery system include,
but are not limited to the delivery of drugs for the
treatment of vaginal yeast infections and for rectal use
for the delivery of hemorrhoidal drugs. The capsules may
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contain odoriferous agents for vaginal or other delivery.
The drug delivery system according to the present
invention may also find internal use for controlled
release delivery of drugs or vitamin nutritional
supplements, or any other beneficial agent. The capsule
is preferably used in the delivery of peptide drugs to
the colon.
The outer compartment or coating preferably -
contains a drug component or active agent and an
excipient component. In one embodiment of the drug
delivery system the drug component or active agent and
the excipient component are solubilized in alcohol, such
as methanol or ethanol. Preferably the concentration of
the drug component or active agent is 8% to 50% w/v. The
excipient component may include CARBOWAX~ 8,000,
CARBOWAXm 4, 600, CARBOWAXn' 3,350 or CARBOWAXIY 1, 450 !
hydroxypropyl methylcellulose (HPMC) or mixtures thereof.
CARBOWAX~ is a trademark of Union Carbide for
polyethylene glycol polymers.
Additionally, when the above solid components are
solubilized in water, methanol or ethanol, they form a
dipping solution or spray coating, the composition of
which ranges from about l0~ : 0% : 8% to about 12.5% :
10% : 50% of Carbowaxes~, hydro~y~Lop~l methylcellulose
and drug, respectively. A preferred method for
constructing the outer, rapid release compartment of the
delivery system Gonsists of an a~lo~liate m;~ing of the
desired drug with polyethylene glycol CARBOWAX~ 8,000;
4,600; 3,350; and 1,450 or a mixture of CARBOWAX~, HPMC
and the drug. The hard capsule can be dipped several
times or spray coated until the appropriate outer
compartment is formed. This procedure may be utilized to
coat hard capsules made from gelatin, starch or a
hydrophilic polymer such as HPMC.
If the drug component or active agent does not
include a deri~ative of polyvinylpyrrolidone (PvP) as an
-
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active ingredient (such as PVP-I), the excipient used in
the capsule may comprise polyvinylpyrrolidone.
Preferably the concentration of the excipient component
is 10% to 12.5% w/v, and alternatively the concentration
of the excipient is 0% to 10% w/v. When the above solid
components are solubilized in water, methanol or ethanol,
they form a coating solution. The composition of the
coating solution preferably ranges from 10%-12.5%
CARBOWAX~, from 0%-10% HPMC, and from 8%-50% drug.
According to the present invention, the drug
delivery system includes an intermeAiate compartment
comprised of a drug component or active agent and a
disintegrant component. The disintegrant component may
comprise from 100 mg to 180 mg of Ac-Si-Sol~, which is a
modified cellulose gum which is an internally cross-
linked form of a sodium salt of carboxymethyl cellulose
of USP purity. The disintegrant absorbs water and swells
and thus contributes to the collapse of the capsule wall,
upon which the contents of the capsule are delivered.
The proportion of the disintegrant to the drug determines
the time of release of the capsule contents in to the
surrounding medium.
In a preferred embodiment the concentration of the
drug component or active agent in the interme~iate
compartment ranges from about 125 to about 170 mg.
The inner compartment may also be comprised of a
drug cGlu~ol~ent or active agent and an excipient
cG."~G..ent. Preferably the excipient of the inner
compartment is selected from lactose, magnesium stearate,
Ac-Di-Sol, or calcium phosphate, or mixtures thereof.
The inner compartment of the drug delivery system
according to the invention includes, in a preferred
embodiment, a pellet formulation comprises from 7% to 70%
w/w drug component or active agent, from 10% to 84% w/w
lactose, and from 6% to 20% w/w magnesium stearate. The
pellets are compressed using pressure of 600-1000 pounds.
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The inner compartment of the drug delivery system of
the present invention is comprised of the desired drug
formulated in a multiparticulate form. For example,
pellets weighing 30 mg each (approximately 3 mm in
diameter) can be dispersed into the inner compartment of
the hard capsule. The pellets contain the drug and
several excipients which determine their physical
characteristics and their rate of dissolution in an
aqueous medium.
AIso contemplated within the scope of the present
invention is a drug delivery system comprising a hard
capsule with differential rates of release of the drug
component or active agent as outlined below. The drug is
preferably completely released from the outer compartment
from 45 to 50 minutes after immersion of the capsule into
an aqueous medium, the initial release of the drug from
the intermediate compartment, for example, occurs from lO
min. to l.5 hours after immersion of the capsule in a
liquid medium and the release of the drug from the
interm~iate compartment is completed from 4 to 5 hours
after i = ersion of the capsule in a liquid medium. The
initial release of the drug from an inner compartment of
the drug delivery system occurs from about l to 2 hours
after immersion of the capsule in a liquid medium and the
release of the drug from an inner compartment is
compleced from about 7 to 8 hours after immersion of the
capsule in a liquid medium.
A preferred method for manufacturing a drug delivery
system according to the invention includes the steps of
forming a capsule comprising at least one inner
compartment surrounding the inner compartment with at
least one intermediate compartment; and surrounding the
int~rm~;ate compartment with at least one outer
compartment, with each compartment comprising at least
one drug component or active agent and wherein the outer
component comprises a mixture of the drug component or
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active agent and an excipient coating the intermediate
compartment.
Coating of the capsule wall which surrounds the
interm~A;Ate compartment may be accomplished by dipping
the capsule in the mixture of drug and excipient.
Coating may also be accomplished by spray coating the
capsule with the mixture of drug and excipient.
Conventional dipping and coating procedures are known and
acceptable for the practice of the present invention and
are outlined in Remin~ton's Pharmaceutical Sciences, 18th
Ed. (1990) published by Mack Publishing Co., Easton, PA,
p. 1666-1675 and are incorporated herein by reference.
Drugs to be administered in the drug delivery device
according to the present invention may be administered in
accordance with daily dosages known in the art and as
outlined in Reminqton's Pharmaceutical Sciences, 18th Ed.
(1990) published by Mack Publishing Co., Easton, PA.
Examples of drugs to be delivered vaginally include
but are not limited to spermicides such as Nonoxynol-9
(nonylphenoxypolyethoxy-ethanol),Octoxynol(diisobutyl-
phenoxypolyethanol), p-methanylphenyl polyoxyethylene,
dodecamethylene glycol molureate, and sodium lauryl
sulfate. Nonoxynol-9 is preferred. Vaginal drugs such
as miconazole, acyclovir, clotrimazole, ticonizole,
hormones such as estrogens; metronidazole, sulfas
including sulfab~n7Amide, sulfacetamide, sulfacytine,
sulfatrizaole; tetracycline hydrochloride, erythromycin,
achromycin, chloromycetin, penicillin, chlortetracycline
bacitracin, and nystatin may be administered in the drug
delivery system according to the present invention.
Anti-inflammatory agents such as aspirin, chlocortolone
pivalate, hydrocortisone, tolmetin sodium, and
indomethacin may also be ~ministered. The drug delivery
system is also useful in the delivery of germicides, such
as benzalkonium and chlorhexidine and virucides, such as
anti-HIV drugs.
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The solubility of the drug in the coating solvent
does create a limitation on the practice of the
invention. The coating procedure can be practiced with
a highly soluble drug as well as a completely insoluble
drug component or active agent by coating the capsule
with a coating suspension as set forth in example 6.
In a preferred embodiment, the capsule of the
invention is used for the colonic delivery of peptide
drugs. Certain peptide drugs can be delivered from the
colon if they are protected from proteolytic destruction
in the particular site of the gastrointestinal tract
(GI).
Absorption enhancers may be used to facilitate the
absorption of these relatively large peptide molecules.
Consequently to achieve drug absorption of these
peptides, the drug formulation preferably contains a
protease (proteolytic enzyme) inhibitor and one or more
absorption enhancers. See M.E.K Kraeling and W.A.
Ritschel, "Development of Colonic Release Capsule Dosage
Form and the Absorption of Insulin", Meth. Find. ExP.
Clin. Pharmacol. (1992), Vol. 14(3), pp. 199-209,
incorporated herein by reference.
In one emhoAiment the multicompartment capsule of
the present invention permits the release of the
absorption enhancer(s) and the protease inhibitor prior
to the release of the peptide drug. This offers the
advantage that the membrane of the colon is predisposed
to permit the crossing of the peptide drug and thus the
colon would be free of proteolytic activity at the time
the drug is released from the capsule.
In this embodiment, the protease inhibitor and the
absorption enhancers could either be present in the outer
compartment or the outer and interm~iate compartments of
the multicnmrArtment capsule. The peptide drug may be
introduced in the intermediate compartment and the inner
slow releasing compartment of the capsule. Alternately,
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the peptide drug may be introduced in only the pelletized
inner compartment of the multicompartment capsule.
To achieve colonic delivery of the capsule contents,
the capsules are coated with such polymer coatings as
Eudragit NE 30, Eudragit SlO0, cellulose acetate
phthalate (CAP), cellulose acetate succinate (CAS),
cellulose acetate trimellitate (CAT) or cellulose acetate
butyrate (CAB). The above polymers are acid resistant
and dissipate from the surface of the capsule via pH-
dependent and time controlled release mechanisms known in
the art.
Examples of peptide drugs which may be used in the
capsule of the present invention include insulin,
calcitonin, interferon, interleukins and proteins in oral
vaccines. Examples of absorption enhancers are fatty
acids, bile salts such as sodium taurocholate, caprylate
myristate, glycerides, such as phosphatidyl choline,
lecitins, salicylates and lauryl sulfate. Examples of
protease inhibitors for use in this embodiment of the
invention, include but are not limited to bestatin,
leupeptin, chymostatin, pepstatin A, papain and
aprotinin.
In a further advantageous embodiment of the
invention, the multicompartment capsule can be used in
the design of oral drug delivery dosage forms generally
referred to as "one a day" formulations. These
formulations are particularly useful in drug delivery
to the elderly.
Compliance in dosage regimen is often difficult to
achieve, particularly among the elderly. It is therefore
desi~able, in the case of several drugs, to take one pill
or dosage form per day ("one a day"). To achieve this
regimen the dosage form has to be a delivery system that
can continuously deliver the drug in a controlled release
manner.
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The delivery of the drug from the multicompartment
capsule of the invention, in a preferred embodiment, is
continuous when the drug is appropriately distributed in
each of the capsule compartments. The capsule of the
invention is much easier to produce and thus more cost
effective than the commercially available PROCARDIA XL
tablet. In addition, the multicompartment capsule
dissipates completely prior to its el;minAtion from the
body of a patient while the PROCARDIA XLTY tablet is
eliminAted in the feces in tact, as an insoluble shell.
This insoluble tablet has the potential to provide
complications to some patients.
Odoriferous agents which may be administered in the
capsule according to the invention, include but are not
limited to aromatic substances, fragrances, and
absorbents. Examples of fragrances which may be included
in the capsule are linalol and geramol and etherial oils
such as lemon oil and lavender oil. In a preferred
embodiment, the capsule contains 10% citronella oil in
admixture with olive oil, as a fragrance extender and
enhancer.
In addition to the foregoing critical components,
various optional ingredients as a conventionally used in
the art, may be employed. These optional ingredients
include, for example, flavorings, colorings, sweeteners,
fragrances, diluents, fillers, preservatives,
antioxidants, stabilizers, and lubricants.
In an alternative em~odiment, the drug delivery
system of the invention can be fabricated into any
convenient shape for insertion into a body cavity or for
administrat.on via the gastrointestinal tract to meet a
wide variety of functional requirements. Shaping can be
affected, for example, by injection molding, compression
molding, hot dipping, extrusion, melt casting and similar
techniques.
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Reference wiil now be made in detail to the figures
including preferred embodiments and methods of the
present invention.
Figure 1 illustrates a hard capsule lO which is
formed from gelatin, starch or hydrophilic polymer, and
which comprises a three compartment delivery system for
its pharmacologically active components. The outer
compartment 12 incorporates a drug and excipients into a
layer which coats the outer part of the capsule. This
outer compartment represents the rapid release portion of
the capsule. The intermp~iate compartment 11 contains a
powder formulation 13 which is introduced into the hard
capsule 10 and provides an intermediate-speed release
portion of the capsule. The inner compartment of the
capsule contains active ingredients which are in the form
of small pellets 14 and which release their drug
component or active agent more slowly than that of the
outer or intermediate compartments.
Figure 2 illustrates the profile of the rate of
release of PVP-I/N-9, which possesses spermicidal and
anti-HIV properties at pH 5.0, from the outer compartment
determined spectrophotometrically measuring the release
of iodine into the medium. In the embodiment illustrated
by Figure 2, a hard gelatin capsule with an outer layer
of an active component and an excipient was placed into
10 mL of water at pH 5.0 and stirred at 24C.
As can be seen from Figure 2, the release of the
active ingredients, as measured by the rate of release of
iodine, from the outer compartment of the capsule begins
at approximately one minute after immersion into an
aqueous medium. Complete release of the PVP-I/N-9 from
the outer compartment of the capsule is attained within
45-50 minutes after immersion of the capsule into the
aqueous medium.
Figure 3 illustrates the profile of the rate of
release of PVP-I/N-9 from the middle or intermediate
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19
compartment, determined by spectrophotometrically
measuring the release of iodine into the medium, into
water at pH 5.0 stirred at 24C. In the embodiment
illustrated by figure 3, the rate of release of drug from
the int~Tme~i~te compartment of the capsule is slower
than the rate of release of drug from the outer
compartment as illustrated in Figure 2.
Figure 3 further illustrates that the release of the
drug from the intermediate compartment begins
approximately one hour after immersion of the capsule
into the aqueous medium, and attains a complete release
within 4 to 5 hours.
Figure 4 illustrates the profile of the release of
the drug PVP-I/N-9 from the inner compartment, measured
spectrophotometrically by following the release of iodine
into the medium, in this case water with a pH of about
5Ø In the example illustrated by Figure 4, a hard
size-0 capsule was packed with about 170 mg of PVP, 170
mg of Ac-Di-Sol and five pellets, each pellet being
compressed under 600 to lO00 pounds of pressure from the
mixture of 70% PVP-I/N-9, 15% calcium phosphate or
lactose, 15% magnesium stearate and 0% Ac-Di-Sol. ~ ~n
be seen from Figure 4, the rate of release of PVP-I/N-9
from the inner compartment is slower than the rate of
release from the intermediate compartment, as illustrated
in Figure 3, and the rate of release from the outer
compartment, as illustrated by Figure 2.
While not intending to limit the scope of the
invention in any manner, the following examples are given
to illustrate various potential embodiments of the
present invention.
Exam~le l
The various coating solutions form the creation of
the outer compartment are made according to the following
general procedure: Stock solutions of 30%-50% w/v of
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CARBOWAX~ 8,000, 4,600, 3,350, or 1,450, 0%-30% w/v
hydroxypropyl methylcellulose (HPMC) and 24%-66.7~ w/v
are made in water or alcohol.
The appropriate amount of CARBOWAX~ stock solution
is mixed with aliquots of HPMC and PVP-I/N-9 stock
solutions in order to obtain the coating solution
composition which ranges from 10% to 12.5% w/v of
CARBOWAX, 0% to 10% w/v of HPMC and 8% to 50% w/v of PVP-
I/N-9.
Subsequently, the hard gelatin capsule, size 0, is
repeatedly coated by the coating solution depending upon
the amount of solution desired for the outer compartment
and dried until a sufficient outer compartment is formed.
The extent of coating of the outer layer on a 0-size hard
gelatin capsule ranges from about 10 to 80 mg. The
amount of the drug in this outer compartment ranges from
about 3 to 64 mg.
Example 2
A coating solution contA; n ing the anti-HIV drug,
3-azido-3-deoxythymidine (AZT) as the active component is
made according to the general procedure described in
Example l; 1 mL of S0% w/v stock solution of CARBOWAX~
1,450 is mixed with 3 mL of 20% w/v stock solution of
AZT, producing the solution of CARBOWAX~ 1,450 and AZT in
a 12.5%/26.7~ w/v ratio. The hard gelatin or starch
capsule, size 0, is coated by the coating solution and
then dried. The extent of the coating of the outer
compartment on a 0-sized starch capsule ranges from about
20 to 30 mg. The amount of AZT in this outer layer
ranges from about 12 to 18 mg.
Example 3
A coating solution was made from a coprecipitate of
nonoxynol-9, polyvinyl pyrrolidone and iodine (PVP-I/N-
9), spermicidal with anti-HIV properties, and CARBOWAX~
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1,450 in the ratio of 50%/12% w/v. The solution
successfully coated a 0-size gelatin or starch capsule.
The extent of coating of the outer surface of a 0-size
gelatin or starch capsule by the above descri~ed method
ranged from 10 to 80 mg. This amount of coating includes
the active component, in this case PVP-I/N-9, and the
excipient, such as CARBOWAX~. The amount of the drug in
the outer layer ranged from 3 to 64 mg. The optimal
ratio of drug to excipients in the coating solution may
be adjusted according to the properties of the drug and
the required extent of coating in the outer layer of the
capsule.
Exam~le 4
A coating suspension contAining the antifungal drug
miconazole nitrate, l-[2,4-Dichloro-~-(2,4-
dichlorobenzyl)oxy]-phenethyl-imidazole mononitrate
(MONISTAT) as the active component is made according to
the following procedure: 1.01 g. of miconazole nitrate is
suspended in 2 mL of 50~ w/v solution of PVP
(polyvinylpyrollidone) in MeOH producing the coating
suspension of PVP and miconazole in a 1:1 ratio. The
hard gelation or starch capsule, size 0, is coated by the
coating suspension and then dried. The extent of the
loading of the outer layer on a 0-size hard capsule
ranges from 110 to 216 mg. The amount of miconazole
nitrate in this outer layer ranges from 50 to 100 mg.
This example illustrates the solubility of the drug
in the coating solvent does not create a limitation on
the practice of the invention. The coating procedure can
be practiced with a highly soluble drug as well as a
completely insoluble drug component or active agent.
- Example 5
Solute (active component) release from the rapidly
releasing compartment of the outer layer is conducted
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under following conditions: the hard gelatin capsule with
the outer layer of the active component and excipient is
placed into 10 mL (this volume is used in order to
achieve similar release environment for the vaginal
application) of water pH 5.0 and stirred at 37C.
Concentration of solute (PVP-IJN-9) in the dissolution
(release) medium is followed by monitoring absorbance of
iodine at 353 nm. Absorbance is con~erted to
concentration using absorptivity of iodine determined
from the calibration measurement. Figure 2 represents an
example of PVP-I/N-9 release measured by the rate of
iodine release from the outer layer of the capsule.
ExamPle 6
Solute release from an intermediary compartment,
represented by the powder formulation of the drug and
excipients inside the capsule, is conducted under the
following conditions: A hard capsule size-0, is filled
with PVP-I/N-9 (125 mg-170 mg) and disintegrant Ac-Di-
Sol~ (100-180 mg). A hard capsule which is packed with
a mixture of PVP-I/N-9 and Ac-Di-Sol, is placed into 10
mL of water pH 5.0 and stirred at 37C. Concentration of
solute (acti~e component PVP-I/N-9) in the release medium
was followed by monitoring the absor~ance of iodine at
353 nm. Absorbance is converted to concentration using
absorpti~ity of iodine determined from the calibration
measurement. Figure 3 is an example of PVP-I/N-9 release
from a hard capsule size 0, packed with 170 mg of PVP-
I/N-9 and 170 mg of Ac-Di-Sol.
Example 7
Solute release from the slow release inner
compartment, represented by a multiparticulate form of
PVP-I/N-9 and other excipients is conducted under the
following conditions: A hard capsule size 0 is packed
with filler polyvinylpyrrolidone (PVP) 170 mg,
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disintegrant Ac-Di-Sol 170 mg and 5 pellets (3 mm
diameter, 30 mg each) are dispersed into the powder
content of the hard capsule. The pellets are compressed
from the mixture of PVP-I/N-9 7%-70%, calcium phosphate
or lactose 84-10%, magnesium stearate 6%-20%, Ac-Di-Sol~
3%-0, using pressure of 600-lO00 pounds.
A hard capsule packed with filler, disintegrant and
five pellets is placed into lO mL of water pH S.0 and
stirred at 37C. Concentration of solute (active
component PVP-I/N-9) in the release medium is followed by
monitoring absorbance of iodine at 353 nm. Absorbance is
converted to concentration as described in Example 3.
Figure 4 is an example of PVP-I/N-9 release from the slow
compartment of a hard gelatin capsule comprised from 5
PVP-I/N-9 pellets, dispersed into a powder cont~ining 170
mg of PVP and 170 mg of Ac-Di-Sol.
ExamPle 8
An example of intermediate compartment delivery is
set forth below. A 0-size hard gelatin capsule was
filled with 125 mg of PVP-I/Nonoxynol-9 powder and lO0
mg. of an internally crosslinked sodium carboxymethyl-
cellulose disintegrant, USP purity, Ac-Di-Sol. In this
embodiment, the time of first release of the drug into
water with a pH of 5.0 at 24C was 2 to 3 hours.
ExamPle 9
An example of inner compartment delivery is set
forth below. A 0-size hard capsule is packed with 170 mg
of a PVP filler and 170 mg of Ac-Di-Sol~ and five pellets
each cont~ini~g 10%-84% calcium phosphate, 6~-20%
magnesium stearate, 0%-3% Ac-Di-Sol, and 7%-70% of the
desired drug, the time of first release of the drug into
water of pH 5.0 at 24C was within a range of l to 2
hours. A complete release of the drug may be attained
within 7 to 8 hours.
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Exam~le 10
Same as example 9, except that the five pellets
are coated with a coating solution to prolong the time
prior of drug delivery from the pellets. This coating
solution adopted for sustained release in the gastroin-
testinal tract may contain mixtures of waxes with
glycerol monostearate, stearic acid, palmitic acid,
shellac and zein-polymers, ethylcellulose acrylic resins
and other materials apparent to those of skill in the art
as outlined in Reminqton~s Pharmaceutical Sciences.
Example 11
An example of a complete three compartment capsule
is set forth below. A 0-size hard capsule is packed with
170 mg of a PVP filler and 170 mg of Ac-Di-Sol~ and five
3 mm pellets, each contAining 10%-84% calcium phosphate,
6%-20% magnesium stearate, 0%-3% Ac-Di-Sol, and 7%-70% of
acyclovir. The intermP~iary compartment, represented by
the powder formulation of acyclovir and excipients is
introduced inside the hard capsule surrounding the pellet
formulation. The intermeAiate compartment consists of
acyclovir powder (125 mg-170 mg) and disintegrant Ac-Di-
Sol~ (100-180 mg).
A coating solution contAining acyclovir as the
active component is made according to the general
procedure described in Example l; 1 mL of 50% w/v stock
solution of CARBOWAX~ 1,450 is mixed with 3 mL of 20% w/v
stock solution of acyclovir, producing the solution of
CARBOWAX~ 1,450 and acyclovir in a 10%/15% w/v ratio.
The hard gelatin or starch capsule, size 0, is coated by
the coating solution and then dried. The coating
solution surrounds the capsule wall and thus surrounds
the interme~iate drug powder compartment. The extent of
the coating of the outer compartment on a 0-sized starch
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capsule ranges from about 20 to 30 mg. The amount of
acyclovir in this outer layer ranges from about 12 to
18 mg.
Exam~le 12
Same as example 11, except that the instead of
acyclovir the capsule contains an odoriferous agent.
Example 13
Same as example ll, except that the instead of
acyclovir the capsule contains Octoxynol, a spermicidal
agent. The drug delivery system hard capsule is for
vaginal delivery.
Exam~le 14
Same as example 11, except that the instead of
acyclovir the capsule contains penicillin, an antibiotic.
The drug delivery system hard capsule is for
gastrointestinal delivery.
Exam~le 15 Peptide Capsule
A zero size hard capsule is packed with 180 mg. of
taurocholate, 180 mg of sodium myristate, and 0.5 mg of
leupeptine, and 10 IU of insulin. As the inner
compartment of the capsule, the capsule contains three
pellets, each con~;ning 10-84% of calcium phosphate, 60-
20 % of magnesium stearate, and insulin 40 IU.
The outer compartment consists of two layers. The
first layer contains 20 mg. of sodium taurocholate, 20
mg. of sodium myristate, 0.5 mg. of leu~e~Line and 3.5 mg
of CARBOWAX 1450. After the first layer is established,
the second layer is created by dipping (or spraying) the
capsule in an aqueous dispersion of Eudragit S100 and
Eudragit NE 30D in a 3:7 ratio.
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Example 1 6
Same as example 15, except that a 0 size hard
capsule is packed with 180 mg of sodium taurocholate, 180
mg of sodium caprylate, 0.5 mg of aprotinin, calcitonin.
As the inner compartment of the capsule, the capsule
contains three pellets, each contAin;ng 10-84% of calcium
phosphate, 60-20 % of magnesium stearate, and calcitonin.
The outer compartment consists of two layers. The
first layer contains 20 mg of sodium caprylate, 20 mg of
sodium taurocholate, 0.5 mg of aprotinin and 3.5 mg of
CARBOWAX 1450.
After the first layer is established, the second
layer is created by dipping (or spraying) the capsule in
an aqueous dispersion of Eudragit NE30 and Eudragit S100
30D in a 7:3 ratio. The capsule is coated with a 10%
cellulose acetate phthalate in acetone/methanol (1:1
ratio) solution.
Example 17 One a Day Capsule
A zero size hard capsule is packed with 10 mg of
nifedipine, 200 ms of lactose, 100 mg of starch and 3
pellets. Each of the pellets of the inner compartment
contains 10mg-20 mg of nifedipine, 10-84% of calcium
phosphate, 60-20 % of magnesium stearate.
The pellets are coated with a coating solution
contA;ning glyceryl monostearate 11% w/w, glyceryl
distearate 16% w/w, white wax USP 3% w/w, carbon
tetrachloride 65% w/w, PVP 2%, starch 2,8% titanium oxide
O.1%, CARBOWAX 1400 0.1%.
The outer compartment is represented by 10-20 mg of
nifedipine 6-13 mg of cARsowAa~ and 12-26 mg of ~I~MC or
HPC.
Example 18
Same as Example 17, except that instead of HPMC the
outer compartment contains PvP.
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The purpose of the above description and examples is
to illustrate some embodiments of the present invention
without implying any limitation. It will be apparent to
those of skill in the art that various modifications and
variations may be made in the capsule and method of the
present invention without departing from the spirit or
scope of the invention.
